Discrepant Cases Research Articles

The Inner Density Cusp of Cold Dark Matter Halos

I report recent results of numerical simulations designed to study the inner structure of Cold Dark Matter (CDM) halos. This work confirms the proposal of Navarro, Frenk & White (NFW) that the shape of ACDM halo mass profiles differs strongly from a power law and is approximately independent of mass. the logarithmic slope of the spherically-averaged density profile, as measured by β = –d ln ρ/d ln r, decreases monotonically towards the center, becoming shallower than isothermal (β < 2) inside a characteristic radius, r–2, and shows no evidence for convergence to a well-defined asymptotic value (β0) at the center. the dark mass contained within the innermost radius resolved by the simulations places strong constraints on β0; cusps as steep as r–1.5 are clearly ruled out in our highest resolution simulations. A profile where the radial dependence of the slope is a simple power law, β(r) ∝ rα, approximates the structure of halos better than the NFW profile and so may minimize errors when extrapolating our results inward to radii not yet reliably probed by numerical simulations. We compare the spherically-averaged circular velocity (Vc) profiles to the rotation curves of low surface brightness (LSB) galaxies in the samples of de Blok et al. and Swaters et al. the Vc profiles of simulated CDM halos are generally consistent with the rotation curves of LSB galaxies, but there are also some clearly discrepant cases. This disagreement has been interpreted as excluding the presence of cusps, but it may also just reflect the difference between circular velocity and rotation speed likely to arise in gaseous disks embedded within realistic triaxial halos.

Fine needle aspiration of the thyroid: a cytohistologic correlation and study of discrepant cases.

Fine needle aspiration (FNA) is a reliable method in the initial assessment of thyroid nodules. The purpose of this study was to evaluate the causes for discordance between the interpretation on FNA and the pathologic findings in the resected thyroid. A computer search of all thyroidectomy specimens with previous FNA from January 1998 to December 2001 was obtained from the files of the Lauren V. Ackerman laboratory of surgical pathology, Barnes-Jewish Hospital. Excluded from the study were those FNAs performed for suspected and confirmed metastatic disease to the thyroid as well as those cases unavailable for review. A total of 45 FNA cases were identified with cytologic and histologic discrepancies. Of the 1253 individual thyroid FNA performed during the study period, 255 patients (20%) subsequently had an open surgical procedure on the thyroid. Of those who underwent surgery, 196 cases (77%) were concordant, whereas 45 patients (18%) were discordant, and 14 cases were excluded due to unavailability of slides for review (for example, returned consult slides). The causes of the 45 discordant cases were: 20 cases (44%) were unsatisfactory for diagnosis, 14 cases (31%) were due to interpretation error (false positive), and 11 cases (24%) were due to sampling error (false negative). The most common causes of our discrepant cases are those whose FNA diagnosis was interpreted as "unsatisfactory for diagnosis," in 20 (7.8%) of 255 surgical cases. The false negative rate due to sampling error in 11 (4%) of 255 cases was mainly due to the presence of microscopic papillary thyroid carcinoma (PTC); the false positive rate was due to interpretation error in 14 (6%) of 255 cases, and those were explained by the occurrence of overlapping cytologic features among adenomatous nodules, follicular neoplasms, the follicular variant of PTC, and Hashimoto's thyroiditis.

Cusps and rotation curves in cold-dark-matter haloes

I report on recent numerical simulations designed to study the inner structure of cold-dark-matter (CDM) haloes. This work confirms and extends earlier indications that the mass profiles of CDM haloes are roughly independent of mass and that the dark-matter density appears to diverge in a central "cusp". Our simulations also show that CDM halo-density profiles get increasingly shallow inwards down to the innermost radius (r(min)) resolved by the simulations, with no evidence for convergence to a well-defined asymptotic value (beta(0)) of the logarithmic slope. The dark mass contained within r(min) places strong constraints on beta(0); cusps as steep as beta(0) approximately -1.5 are clearly ruled out in our highest resolution simulations, although beta(0) less, similar -1 is consistent with the numerical data. The circular-velocity curves of the simulated CDM haloes are generally consistent with the rotation curves of low-surface-brightness (LSB) galaxies in the literature, but there are also some clearly discrepant cases. This disagreement has been interpreted as excluding the presence of cusps, but I argue that it may just reflect the difference between circular velocity and rotation speed likely to arise in gaseous discs embedded within realistic triaxial haloes. The perceived challenge to the CDM paradigm stemming from LSB rotation curves may thus plausibly result from the complex three-dimensional structure of CDM haloes, and might be resolved without appeal to a drastic revision of the paradigm.

