A study of the Influence of mevalonic acid and its metabolites on the morphology of swiss 3T3 cells.

We used two model systems to investigate the effect of compactin, a competitive inhibitor of beta-hydroxy beta-methylglutarylcoenzyme A reductase, on the shape of Swiss 3T3 cells. We maintained cells in a quiescent state in medium deficient in platelet-derived growth factor (PDGF), or we added PDGF to quiescent cells to initiate traverse through a single cell cycle. In both systems, the cells responded to compactin by acquiring a characteristic rounded shape. Cell rounding seemed to depend on an induced deficiency of mevalonic acid (MVA) since the response could be prevented or reversed by adding MVA to the culture medium. Compactin-induced rounding appeared in PDGF-stimulated cells concomitantly with a compactin-mediated inhibition of DNA synthesis, and both effects had similar sensitivities to exogenous compactin and MVA. However, cell rounding seemed to be unrelated to other, previously observed effects of MVA deficiency. Compactin did not influence the total content of cell cholesterol, and little cholesterol was formed when we added radioactive MVA to round cells to effect shape change reversal. Measurement of the dolichol-dependent glycosylation of cell protein revealed no evidence of dolichol deficiency. In addition, reversal of cell rounding by MVA was not prevented by concentrations of tunicamycin that effectively blocked the incorporation of radioactive mannose into cell protein or by concentrations of cycloheximide that blocked protein synthesis. Taken together, our results suggest a new role for MVA or its products in the maintenance of cell shape.

Mummified pleistocene ostracods in alaska.

Preserved soft parts of ostracod specimens were recovered from beach and lagoon sediments from the Gubik Formation, of Quaternary age, at Barrow, Alaska.

Full-field acoustomammography using an acousto-optic sensor.

In this Letter the authors introduce a wide-field transmission ultrasound approach to breast imaging based on the use of a large area acousto-optic (AO) sensor. Accompanied by a suitable acoustic source, such a detector could be mounted on a traditional mammography system and provide a mammographylike ultrasound projection image of the compressed breast in registration with the x-ray mammogram. The authors call the approach acoustography. The hope is that this additional information could improve the sensitivity and specificity of screening mammography. The AO sensor converts ultrasound directly into a visual image by virtue of the acousto-optic effect of the liquid crystal layer contained in the AO sensor. The image is captured with a digital video camera for processing, analysis, and storage. In this Letter, the authors perform a geometrical resolution analysis and also present images of a multimodality breast phantom imaged with both mammography and acoustography to demonstrate the feasibility of the approach. The geometric resolution analysis suggests that the technique could readily detect tumors of diameter of 3 mm using 8.5 MHz ultrasound, with smaller tumors detectable with higher frequency ultrasound, though depth penetration might then become a limiting factor. The preliminary phantom images show high contrast and compare favorably to digital mammograms of the same phantom. The authors have introduced and established, through phantom imaging, the feasibility of a full-field transmission ultrasound detector for breast imaging based on the use of a large area AO sensor. Of course variations in attenuation of connective, glandular, and fatty tissues will lead to images with more cluttered anatomical background than those of the phantom imaged here. Acoustic coupling to the mammographically compressed breast, particularly at the margins, will also have to be addressed.

Automated detection of microcalcification clusters for digital breast tomosynthesis using projection data only: a preliminary study.

Digital breast tomosynthesis (DBT) is a promising modality for breast imaging in which an anisotropic volume image of the breast is obtained. We present an algorithm for computerized detection of microcalcification clusters (MCCs) for DBT. This algorithm operates on the projection views only. Therefore it does not depend on reconstruction, and is computationally efficient. The algorithm was developed using a database of 30 image sets with microcalcifications, and a control group of 30 image sets without visible findings. The patient data were acquired on the first DBT prototype at Massachusetts General Hospital. Algorithm sensitivity was estimated to be 0.86 at 1.3 false positive clusters, which is below that of current MCC detection algorithms for full-field digital mammography. Because of the small number of patient cases, algorithm parameters were not optimized and one linear classifier was used. An actual limitation of our approach may be that the signal-to-noise ratio in the projection images is too low for microcalcification detection. Furthermore, the database consisted of predominantly small MCC. This may be related to the image quality obtained with this first prototype.

