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BackgroundDilute Russell’s viper venom time (dRVVT) is indispensible in lupus anticoagulant (LA) detection yet commercial reagents from different suppliers perform variably, no gold standard assays exist and therapeutic anticoagulation interference is problematic.ObjectiveThe objective of this study was to compare a new formulation dRVVT with two currently available dRVVTs.Materials and methodsLife Diagnostics (LD) dRVVT and Stago PTT-LA were routinely used for lupus anticoagulant detection, plus Taipan snake venom time/ecarin time (TSVT/ET) for patients on warfarin or rivaroxaban. Siemens dRVVT and the new HYPHEN BioMed (HBM) dRVVT were tested with 193 patient samples. Group 1, 59 non-anticoagulated patients (NAPs) LA-positive in LD dRVVT; Group 2, 15 PTT-LA-positive/dRVVT-negative NAPs; Group 3, 24 LA-positive warfarinized patients; Group 4, 13 patients on rivaroxaban; Group 5, 62 LA-negative thrombotic NAPs; Group 6, 20 warfarinized, non-antiphospholipid syndrome patients.ResultsAccepting that the Life Diagnostics reagents were acting as a pseudo-gold standard, Siemens dRVVT detected 56/59, (95%) Group 1 LA and HBM dRVVT 46/59, (76%), one each from Group 2, and Siemens dRVVT detected one in Group 5. The lower HBM dRVVT detection rate mainly concerned weaker LA, where between-reagent concordance is problematic. All Group 3 patients appeared LA-positive in undiluted plasma with Siemens dRVVT, as did 16/24 (67%) with HBM dRVVT but the fewer LA-positives in mixing tests better mapped to clear LA-positives with LD dRVVT. LD and Siemens dRVVTs exhibited 87% and 95% false-positivity for Group 6 whilst HBM dRVVT had none. Increasing the cut-off improved accuracy. Applying higher cut-offs improved accuracy in Group 4 patients.ConclusionHBM dRVVT exhibited improved specificity, mainly due to less interference by anticoagulation, but reduced sensitivity, compared to the other dRVVTs employed.

Updates to guidelines covering lupus anticoagulant (LA) detection have recently been published by the International Society on Haemostasis and Thrombosis (ISTH) and British Committee for Standards in Haematology (BCSH), in 2009 and 2012, respectively. The Clinical and Laboratory Standards Institute (CLSI) published its first LA guideline in 2014. Cross-panel agreement exists on sample manipulation, use of dRVVT analysis, conversion of clotting times to ratios, calculations to demonstrate phospholipid dependence, mixing test interpretation and provision of interpretive reporting. Whilst ISTH restricts assay choice to just dRVVT and activated partial thromboplastin time, BCSH and CLSI consider the case for additional tests. All panels acknowledge the potential for false-negative mixing tests, yet they remain mandated by ISTH and BCSH, the latter, however, indicating that a negative mixing test need not exclude a LA if testing on undiluted plasma is unequivocal. CLSI reprioritizes test order to screen-confirm-mix to reduce false-negative reporting when antibodies are diluted to undetectable levels in mixing tests. Recommendations differ on how to derive cut-off levels, particularly in view of the realities of relatively low donor numbers. Each guideline considers testing of anticoagulated patients, BCSH and CLSI endorsing Taipan snake venom time as a useful supplementary assay in patients on vitamin K antagonists. Although full consensus is not apparent, these publications represent significant moves towards engendering common practices.

In diagnostic ultrasound examinations, transducer “health” is key to diagnostic efficacy. It is known that individual transducer element integrity within an array is central to overall probe performance and over time, with normal use, elements can cease working or lose sensitivity, leading to a potentially negative impact on the clinical efficacy of the ultrasound examination. Investigating this issue, the authors evaluated transducers with selected elements disabled compared to fully functioning arrays, examined how dead elements affected ultrasound beams, acoustic parameters, flow phantom/tissue phantom results as well as human imaging. Results: As few as 2 consecutive dead elements can materially impact the beam profile; four or more can significantly reduce resolution and penetration, increase the noise floor, and cause Doppler peak velocity errors, flow ambiguity and spectral broadening. Tissue phantoms proved to be equivocal in spotting defective elements. Conclusion: array heath is critical to high-quality, efficacious ultrasound studies and the potential for misdiagnosis increases as array elements degrade.

Regional blood centers recently increased the number of tests used to protect transfusion recipients from infectious disease. The Food and Drug Administration has noted that computer systems for managing these data have lost donor data or failed to recognize all deferrals. Of 118,396 consecutive donations, including 4,859 records with at least one positive test result, records were analyzed to determine the number and frequency of distinct combinations of test data. A modular precedence-logic expert system assigned donor deferrals and unit dispositions. Ten combinations of data accounted for 4,334 records (89%); the remaining 525 records (11%) were distributed among 85 combinations of test data. The expert system correctly assigned all records. Regional blood centers must interpret a growing number of test results, including donations with a complicated pattern of multiple positive screening test results. The distribution of these data is described and the expert system's ability to monitor deferrals and ensure database completeness is demonstrated.