Fine Needle Aspiration in the Management of Thyroid Nodules: Experience at King Khalid National Guard Hospital, Jeddah

Fine Needle Aspiration in the Management of Thyroid Nodules: Experience at King Khalid National Guard Hospital, Jeddah

Convergence between structured diagnostic interviews and clinical assessment on the diagnosis of pediatric-onset mania

BackgroundUncertainties remain as to the utility of structured diagnostic methodology to aid in the diagnosis of manic symptomatology in youth. To this end, this study compared structured diagnostic interview based diagnoses of mania in children and adolescents with that of an expert clinician. MethodsWe separately and independently assessed 69 youths recruited for a study of mania in childhood, all but 2 of whom experienced mania, with a structured diagnostic interview administered by trained psychometricians and a clinical assessment by a board-certified child and adolescent psychiatrist (JW) who was blind to the structured interview results. ResultsStructured interviews and clinical evaluations converged in all but two cases (67 of 69 or 97% agreement). In one discrepant case, the structured interview diagnosed a full case of mania, but the clinical interview diagnosed cyclothymia/subthreshold mania; in the other discrepant case, the structured interview failed to diagnose mania, but the clinical interview did diagnose mania. ConclusionsIn children referred for evaluation of suspected bipolar disorder, a structured interview diagnosis of mania is very likely to be corroborated by a clinical interview.

Cytologic-histologic correlation of nongynecologic cytopathology cases: separation of determinate from indeterminate cytologic diagnoses for analysis and monitoring of laboratory performance.

Much of the literature on the quality-assurance aspect of cytologic-histologic correlation (CHC) has focused on gynecologic cytology. For nongynecologic cytopathology, the process is complicated by the use of determinate (positive for malignant cells, negative for malignant cells) and indeterminate (atypical, suspicious, or follicular lesion) diagnostic categories. Here, we illustrate our routine methodology for analyzing CHC data on nongynecologic cytopathology cases by separating determinate from indeterminate cases. A focused list of determinate and indeterminate cytopathology cases with surgical pathology correlation is generated each week. The determinate cases are ascertained as true positive (TP), true negative (TN), false positive (FP), or false negative (TN). The discrepant cases (FP and FN) are investigated to determine the cause (sampling, interpretation, or screening). For indeterminate cases, the surgical pathology outcome (benign, malignant) and suitability of the cytopathology category utilized are reviewed. For the focused period of 4 mo, sensitivity was 70% and specificity was 100%. The most common reason for false-negative diagnoses was a sampling problem in the cytologic specimen; there were no false-positive diagnoses. Malignant outcomes for follicular lesion, atypical, and suspicious diagnoses were 29%, 40%, and 76%, respectively. Data derived from regularly performed CHC are useful in reviewing the diagnostic performance of the laboratory.

Overexpression of p16INK4A in liquid-based specimens (SurePath) as marker of cervical dysplasia and neoplasia.