STATUS OF CACAO WITCHES' BROOM: biology, epidemiology, and management.

Origins of Theobroma cacao and Crinipellis perniciosa occurred in the Amazon Basin region of South America, and their interaction, the witches' broom disease, was first described in the late 1700s. The 100 years of scientific investigations of witches' broom of cacao that began in the 1890s developed the present state of knowledge of the biology and epidemiology of witches' broom that are discussed. Recommended management to reduce the deleterious effects of witches' broom on cacao production include the use of phytosanitation (removal of diseased plant parts), applications of chemical fungicides, and the use of host resistance. At present, there is a paucity of resistant planting materials, and efforts to evaluate germplasm for resistance to witches' broom are described. Research topics to augment present knowledge about witches' broom of cacao are presented with the hope that disease management can be improved.

Smooth muscle and bone neoplasms in transgenic mice expressing SV40 T antigen.

Transgenic mice carrying the SV40 early region fused to the Drosophila hsp70 promoter developed smooth muscle and bone neoplasms. The smooth muscle tumors appeared in aged mice and were preferentially located on the muzzle or eyelids. Multiple neoplasms were often present and each appeared to be an independent proliferation. In contrast, the bone tumors typically developed in the petrous ridge and had all the features of osteogenic sarcomas, displaying distant metastasis and invasion of the brain. Cells in both types of tumors exhibited nuclear expression of SV40 T antigen. Mice homozygous for the transgene had a shorter latency for appearance of smooth muscle tumors and developed osteosarcomas more frequently than hemizygous mice. This model system implicates the cellular T antigen-binding proteins, such as Rb and p53, in the pathogenesis of bone and soft tissue neoplasms in mice.

Molecular characterization of the Spirometra mansonoides genome: renaturation kinetics, methylation, and hybridization to human cDNA probes.

High molecular weight DNA from pleroceroid larvae of the tapeworm Spirometra mansonoides was purified from isolated nuclei by conventional techniques. The DNA so isolated has a melting temperature (Tm) of 87 degrees C and a guanine plus cytosine (G/C) content of 44%. 5-Methyl cytosine could not be detected in plerocercoid DNA by HPLC analysis of DNA hydrolysates, by radiolabeling 5'-termini of MspI digests with polynucleotide kinase, or by comparing restriction patterns generated by MspI and HpaII. Renaturation kinetics demonstrated that the genome of S. mansonoides contains repetitive as well as single copy sequences and has a genome size estimated at approx. 1.6 X 10(9) bp. Hybridization was carried out between plerocercoid DNA and cDNAs for human beta-actin, alpha-tubulin and growth hormone (hGH). Rationale for this analysis was based on known homologies among actin and tubulin genes in numerous species and on apparent similarities between hGH and a plerocercoid growth factor that may be reflected in similar DNA sequence. Scanning densitometry of dot blots demonstrated that the hGH probe annealed to the same extent at low stringency (1 M NaCl, 55 degrees C) to DNA from plerocercoids, rat liver and chicken erythrocytes; but this interaction was less than to DNA from human lymphocytes, calf thymus and mouse skin. Similar results were obtained when restriction endonuclease digests of these DNAs were analyzed by Southern transfer. Little or no hybridization of the growth hormone probe to plerocercoid DNA was evident at higher stringency (1 M NaCl, 65 degrees C). In contrast, human tubulin and actin probes showed extensive hybridization to pleroceroid restriction fragments under the high stringency conditions.

Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography.

