Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace.

Amyloid fibrils were isolated from the leptomeningeal blood vessels obtained at autopsy from three Icelandic patients dying of Hereditary Cerebral Hemorrhage with Amyloidosis (HCHWA) and verified by Congo red staining and electron microscopy. Gel filtration on Sephadex and Ultrogel columns yielded predominantly one component (molecular weight 11,500 daltons) and also another minor component (molecular weight 15,800 daltons). Automated amino terminal sequencing showed these proteins to be similar (36 residues) to a recently described human protein, gamma trace, beginning at its eleventh amino terminal residue. The amyloid deposits in all three patients stained with rabbit anti-gamma trace antiserum. Although the function of gamma trace is not known, it appears to have structural homology with several hormones and has been localized to the brain, pancreas and pituitary. The amyloid fibril subunits seem to have polymerized after cleavage of the amino terminal decapeptide from gamma trace-related proteins. Therefore, HCHWA appears to be the first genetically determined disease related to the gastroenteropancreatic neuroendocrine system.

Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland.

To investigate the role of beta-catenin in mammary gland development and neoplasia, we expressed a stabilized, transcriptionally active form of beta-catenin lacking the NH(2)-terminal 89 amino acids (Delta N 89 beta-catenin) under the control of the mouse mammary tumor virus long terminal repeat. Our results show that Delta N 89 beta-catenin induces precocious lobuloalveolar development and differentiation in the mammary glands of both male and female mice. Virgin Delta N 89 beta-catenin mammary glands resemble those found in wild-type (wt) pregnant mice and inappropriately express cyclin D1 mRNA. In contrast to wt mammary glands, which resume a virgin appearance after cessation of lactation, transgenic mammary glands involute to a midpregnant status. All transgenic females develop multiple aggressive adenocarcinomas early in life. Surprisingly, the Delta N89 beta-catenin phenotype differs from those elicited by overexpression of Wnt genes in this gland. In particular, Delta N 89 beta-catenin has no effect on ductal side branching. This suggests that Wnt induction of ductal branching involves additional downstream effectors or modulators.

Glomerular injury in uninephrectomized spontaneously hypertensive rats. A consequence of glomerular capillary hypertension.

Micropuncture and/or morphologic studies were performed in intact Wistar-Kyoto rats (WKY) (group 0), intact spontaneously hypertensive rats (SHR) (groups 1 and 5), uninephrectomized (UNX) WKY (groups 2 and 6), and UNX SHR (groups 3 and 4, 7 and 8). UNX was performed when rats were 5 wk of age. Groups 0-4 were observed for 34 wk after which whole kidney clearance and morphologic studies were performed. Groups 5-8 underwent micropuncture study at 10 wk of age. Groups 4 and 8 were fed a diet containing 6% protein. All other rats ingested standard laboratory diet. 5 wk after UNX, normotensive group 6 had higher single nephron glomerular filtration rate (SNGFR) and initial glomerular plasma flow rate (QA) than intact, hypertensive group 5. Glomerular transcapillary hydraulic pressure difference (delta P) was similar in these two groups. Hypertensive group 7 exhibited less elevation in SNGFR and QA than group 6, but delta P was significantly increased. The presence of glomerular capillary hypertension in UNX SHR at 10 wk was associated with the development of significant proteinuria and an increased incidence of mesangial expansion and glomerular sclerosis at 7 mo (group 3) as compared with groups 0, 1, and 2. Protein restriction prevented the development of increased delta P in UNX SHR (group 8) and also conferred long-term protection from increased urinary protein excretion and glomerular injury (group 4). These studies suggest that glomerular capillary hypertension predisposes to glomerular injury in this model of hypertension with reduced renal mass.

Initiation of translation from a downstream in-frame AUG codon on BRCA1 can generate the novel isoform protein DeltaBRCA1(17aa).

