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Biomedical subjects

P Thorner

Publications and source records attributed to P Thorner.

At least 91 records · Page 5Linked to original sources
PubMed1986

Mode of inheritance of Samoyed hereditary glomerulopathy: an animal model for hereditary nephritis in humans.

The pedigree of a line of Samoyed dogs with Samoyed hereditary glomerulopathy (SHG) was investigated to determine the mode of inheritance. Sixty percent of males were affected with severe renal disease that progressed to renal failure before 15 months of age. In contrast, female carriers showed less severe involvement and their disease did not progress to renal failure. This pattern is consistent with the inheritance of an X-linked dominant gene. A similar mode of inheritance has been postulated in some families with hereditary nephritis. Further similarities between SHG in dogs and hereditary nephritis in humans have been demonstrated previously in clinical and renal morphologic studies. The present study supports the view that this line of Samoyed dogs would be an appropriate model for studying the human disease.

Animals↗
PubMed1986

Samoyed hereditary glomerulopathy (SHG). Evolution of splitting of glomerular capillary basement membranes.

Samoyed hereditary glomerulopathy (SHG) in dogs resembles hereditary nephritis (HN) in man. Affected males and carrier females spontaneously develop proteinuria, but only males progress to renal failure. We examined the evolution of splitting of glomerular capillary basement membranes (GCBM) in affected male and carrier female dogs. At birth, examination by light microscopy (LM) in all dogs showed normal glomerular capillaries, but by electron microscopy (EM), many GCBM showed separation of endothelial from visceral epithelial cell basement membranes. By LM, glomerular capillaries of affected males appeared normal for up to 4 months, but then isolated and eventually all capillaries became thickened and split. However, by EM, a bilaminar appearance of the GCBM was seen within 1 month which evolved into multilaminar splitting that became extensive as renal failure ensued. Carrier females showed mild nonprogressive changes in GCBM. These results with SHG permitted speculation on the evolution of splitting of GCBM in human HN.

Animals↗
PubMed1985

Immunohistochemical staining of macrophages in the skin lesions of leprosy: the role of antibody to mycobacteria in human serum and various polyclonal immune rabbit antisera.

Immunohistochemical staining of tuberculoid and lepromatous leprosy skin lesions was performed using various rabbit antisera. Macrophages in both stained with serum containing antibodies against lysozyme and alpha-1-antitrypsin, while macrophages in lepromatous leprosy also reacted with other antibodies. An immunoglobulin fraction of positive serum stained following pepsin digestion, indicating that reactivity was not Fc dependent. Positive serum contained antibody against Mycobacterium butyricum, which caused macrophage staining, since affinity-purified antibody did not stain and absorption with M. butyricum removed staining. Staining was also produced by serum of subjects with leprosy or a positive tuberculin test. By immunoblotting, the anti-mycobacterial antibody was directed against surface components of M. butyricum of molecular weights 20 000-70 000. Electron microscopy showed M. leprae in phagolysosomes of macrophages, while immunoelectron microscopy demonstrated labelling along bacterial cell membranes. Therefore, macrophages in lepromatous leprosy skin lesions stain because they contain M. leprae, which reacts with antibody to either M. leprae, M. tuberculosis or atypical mycobacteria in human serum and with antibody to M. butyricum in serum from rabbits immunized with various antigens and Freund's complete adjuvant. These results indicate that immunohistochemical studies on leprosy are misleading if performed using intact polyclonal immune sera rather than affinity purified or monoclonal antibodies.

Antibodies, Bacterial↗
PubMed1985

Minimal lesion disease followed by membranous glomerulonephropathy in two children with nephrotic syndrome.

Two children with nephrotic syndrome are described whose clinical course, initial response to steroids, and renal biopsies were consistent with a diagnosis of minimal lesion disease (MLD). Both children subsequently became resistant to steroids and repeat renal biopsies 7 and 8 years after initial biopsies showed membranous glomerulonephropathy (MGN). Explanations are suggested which may account for the occurrence of MLD followed by MGN in a single patient. These cases illustrate the necessity of performing repeat renal biopsies in patients with nephrotic syndrome if the clinical behavior and response to steroids are not typical for MLD.