Tumor proliferation has prognostic value in resected early-stage non-small cell lung cancer (NSCLC). We evaluated whether [F-18]fluorodeoxyglucose (FDG) uptake of NSCLC correlates with tumor proliferation and, thus, could noninvasively grade NSCLCs (refining patient prognosis and therapy). Thirty-nine patients with potentially resectable NSCLC underwent whole-body FDG positron emission tomography (PET) 45 min after i.v. injection of 10 mCi of FDG. Tumor FDG uptake was quantitated with the maximum pixel standardized uptake value (maxSUV). The lesion diameter from computed tomography was used to correct the maxSUV for partial volume effects using recovery coefficients determined for the General Electric Advance PET scanner. Thirty-eight patients underwent complete surgical staging (bronchoscopy and mediastinoscopy, with or without thoracotomy). One stage IV patient by PET underwent bronchoscopic biopsy only. Immunohistochemistry for Ki-67 (proliferation index marker) was performed on all of the 39 NSCLC specimens (35 resections, 1 percutaneous, and 3 surgical biopsies). The specimens were reviewed for cellular differentiation (poor, moderate, well) and tumor type. Lesions ranged from 0.7 to 6.1 cm. The correlation found between uncorrected maxSUV and lesion size (Rho, 0.56; P = 0.0006) disappeared when applying the recovery coefficients (Rho, -0.035; P = 0.83). Ki-67 expression (percentage of positive cells) correlated strongly with FDG uptake (corrected maxSUV: Rho, 0.73; P < 0.0001). The correlation was stronger for stage I lesions (11 stage IA, 15 stage IB): Rho, 0.79; P < 0.0001) and strongest in stage IB (Rho, 0.83; P = 0.0019). A significant association (P < 0.0001) between tumor differentiation and corrected SUV was noted. FDG PET may be used to noninvasively assess NSCLC proliferation in vivo, identifying rapidly growing NSCLCs with poor prognosis that could benefit from preoperative chemotherapy.

Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors.

Synovial sarcoma is a relatively common sarcoma in adults, which in its classic bimorphic form infrequently poses a diagnostic problem. Monomorphic spindled variants, as well as the less common poorly differentiated variants, may be confused with other soft-tissue sarcomas; the poorly differentiated variant (PDSS), in particular, may be histologically indistinguishable from other small, blue, round cell tumors, including primitive neuroectodermal tumors (PNETs). Detection of the synovial sarcoma-associated t(X;18) by either cytogenetic or molecular genetic approaches may be necessary to confirm the diagnosis of synovial sarcoma in difficult cases. We evaluated 10 cases of PDSS from eight patients using a panel of antibodies (including those to intermediate filament proteins, nerve-sheath associated markers, and neuronal and neuroectodermal associated markers) in order to better establish the immunophenotype of this tumor and to help distinguish it from the tumors with which it may be confused, particularly PNETs and high-grade malignant peripheral nerve sheath tumors (MPNSTs). Our results showed PDSS to have significant immunophenotypic overlap with both PNETs and MPNSTs. In most instances these three entities may be differentiated by a panel of antibodies that should include those to both low and high molecular weight cytokeratins, epithelial membrane antigen, type IV collagen, CD99, CD56, and S-100 protein. Our results also suggest that synovial sarcoma may be a tumor showing combined neuroectodermal and nerve sheath differentiation--perhaps because of translocation-associated expression of specific proteins--rather than a carcinosarcoma of soft tissues or a tumor of specialized arthrogenous mesenchyme.

Successful treatment of severe hepatitis C-associated pulmonary vasculitis in a liver transplant recipient.

BACKGROUND: We report the clinical course of a patient who developed fever, hypoxia, and bilateral pulmonary infiltrates two and a half years after orthotopic liver transplantation (OLT) for cirrhosis due to hepatitis C. The patient had a history of hepatitis C-associated vasculitis manifested by purpuric skin rashes, renal abnormalities, and elevated cryoglobulins, and was receiving interferon-alpha at the time of presentation. RESULTS: The results of bronchoscopy with bronchoalveolar lavage were unrevealing, and open lung biopsy revealed active small vessel vasculitis. The patient responded dramatically to plasmapheresis and the addition of high-dose corticosteroids with resolution of hypoxia, pulmonary infiltrates, and glomerulonephritis. This is, to our knowledge, the first report of the successful treatment of hepatitis C-associated pulmonary vasculitis after OLT. CONCLUSIONS: We conclude that hepatitis C-associated pulmonary vasculitis should be included in the differential diagnosis of a patient presenting with fever, hypoxia, and pulmonary infiltrates after OLT for hepatitis C. Treatment with plasmapheresis and high-dose corticosteroids may be effective in patients with this disorder.

