Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization.

Field cancerization denotes the occurrence of aberrant cells in tumor adjacent histologically normal tissues (TAHN). To characterize field cancerization in prostate cancer, we used RNA from paired patient tumor and TAHN tissues excised at 1 cm from the tumor margin and subjected them to microarray expression analysis comparative to RNA from normal cancer-free prostatic tissues. Eleven novel transcripts were significantly up-regulated in TAHN tissues and also in tumors. Expression of early growth response protein 1, tristetraprolin, testican, and fatty acid synthase, mutually up-regulated at different levels in tumors and TAHN tissues was confirmed by quantitative reverse transcriptase PCR in the experimental and in an independent validation set. This study offers proof of expressional changes in field cancerized prostatic TAHN tissues at defined distances from tumor margins. Markers of field cancerized prostatic tissues could be early diagnostic indicators in biopsies after abnormal prostate-specific antigen and digital rectal examination and independent of cancerous histology and/or early targets for chemo-preventive intervention in pre-malignant disease.

A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.

Tissue factor (TF), the protease receptor initiating the coagulation system, functions in vascular development, angiogenesis, and tumor cell metastasis by poorly defined molecular mechanisms. We demonstrate that immobilized ligands for TF specifically support cell adhesion, migration, spreading, and intracellular signaling, which are not inhibited by RGD peptides. Two-hybrid screening identified actin-binding protein 280 (ABP-280) as ligand for the TF cytoplasmic domain. Extracellular ligation of TF is necessary for ABP-280 binding. ABP-280 recruitment to TF adhesion contacts is associated with reorganization of actin filaments, but cytoskeletal adaptor molecules typically found in integrin-mediated focal contacts are not associated with TF. Chimeric molecules of the TF cytoplasmic domain and an unrelated extracellular domain support cell spreading and migration, demonstrating that the extracellular domain of TF is not involved in the recruitment of accessory molecules that influence adhesive functions. Replacement of TF's cytoplasmic Ser residues with Asp to mimic phosphorylation enhances the interaction with ABP-280, whereas Ala mutations abolish coprecipitation of ABP-280 with immobilized TF cytoplasmic domain, and severely reduce cell spreading. The specific interaction of the TF cytoplasmic domain with ABP-280 provides a molecular pathway by which TF supports tumor cell metastasis and vascular remodeling.

IgA nephropathy in the triethnic population of New Mexico.

AIMS: IgA nephropathy (IgAN) is the most frequent glomerulonephritis around the globe, but its incidence in the United States is unknown. The disease has a preponderance for certain racial/ethnic groups. Our goals were to retrospectively analyze a series of IgAN biopsies from the state of New Mexico and to calculate an estimated incidence. Then we compared the racial/ethnic composition of our patient cohort to the composition of the New Mexico population and examined the three main racial/ethnic groups for differences in clinical and pathologic parameters. MATERIALS AND METHODS: Renal biopsies and clinical data from IgAN cases newly diagnosed in New Mexico between 2000 and 2005 were reviewed. We compared the racial/ethnic composition of our patient cohort to the demographic composition of the New Mexico population. Demographic, clinical, and histopathologic variables were analyzed with respect to the patients' race/ethnicity. RESULTS: The incidence of IgAN in New Mexico was 10.2 cases per million persons per year (9.3 when Henoch-Schönlein purpura cases were excluded). American Indians were twice as frequent in our patient cohort when compared to their demographic representation, with the reverse finding for Non-Hispanic Whites. Hispanics more frequently had nephrotic range proteinuria than Non-Hispanic Whites and American Indians. On renal biopsy, endocapillary proliferative glomerulonephritis was the most common glomerular abnormality, followed by the focal segmental glomerulosclerosis (FSGS)-like pattern. The FSGS-like pattern was more frequent in American Indians and Hispanics than in Non-Hispanic Whites. CONCLUSIONS: This is the first report of an incidence figure of IgAN for an entire state in the US. American Indian and Hispanic patients had a stronger representation in our cohort than Non-Hispanic Whites, when compared to the general New Mexico population.

Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor.