Expression of the breast and ovarian cancer gene BRCA1 is regulated at both the transcriptional and post-transcriptional levels. We found that the expression of the BRCA1 protein may also be regulated at the translational level. In addition to an AUG start codon at position 1, BRCA1 mRNA has a second in-frame AUG (+17) that acts as an alternative start codon to generate a novel BRCA1 protein that lacks the first 17 amino acids (DeltaBRCA1(17aa)). We fused cDNAs encoding the second exon of BRCA1 of the wild-type BRCA1 gene (wt-BRCA1) and a mutated BRCA1 gene (mt-BRCA1), in which the first initiation site and its Kozak consensus sequence were abolished, with the nucleophosmin (NPM) reporter gene and used them for in vitro and in vivo translation assays. In both systems, the wt-BRCA1-NPM constructs produced two distinct proteins (18 and 16 kD) begun from the first and second AUGs. The mt-BRCA1-NPM constructs produced only the shorter 16-kD protein lacking the first 17 amino acids of the BRCA1 gene. Next, we analysed the N-terminal protein sequence of purified BRCA1 protein from normal thymocytes and found two different BRCA1 proteins, derived from translation of the first and second in-frame AUGs. Thus, BRCA1 protein expression can be regulated at the translation level in normal cells. Characterization of DeltaBRCA1(17aa) may shed light on the function and regulation of BRCA1 in normal cells as well as the pathogenesis of breast and ovarian cancers. Oncogene (2000).

gamma-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line.

gamma-heregulin is a recently described novel isoform of the heregulin/neuregulin class of EGF-like ligands that bind to and activate receptors of the ErbB family. Deregulated signaling through the heregulin-ErbB pathway is thought to be implicated in the development of a subset of human breast cancers. gamma-heregulin has been found to be expressed in the culture supernatant of MDA-MB-175, a breast carcinoma cell line. gamma-heregulin is characterized by the presence of a large N-terminal peptide extension that is not found in other heregulin isoforms. Here we report that this unique N-terminal extension of gamma-heregulin is identical to the N-terminus of DOC4, a product of a recently identified CHOP-dependent stress-induced gene. Human DOC4 and the heregulin-encoding genes map to different chromosomes and the MDA-MB-175 cell line contains a chromosomal translocation that leads to the fusion of DOC4 and HGL, on chromosomes 11 and 8, respectively. Thus, gamma-heregulin is a product of a mutant fusion gene and not a bona fide normal isoform. We speculate that the mutation may be selected for by virtue of its ability to activate ErbB signaling through the production of an autocrine ligand.

Intracardiac leiomyomatosis: diagnosis and treatment.

Intracardiac leiomyomatosis is the presence of a benign smooth muscle tumor within a cardiac chamber reaching the heart by direct intravenous extension from an extracardiac source. After a case report and a review of the 13 previously reported cases, the clinical features, diagnostic considerations, differential diagnosis and treatment modalities of intracardiac leiomyomatosis are discussed.

Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension.

The objective of this study was to determine whether the calcium antagonist amlodipine could slow the progression of chronic renal disease. We examined the effects of amlodipine on kidney structure and function in two experimental models of hypertension. In the first study, adult, male Munich Wistar rats underwent uninephrectomy and were given weekly injections of desoxycorticosterone and 1% saline for drinking. Rats ingested normal chow or chow containing amlodipine for 8 weeks. The drug reduced systemic blood pressure, but glomerular filtration rate, kidney weight, proteinuria, and morphological evidence of glomerular injury were not affected. In the second study, male spontaneously hypertensive rats underwent uninephrectomy at 5 weeks of age and were followed for 6 months, during which they received no therapy or amlodipine. The drug dose was determined in preliminary studies to be the highest dose not associated with marked growth retardation. Again, although systemic blood pressure was significantly reduced by amlodipine, proteinuria and the prevalence of glomerulosclerosis were similar in amlodipine-treated and control spontaneously hypertensive rats. Micropuncture studies revealed that glomerular pressure remained elevated in amlodipine-treated spontaneously hypertensive rats. Kidney weight and glomerular volume were also similar in amlodipine-treated and control rats. Amlodipine also failed to inhibit platelet aggregation. Therefore, antihypertensive therapy with amlodipine fails to reduce glomerular pressure in spontaneously hypertensive rats as well as glomerular size and injury in spontaneously hypertension rats and desoxycorticosterone-salt hypertension. Although other dihydropyridine calcium antagonists have been found to reduce experimental glomerular injury, these data suggest that amlodipine may not prevent hypertensive nephrosclerosis.

Membranes nephropathy associated with renal cell carcinoma. Evidence against a role of renal tubular or tumor antibodies in pathogenesis.