Basement Membrane↗
PubMed1984

Membranoproliferative glomerulonephritis type I in children: correlation of clinical features with pathologic subtypes.

Renal biopsies from 33 patients with membranoproliferative glomerulonephritis (MPGN) type I were reviewed to identify pathologic subtypes of this disease and assess their correlation to clinical features. The patients were divided into two groups: group A included 16 patients in chronic or end-stage renal failure and group B 17 patients with no evidence of renal insufficiency. At presentation, a nephrotic or nephritic syndrome and azotemia were equally common in both groups. The incidence of hypertension was significantly increased in group A (P less than 0.05), while recurrent gross hematuria was more common in group B. Nephrotic syndrome was more common during the course of illness in group A. Three subtypes of MPGN type I were recognized, based on whether duplication of glomerular capillary basement membranes was focal segmental (FS; 9 cases), diffuse global (DG; 18 cases), or mixed segmental and global (6 cases). Eight of nine patients showing FS MPGN type I were in group B (p less than 0.05). In contrast, 11 of 18 patients with DG MPGN type I and 4 of 6 with a segmental and global pattern were in group A (P = not significant). Therefore, FS MPGN is a good predictor of a favorable clinical outcome, whereas the other two subtypes are not. This was confirmed by a 100% actuarial kidney survival for the nine patients with FS MPGN and a 50% kidney survival of 7.5 years for patients with the other two subtypes.

Adolescent↗
PubMed1984

Wilms' tumor and glomerular disease. Occurrence with features of membranoproliferative glomerulonephritis and secondary focal, segmental glomerulosclerosis.

A case of bilateral Wilms' tumor occurred in which a renal biopsy performed for proteinuria showed features of membranoproliferative glomerulonephritis (MPGN) type 1 and focal segmental glomerulosclerosis (FSGS). A review of the literature for similar cases revealed 24 patients with Wilms' tumor associated with glomerular disease; MPGN was present in one of these cases and FSGS in six. In our patient, circulating immune complexes were detected in the serum and likely played a role in the pathogenesis of the MPGN; the FSGS may have resulted from hyperperfusion of the remaining glomeruli in a kidney that was largely replaced by Wilms' tumor.

Antigen-Antibody Complex↗
PubMed1984

Clinical features and glomerular immunofluorescence of renal biopsies from children with nephrotic syndrome due to minimal change disease and two variants of mesangial proliferative glomerulonephritis.

Response to initial course of prednisone and clinical outcome were reviewed in 82 children with nephrotic syndrome (NS) due to minimal change disease (MCD) and 2 variants of mesangial proliferative glomerulonephritis (MesPGN). Renal biopsies in Type I MesPGN showed only increased mesangial cells and matrix, whereas those in Type II MesPGN also showed interstitial fibrosis, tubular atrophy, global glomerulosclerosis and hyalinosis. Response to prednisone was complete in most cases (95% in MCD, 82% in Type I and 72% in Type II MesPGN). Remission of NS for more than 1 year while off prednisone occurred in 91% of patients with Type I MesPGN and 49% with MCD, but in only 14% with Type II MesPGN. The influence of immunoglobulins +/- complement in mesangial regions of glomeruli on initial response and outcome was assessed. Response to prednisone and outcome did not differ in IMF-positive and -negative MCD or in Type I and Type II MesPGN.

Adolescent↗
PubMed1984

Response to cyclophosphamide in steroid-resistant focal segmental glomerulosclerosis: a reappraisal.