Human papillomavirus (HPV) is recognized as a causal agent for cervical carcinomas. Assimilation of HPV oncogenes E6 and E7 into the host DNA promotes upregulation of cyclin dependent kinase inhibitor (CDKI) p16(INK4A), detectable by monoclonal antibody in the developing cervical cancer cells. The aim of this study was to 1) develop a protocol for p16(INK4A) immunocytochemical staining on SurePath preparations, and 2) determine its utility as an HPV marker on a spectrum of cervical reactive and neoplastic lesions. Seventy-two specimens consisting of 28 nonneoplastic/nondysplastic cases (NN), one reactive glandular cells (RGC), 27 low-grade squamous intraepithelial lesions (LSIL), 10 high-grade squamous intraepithelial lesions (HSIL), one squamous cell carcinoma (SCCA), four atypical glandular cells (AGUS), and two adenocarcinomas (ADCA) were reprepped by SurePath and antibody to p16(INK4A) applied at 1:100 dilution using the Dako Envision + System on the Dako Autostainer. Expression of p16(INK4A) within the nucleus principally and cytoplasm of at least 10-15 cells was considered positive. All initial Papanicolaou-stained discrepant cases (p16(INK4A) positivity of NN and RGC cases and lack of reactivity in LSIL, HSIL, and AGUS) were reviewed. Nine of ten (90%) HSIL, one (100%) SCCA, 21/27 (78%) LSIL, and some reactive and inflammatory specimens demonstrated the presence of p16(INK4A). Reevaluation of discrepant cases revealed that several were underinterpreted (four NN were LSIL, one RGC was AGUS) or overinterpreted (one LSIL was NN). Following reassessment, false-positive staining was present in only 1/25 (1.4%) NN. Six of 30 (20%) LSIL lacked p16(INK4A) positivity. One of 10 (10%) HSIL had no staining. Two of four AGUS did not react with p16(INK4A) antibody. Both SCCA (1) and ADCA (2) had positive expression. This study confirms the intimate relationship between p16(INK4A) and HPV cytopathic effect. The p16(INK4A) immunocytochemical stain can be applied to liquid-based cervical preparations. This technique offers a more objective approach to deciphering "gray areas" of gynecologic cytopathology.

Chromogenic In Situ Hybridization: A Novel Approach to a Practical and Sensitive Method for the Detection of HER2 Oncogene in Archival Human Breast Carcinoma

The high incidence of HER2 overexpression on the cell surface of breast cancer cells and the recognized prognostic and potentially predictive value of HER2 render this cell surface receptor a novel and important therapeutic target. Although immunohistochemistry (IHC; HercepTest) and fluorescence in situ hybridization (FISH; PathVysion and INFORM)—both approved by the Food and Drug Administration—have emerged as the most viable assays for evaluation of HER2 status in routine clinical practice, there is still no consensus on which is the best method for assessing HER2 status. Therefore, our specific objective was to establish a chromogenic in situ hybridization (CISH) assay for the detection of HER2 amplification on a cohort of 173 archival invasive breast carcinomas. Results were compared with HercepTest, which is the most frequently used method for detecting HER2 alteration. Additionally, HER2 gene copy number was investigated using differential PCR (dPCR) as a testing system. HER2 overexpression was found by IHC in 24.3%; HER2 amplification was found by CISH in 19.1% and by dPCR in 9.2% of the tumors. The overall concordance rate was 95.9% between CISH and IHC and 85.0% between dPCR and IHC. Kappa statistics revealed an excellent agreement between IHC and CISH (κ = 0.878), but only a moderate agreement was found between IHC and dPCR (κ = 0.482). Discrepant cases between CISH and HercepTest and all IHC-positive cases (+2 and +3), a total of 42 cases, were analyzed with the FISH PathVysion (Vysis) assay. Among 25 HercepTest-positive cases (score +3), 2 showed no gene amplification by FISH or CISH. Four of 13 tumors with weak HER2 overexpression (score +2) were negative with both FISH and CISH. Concordance between CISH and FISH was 100% for the 38 cases analyzed. The current study showed that CISH represents a practical and simple assay for evaluating HER2 gene amplification in archival material, offering a promising alternative to IHC or FISH for the routine diagnostic setting.