Tissue factor (TF), the cell-surface receptor for coagulation factor VIIa, supports metastasis. Equally important for this process are (a) interactions of the TF cytoplasmic domain, which binds the mobility-enhancing actin-binding protein 280, and (b) the formation of a proteolytically active TF-VIIa complex on the tumor cell surface. In primary bladder carcinoma cells, we find that this complex localizes to the invasive edge, in proximity to tumor-infiltrating vessels that stain intensely for TF pathway inhibitor (TFPI-1), the major inhibitor of the protease activity of the complex. In culture, binding of VIIa to TF-expressing tumor cells is sufficient to allow cell adhesion, migration, and intracellular signaling on immobilized TFPI-1. Immobilized heparin, a mimic for extracellular matrix-associated proteoglycans, binds physiological concentrations of TFPI-1 in a conformation that supports TF-VIIa-dependent cell adhesion. Consistent with a functional role of TFPI-1 in complex extracellular matrices, we show that TF cooperates with integrin-mediated adhesion and migration on composite matrices that contain ligands for both integrins and the TF-VIIa complex. This study thus provides evidence for a novel mechanism of protease-supported migration that is independent of proteolytic matrix degradation but rather involves protease-dependent bridging of TF's extracellular domain to an ECM-associated inhibitor.

Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells.

The human melanoma cell line M24met expresses tissue factor, the cellular initiator of the blood coagulation cascade. Blocking of the coagulation pathways at the level of tissue factor, factor Xa, or thrombin inhibits hematogenous M24met metastasis in SCID mice, implicating a role for thrombin generation in this process. Dependent on cell surface tissue factor activity, M24met cells generate thrombin in vitro. Thrombin and the thrombin receptor agonist peptide TRP-14 activate a signaling pathway in M24met cells that involves an increase in intracellular calcium and induces cell proliferation. Immunofluorescence evidences expression of the signaling thrombin receptor on these cells. Thus, M24met melanoma cells express both the initiating cell surface receptor for the coagulation pathways and the central signaling receptor of the coagulation system, suggesting the in situ generation of proliferative signals which can contribute to the malignant phenotype.

Physiological aspects of visual perception. II. The subcortical visual direction of behavior.

The second part of the Bennett Lecture for 1975 by Denny-Brown examined the subcortical representation of the dissociation of function described by Denny-Brown and Chambers. Complete removal in the macaque monkey of the corticomesencephalic fibers where they pass from pulvinar to colliculus, and of the colliculus, resulted in the same loss of visual object identification, binocular fixation, and visuosocial behavior that followed removal of area 17. Vision for peripheral movement and spatial orientation ("panoramic vision") remained excellent, with release of catatonia. Conversely, unilateral electrolytic lesions of the mesencephalic tegmentum produced visuospatial distortion, asymmetry of optic righting, and directional difficulties in eye movement (Parinaud syndrome and skew deviation). When bilateral, tegmental lesions produced great constriction of visual field with release of convergence and fixation spasm. Suppression of peripheral attention resulted from perceptual rivalry.

Diverse functions of protease receptor tissue factor in inflammation and metastasis.

Accumulating evidence suggests that protease receptors and their cognate protease ligands play important roles in cell-signaling events that regulate cell adhesion and migration in inflammation as well as tumor invasion and metastasis. Tissue factor (TF), the cell surface receptor for the serine protease VIIa and the initiator of the coagulation pathways, supports metastatic implantation by activating extracellular, protease-dependent signaling pathways and by intracellular links to the actin cytoskeleton. The adhesion of TF-expressing tumor cells can be mediated by interactions of the receptor-protease complex with specific matrix-associated inhibitors, suggesting a novel bridging mechanism by which proteases participate in migratory functions of cells.

Neurologic complications of cardiac catheterization.

A retrospective survey was made of neurologic complications of cardiac catheterization. Of 10 patients, only one had a diffuse disorder, with seizures of a type associated with reaction to contrast agents. Disorders in the other nine patients appeared to be embolic in nature. Five of these nine involved deficits indicating damage in the vertebrobasilar territories, suggesting local trauma to vessels as a source of the embolic material.

Migration assay for endothelial cells in multiwells. Application to studies on the effect of opioids.

An assay system is described which permits rapid and effective evaluation of endothelial cell repair, using cells growing in a monolayer. With this method it was possible to obtain highly significant results. For example, endothelial growth factor and heparin, significantly enhanced cell migration and/or proliferation, whereas beta-endorphin, an endogenous opioid, had no effect on the migration and/or proliferation of human umbilical vein endothelial cells. This model may be used to study the cell migration of a variety of cell types which under certain experimental conditions (e.g., irradiation) do not proliferate.

Pre-radiation chemotherapy for infants and poor prognosis children with medulloblastoma.

