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.

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.

Cholesterol granulomas of the lungs associated with microangiopathic hemolytic anemia and thrombocytopenia in pulmonary hypertension.

Cholesterol granulomas unrelated to endogenous lipoid pneumonia, pulmonary alveolar proteinosis, or cholesterol pneumonia are a rare finding during pneumectomy or autopsy. They have been occasionally reported in association with pulmonary hypertension. We report a case where these lesions were associated with long-standing pulmonary hypertension and microangiopathic hemolytic anemia and thrombocytopenia. Plexiform lesions were present in the pulmonary vasculature secondary to pulmonary hypertension, causing hemolysis and thrombocytopenia. We suggest that destruction of red blood cells and platelets could provide membrane lipids that are taken up by phagocytic cells, which promotes the formation of these cholesterol deposits.

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.

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.

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.

MRI of infarction of a cavernous sinus tumor in Nelson's syndrome.

We report the MRI appearances of an infarcted cavernous sinus tumor in a patient with Nelson's syndrome. Invasive tumors of the pituitary extending to the cavernous sinus are discussed and the role of MRI in preoperative investigation is highlighted.

Posterior fossa decompression for Chiari I deformity, including resection of the cerebellar tonsils.

This is an analysis of 19 consecutive cases of symptomatic patients with Chiari I deformities, undertaken to evaluate the long-term effect of posterior fossa decompression and duraplasty, assessed by postoperative imaging. Sixteen of the patients had syringomyelia and three had foramen magnum syndromes without a syrinx. Eighteen patients underwent posterior fossa craniectomy, subpial resection of the cerebellar tonsils, and duraplasty. Four patients were 16 years of age or younger. One of the children with syringomyelia had a posterior fossa decompression without resection of the tonsils. In the 15 patients with syringomyelia whose surgery included resection of the tonsils, the syrinx was reduced or resolved in 14. The patient whose syrinx did not change was a child with a lumbosacral lipoma. Three patients had syndromes of the foramen magnum without a syrinx, and of these only a patient with prior chemical and bacterial meningitis caused by a lumboureteral shunt failed to improve dramatically. When our patients are combined with 40 in the literature treated by decompression and duraplasty, 51 of 55 patients had reduction or resolution of the syrinx. Although it does not clearly affect the result, resection of the tonsils can be done safely.

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.

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.

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.

In vitro studies on PMN-independent endothelial cell damage in trauma: decrease of PMN-endothelial cell adherence by fibrinogen degradation products and disturbance of endothelial cell membrane integrity by trauma serum.

Trauma favors the development of adult respiratory distress syndrome (ARDS). Adherence of polymorphonuclear leukocytes (PMN) to endothelial cells (EC) with subsequent EC damage by the respiratory burst products and proteases of the PMN is thought to be one of the basic mechanisms in the pathogenesis of ARDS. Recent studies have shown that there might also be PMN-independent mechanisms of EC damage. It would speak for PMN-independent EC damage if in the state of risk for this damage factors were found which decrease PMN activity or if EC damage appeared without PMN. Because in trauma and sepsis pathologic coagulation with high levels of fibrinogen degradation products (FDP) is often diagnosed, we investigated whether FDP-D and FDP-E might influence PMN adherence to EC. We also investigated whether serum of traumatized patients might provoke EC damage in a PMN-independent system in vitro. To achieve this we evaluated the viability of EC using a fluorescence staining method. We found that both FDP-D and FDP-E decreased PMN adherence to human EC significantly (p < 0.01) at a concentration of 50 micrograms/ml. Furthermore we found that EC membrane integrity can be disturbed by serum of trauma patients. These results suggest that in trauma also PMN-independent mechanisms are important for EC damage.

Effect of fibrinogen fragments D and E on the adhesive properties of human granulocytes to venous endothelial cells.

In hyperfibrinolytic conditions, e.g. in disseminated intravascular coagulation or the adult respiratory distress syndrome, high levels of fibrinogen degradation products (FDPs) D and E are found in human plasma. This study investigates the influence of these fragments on cell attachment of human granulocytes in vitro. While leaving unaffected the adhesion of human umbilical vein endothelial cells (HUVEC) on gelatine-coated glass, both FDP fragments at 50 micrograms/ml inhibited granulocyte attachment to glass as well as to HUVEC monolayers. At the same concentration, the fragments diminished the superoxide release of stimulated granulocytes. These results suggest a modulatory role of pathologically elevated FDPs on the granulocyte function cascade.