On the Absolute Magnitudes of the O Stars

The conclusion published in 1992 by Garmany & Stencel from study of northern OB associations, that the absolute magnitudes of the O stars show a large scatter ... intrinsic to the classification system, is critically examined. It is found that the differences between their derived absolute magnitudes of O stars and this author's 1973 calibration exhibit large systematic effects in several associations, ranging from -0.74 to +1.02 mag with substantially smaller dispersions. Of course, when these results are combined, the scatter equals the full range of the systematic effects. To investigate the possibility of distance errors, the Garmany & Stencel B0–B2.5 stars in the same associations are subjected to the same analysis. The results for the B stars show no significant systematic differences, eliminating errors in the association distances derived by Garmany & Stencel from the B stars as the source of the differences found for the O stars. It is noteworthy that the dispersions in the absolute magnitudes of the B stars within given association are similar to or larger than those of the O stars. An examination of the distribution on the sky of the stars shows that the O and B stars in the discrepant associations are generally not colocated; such was already known to be the case for the important Perseus OB1 association. It is suggested that despite their efforts to improve them, significant problems remain with the association memberships adopted by Garmany & Stencel; the relatively small dispersions of the O star absolute magnitudes even in the discrepant cases indicate that they belong to different, usually more distant associations near the lines of sight to the B associations with which they have been mistakenly connected. Several individual cases of unrecognized multiple systems and classification errors are also found in the Garmany & Stencel sample. It is concluded that the scatter in the absolute magnitudes of the O stars is not as large as found by Garmany & Stencel, and not larger than that of the B stars.

Management and Complications of Anterior Cruciate Ligament Injuries in Skeletally Immature Patients: Survey of The Herodicus Society and The ACL Study Group

Expert opinion regarding experience with the management and complications of pediatric anterior cruciate ligament (ACL) injuries was studied by surveying members of The Herodicus Society and The ACL Study Group. There was large practice variation in initial management and ACL reconstruction technique. There were 15 reported cases of growth disturbance: 8 cases of distal femoral valgus deformity with arrest of the lateral distal femoral physis, 3 cases of tibial recurvatum with arrest of the tibial tubercle apophysis, 2 cases of genu valgum without arrest, and 2 cases of leg length discrepancy. Associated factors included fixation hardware across the lateral distal femoral physis in 3 cases, bone plugs of a patellar tendon graft across the distal femoral physis in 3 cases, large (12 mm) tunnels in 2 cases, fixation hardware across the tibial tubercle apophysis in 3 cases, lateral extra-articular tenodesis in 2 cases, and over-the-top femoral position in 1 case. Based on this experience, we recommend a guarded approach to ACL reconstruction in the skeletally immature patient with careful attention to technique and follow-up.

High-resolution carotid artery MRA. Comparison with fast dynamic acquisition and duplex ultrasound scanning

Abstract Purpose: To determine whether the diagnostic accuracy of contrast-enhanced MR angiography (CE-MRA) of the carotid arteries is improved by using a slow-injection, high-resolution technique. Material and Methods: In 22 patients suspected to have internal carotid artery (ICA) stenosis at duplex ultrasound scanning (DUS), CE-MRA was performed both with a fast, dynamic (8 s/phase) and with a slower, high-resolution technique (scan time 2:20 min). Results: There was conformity between the CE-MRA techniques regarding the degree of stenosis in 34/40 extracranial ICAs. In 3/6 discrepant cases, short occlusions were seen with the fast dynamic technique, whereas both the high-resolution CE-MRA technique and DUS showed patent vessels. There was an overall tendency toward higher stenosis grading with the dynamic technique. Overlying veins could be removed on a workstation in all high-resolution examinations. Conclusion: The high-resolution carotid CE-MRA technique proposed herein seems to improve the diagnost...

Closure to discussion of "z-bus loss allocation"

km . Thus, all lines no matter how short have both susceptance and reactance. The susceptances of a realistic transmission network statistically described below in item 9) clearly show that these shunt elements are nonzero. 2) The discussers also bring up “other cases” where property (g) may not be satisfied, however they do not provide much detail to justify this claim. In one case, with very small shunt susceptances, it is claimed that the real part of -bus matrix is very sensitive to transformer resistances. However, when we analyzed their five-bus test network with and without transformer resistances, the differences in both the real and imaginary parts of the -bus matrix were very small. 3) The authors provided simulation results for five cases on their test network. For each case, the load flow and the corresponding loss allocation factors, , were calculated. We successfully reproduced two cases: 1) base case and 2) case with and . However our results differed substantially for the other three cases in the system losses computed. In the three discrepant cases, our load flows, run using PowerWorld 7.0 (http://www.powerworld.com), gave substantially lower system losses and, therefore, different loss allocation factors. Nevertheless, in the next point we discuss the two cases in common, to which we add the results we obtained for one of the discrepant cases.