The basis for persistence of the left superior vena cava (LSVC), usually associated with cardiac malformations, is poorly understood. We examined 351 staged, serially sectioned human embryos in the Carnegie Embryological Collection and 1208 specimens with congenital cardiovascular malformations in the Pathology Collection of the Johns Hopkins Hospital. A standardized questionnaire was answered for each embryo and autopsy case and a computer program was employed to tabulate concurrent anatomic features. In the normal embryos a symmetric venous system appeared with the heart tube at Carnegie stage 9; the sinoatrial junction translocated to the right and the relationship of the coronary sinus to the LSVC was established by stage 12. The LSVC was patent through stage 20 and subsequently underwent luminal obliteration by compression between the left atrium and the hilum of the left lung. Among the 1208 hearts with a congenital abnormality, 104 (9%) had a persistent LSVC with a coronary sinus connection. Statistically, significantly more frequent associations were found between persistent LSVC and atrioventricular canal defects, cor triatriatum, and mitral atresia and a significantly less frequent association was observed between persistent LSVC and atrial septal defect or patent foramen ovale as a primary defect. The normally late embryonic obliteration of the LSVC suggests that its persistence would be secondary to reduce cardiac compression or to blood flow redistribution at an early stage, and the malformations associated with persistent LSVC support that view. Identification of a persistent left superior vena cava with coronary sinus connection should suggest an associated malformation, especially atrioventricular canal, cor triatriatum, or mitral atresia.

Although ultrasound transducer technology and system design have advanced dramatically over the last 25 years, the ability to assess transducer performance within the clinical setting has remained stagnant. Tissue-mimicking phantoms are still the most widely used quality assessment tool. Recent papers [Weigang, et al., 2003] have shown that images from tissue-mimicking phantoms are not sufficient to determine the existence of dead elements in an array even though missing elements result in "off axis" grating lobes that can materially degrade the quality of a clinical Doppler study. To address the need to detect dead elements or system channels, an inexpensive hand-held test device was developed. A special purpose multilayer broadband (1-20 MHz) PVDF transducer was developed. Transducer sensitivity is sufficient to produce a 100 mVp-p output (non-amplified) from a single element of a 3 MHz array driven at 100 Vp-p The PVDF transducer is interfaced to a low noise preamplifier and signal detection system to indicate the presence of transmitted acoustic pulses from individual array elements. The device provides an LED indication to the user if pulses are detected. Further, the device injects a simulated echo that is displayed in the image and in Doppler, as a check of the ultrasound system's receiver chain. The PVDF transducer contact dimension is very small (0.15 times 2.8 mm) to allow identification of a single missing element in a fine pitch array. In a small-scale randomized trial, three trained operators tested four probe types on two imaging systems. All operators detected single missing elements on probes with pitches near 0.2 mm. There were no false positives or false negatives. The probe types tested included cardiac phased arrays, high frequency linear arrays and tightly curved transvaginal probes, encompassing a frequency range from 3-10 MHz. The device as developed has potential as a simple yet effective tool for quality assurance checks within a clinical setting

The Autopsy Committee of the College of American Pathologists has prepared this revised guideline to reflect changes that have occurred in the reporting of autopsies since the original guideline was published in February 1995. It is intended to be an instrument to assist pathologists in the reporting of autopsies. The guideline is to be regarded as being primarily an educational tool. Application of these recommendations on autopsy reporting is to be made on the basis of the judgment of the pathologist engaged in a specific case.

The usual ranges for prostate-specific antigen (PSA) are derived from a community-based population of White men but are used for screening on all men on the assumption that the differences between the PSA levels of different racial groups are small or have no clinical significance. Recently published reports, however, suggest that PSA levels in a specific racial population may vary directly with the relative risk of prostatic cancer within that population. PSA ranges were determined in Black and White men registered with the Veterans Affairs Maryland Health Care System, Baltimore, Maryland. The total patient census of 122,602 has near-equal numbers of Black and White men and maintains records of race designation for inpatients. Among the male patients with no known prostatic cancer, there were 10,808 men 40 years of age or older and 19,482 PSA test results. In this group, there were 3274 men identified as Black; 2993 identified as White, Not of Hispanic Origin, and 4541 identified as Other Race or Race Unknown. The 95th percentile PSA values in Black men and White men 40 through 49 years of age were 2.80 ng/mL and 2.01 ng/mL, respectively; 50 through 59 years old, 5.40 ng/mL and 4.19 ng/mL, respectively; 60 through 69 years old, 9.59 ng/mL and 7.00 ng/mL, respectively; 70 through 79 years old, 15.45 ng/mL and 9.40 ng/mL, respectively; and for men older than 80 years of age, the 95th PSA values were 21.05 ng/mL in Black men and 18.25 ng/mL in White men. In every age group, Black men had a higher range (for the 95th percentile) than did White men. The largest difference was found in men 70 through 79 years old; in this age group, the ratio of the upper limit of PSA for Black men compared with White men was 1.6 ng/mL.

