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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.

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.

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.

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.

Recent reports suggest an increased risk of cancer of the pancreas after partial gastrectomy. We investigated this putative relationship by performing a case-control study on autopsy subjects. Our findings suggest a three-fold risk of pancreatic carcinoma in postgastrectomy patients. Increased production of carcinogens in the gastric remnant, excretion of the carcinogens by the liver into the bile, and subsequent bile reflux into the pancreatic duct is proposed as a working hypothesis for pancreatic carcinogenesis. This study illustrates the usefulness of autopsy series as an instrument for checking a straightforward hypothesis before designing more extensive and expensive studies. Moreover, efficient use of autopsy data was accomplished by computerized data base retrieval of autopsy records, emphasizing that this method of record retrieval is an important precondition for prospective studies.

The reason that the normal ductus arteriosus has a muscular media, contrasting with the elastic lamellar structure of the adjacent great arteries, is unknown. We examined the hypothesis that the anatomic relationship of the ductus arteriosus to the vagus and recurrent laryngeal nerves during early development might be of importance in influencing ductal morphology. Normal human embryos from the Carnegie Embryological Collection and embryos and fetuses from the Hopkins Pathology Collection were studied microscopically, by reconstructions made from serial histologic sections, or by gross dissection. At Carnegie stage 16 the recurrent laryngeal nerves pass medially from the vagus nerve to the laryngeal area and are caudal to the bilaterally symmetric sixth aortic arches. By stage 18 the right sixth aortic arch has disappeared and the left sixth aortic arch is in a more caudal position relative to the larynx. The left vagus nerve and its recurrent laryngeal branch form a sling supporting the distal (or ductus arteriosus component) of the left sixth aortic arch. In subsequent development there is greater relative separation of the larynx and ductus arteriosus. The media of the ductus arteriosus beneath the supporting nerves is thinner and has less elastic fiber formation than the elastic lamellar media of the adjacent aortic arches. The study shows that the vagus and recurrent laryngeal nerves are in a position to provide mechanical support to the ductus arteriosus during its development and that the morphology of the media of the supported ductus arteriosus differs from that of the adjacent unsupported aortic arches. It is suggested that this local mechanical support may be the reason that the normal ductus arteriosus differentiates as a muscular artery and is therefore able to obliterate its lumen in postnatal life. Without such support the ductal media could develop the abundant elastic fibers characteristic of the normal unsupported aorta and pulmonary trunk and become an abnormal, persistently patent ductus arteriosus.

Etude de 14 malades atteints d'uremie, dont 4 sous hemodialyse depuis quelques mois. Comparaison avec 11 temoins normaux. L'evacuation du contenu de l'estomac, evaluee au moyen d'un radioisotope, est retardee en cas d'insuffisance renale. Il faudrait en tenir compte dans le traitement, et peut-etre administrer a ces malades un agent stimulant la motilite gastrique

It is not known why the coronary arteries almost always originate only from the right and left aortic sinuses of Valsalva, since the structure and conditions appear to be the same for all six sinuses of the embryonic great arteries. We sought a possible mechanical explanation for the phenomenon by studying the development of the coronary vasculature in 351 staged, serially sectioned human embryos of Carnegie stages 9 through 23 from the Carnegie Embryological Collection. A plexus of blind epicardial capillaries appears on the heart in Carnegie stage 14 or 15 and acquires a coronary sinus connection in stage 15, 16, or 17. The connection of the proximal coronary arteries to the aorta does not appear until stage 18. We found no histologic features of the cardiac nerves or any other component of the tissues to account for the consistent origin of coronary arteries from the right and left aortic sinuses of Valsalva. However, serial section reconstructions showed that the two sinuses where coronary arteries develop acquire a positive transverse curvature and a negative longitudinal curvature, i.e., a catenoidal or saddle-shaped configuration, before the appearance of the coronary arteries. The four noncoronary sinuses also have a positive transverse curvature, but longitudinally, in contrast, they have a positive curvature or are straight. The results suggest that the coronary arteries originate from those sinuses of Valsalva where wall tension is increased by a catenoidal configuration.

Summary Feulgen-stained normal breast epithelium (4 cases) and breast carcinoma (8 cases) were analyzed by means of cytophotometric scanning measurements. Besides the DNA content, DNA concentration, and area of the cell nucleus, the number and absolute as well as relative amount of condensed chromatin was determined. In addition, the DNA concentration, area, and form of the condensed chromatin was evaluated. It was demonstrated that nuclear DNA is elevated (near tetraploid stemlines) in carcinoma cells, the DNA concentration is more highly variable, and that the elevated DNA amounts are largely attributable to elevated nuclear area values. The number of “heterochromatic” particles is more variable in tumor cell nuclei than in normal cell nuclei. Significantly more chromocenters were demonstrable in only one case. The absolute DNA content in condensed chromatin of carcinoma cells is also highly variable (significantly elevated only in a single case). The most important result of the foregoing investigation seems to be that the percentage DNA content in condensed chromatin is greatly decreased in all tumors (6%) as compared to normal cell nuclei (13%). Regarding the form of the condensed chromatin particles, the particles ares more spherical in tumor cells as contrasted to more pointed in normal cells. The results are discussed in relationship to biochemical determinations of heterochromatin.