Computerized characterization of mammographic masses: analysis of spiculation.

Although general rules for the differentiation between benign and malignant breast lesions exist, only 10 to 20% of masses referred for surgical breast biopsy are actually malignant. We are developing, as an aid to radiologists, a computerized scheme for the classification of masses appearing on mammograms to reduce the number of false-positive diagnoses of malignancies. The classification scheme involves the extraction of the margin of masses in order to quantify the degree of spiculation, which, in turn, is related to the likelihood of malignancy. When two measures of spiculation are used as input to an artificial neural network, the scheme achieves a performance similar to that achieved when radiologist's spiculation ratings alone are used for a clinical database of 53 masses. The computerized classification scheme therefore has the potential to effectively aid radiologists in determining appropriate patient management.

Tissue invasion by Pneumocystis carinii: a possible cause of cavitary pneumonia and pneumothorax.

Pulmonary cavitation and pneumothorax may complicate severe cases of Pneumocystis carinii pneumonia. Both complications likely result from tissue necrosis, although how such injury occurs is unknown. To investigate mechanisms of tissue destruction in P carinii pneumonia, histochemical, immunocytochemical, and electron microscopic studies were conducted in pulmonary wedge resections or autopsy specimens from patients with the acquired immunodeficiency syndrome (n = 7) or leukemia (n = 2). Tissue invasion, defined as Pneumocystis organisms in the interstitial compartment, was present in eight of nine cases. Organisms were found in alveolar septa (eight cases), pleura (six cases), and vessel walls (two cases). All cases with tissue invasion exhibited regional necrosis as well as extensive invasion of apparently viable parenchyma. Pulmonary cavitation occurred in seven of eight cases with tissue invasion, and six of these patients developed pneumothoraces. Despite extensive tissue invasion and necrosis there was little host inflammatory or stromal response. Ultrastructurally, both the tissue-invasive and intra-alveolar organisms were predominantly of the trophozoite form; they were present in much greater numbers than suggested by routine silver stains (which detect only cysts). Immunocytochemical techniques, which detect both trophozoite and cyst forms, were much more sensitive than silver stains. These results indicate that extensive tissue invasion by P carinii can occur in severe P carinii pneumonia. We hypothesize that such invasion is an important step in the development of pulmonary necrosis, cavitation, and pneumothorax.

The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: A prospective study.