Beginning in 1984, we started a prospective study to evaluate the role of postoperative, pre-radiation chemotherapy in the treatment of infants and poor prognosis children with medulloblastoma. The study was designed to evaluate the role of pre-radiation chemotherapy in two specific patient populations: (a) children under the age of 2 years in which there was an attempt to delay definitive radiation and thus reduce the risk of toxicity to the developing nervous system; and (b) children over age 2 years with Stage T3 and T4 disease who were known to have a relatively poor prognosis with surgery and radiation. The five patients under age 2 years received cisplatinum (100 mg/m2) every 3 weeks and weekly vincristine (1.5 mg/m2) for a total of 9 weeks. Nitrogen mustard (6 mg/m2), procarbazine (100 mg/m2), and vincristine (1.5 mg/m2) (MOP) were given in 28 day cycles as long as there was no disease progression or until the child's second birthday, at which time the children were referred for radiation therapy. The 13 patients over 2 years of age received the 9 week course of cisplatinum and vincristine and then began radiation. Responses measured by computed tomography were obtained in 10 of 12 children with measurable disease at the start of chemotherapy. With a median follow-up of 22 months, 15 of 18 children were alive and free of disease. Except for mild ototoxicity in one child, the acute side effects have been well tolerated. In conclusion, it appears that some infants can have their radiation delayed until the age of 2 years. Although the follow-up time was short, all but three patients were free of disease, time exceeding the median time to failure with radiation alone. Pre-radiation chemotherapy might improve local control and survival in children with advanced stage medulloblastoma.

20-year experience in childhood craniopharyngioma.

PURPOSE: The management of craniopharyngioma is controversial, and surgery alone is frequently advocated. The purpose of this study was to assess the long-term impact of various treatments in childhood craniopharyngioma. METHODS AND MATERIALS: Sixty-one children < or = 21 years of age at diagnosis were treated for craniopharyngioma at Children's Hospital and the Joint Center for Radiation Therapy in Boston from 1970 to 1990. The median age was 7.5 years (range 10 months-21 years). There were 33 females and 28 males. The median follow-up was 10 years (range 2-20.5 years). Neuroimaging was available for detailed review in 53. Nine children were treated with radiotherapy alone, 15 were treated with surgery alone, and 37 were treated with both surgery and radiotherapy. All patients in the radiotherapy and surgery plus radiotherapy groups were treated with megavoltage radiation with a median dose of 5464 cGy. RESULTS: All nine of the children treated with radiation therapy alone are alive; none have recurred. Nine of the 15 children treated with surgery alone have recurred (p = 0.007 Fisher exact test). Two are alive with disease, and seven are alive without disease after treatment at relapse with radiation therapy, surgery, or both. Seven of the 37 patients treated with surgery plus radiotherapy have recurred. Three of the seven patients are dead of disease, three patients are alive with disease, and one patient is alive without disease after further treatment. The 10-year actuarial overall survival was 91% for all patients. The 10-year actuarial freedom from progression for the surgery group was 31% compared with 100% for patients treated with radiation therapy only (log rank p = 0.01), and 86% for patients treated with surgery plus radiotherapy at diagnosis (p = 0.001). There were two treatment related deaths, both in the surgery plus radiotherapy group. A higher incidence of visual loss and diabetes insipidus was associated with the use of aggressive surgery. The size of the tumor at presentation correlated with an increased risk of recurrence; 5 of 6 patients with tumors > or = 5 cm experienced recurrences while only 6 of 30 recurred when the tumor was < 5 cm. CONCLUSIONS: Overall survival in childhood craniopharyngioma is excellent. However, patients treated with surgery alone have a significantly worse freedom from progression when compared to patients treated with surgery and radiation therapy or radiation therapy alone.

Cell shape of polymorphonuclear leukocytes is influenced by opioids.

The effects of beta-endorphin(beta-End), an endogenous opioid, were tested in vitro on shape changes in polymorphonuclear leukocytes (PMNs). Cell shape changes indicate alterations of the functional status of the cells. Within 2 min, beta-End but not the opioid alkaloid levorphanol or the antagonist, diprenorphine, induced a cell spreading. Subsequently, beta-End and levorphanol (10(-8) M), but not the dextrorotatory isomer, stimulated an elongation of the cells. Both effects of beta-End could be antagonized by diprenorphine in an equimolar concentration. Thus, the effects were stereo-specific and antagonizable. In this test system, the morphological changes evoked by beta-End were equal to the effects of FMLP, a chemotactic substance, used as a reference. Our findings indicate that endogenous opioids might play a role in modulating the initial phase of the PMNs' offensive behaviour, presumably cell adherence and motility.