A patient with the nephrotic syndrome due to membranous nephropathy was found to have renal cell carcinoma. Since membranous nephropathy in patients with malignancies has been attributed to a tumor antigen-antibody complex form of glomerulonephritis, an attempt was made to implicate tumor antigens and/or renal tubular epithelial antigens in the pathogenesis of membranous nephropathy in our patient with renal cell carcinoma. Antibodies directed against tumor antigens and renal tubular antigens and renal tubular eipthelial antigens were sought in his serum and in eluates of his glomeruli; no such antibodies were found. The concurrence of the two renal lesions may have been fortuitous in this patient. However, their association temporally suggests that they were related, and our immunologic studies demonstrate that tumor antigen-antibody complexes are not invariably involved in the pathogenesis of malignancy-associated membranous nephropathy.

Multiplex genotype analysis of invasive carcinoma and accompanying proliferative lesions microdissected from breast tissue.

To understand the genetic basis of breast cancer in a comprehensive way, purported precursor lesions need to be analyzed at a large number of genetic marker loci and compared with each other and with the invasive components. However, the microscopic size of most of these lesions and the very small amount of material that can be obtained through microdissection limit the number of loci that can be included in the analysis. To address this issue, a multiplex genotyping approach has been developed. With this approach, polymorphic sequences at 28 marker loci were amplified simultaneously from the micro-dissected components in 5-microm paraffin-embedded breast tissue sections. The genotypes of the lesions were determined after resolving the amplified allelic products by denaturing gradient gel electrophoresis. Because the material isolated from each lesion in a single 5-microm section was sufficient for several 28-locus assays and several successive tissue sections with the same set of lesions may be prepared, it is possible to determine the genotype of each lesion at hundreds of genetic marker loci that may well cover the human genome. Analyzing a sufficient number of cases may yield information that could be used to understand the genetic basis of breast cancer development in a comprehensive way.

Papillary elastofibroma of the left ventricular septum.

Papillary elastofibromas of the heart are usually incidental findings at autopsy. They occur more commonly on the surfaces of the valves than on the mural endothelium and are characterized by a papillary configuration with fronds composed of a collagenous and elastic tissue core lined by hyperplastic endothelial cells. Echocardiography and cardiac catherization demonstrated the lesion preoperatively in this case.

Carcinoma of the prostate with atypical immunohistological features. Clinical and histologic correlates.

In seven patients with undifferentiated carcinoma of the prostate, the immunohistochemical stain for prostate-specific antigen was negative. The stain for prostatic acid phosphatase done on the same tissue samples was diffusely positive in three, focally positive in three, and negative in one. Only the three with diffusely positive immunostaining had elevated serum acid phosphatase levels, although five had evidence of metastatic disease. All seven neoplasms were histologically similar, being composed of large cells with large nuclei, a moderate amount of cytoplasm, and indistinct cell borders. All tumors grew as broad sheets within the prostatic stroma as well as in the prostatic urethra; in six cases. Thus, prostatic carcinoma with this histologic pattern frequently loses prostate-specific antigen immunoreactivity. Awareness of this occurrence should prevent a misdiagnosis of urothelial carcinoma in such cases. The prostatic origin of these neoplasms can usually be verified by prostatic acid phosphatase immunostaining, which proves to be more sensitive in this particular setting.

Breast sarcoma with giant cells and osteoid. A case report and review of the literature.

Breast sarcomas with giant cells and osteoid are rare and usually fatal. They should be distinguished from carcinomas with sarcomatous metaplasia. Our case is presented together with eight similar ones reported in the English literature. Their clinical, radiologic, gross, and histologic characteristics are analyzed. Most patients died within 1 1/2 years of diagnosis, survival apparently being related to the size of the tumor. Diagnosis is delayed because the tumor can be confused clinically and radiologically with a large fibroadenoma. Awareness of this problem, fine-needle aspiration, and computerized tomography may lead to earlier diagnosis and, consequently, improved survival. In our case, immunohistochemical studies supported the notion that the lesion was a primary sarcoma, rather than a carcinoma with sarcomatous metaplasia.

Long-term effects of etretinate on the liver in psoriasis.