Pathology departments have invested considerable energy, sometimes extending over several decades, toward coding their anatomic pathology reports. As a result of these labors, there is now a vast amount of electronically coded data from surgical pathology reports, holding a wealth of information relevant to virtually every recognized pathologic entity. The original intent of the Systematized Nomenclature of Medicine (SNOMED) was to prepare population-based disease data from pathology reports, but no such studies have emerged in the medical literature. This is due in part to the nonuniform, idiosyncratic, and incomplete manner in which most SNOMED databases are constructed. Automatic (computer-driven) coding provides uniformity and completeness of SNOMED databases and offers the possibility of customized recoding for an entire collection of reports using any nomenclature and any set of coding algorithms. In prior investigations, we described a computer program that SNOMED-codes surgical pathology reports, and we provided an analysis of a large surgical pathology SNOMED database. In this report, we describe the importance of coded surgical pathology databases for research, teaching, hospital administration, and public health, and we explain the functional differences between coded databases and free-text collections of surgical pathology data. Surgical pathology departments and vendors of laboratory information systems can ensure that surgical report files can be automatically coded or recoded with any chosen nomenclature by adhering to simple guidelines.

To demonstrate that cause-of-death statements can be generated by a computer algorithm from an autopsy database composed of diagnostic terms.Over 49 000 autopsy facesheets contributed by over a dozen institutions were collected from a publicly accessible Internet autopsy database. This database is available at the following web site: http:@www.med.jhu.edu/pathology/iad.htmlTo test the feasibility of creating and using a publicly available autopsy database, and to identify the technical and medicolegal problems that may arise with such a novel resource, a prototype study was designed by selecting autopsy facesheets from fetal and neonatal deaths. An algorithm was developed to determine the cause of death from the listing of anatomic diagnoses.One thousand six hundred twenty-five fetal and neonatal autopsy facesheets were selected encompassing fetal and neonatal deaths occurring up to 28 days after birth.The algorithm determined causes of death from autopsy facesheet data in all cases. On review by an experienced pediatric pathologist, these automatically generated cause-of-death statements required no modification or only slight modification in over 90% of cases.A large multi-institutional autopsy database composed of demographic and diagnostic information has been deposited on the Internet. This information can be freely downloaded and used by any researcher without violating patient confidentiality. As a demonstration of one possible application of the database, fetal and neonatal autopsies generated cause-of-death statements using a computer algorithm. One can anticipate that the wealth of information contained in autopsy facesheets can be assembled into a database that will serve the public interest.

The Internet provides the opportunity of permitting public access to large databases containing patient information that can be shared and utilized by epidemiologists, health planners, and medical researchers. Until now, large databases containing patient information have been held in strict confidence, with database access available only to approved researchers or to researchers with access limited to only specific portions of the database. The Internet Autopsy Database (IAD) consists of demographic and pathologic data from over 49,000 autopsies contributed by over a dozen academic medical institutions. Each autopsy record in the public database consists of a uniform set of demographics and SNOMED-compatible terms. To make the database publicly available, a strategy had to be devised that assured the privacy of every person included in the database. A key step involved translating the autopsy facesheets into a listing of SNOMED-compatible terms that effectively eliminated identifying terminology, replacing free text with a generic nomenclature that preserves diagnostic information. The entire database is available on the Internet at: http:@www.med.jhu.edu/pathology/iad.html

Skepticism regarding prostate-specific antigen (PSA) screening arises from the possibility that screening procedures increase the yield of diagnosed prostate cancers occurring in an indolent form that does not require treatment. If PSA screening serves only to increase the yield of clinically trivial prostate cancer, one would expect a drop in the average Gleason score of prostate cancers detected with PSA screening compared with prostate cancers detected before the advent of PSA screening. In a 3-yr study of newly diagnosed prostate cancer, there was almost a 7-fold increase in PSA screening tests ordered between 1989 and 1992 and a greater than 2-fold increase in the number of newly diagnosed prostate cancers. In the same time period, the average Gleason scores of newly diagnosed prostate cancer increased slightly (from 6.2 to 6.5). In this study there was no prognostic difference (as predicted by Gleason score) between prostate cancers in populations whose cancers were diagnosed before and after the increased use of PSA as a screening tool.

Medical coding has become an important new industry that has originated from the field of medical informatics. Automatic coding of specimens has emerged as a way of relieving hospitals from the cost of paying professional coders and for achieving uniform coding for all specimens. Unfortunately, automatic coding, like manual coding, has numerous pitfalls. Further, the coding algorithms employed by manufacturers of automatic coders are typically proprietary. We have developed a method for automatic coding of pathology reports. Using this public domain autocoder, we have previously demonstrated that automatic SNOMED coding was superior to manual coding in several measurable categories, including the overall number of codes generated and the number of distinct code entities provided. In this report, we describe an algorithm that executes this strategy in the M-Technology environment.

The National Cancer Institute established the Registry of Experimental Cancers in March 1970. This registry consists of a permanent collection of pathological materials on spontaneous and induced lesions in laboratory animals that includes histological slides, paraffin blocks, autopsy findings, pathological diagnoses, photographs, and experimental records. The material presently is composed of approximately 60,000 consecutive records and is a valuable resource for researchers interested in tumors and other lesions arising spontaneously or from specific induction protocols in experimental animals. The entire registry database was transferred to an object-oriented database that permits registry staff to write programs for the different data field objects, thus customizing searches and other database functions. Twenty-seven animal species are represented and a total of 6,496 diagnostic entities and 1,106 treatment and control protocols are listed. Archival material may be retrieved for analysis of molecular markers.