STUDY OBJECTIVES: Presently, surgical (open or thoracoscopic) lung biopsy (SLB) is the gold standard for the diagnosis of new-onset idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). The accuracy of a clinical diagnosis of IPF and other subsets of ILD has never been established in prospective studies. We investigated the accuracy and validity of a clinical diagnosis of IPF and ILD other than IPF. DESIGN: Prospective, independent evaluation of patients and clinical data by an ILD expert, of chest radiographic and high-resolution computed tomography (HRCT) features by a chest radiologist, and of histologic features of lung biopsy by a pulmonary pathologist in consecutive patients referred for a diagnostic evaluation of ILD. SETTING: Tertiary university medical center with recognized expertise in management of ILD. PATIENTS: Community patients referred for further definitive diagnostic evaluation of new-onset, untreated nonspecific ILD. INTERVENTION: By comparing the histologic features of SLB in 59 patients consecutively referred for further diagnostic evaluation of new-onset ILD with the clinical and radiologic diagnoses, we determined the sensitivity and specificity of clinical diagnosis and radiologic diagnosis (based on chest radiograph and HRCT features alone) of IPF and ILD other than IPF. A specific clinical diagnosis was independently made by the ILD expert after a thorough clinical assessment that included evaluation of an HRCT scan and bronchoscopic findings. The chest radiographs and HRCT scans were separately reviewed by the chest radiologist, who made a radiologic diagnosis independently. All patients underwent SLB within a month of preoperative "clinical" diagnosis. The clinician's and radiologist's diagnoses were then compared with the gold standard of histologic diagnosis. MEASUREMENTS AND RESULTS: Prior to the clinical evaluation at our center, 85% of patients who underwent SLB had nondiagnostic transbronchial biopsy. The diagnosis of IPF and ILD other than IPF was accurately made by clinical features alone in 62% of cases. The correct radiographic diagnosis of non-IPF ILD was made in 58% of the cases. The sensitivity and specificity of the clinical diagnosis of ILD other than IPF were 88.8% and 40%, respectively. The sensitivity and specificity of the radiographic diagnosis of ILD other than IPF were 59% and 40%, respectively. However, the sensitivity and specificity of the diagnosis of IPF on clinical grounds were 62% and 97%, respectively. The sensitivity and specificity of the radiologic diagnosis of IPF were 78.5% and 90%, respectively. CONCLUSIONS: In a center with recognized expertise in the management of ILD, the specificity of diagnosis of new-onset IPF based on a thorough clinical assessment or HRCT features alone is very high (97% and 90%, respectively), but the sensitivity is low (62% and 78.5%, respectively). Thus, not all patients with new-onset IPF require SLB for diagnosis, but a diagnosis of IPF will be missed in nearly one third of new-onset IPF cases despite evaluation by experts. The relatively low sensitivity and specificity of the diagnosis of ILD other than IPF also emphasizes that an SLB is indicated in patients with ILD in whom the diagnosis is unclear.

Comparison of bilateral-subtraction and single-image processing techniques in the computerized detection of mammographic masses.

RATIONALE AND OBJECTIVES: Identification of regions as possible masses on digitized screen film mammograms is an important initial step in the computerized detection of breast carcinomas. Possible masses may be initially extracted using criteria based on optical densities, geometric patterns, and asymmetries between corresponding locations in right and left mammograms. In this study, the usefulness of information arising from mammographic asymmetries for the identification of mass lesions is investigated. METHODS: Two techniques are investigated--a nonlinear bilateral-subtraction technique based on image pairs and a local gray-level thresholding technique based on single images. Detection performances obtained with the two techniques in combination with various feature-analysis techniques are evaluated using 154 pairs of mammograms and compared using free-response receiver operating characteristic (FROC) analysis. RESULTS: The nonlinear bilateral-subtraction technique performed better than the local gray-level thresholding technique. CONCLUSION: The incorporation of asymmetric information appears to be useful for computerized identification of possible masses on mammograms.

Computer-aided detection of microcalcifications in mammograms. Methodology and preliminary clinical study.

The authors investigated the feasibility of using computer methods for automated detection of clustered microcalcifications on clinical mammograms. A new difference-image approach using a matched filter/box-rim filter combination effectively removed the structured background from the image. A locally adaptive gray-level thresholding technique was then used for extraction of the signals from the resulting difference image. Signal-extraction criteria based on the size, contrast, number, and clustering properties of microcalcifications were next imposed on the detected signals to distinguish true signals from noise or artifacts. The detection accuracy of the computer scheme was evaluated by means of a free response receiver operating characteristic (FROC) analysis. It was found that, for simulated subtle microcalcifications superimposed on normal mammograms, the difference-image approach with a matched filter/box-rim filter combination could yield a true-positive cluster detection rate of 80% at a false-positive detection rate of one cluster per image. In a study of 20 clinical images containing moderately subtle microcalcifications, the automated computer scheme obtained an 82% true-positive cluster detection rate at a false-positive detection rate of one cluster per image. These results indicate that the automated method has the potential to aid radiologists in screening mammograms for clustered microcalcifications.