Benefits of monitoring blood glucose by collection of blood on filter paper strips

AbstractBackgroundThe accuracy of blood glucose meters has been questioned and the quality control remains rudimentary. Collection of blood spots on filter paper strips allows laboratory estimations whilst maintaining the convenience of blood collection in the patient's own home.MethodPatients provide blood spots on specially prepared filter paper strips and post them to the laboratory for analysis.ResultsIn 12 months, eight of 19 pregnant diabetic patients had their meter changed because of inconsistency between meter readings and filter paper results. In six consecutive cases of discrepancy between HbA1c and home monitoring, filter paper glucose all proved higher than home monitoring results. This led to a change of meter in three cases, and of insulin regime in all cases, resulting in a mean absolute reduction in HbA1c of 1.92 % (SD 0.9, p < 0.01).Over the past two years, nine patients without diabetes have been investigated for hypoglycaemia by self‐collection of blood spots when symptomatic. In eight cases hypoglycaemia was excluded, but was confirmed in the remaining case, and an insulinoma was subsequently diagnosed and excised.ConclusionMonitoring of blood glucose levels using filter strips proved a useful tool in pregnancy management, in evaluating discrepancies between HbA1c and home monitoring results, and investigating unexpected hypoglycaemia in non‐diabetic patients. Copyright © 2002 John Wiley & Sons, Ltd.

Restrictive left ventricular filling and preserved ventricular function: A limitation in the noninvasive estimation of pulmonary wedge pressure by Doppler echocardiography

Pulmonary wedge pressure (PWP) can be estimated from the ratio of transmitral early peak flow velocity to flow propagation velocity measured by Doppler. Discrepancies observed in the application of the method prompted us to design this prospective study, aimed at detecting potential limitations of the method. We studied a total of 32 patients admitted to a cardiac intensive care unit, using a Swan-Ganz catheter. Correlation between invasive- and Doppler-estimated PWP was fairly good (r = 0.58). Analysis of discrepant cases led to the identification of a subgroup of 6 patients in whom PWP was largely underestimated because of unexpectedly high values of flow propagation velocity (71 ± 15 cm/s vs 37 ± 10 cm/s in the rest of the group; P =.0001). All of them had in common a restrictive Doppler filling pattern and preserved left ventricular systolic function. Exclusion of this group showed an improvement in the correlation coefficient to r = 0.72. In conclusion, PWP can be estimated by the Doppler early peak flow velocity to flow propagation velocity ratio, although a significant underestimation of PWP may be observed in patients with a restrictive filling pattern and preserved ventricular function. (J Am Soc Echocardiogr 2002;15:334-8.)

Pathological Determinants of the Transition to Clinical Dementia in Alzheimer's Disease

The authors developed multivariate models to examine the association between Clinical Dementia Rating (CDR) scale scores and the spatial distribution of paired helical filament tau (PHF-tau) pathology. Severity of tauopathy was examined in 14 cortical regions of interest (ROIs). Classification trees were used to test the independent hierarchical contributions of each ROI to dementia. Multiple-regression and cluster analyses were performed to determine the relative contributions of select ROIs to dementia. Dementia (CDR S 1) was modeled as a dichotomous variable. Autopsy material was obtained from 124 demented and nondemented elderly patients. All ROIs except the hippocampus made significant contributions to dementia. However, they were not independent. In multivariate models, only a single step (Step 7 in a hierarchical progression), which contained four ROIs, contributed significantly to dementia. A classification tree resulted in a single decision split, suggesting that only Step 7 ROIs need be considered. A total of 89.4% of the cases were correctly classified (p < .0001). Twelve discrepant cases all had superimposed vasculopathy that might also have affected the function of Step 7 ROIs. The transition to clinical dementia was associated with the presence of tauopathy in A9/10, A22, A23, and A39. Animal studies suggest that these represent a single distributed cortical network focusing on prefrontal regions that provide "executive control" over complex goal-directed behaviors. A22, A23, and A39 provide major afferents to other frontal systems and have previously been implicated in very early clinical Alzheimer's disease.