A variety of experimental and clinical examples of preneoplasia demon­ strate that regression of early lesions is common. This paper examines the hypothesis that early lesions operate under the identical growth kinetics of 'late' lesions (neo­ plasms), but that kinetic features favouring continuous growth in established lesions tend to favour extinction of lesions composed of small numbers of cells. Growth sim­ ulations of early lesions were produced using the Monte Carlo method, a technique demanding intensive computations. With the advent of powerful personal computers, this technique is now widely available to biologists. Simulating growth under condi­ tions of cell loss similar to those observed in established turn ours, the model predicts that the great majority of initiated cell clusters are expected to reach extinction within a few cell doubling times, and most early (promoted) lesions would not likely progress to the size of a clinically detectable lesion within the life span of the host organism. These Monte Carlo simulations provide a model of initiated cell growth consistent with the recently demonstrated role of early lesion cell death in the development of human lymphomas and in transgenic mice expressing the bcl-2 oncogene. The model demonstrates that small increments in the intrinsic cell loss probability in even the earliest progenitors of malignancy can strongly influence the subsequent development of neoplasia from initiated foci.

The paradigm of pathology research as an endeavor among grant-funded principal investigators resulting in first-author publications is unsupported by quantitative examination of author profiles extracted from the scientific literature. Publications in six pathology journals (Modern Pathology, American Journal of Surgical Pathology, Human Pathology, Acta Cytologica, Archives of Pathology and Laboratory Medicine, and American Journal of Clinical Pathology) and three general science journals (Science, New England Journal of Medicine, and Proceedings of the U.S. National Academy of Sciences) were reviewed. Twenty articles per journal from each of three years (1987, 1989, and 1991) were examined (a total of 520 articles). Of these, 295 articles were first-authored by a member of a department of pathology. Of the 295 articles first-authored by a member of a pathology department, 47 (16%) articles listed competitive grant support. Of the grant-supported articles, 20 articles listed NIH support, but only four had an NIH-supported principle investigator as the first author of the article. Unfunded research represented the vast majority (84%) of work produced by pathologists. A review of the ISI Citation Index showed that those articles written by funded pathologists averaged 8.7 (S.D. 7.8) citations per article, compared to 10.4 (S.D. 12.1) citations per article for unfunded pathologists. Results suggest that unfunded research accounts for the majority of pathology research activity as well as their resulting literature citations.

Current cancer treatment protocols are designed to release the tumour burden down to a small number of cells. In this study, we use Monte Carlo simulations to show that small populations of cells with intrinsic cell loss rates comparable to the cell loss rates observed clinically in human tumours, may regress spontaneously. Large populations of cells tend to grow under the same conditions of cell loss that result in extinction of small clones. Furthermore, minor variations in the intrinsic cell death probability near 0.50 result in large differences in the number of surviving cells calculated at the 100th generation. When Monte Carlo simulations of clonal growth resulted in clones with large populations (50 cells), the population as a whole behaved in a deterministic fashion (logarithmic growth) similar to those observed in clinically observed neoplasms and consistent with other published models of tumour growth. These findings provide a plausible explanation for the clinically observed failure of tumours to recur in instances where tumour burden remains following cancer therapy. The findings also demonstrate the usefulness of the Monte Carlo method to simulate biologic events in populations where the fate of each member of a population can be modeled probabilistically.

Keratoacanthomas (KAs) are rapidly growing cutaneous lesions that frequently look much like well-differentiated squamous cell carcinomas (SCCs) but spontaneously regress. It is uncertain whether KA is a reactive hyperplastic lesion that mimics a neoplasm or a true (but defective) neoplasm that cannot sustain progressive growth. To address this question, we performed DNA flow cytometric analysis on 14 KAs and 10 cutaneous SCCs for comparison. By multiparameter DNA flow cytometry using forward scatter and orthogonal scatter, 10 KAs and 4 SCCs had peridiploid DNA aneuploid populations (DNA indices of 1.03-1.14), and 2 SCCs had grossly aneuploid populations (DNA index, 1.69 and 2.33). Our data thus support aneuploidy in KAs. It is argued that KA is a true neoplasm.

Clear cell dysplasia of the bladder is a well-described morphologic entity that has been found in association with transitional cell carcinoma of the bladder. Its biologic role in bladder tumorigenesis is unknown, and no instances of its polidy analysis have been reported. The authors describe a case of clear cell dysplasia of the bladder found in association with a primary adenocarcinoma of the bladder. Flow cytometric analysis of bladder tissue involved by clear cell dysplasia, adenocarcinoma and cystitis cystica (all from the same bladder) demonstrated no DNA aneuploid populations. Cells from the area of clear cell dysplasia had an S + G2 + M fraction of 7%, indicating that it was a proliferative lesion. Cells from the adenocarcinoma had an S + G2 + M phase of 18%, and cells from an area of cystitis cystica had an S + G2 + M phase of 4%.