Craniopharyngiomas in children. Long-term effects of conservative surgical procedures combined with radiation therapy.

Thirty-seven patients with craniopharyngioma were treated at Children's Hospital, Boston, between 1972 and 1981, the mean follow-up period now being 10.5 years. Twenty of these patients are old enough to have finished high school and have been queried about their college or job activity. None of the four patients who had undergone radical excision of their tumor and who had reached the age of finishing high school was able to work independently. Among the 16 patients who reached this age and who were treated by more conservative operations and irradiation or irradiation alone, job performance or college attendance varied considerably, indicating that psychosocial impairment occurred in this group, but suggesting that the risk was less. The rate of tumor recurrence or of failure to respond to treatment was 57% (four of a total of seven survivors) following radical surgery and 7% (two of 27 survivors) after conservative operations and irradiation. The overall mortality rate was 8%; the causes of the three deaths were: "hypothalamic crisis" 1 year after radical resection; progressive tumor growth despite two attempts at resection and irradiation; and a brain-stem glioma in the field of irradiation 8 years after treatment.

Opioid influence on the adherence of granulocytes to human umbilical vein endothelial cells in vitro.

Recent studies revealed the existence of opioid receptors on human polymorphonuclear leukocytes (hPMN) and reported the effects of endogenous opioids on hPMN migration and adherence on glass or serum coated glass. Extending these studies, two different assay systems served to quantify the two basic events of adherence: attachment and spreading. hPMN in suspension were allowed to settle under the influence of beta-endorphin on human umbilical vein endothelial cells. After 30 and 240 sec the number of attached cells was enhanced 2.5-fold. Studying the spreading of cells, beta-endorphin increased the area 1.5-fold. Since adherence precedes the migration of hPMN through the endothelial layer towards foci of inflammation, the results suggest a modulatory role of endogenous opioids in defence mechanisms.

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.

Differential expansion of human endothelial monolayers on basement membrane and interstitial collagens, laminin and fibronectin in vitro.

In this study the ability of a human endothelial cell monolayer to expand over specific components of the basement membrane and extracellular matrix was investigated over a 5-day period. The method was intended as a model to study the mechanisms of endothelial regeneration. All components were coated onto sterile coverslips at a concentration of 10 micrograms/ml. The highest expansion was obtained on fibronectin, laminin and collagen type III, all three being statistically significantly greater than on the uncoated control surface (0.002 greater than p greater than 0.0001). Collagens types I and IV and a high molecular weight fragment mixture of type IV (IV-F, consisting of 75, 120 and 140 kD fragments) elicited approximately similar expansion rates, significantly higher than the control (0.02 greater than p greater than 0.003), although significantly lower (approximately 15%) than collagen type III, fibronectin and laminin (p less than 0.001). The high monolayer expansion on collagen type III is surprising, as it is a relatively minor biosynthetic product of the endothelial cell. It could, however, be of significance in wound healing, in which endothelial cells come into contact with this interstitial collagen. In addition, the similar results obtained with collagens IV and IV-F indicate that expansion of the endothelial monolayer is not dependent on the integrity of the tetrameric structure of type-IV collagen.

In vitro studies on the expansion of endothelial cell monolayers on components of the basement membrane.

The purpose of the present study was to observe the expansion of a monolayer of endothelial cells over specific components of the basement membrane. This was performed in vitro in a monolayer expansion assay over 5 days. The control surface was uncoated glass in the form of coverslips. Test substances were coated at a concentration of 10 micrograms/ml. The highest expansion was obtained with a high molecular weight fragment mixture of collagen type IV (IV-F, consisting of 75, 120 and 140 KD fragments), followed by fibronectin. Collagens type I, III and IV tetramer gave similar results, less than fibronectin or collagen type IV-F, although all of the above basement membrane coatings promoted expansion significantly above that of the control (P less than 0.01). The poorest expansion was obtained with laminin, which was significantly less than the control. The pentapeptide GRGDS, related to the fibronectin cell binding region, gave expansion significantly below that of the intact fibronectin molecule, as did the intact collagen type IV molecule compared with type IV-F (P less than 0.025). This indicates that sequences of the fibronectin molecule other than the cell binding sequence may be involved in promoting endothelial cell expansion. In addition, the integrity of the collagen type IV molecule does not appear necessary for this effect. On the contrary, the higher movement on IV-F may represent an inherent repair mechanism in damaged endothelium. Autoradiographic studies show that endothelial cell proliferation at the expanding front is involved in the migration assay.

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.