Improvement in radiologists' detection of clustered microcalcifications on mammograms. The potential of computer-aided diagnosis.

Relatively simple, but important, detection tasks in radiology are nearing accessibility to computer-aided diagnostic (CAD) methods. The authors have studied one such task, the detection of clustered microcalcifications on mammograms, to determine whether CAD can improve radiologists' performance under controlled but generally realistic circumstances. The results of their receiver operating characteristic (ROC) study show that CAD, as implemented by their computer code in its present state of development, does significantly improve radiologists' accuracy in detecting clustered microcalcifications under conditions that simulate the rapid interpretation of screening mammograms. The results suggest also that a reduction in the computer's false-positive rate will further improve radiologists' diagnostic accuracy, although the improvement falls short of statistical significance in this study.

Wilms' tumor gene (WT1) expression in lung cancer, colon cancer and glioblastoma cell lines compared to freshly isolated tumor specimens.

The Wilms' tumor gene (WT1) encodes a transcriptional regulator involved in growth and differentiation of various tissue types. A continuous over-expression of WT1 was found in leukemic blasts, thus suggesting an oncogenic function. Solid cancer entities have also been described as expressing WT1. We systematically analyzed WT1 expression in small-cell and non-small-cell lung cancer, colon cancer and glioblastoma patients and in the respective tumor cell lines. Using reverse transcription/polymerase chain reaction, we found WT1 expression in glioblastoma (5 of 8), lung (5 of 11), and colon cancer (5 of 15) cell lines. While WT1 was expressed in only 1 of 12 lung cancer and 1 of 5 glioblastoma specimens, it was not detected in colon cancer or macroscopically tumor-free colon and lung tissue. In addition, HT29 colon cancer cells showed a loss of WT1 expression when grown to confluence or induced to differentiate by sodium butyrate. From this evidence, testing for WT1 expression is not clinically relevant for colon cancer, lung cancer, or glioblastoma patients. WT1 expression in cancer cell lines can probably be attributed to optimized in vitro growth conditions.

Granular cell tumor of the breast mimicking carcinoma in pregnancy.

A granular cell tumor of the breast in a 20-year-old black pregnant woman is reported. Malignancy had been suspected clinically, radiologically, and on gross pathologic examination. Frozen section provided the correct diagnosis and the lesion was excised, obviating more radical surgery.

Acquired immunodeficiency syndrome-related lymphoma of the lung presenting as empyema thoracis.

B-cell lymphoma in patients infected with the human immunodeficiency virus is usually a disseminated process that occasionally involves the lungs. Surgical diagnosis is often necessary to distinguish this from other neoplasms or opportunistic infections of the lung. We report a case of pulmonary B-cell lymphoma in a patient infected with human immunodeficiency virus who presented with a left empyema thoracis and an associated left lower lobe abscess secondary to bronchial obstruction. Resection was performed and the patient subsequently recovered from the acute process and survived an additional 6 months. This report demonstrates that surgical intervention may be necessary for both the diagnosis of pulmonary lymphoma and the definitive management of infectious complications that may arise as a result of pulmonary neoplastic disease in patients with acquired immunodeficiency syndrome.

Schwannoma of the left atrium: diagnostic evaluation and surgical resection.

A case of primary benign schwannoma of the left atrium is reported. A 35-year-old man presented with new onset atrial fibrillation. Noninvasive evaluation revealed a 4 x 7-cm mediastinal mass either directly posterior to or involving the left atrium. The histologic diagnosis and specific location of the mass were established by incisional biopsy through a left thoracotomy. On cardiopulmonary bypass the tumor was resected by widely excising the posterior left atrium. The residual 20-cm2 left atrial defect was patched with pericardium. This unusual case illustrates that left atrial tumors originating near the pulmonary veins may be nonmyxomatous neoplasms of neural origin. Diagnosis may be difficult and require a surgical transthoracic approach.