Pathologists frequently need to judge whether basal cell carcinomas have been excised adequately. Traditionally, excision adequacy is assessed by looking for the presence of tumor at the margins of resection. This time-honored activity has questionable value, since it has been demonstrated that the majority of tumors with positive margins do not recur, and a substantial minority of tumors with negative margins do recur. It is proposed that excision adequacy can be evaluated by considering the pattern of tumor growth. Tumors composed of widely dispersed nests need wider margins than tumors that grow as tight clusters of tumor nests, and this assertion can be evaluated statistically. A morphometric study of 28 basal cell carcinomas (BCCs) was performed, in which the distribution of tumor cell nests seen in cross-section was analyzed. The average distance from the center varied greatly (272 to 2273 microns) among these tumors. Standard deviations were calculated from distances between the tumor center to each nest within the tumor, and one-tailed Student's t tests were used to obtain 90%, 95%, and 99% confidence limits for distances beyond which no additional tumor nests are expected. These distances, in tumor radii, ranged from 0.8 to 1.9 and from 1.03 to 4.89, for 90% and 99% confidence limits, respectively. Conventional methods used to determine margin adequacy do not account for the discontinuous appearance of BCC in histologic sections. This theoretical model demonstrates that an alternate way of assessing excision adequacy can be achieved with a statistical analysis of the pattern of tumor growth, rather than looking for absence of tumor at the resection margin.(ABSTRACT TRUNCATED AT 250 WORDS)

Automated coding of surgical pathology reports is demonstrated. This public-domain translation software operates on surgical pathology files, extracting diagnoses and assigning codes in a controlled medical vocabulary, such as SNOMED. Context-sensitive translation algorithms are employed, and syntactically correct diagnostic items are produced that are matched with controlled vocabulary. English-language surgical pathology reports, accessioned over one year at the Baltimore Veterans Affairs Medical Center, were translated. With an interface to a larger hospital information system, all natural language pathology reports are automatically rendered as topography and morphology codes. This translator frees the pathologist from the time-intensive task of personally coding each report, and may be used to flag certain diagnostic categories that require specific quality assurance actions.

We are reporting the first results of a comparative study of 100 consecutive autopsies and their clinical diagnoses, observed at the Johns Hopkins Medical Institutions (JHMI) and at the Institut neuchâtelois d'anatomie pathologique (INAP). The diagnoses of the two series were coded according to the two different systems used currently at the two institutions. The data from Baltimore were automatically classified by a special "key word method" using the categories of the Index Medicus (MeSH = Medical subject headings). We proceeded then to a second recording by SNOMED codes, introduced into the computer system in the same way as we document the autopsy diagnoses in Neuchâtel. The two series could be compared in detail according to topographical, morphological and aetiological parameters. The over-all repartition of the examined cases shows a higher incidence of newborns in Baltimore (23), in Neuchâtel we observed only 7 newborn autopsies. The mean age was inferior in Baltimore (males: 53.5 years for JHMI, 73.1 years for INAP; females: 58.4 years for JHMI, 66.2 years for INAP). The number of diagnoses per autopsy was 31.9 at JHMI, and 50.1 in Neuchâtel. The topographical distribution of clinical and autopsy diagnoses showed a higher frequency of central nervous system lesions in JHMI which might be explained by the activity of a neuropathological division. Findings concerning the morphological categories revealed a higher frequency in JHMI for traumatic abnormalities (7.2% vs 2.5%), malformations (4.3% vs 0.8%), whereas inflammation and fibrosis and degenerative lesions were more often encountered in Neuchâtel. The differences in morphological observations could be attributed to a higher proportion of newborn cases in JHMI with complex malformation syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)

A recent study by Bangert et al suggests that there are quantitative histologic differences that distinguish discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Utilizing criteria proposed by these authors, we examined 77 biopsy specimens from 63 patients with various forms of lupus erythematosus, but we were unable to predict the correct clinical subset. Using the clinical diagnosis of DLE as a positive reference standard, the sensitivity and specificity for the overall pathologic diagnosis of DLE were 55% and 42%, respectively. Statistically significant histologic factors favoring the diagnosis of DLE over SCLE in the present study were pilosebaceous atrophy, hyperkeratosis, parakeratosis, basement membrane thickening around the follicles, subepidermal edema, and vascular ectasia. These histologic variables were entered into a forward stepwise multivariate regression analysis to determine distinct predictors of DLE vs SCLE. This analysis showed that pilosebaceous atrophy was the only distinct significant predictor of DLE vs SCLE. These results suggest that the histologic differentiation of clinically defined DLE and SCLE cannot be established from the histologic features examined.

SummaryComputer translation programs for foreign language texts have recently become available commercially and in the public domain, but large medical lexicons for these programs are not readily available. It has been shown that many English words can be “respelled” to form their corresponding translations in other Western European languages. We have used lists of 139,451 English and 185,137 German medical terms to generate respeliings in the Dutch language. The English list yielded 39,035 Dutch respeliings, and the German list yielded 56,683 respeliings. Medical respelling rules can substantially lower the effort of installing and maintaining a medically oriented computer translation program.

SummaryDespite many investigations of the potential role of formal symbolic logic in medicine, little attention has been paid to the distribution of words in large quantities of natural language text and how this might affect the choice of a logic system. With the emergence of communicating word processor technology, it is now possible to enter large amounts of routine medical text in computer-readable form and study its implications for symbolic logic formalisms.We examined the word distribution in the Anatomical Diagnosis reports of 7,000 consecutive autopsied patients from the Department of Pathology of The Johns Hopkins Hospital. We found that uncommon disease entities consisting of common component words were best recovered using a search algorithm which examines conjunction (and) logic in ascending order of word frequency and alternation (inclusive or) logic in descending order of word frequency. This logic is non-Abelian, non-distributive, and associative for conjunction but not for alternation. Our results suggest that natural language text analysis, which is essential for studying medical documents by computer, may require heretofore little studied variant forms of symbolic logic.