Revision of Total Hip Arthroplasty Using Wagner Femoral Revision Stem

Purpose : The aim of this study was to see the results of total hip arthroplasty revision using Wagner femoral revision stem. Materials and Methods : From January 1994 and December 1998, we implanted to twenty-three Wagner revision stems in 22 patient (23 cases). The patients’average age was 54 years and the average follow-up time was 48 months. The causes of the revision were as follows: aseptic loosening (18 cases), periprosthetic fractures with loosening (4 cases), and septic loosening (1 case). Results : The preoperative Harris hip score was 47 points, and this improved to 90.5 points postoperatively. There were 3 cases of inguinal pain, 2 cases of thigh pain, 3 cases of leg length discrepancy, and one case of subsidence of stem exceeding more than 5 mm. Postoperative complications included 2 cases of hip posterior dislocation, and 2 cases of heterotopic ossification. Conclusion : No patient required re-revision surgery to treat stem loosening or other problems. The results of the operations were excellent. However, we had difficulty selecting the optimal stem size with respect to preventing subsidence problems.

Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations.

We reviewed 500 consecutive soft tissue lesions referred for expert consultation to determine types of lesions and/or situations in which major discrepancies occur. Of 266 cases (53.2%) accompanied by a diagnosis, essential agreement with the second opinion was noted in 68%, minor discrepancy in 7%, and major discrepancy in 25%. The 65 major discrepancies were distributed proportionally to the referring sources and could be divided into 4 groups: benign mesenchymal lesions diagnosed as sarcomas (45%), sarcomas diagnosed as benign tumors (23%), nonmesenchymal lesions diagnosed as sarcoma (20%), and major grading discrepancies (12%). Relatively few lesions accounted for a major proportion of major discrepancies. Problematic lesions were lipoma and fasciitis and their variants and desmoplastic-neurotropic melanoma. Needle biopsy specimens were somewhat more likely to be associated with a discrepant opinion. With the exception of nonmesenchymal lesions, the diagnosis for all major discrepant cases could be made on the basis of the H&E-stained slides, suggesting that failure to perform immunostains did not account for discrepancies. Lack of familiarity with rare or unusual lesions is probably more significant in explaining diagnostic discrepancies than is the increasing use of needle biopsy or the failure to perform immunohistochemical analysis.

Salivary Gland Fine Needle Aspiration Using the ThinPrep® Technique

To retrospectively assess the diagnostic accuracy, cytologic features and pitfalls of ThinPrep (TP) (Cytyc Corporation, Marlborough, Massachusetts, U.S.A.) versus conventional (smear) preparation (CP) in salivary gland fine needle aspiration biopsies (FNABs) and second, to evaluate the reproducibility of the cytomorphologic criteria used in the evaluation of FNABs prepared by CP versus TP. All salivary gland fine needle aspiration biopsies (SGFNABs) between January 1996 and June 1999 were retrieved from the cytology files of the University of Michigan Hospital. Histologic correlation was identified when available. Two cytopathologists reevaluated the slides for artifacts, cellular preservation, background material, cellularity, and cytoplasmic and nuclear details. Seventy-four of the 134 (55%) cases identified had histologic follow-up. Fifty (68%) cases were processed by TP and 24 (32%) by CP. FNAB processed by TP and CP correctly identified malignancy in 14 and 9 cases, respectively. There were three (4%) false negative cases. These included two acinic cell carcinomas and one mucoepidermoid carcinoma. There were 37 true negative cases (24 TP and 13 CP) and one false positive case of cellular pleomorphic adenoma (cytologic interpretation, mucoepidermoid carcinoma). All discrepant cases were processed using the TP method. The overall specificity and sensitivity were 98% and 88%, respectively. However, specificity and sensitivity for TP-processed SGFNABs were 96% and 82% as compared to a 100% specificity and sensitivity for CP. Additionally, there were 10 (14%) nondiagnostic cases, 8 of which were processed by TP. Cytologic artifacts associated with TP included diminished/distorted extracellular and stromal elements, cellular shrinkage and tissue fragmentation The diagnostic accuracy of TP-processed SGFNABs approaches that of the CP. However, there are several artifacts that may lead to erroneous diagnoses. Additional studies, that depend on real-life clinical samples processed by TP are suggested to modify current diagnostic criteria.