The response to and clinical outcome of cyclophosphamide therapy were retrospectively assessed in 29 steroid-resistant patients with idiopathic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) to determine whether a partial response to this drug was associated with long-term clinical benefits. Twenty of the patients were nephrotic when cyclophosphamide was started and 9 were not. Three of the nephrotic patients had a complete response (i.e., sustained remission of disease) to cyclophosphamide. Nine nephrotic patients had partial responses. Of these, 8 have residual proteinuria and one has progressed to end-stage renal disease (ESRD). In contrast, of the 8 nephrotic patients who were resistant to cyclophosphamide, only one has residual proteinuria, while 7 have chronic renal failure (CRF) or ESRD. The incidence of CRF or ESRD in patients with a partial response to cyclophosphamide (1 of 9) was significantly lower (p = 0.004) than that in patients who were resistant to cyclophosphamide (7 of 8). The benefit of cyclophosphamide in patients who were not overtly nephrotic was less certain. This study indicates that a partial response to cyclophosphamide leads to improvement in the clinical outcome of many steroid-resistant nephrotic patients with FSGS.

Adolescent↗
PubMed1982

Extraglomerular dense deposits in dense deposit disease.

A search was made for dense deposits in sites other than kidney with the use of skin biopsy specimens obtained from patients with dense-deposit disease (DDD) and tissues from autopsy material. Dense deposits were not present in basement membranes at the epidermal-dermal junction or around dermal capillaries in three skin biopsy specimens. Three cases of DDD involving the kidneys (from 1937, 1940, and 1945) were found on reviewing 200 autopsy cases in which the cause of death was renal failure. Paraffin blocks of various tissues from these cases were examined by electron microscopy. Dense deposits were noted in sinusoidal basement membranes of the spleen in the two cases in which spleen was available. No dense deposits were found in brain, heart, lungs, liver, adrenals, or pancreas. We conclude that DDD involves the kidneys and spleen.

Basement Membrane↗
PubMedDate not supplied

Association of alveolar rhabdomyosarcoma with the Beckwith-Wiedemann syndrome.

Rhabdomyosarcoma (RMS) is a soft tissue tumor of childhood frequently diagnosed between the first and fifth year of life. Children with the Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth syndrome characterized by exomphalos, macroglossia, and macrosomia, have an increased risk of developing childhood tumors including Wilms tumor, hepatoblastoma, neuroblastoma, and RMS. Although an association between RMS and the BWS is well accepted, only four cases have been reported to date, and of these, three were reported as embryonal RMS. Based on these data, an association between BWS and embryonal RMS has been proposed. We report three additional cases of BWS with RMS and review the clinical data for each patient as well as the pathology of their tumors. All three cases of BWS had histology consistent with alveolar RMS and were diagnosed at 6 weeks and 5 and 13 years of age. In two of these BWS cases, constitutional defects of 11p15 imprinting were demonstrated. Furthermore, cytogenetic analysis of the tumors did not detect the t(2;13) or t(1;13) translocations that generate the PAX3- or PAX7-FKHR fusion proteins common to alveolar RMS. These observations suggest that the development of alveolar RMS tumors in BWS may occur without the chromosomal rearrangement producing the PAX-FKHR fusion protein. In summary, we present three new cases of RMS demonstrating a new association between BWS and an uncommon subtype of alveolar RMS. The absence of the translocations commonly associated with alveolar rhabdomyosarcoma suggests a common 11p15 pathway for alveolar RMS and BWS.

Adolescent↗
PubMedDate not supplied

Use of multicolor spectral karyotyping in genetic analysis of pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare, malignant intrathoracic pediatric tumor. It arises from the lung, pleura, or mediastinum and its pathogenesis and relationship to other pediatric solid tumors is not well understood. In this study, a case of PPB in a 3-year-old girl was studied using a combination of molecular genetic methods and cytogenetics. Molecular analysis of the commonly encountered fusion translocation gene products of pediatric solid tumors failed to detect a rearrangement. Cytogenetic analysis, supplemented by multicolor spectral karyotyping (SKY), identified an unbalanced translocation between chromosomes 1 and X, resulting in additional copies of 1q, an extra copy of Xq, and loss of part of Xp. In addition, trisomy 8 was detected. The identification of new chromosomal alterations and confirmation of previously reported ones in this rare neoplasm helps to improve our understanding of its pathogenesis and association with other pediatric tumors.