The sequence of events in the development of the brain in human embryos, already published for stages 8-15, is here continued for stages 16 and 17. With the aid of a computerized bubble-sort algorithm, 71 individual embryos were ranked in ascending order of the features present. Whereas these numbered 100 in the previous study, the increasing structural complexity gave 27 new features in the two stages now under investigation. The chief characteristics of stage 16 (approximately 37 postovulatory days) are protruding basal nuclei, the caudal olfactory elevation (olfactory tubercle), the tectobulbar tracts, and ascending fibers to the cerebellum. The main features of stage 17 (approximately 41 postovulatory days) are the cortical nucleus of the amygdaloid body, an intermediate layer in the tectum mesencephali, the posterior commissure, and the habenulo-interpeduncular tract. In addition, a typical feature at stage 17 is the crescentic shape of the lens cavity.

Two adult males are described with congenital adrenal hyperplasia (21-hydroxylase deficiency). Patient 1 was receiving therapy with cortisone acetate and presented with clinical features of glucocorticoid excess and uncontrolled adrenal androgen activity. It was established that the short-acting steroid which the patient was receiving was cleared so rapidly that endogenous ACTH secretion was not inhibited. Patient 2 presented with enlarged and painful testes in association with poor compliance with corticosteroid therapy. The histologic picture of the testis was compatible with 'Leydig cell hyperplasia'. However, successful response to dexamethasone therapy suggests that the testes harboured an adrenal rest. These observations highlight the need for careful follow-up and treatment of adult male patients with congenital adrenal hyperplasia.

A catenoidal, or saddle-shaped, configuration of the interventricular septum, concave toward the left ventricular cavity in the transverse plane, but convex toward the left ventricular cavity in the apex to base plane, occurs in idiopathic hypertrophic subaortic stenosis and possibly may lead to septal hypertrophy and immobility. The authors also have observed catenoidal shape of the interventricular septum in hearts with myocardial infarcts. They reviewed 1,415 hearts examined after postmortem arteriography and fixation in distention from patients autopsied at The Johns Hopkins Hospital. Among 586 hearts with myocardial infarcts, there were 54 (9%) with a catenoidal shape of the interventricular septum. The infarcts, 45 anterior septal and 9 inferior and lateral, appeared to account for the reversal of normal apex to base curvature, although coexistent idiopathic hypertrophic subaortic stenosis could not be excluded in 3 patients. There was moderate or marked infarct expansion in 25/54 (46%) and septal or free wall rupture in 8 (15%) hearts. Reduced average net septal curvature in the 54 hearts, highly significant compared with that in 80 hearts without infarcts (P less than 0.001), would reduce the septum's contribution to left ventricular function and may contribute to the observed postinfarct congestive failure, 30/54 (56%), and hypoperfusion, 7/54 (13%). The results suggest that some myocardial infarcts may produce a catenoidal shape of the interventricular septum that could reduce the functional activity of the surviving uninfarcted basilar portion of the septum and thereby contribute to postinfarction cardiac dysfunction.

To gain further insight into the supramolecular structure and behavior of chromatin, a set of parameters has been developed for the description of cell nuclear images. These images are obtained from Feulgen-stained nuclei in semithin sections. Data are extracted by a scanning microphotometer, printed on paper tape and processed by an electronic computer. The essential principles for the selection of descriptors were that: (a) they should correspond to characteristics that are employed in classical morphology and (b) they should be subject to interpretation in categories of biochemistry or molecular biology insofar as possible. Some of these parameters deal with the size and shape of the nucleus and its deoxyribonucleic acid content or staining behavior. Efforts were made to determine the relative amount of chromatin in the condensed state, because it may be assumed that the degree of condensation correlates with the activity of the chromatin. To demonstrate the power of the method, results from methylthiouracil-activated thyroid nuclei are presented. In stimulated nuclei the diffuse chromatin expands and fills the increasing nuclear volume, while the condensed chromatin retains its degree of condensation, and, probably, does not change in amount.

The anatomic relationship of the aortic and mitral valves is a useful landmark in assessing congenital heart malformations. The atrioventricular and semilunar valve regions originate in widely separated parts of the early embryonic heart tube, and the process by which the normal fibrous continuity between the aortic and mitral valves is acquired has not been clearly defined. The development of the aortic and mitral valve relationship was studied in normal human embryos in the Carnegie Embryological Collection, and specimens of Carnegie stages 13, 15, 17, 19, and 23, prepared as serial histologic sections cut in the sagittal plane, were selected for reconstruction. In stage 13, the atrioventricular valve area is separated from the semilunar valve area by the large bend between the atrioventricular and outflow-tract components of the single lumen heart tube created by the left interventricular sulcus. In stages 15 and 17, the aortic valve rotates into a position near the atrioventricular valves with development of four chambers and a double circulation. In stage 19, there is fusion of aortic and mitral endocardial cushion material along the endocardial surface of the interventricular flange, and this relationship is maintained in subsequent stages. Determination of three-dimensional Cartesian coordinates of the midpoints of valve positions shows that, while there is growth of intervalvular distances up to stage 17, the aortic to mitral distance is essentially unchanged thereafter. During the period studied, the left ventricle increases in length over threefold. The relative lack of growth in the saddle-shaped fold between the atrioventricular and outflow tract components of the heart, contrasting with the rapid growth of the outwardly convex components of most of the atrial and ventricular walls, may be attributed to the different mechanical properties of the two configurations. It is postulated that the pathogenesis of congenital heart malformations, which characteristically have failure of development of aortic and mitral valve continuity, may involve abnormalities of rotation of the aortic region or malpositioning of the fold in the heart tube.