Factors affecting R6 fungicide toxicity on sea urchin fertilization and early development: roles of exposure routes and mixture components.

A technical fungicide mixture, R6 and its components, cymoxanil (CYM) and cupric oxychloride (Cu-OCl), were tested by sea urchin bioassays (Paracentrotus lividus and Sphaerechinus granularis). A set of toxicity endpoints was evaluated including both lethal and sublethal effects with the following endpoints: (a) acute embryotoxicity, (b) developmental defects, (c) changes in sperm fertilization success, (d) transmissible damage from sperm to the offspring, and (e) cytogenetic abnormalities. Acute effects on developing embryos were observed as early (prehatch) mortality at R6 levels > or =25 microg/ml. The pesticide mixture R6 was tested at realistic concentrations, ranging from 25 ng/ ml to 2.5 microg/ml, and the two components, CYM and Cu-OCl, were tested, either alone or in mixture, at concentrations equal to their levels in the corresponding R6 solutions. R6 was either dissolved in filtered seawater (water only, W-O), or spiked in "pristine" silt-clay sediment or soil samples before bioassays. Developmental toxicity of R6, following W-O dissolution, displayed a significant dose-related increase of larval malformations and differentiation arrest at concentrations of 750 ng/ml to 2.5 microg/ml both in P. lividus and in S. granularis larvae. Developmental toxicity was removed in spiked sediment up to R6 nominal levels (25 microg/ml), 10-fold above the embryotoxic R6 levels in W-O exposure. No significant developmental toxicity was exerted by CYM or Cu-OCl (W-O exposure) up to their concentrations equivalent to 2.5 microg/ml R6. The laboratory-prepared mixture of CYM and Cu-OCl, in the same concentration range, only resulted in minor effects, as larval retardation, suggesting the presence of toxic impurities (or additional components) in the R6 formulation. When sperm from either P. lividus or S. granularis were exposed to R6 before fertilization, a W-O exposure resulted in a dose-related decrease in fertilization of P. lividus sperm (up to 250 microg/ml R6), whereas S. granularis sperm underwent a significant increase of fertilization rate at the highest R6 nominal levels (up to 25 microg/ml). Equivalent CYM or Cu-OCl levels were ineffective on sperm fertilization success in both species. The offspring of S. granularis sperm exposed to 25 microg/ml R6 showed a significant increase in larval malformations, which were not detected in the offspring of R6-exposed P. lividus sperm. Again, CYM or Cu-OCl was unable to exert any transmissible damage from sperm to the offspring in either species. The present study raises the case of possible discrepancies between toxicity of a technical mixture and of its analytical-grade components, also providing evidence for a loss of pesticide toxicity following dispersion in an environmental matrix such as sediment or soil.

Defining a Test for HER-2/neu Evaluation in Breast Cancer in the Diagnostic Setting

In breast cancer amplification of the HER-2/neu oncogene and over-expression of the protein product is associated with poor prognosis, predicts response to some chemotherapeutic regimens and is the target for Herceptin treatment. To date there are several methods to assess the amplification/over-expression of HER-2/neu with each having advantages and disadvantages. We have studied amplification and over-expression of HER-2/neu in 250 consecutive cases of breast cancer (220 invasive and 30 in situ carcinomas) presenting to the Department of Pathology at Women's College Campus of Sunnybrook and Women's College Health Sciences Center. Thirty percent of the invasive carcinomas were node positive. HER-2/neu protein over-expression was assessed by immunohistochemistry (IH) using antibody CB11 and amplification of the gene by differential PCR. The percentage of tumor cells showing CB11 staining was determined and the most significant cut off point for positivity was ≥10% moderate or strong complete membranous staining. The gene was considered amplified if the density score of the product was ≥2. There was 94% concordance between the two methods (P value .0001). Both methods were positive in 16% of cases and negative in 78% of cases. Discrepant cases were examined by FISH which confirmed the IH results in 9/11 invasive carcinomas. These results show that there is excellent concordance between IH and PCR. However, immunohistochemistry is easier to perform and cheaper than PCR and could be used in routine assessment of HER-2/neu in breast cancer patients.