Interaction of met-enkephalin with human granulocytes.

Met-enkephalin has been found to have an effect on cell shape and motility of human polymorphonuclear leukocytes (PMNs). Specific binding of tritium-labeled Met-enkephalin to the cells could not be demonstrated. There was a rapid proteolytic degradation of the peptide in the medium, followed by uptake of the labeled tyrosine. The peptidase recognizes the N-terminal sequence of various endogenous opioid peptides. The protease inhibitors bestatin and bacitracin had but little effect on the degradation of Met-Enk.

Glutamic acid diethyl ester induces catalepsy in rats. A new model for schizophrenia?

The glutamate antagonist glutamic acid diethyl ester is found to produce catalepsy in rats, when administered into the lateral ventricle. Since the cerebrospinal fluid content of glutamate is reduced in patients with schizophrenia, the central effects of glutamate antagonists are a possible experimental model for schizophrenia.

Are there antilymphocyte autoantibodies in multiple sclerosis patients?

Immunoglobulins were separated from sera of 40 multiple sclerosis (MS) patients and 40 healthy controls by density and affinity chromatography. In IgM and IgG fractions of the sera of patients and controls no lymphocyte-specific binding could be detected with the help of FITC-conjugated anti-mu and anti-Fc antibodies.

Spinal epidural abscess in children.

This is a report of three children with spinal epidural abscess. The literature is reviewed and the features of this condition in children are noted. Because of the nonspecificity of presenting symptoms in children, the diagnosis may be delayed, resulting in a worse outcome, especially in children under 1 year of age. The extensive laminectomy advised for the treatment of spinal epidural abscesses in adults is undesirable in children because of the risk of spinal deformity and in most cases is probably not necessary.

Reversible visual deficit following debulking of a Rathke's cleft cyst: a tethered chiasm?

Delayed chiasmal syndromes after emptying of a Rathke's cleft cyst have not been reported previously. When these deficits occur following the treatment of parasellar lesions they are usually associated with the descent of a scarred optic system into an empty sella, and vision often improves promptly when the optic system is elevated. Two months after transsphenoidal surgery with emptying of a large intrasellar cyst, a 22-year-old man developed recurrent bitemporal visual field deficits over a 3-day period. Sagittal magnetic resonance images demonstrated an enhancing band of tissue extending anteriorly from the normally placed chiasm down to the anterior portion of the sella turcica. At craniotomy the enhancing tissue was found to be scar extending from the anterior border of the chiasm to the diaphragma sellae. The anterior portion of the diaphragm was resected as widely as possible without dissecting the scar itself from the chiasm. A membrane consistent with the wall of a Rathke's cleft cyst was found attached to the resected tissue. The patient's vision was improved 2 days after surgery. This case illustrates that traction by scar extending from the chiasm to the diaphragm, even when the chiasm is in its normal anatomical location, may cause progressive visual loss; and that untethering of the chiasm by resecting the diaphragm while leaving the scar intact can result in improved vision.

Consequences of dural defects acquired in infancy.

Four infants underwent craniectomy for craniosynostosis and subsequently developed an expanding cranial defect with herniation of brain. All four had an unrepaired laceration of the dura. The pathophysiology of this entity and of the growing fracture of childhood are discussed, and a unified interpretation of the consequences of unrepaired dural defects is proposed.

Syringomyelia following lumboureteral shunting for communicating hydrocephalus. Report of three cases.

Three patients are described in whom syringomyelia was identified long after the treatment of communicating hydrocephalus by a lumboureteral shunt. The reason for syrinx formation in these cases could not be determined. In two there was either autopsy-proven or presumed evidence for arachnoiditis, and in the third patient the symptoms of syringomyelia were acutely aggravated by temporary obstruction of shunt. The development of a pressure drop from the intracranial compartment to the spinal compartment with crowding at the foramen magnum is also a suggested mechanism.

Congenital hemihypertrophy and abnormalities of the cerebral vasculature. Report of two cases.

Two patients are described with congenital hemihypertrophy and vascular abnormalities of the brain on the side of the hypertrophy and in the posterior fossa. The abnormalities observed included giant aneurysm, capillary hemangioma, and arteriovenous malformation. Vascular anomalies in the affected limbs are common in congenital hemihypertrophy, and neurological abnormalities and hypertrophy of the brain have been reported. The presence of vascular abnormalities of the brain in this condition may provide an opportunity to further the understanding of the development of cerebrovascular malformations.