Child, Preschool↗
PubMedDate not supplied

Telomerase activity as a prognostic factor in neuroblastomas.

Neuroblastoma is the most common extracranial solid tumor of early childhood. This tumor demonstrates significant heterogeneity with respect to pathologic, genetic, and clinical features. The outcome varies from spontaneous regression or maturation to rapid progression, despite aggressive therapy. Prognostic factors have been found that identify those tumors which have a high probability of aggressive behavior; these factors include unfavorable histology, MYCN copy number, deletions of the short arm of chromosome 1, DNA content, and TRK-A (high-affinity receptor protein for nerve growth factor) expression. Recent studies have suggested that high levels of telomerase activity also correlate with poor clinical outcome. We investigated this relationship in 40 patients with untreated neuroblastoma, using a PCR-ELISA assay for telomerase activity. In these patients, 23 tumors had no or minimal telomerase activity whereas 15 had high levels of activity. In two tumors, telomerase activity was not assessable. There was significant correlation between the telomerase activity and MYCN copy number, 1p deletions, and TRK-A expression, as well as patient age, clinical stage, and outcome. The histological classification of the tumors was not significantly different between the two groups, being predominantly unfavorable by the Shimada classification. In addition, for 17 patients tumor tissue was assessed for telomerase activity post-chemotherapy. In those cases where the tumor was negative for telomerase activity before and after chemotherapy, the patients uniformly did well. In cases where the tumor was positive before and negative or weakly positive after treatment, two of the seven patients did well clinically. However, in cases that were positive after chemotherapy, all had recurrence or died. In conclusion, telomerase activity appears to be a prognostic factor for neuroblastomas. In addition, assessment of tumors post-chemotherapy may be a further indicator of clinical outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Melanotic neuroectodermal tumor of infancy: a molecular genetic study.

Melanotic neuroectodermal tumor of infancy is a rare but well-recognized entity in pediatric pathology. However, the relationship of this tumor to other pediatric small cell tumors with neuroectodermal features (such as neuroblastoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor, and desmoplastic small round cell tumor) is undetermined. Molecular genetic studies of melanotic neuroectodermal tumor of infancy have not been reported. We studied three typical cases of melanotic neuroectodermal tumor of infancy in an attempt to link this tumor to other small cell tumors with well-characterized molecular genetic changes. Tests performed included: detection of MYCN gene amplification and deletion of 1p (all 3 cases), and presence of the t(11;22)(q24;q12) and the t(11;22)(p13;q12) translocations (2 of 3 cases). None of these tests yielded positive results. Thus, there is no genetic basis at present to link melanotic neuroectodermal tumor of infancy to neuroblastoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor, or desmoplastic small round cell tumor.

Female↗
PubMedDate not supplied

Diffuse leiomyomatosis of the esophagus: disorder of cell-matrix interaction?

Diffuse leiomyomatosis (DL) is rare condition characterized by proliferation of smooth muscle in the upper gastrointestinal tract. Most cases are associated with X-linked Alport syndrome and have partial deletions in the genes encoding both the alpha5 and alpha6 chains of collagen type IV. We studied aspects of cell-matrix interaction of myocytes in an esophagogastrectomy specimen from a 12-year-old patient with DL. Myocytes had central areas of cytoplasmic rarefaction, which were actin positive and desmin poor, with the reverse pattern of staining at the cell periphery. Electron microscopy (EM) showed that the areas of rarefaction consisted of disorganized aggregates of filaments. The basement membranes ranged from thickened to thinned or absent. Immunohistochemical staining for the alpha1-alpha4 chains of collagen type IV, the alpha1, alpha2, beta2, and gamma1 chains of laminin, nidogen, type VI collagen, and fibronectin was normal. There was loss of the alpha5 and alpha6 chains of collagen type IV and the beta1 chain of laminin. Normal staining for alpha1, alpha2, alpha3, alpha4, alpha6, alpha8, and beta1 integrins was noted. Staining for alpha5 integrin varied from normal to reduced or negative in different cells. In DL, a primary abnormality of basement membrane may be associated with disorganization of the contractile apparatus and alterations of certain integrins. This may reflect a disturbance of cell-matrix interactions that play a role in cell differentiation and internal organization.