Clinical and laboratory findings of 237 consecutive patients who had 250 temporal artery biopsies performed at the Wilmer Institute during a 15-year period were reviewed. Biopsies were reviewed independently on three separate occasions by four observers who, unaware of the clinical history, made one of the following histopathologic diagnoses: active arteritis, healed arteritis, arteriosclerosis, atherosclerosis, normal, or other. Biopsies were reviewed a fourth time by the observers together to establish a consensus diagnosis. The frequency of intraobserver disagreement in biopsy interpretation ranged from 4.4 to 25.6% of cases. The frequency with which observers disagreed with the consensus diagnosis (interobserver variation) ranged from 4.3 to 13.5% of cases. Pre-biopsy steroid therapy for seven to eight weeks or longer was associated with loss of the histopathologic features of active arteritis. We recommend biopsies for all patients with known contraindications to steroid therapy. In addition, multivariant regression analysis suggests that certain patients can be selected who are likely to have positive biopsies. For some patients, the clinical diagnosis of temporal arteritis can be based on the clinical signs and symptoms and their response to a therapeutic trial of steroids.

The mechanism by which myocardial blood flow varies in response to metabolic demand is obscure. One hypothesis is a countercurrent regulation of arterial caliber by diffusible substances carried in venous blood. To study the anatomic basis for blood flow regulation, we performed combined arterial and venous injections in 20 human hearts and studied left ventricular intramyocardial vessels with radiography, 100 micron thick sections, and reconstructions of serial histologic sections. Penetrating arteries lie in interstitial spaces and are closely related to accompanying veins. These interstitial veins partially surround and are indented by branch arteries. A second system of veins lies within muscle fascicles between interstitial spaces and is not related to arteries. The isolated veins have collateral connections with interstitial veins and join them in the subepicardium. This vascular anatomy could allow arterial caliber to be regulated by diffusible substances carried in the interstitial veins. Arterial dilatation might prolong this effect by partial obstruction of interstitial veins, with the isolated venous system providing an alternative pathway for venous drainage and washout. The study shows that a vascular arrangement is present in human left ventricular myocardium that could provide a countercurrent regulation of blood flow with diffusible substances carried in venous blood.

Atherosclerosis of the pulmonary arteries is a common autopsy finding and is associated with a variety of clinical conditions. To delineate the morphologic changes associated with pulmonary artery atherosclerosis, autopsies of 337 consecutive adults (greater than 15 years of age) were studied. For each, 35 features were studied, including age, coronary vascular disease, cardiac chamber hypertrophy and dilation, pulmonary artery and aortic atherosclerosis, and pulmonary thromboemboli and emphysema. These were compared using correlation coefficients and forward and backward stepwise regression procedures for selected variables. Pulmonary artery atherosclerosis correlated significantly with age, right ventricular dilation and hypertrophy, pulmonary emphysema, and aortic atherosclerosis. Regional evaluations of systemic and pulmonary atherosclerosis showed highly significant internal correlations. In the ligamentum arteriosum, the intensity of atherosclerosis over the aortic insertion correlated with the severity of a similar atheroma at the pulmonary artery insertion. With the multiple-regression procedure, pulmonary artery atherosclerosis was a significant predictor of aortic atherosclerosis, right ventricular hypertrophy, and pulmonary embolization. Our study shows that pulmonary embolization. Our study shows that pulmonary embolization. Our study shows that pulmonary artery atherosclerosis is accelerated in patients with atherosclerosis of the systemic arteries and the pathologic lesions associated with hypertensive pulmonary vascular disease.

In order to aid in the identification of a group of breast cancer patients at high risk of recurrence in whom the possible value of adjuvant chemotherapy might be most readily demonstrable, the authors reviewed the clinicopathologic features of 74 women with infiltrating, Stage I, estrogen receptor-negative breast carcinoma. They found significant correlations between short-term recurrence (within 2 years) and extensive necrosis (P less than 0.005), anaplastic tumor nuclear morphology (P less than 0.01), a positive family history of breast carcinoma (P less than 0.05), diffuse hyperplasia of axillary lymph nodes (P less than 0.05), and young age (P less than 0.05). Twenty percent of all patients experienced recurrence within 2 years, while recurrence was noted in 32% of patients with highly pleomorphic nuclei, 38% of those with extensive necrosis, and 45% of those with a positive family history. Recurrence was noted in 55% of the small number of patients with both anaplastic nuclear morphology and a positive family history. These apparent risk factors for early recurrence may be helpful in prospectively selecting patients most eligible to receive adjuvant chemotherapy.