Barrett Esophagus↗
PubMedDate not supplied

Expression of WT1 in pediatric small cell tumors: report of two cases with a possible mesothelial origin.

The WT1 gene is normally expressed in fetal kidney and mesothelium, and its expression has been suggested as a marker for Wilms tumor and mesothelioma. We examined WT1 expression levels by reverse-transcriptase polymerase chain reaction (RT-PCR) in 38 childhood small-cell tumors including Wilms tumor, embryonal and alveolar rhabdomyosarcoma, Ewing sarcoma, lymphoma, desmoplastic small round-cell tumor (DSRCT), synovial sarcoma, extrarenal rhabdoid tumor, and two tumors that were atypical for this group of tumors. WT1 expression was only detected in Wilms tumor, rhabdoid tumor, and in these two cases of uncertain histogenesis. Both arose in the peritoneal cavity and by immunohistochemistry were diffusely positive for vimentin, keratin, and desmin. Tonofilaments were identified by electron microscopy in one of the cases. RT-PCR failed to detect the t(11;22) translocation associated with DSRCT in either case. Our results suggest that WT1 expression is an unusual feature of childhood non-Wilms tumors and, in the right setting, it may indicate a mesothelial origin. The expression of WT1 may play a role in mesodermal cells acquiring epithelial characteristics, a concept supported by the mixed epithelial and mesenchymal phenotype of these two cases.

Biomarkers, Tumor↗
PubMedDate not supplied

Variant EWS-WT1 chimeric product in the desmoplastic small round cell tumor.

Chromosome translocations found in neoplasms often result in the creation of hybrid genes encoding chimeric proteins. Desmoplastic small round cell tumor (DSRCT) is a recently described aggressive malignancy associated with a unique chromosomal translocation t(11;22)(p13;q12). This translocation has recently been characterized, revealing the rearrangement and fusion of the WT1 gene on chromosome 11 to the EWS gene on chromosome 22. Fusion of these two genes results in the production of a putative oncogenic protein composed of the zinc finger DNA-binding domains of WT1 linked to the potential transcriptional regulatory domains of EWS. The typical chimeric transcript consists of the first 7 exons of EWS and the last 3 exons of WT1. We report here the first case of DSRCT with a variant EWS-WT1 chimeric product that includes 9 exons of EWS and 3 exons of WT1.

Adolescent↗
PubMedDate not supplied

Renal cell carcinoma in children with diffuse cystic hyperplasia of the kidneys.

We report the clinical, pathologic, and genetic features of renal malignancy in two children with diffuse cystic hyperplasia. Both presented with massive bilateral nephromegaly. Neither had a family history or clinical findings suggestive of tuberous sclerosis or von Hippel-Lindau disease. The kidneys of both children were extensively replaced by tubulocystic hyperplasia with large eosinophilic epithelial cells. The masses of hyperplastic tissue were nodular, compressing remnants of uninvolved renal parenchyma. Tubulopapillary carcinoma was present in both children, one of whom had bilateral multicentric carcinoma. No loss of heterozygosity was detected in the tumors at the TSC1, TSC2, or VHL gene regions, and no alterations in the VHL gene were detected using single-strand conformation polymorphism analysis. These cases of bilateral renal enlargement with diffuse cystic hyperplasia appear to represent a new clinical syndrome that may warrant bilateral nephrectomy because of the risk of malignancy.

Adenocarcinoma↗