The nature and frequency of pulmonary involvement in systemic lupus erythematosus (SLE) is controversial. We reviewed the clinical and pathologic features of 120 patients with SLE described in autopsy records at The Johns Hopkins Hospital to determine the pulmonary parenchymal changes that could be attributed directly to SLE. Each case was reviewed to determine the extent of extrapulmonic SLE and possible alternative explanations for the observed lung pathology. Moderate or severe pulmonary parenchymal alterations that were attributed to SLE were found in 22 patients (18 percent). Five patients with interstitial fibrosis, two with pulmonary vasculitis, and one with pulmonary hematoxylin bodies were attributable only to SLE, as were 11 of 15 (73 percent) patients with interstitial pneumonitis. Alternative explanations for findings previously attributed to SLE included congestive heart failure, renal failure, infection, aspiration, oxygen toxicity and increased intracranial pressure. Alveolar hemorrhage, thought to be a feature of acute lupus pneumonitis, was unexplained in only two of 29 (7 percent) patients, alveolar wall necrosis was unexplained in one of seven (14 percent) and edema was unexplained in three of 70 (4 percent). Hyaline membranes, present in four patients, were always explained. Pleuritis and pleural effusions were attributed to SLE in 22 of 36 (61 percent) and three of 28 (11 percent) patients, respectively. The findings suggest that many nonspecific pulmonary lesions previously attributed to SLE, such as alveolar hemorrhage, alveolar wall necrosis, edema and hyaline membranes, are probably secondary to intercurrent infection, congestive heart failure, renal failure or oxygen toxicity.

The diagnosis of asbestos-related pulmonary disease is frequently based in part on the identification of pleural plaques; however, postmortem observations have suggested that pleural plaques may occur without associated pulmonary disease. To examine this issue, we compared the pulmonary parenchymal pathology in 93 patients with pleural plaques to 93 control patients matched for age, race, and sex, all autopsied at The Johns Hopkins Hospital between Jan 1, 1981 and March 31, 1986. Pulmonary sections were graded without knowledge of the patient's group for peribronchiolar fibrosis, other types of fibrosis, emphysema, and pleural changes. Correlations were found between the presence of pleural plaques and peribronchiolar fibrosis (p less than 0.001), alveolar fibrosis (p less than 0.05), large scars (p less than 0.02), scar-related emphysema (p less than 0.02), and pleural thickening (p less than 0.005). A history of smoking was also associated with pleural plaques (p less than 0.05). Interstitial fibrosis was not significantly different between the two groups. Peribronchiolar fibrosis was neither universally nor exclusively present in patients with pleural plaques, being found in 49 (53 percent) of 93 subjects with and 36 (39 percent) of 93 subjects without plaques. The results suggest that caution must be exercised in extrapolating from the identification of pleural plaques to a diagnosis of asbestos-related pulmonary disease.

To evaluate the possible reproductive potential in patients who receive chemotherapy for leukemia, we reviewed the gonadal histologic findings at autopsy in 183 treated leukemic patients and in 183 age- and sex-matched control subjects. The 103 male leukemic patients had significantly reduced spermatogenic activity and tubular fertility index and increased interstitial fibrosis as compared with control subjects (p less than 0.001). The 80 females had marked reduction of secondary follicles (p less than 0.001). These lesions showed no predilection for grouping by sexual maturity or by leukemia diagnosis. There was no correlation with the type of chemotherapy or time since last dose of any antileukemic agent. Despite these extensive pathologic changes, there was histologic evidence of residual reproductive potential--a tubular fertility index greater than zero in 65 percent of males and intact primary follicles in 81 percent of premenopausal females. Testicular leukemia was present in 25 percent of males; all of the patients with testicular leukemia had additional foci of leukemia in other organs. The study shows histologic evidence of possible reproductive potential in treated leukemic patients of both sexes and does not support the concept of the testis as a tumor sanctuary in leukemia.

Computerized indexing and retrieval of medical records is increasingly important; but the use of natural language versus coded languages (SNOP, SNOMED) for this purpose remains controversial. In an effort to develop search strategies for natural language text, the authors examined the anatomic diagnosis reports by computer for 7000 consecutive autopsy subjects spanning a 13-year period at The Johns Hopkins Hospital. There were 923,657 words, 11,642 of them distinct. The authors observed an average of 1052 keystrokes, 28 lines, and 131 words per autopsy report, with an average 4.6 words per line and 7.0 letters per word. The entire text file represented 921 hours of secretarial effort. Words ranged in frequency from 33,959 occurrences of "and" to one occurrence for each of 3398 different words. Searches for rare diseases with unique names or for representative examples of common diseases were most readily performed with the use of computer-printed key word in context (KWIC) books. For uncommon diseases designated by commonly used terms (such as "cystic fibrosis"), needs were best served by a computerized search for logical combinations of key words. In an unbalanced word distribution, each conjunction (logical and) search should be performed in ascending order of word frequency; but each alternation (logical inclusive or) search should be performed in descending order of word frequency. Natural language text searches will assume a larger role in medical records analysis as the labor-intensive procedure of translation into a coded language becomes more costly, compared with the computer-intensive procedure of text searching.