Etretinate is an aromatic retinoid and derivative of vitamin A soon to be approved for general use in the U.S. as therapy for severe psoriasis. We report on liver morphology and function in 18 subjects who received the drug for at least 5 years as part of a clinical trial. The majority (14) suffered no or mild and reversible structural liver changes; mild transient elevations in serum triglyceride and liver enzymes were noted occasionally. Of the remaining four patients, mild periportal fibrosis was documented in two, another had changes similar to chronic active hepatitis, and a fourth had cirrhosis that was unrelated to alcohol use. Liver function data, cumulative drug dose, and treatment duration were generally not reflective of these changes. The results of this study suggest a need for periodic liver biopsy to monitor patients on long-term etretinate therapy.

Primary localized amyloidosis of the nose and paranasal sinuses. A case report with immunohistochemical observations and a review of the literature.

Primary localized amyloidosis of the nose and nasopharynx is a rare disease. We present a case and review seven additional cases from the English literature. The ages of the patients ranged from 8 to 86 years; there was no sex predominance. Symptoms were nasal obstruction, epistaxis, and impaired hearing. Physical examination revealed a nasal mass or glue ears. The lesions were composed of amyloid and chronic inflammatory cells, mainly plasma cells. Ours is the first case of nasal amyloidosis in which the type of amyloid was determined immunohistochemically to be amyloid light chain (AL) lambda. The main treatment was surgical. Recurrences developed. Determination of the biochemical nature of this amyloid clarified its pathogenesis and may influence treatment. Amyloidosis should be considered in the differential diagnosis of nasal obstruction, epistaxis, and glue ears, even in the pediatric age group.

Congenital cystic adenomatoid malformation of the lung in adults.

Congenital cystic adenomatoid malformation of the lung presents mainly in neonates, is rare in children beyond infancy, and has not been reported in adults. Two adult males (aged 24 and 35) had congenital cystic adenomatoid malformation of the right and left lower lobes respectively. A third case, that of a 7-year-old girl, provided the link between the typical neonatal and these adult cases. All three lesions consisted of single or multiple macroscopic cysts, as well as a network of interconnecting spaces (the adenomatoid component). The lining varied from pseudostratified columnar ciliated, to simple mucinous and cuboidal epithelium. Abundant smooth muscle was present in two cases. Cartilage was absent in all three cases. The absence of inflammation is typical of the lesion in neonates. By contrast, all three of our patients had clinical and pathologic evidence of chronic inflammation. We postulate that congenital cystic adenomatoid malformation, when confined to a lobe or segment, may be clinically silent in infancy and may present as pneumonia associated with a cystic lesion on chest x-ray in childhood or later life.

The role of electron microscopy in the diagnosis of unusual peripheral lung tumors.

The ultrastructure of the lung provides a cytomorphologic basis for the identification of unusual pulmonary neoplasms or unusual histologic variants of more common pulmonary lesions. Comparison of tumor cells with bronchioloalveolar lining cells and with pleural components has aided in the diagnosis of a spindle cell variant of a peripheral neuroendocrine cell tumor (carcinoid) and a tumor composed of cells resembling bronchioloalveolar epithelium (sclerosing hemangioma of lung).

Relationship of tissue deposits of cryoglobulin to clinical features of mixed cryoglobulinemia.

Two patients with type 2 mixed cryoglobulinemia had tissue deposits of serum cryoproteins. Patient 1, a 72-year-old man, had purpura and glomerulonephritis. The serum cryoglobulin consisted of monoclonal IgM kappa and polyclonal IgG. Renal biopsy revealed diffuse proliferative glomerulonephritis with abundant IgG, IgM, kappa light chain, and complement in glomerular capillary walls. These immunoglobulins, but no complement, were also present in histologically normal cutaneous blood vessels. Ultrastructurally, cutaneous vascular deposits were identical to the renal deposits and to the crystalline mixed IgM-IgG serum cryoprecipitates and renal deposits previously described. Patient 2 was a 68-year-old man with sensorimotor peripheral polyneuropathy and purpura. His serum cryoglobulin consisted of monoclonal IgA lambda and polyclonal IgG. Sural nerve and skin biopsies revealed vasculitis involving small arteries and arterioles. Immunoglobulin A and complement were present in perineurial arteriolar walls of the sural nerve. Cryoprecipitates in both cases had strong rheumatoid factor activity. These findings support the view that in type 2 cryoglobulinemia tissue deposits consist of cryoprotein immune complexes. The presence of these deposits in histologically normal blood vessels in patient 1 suggests that deposition of cryoproteins precedes and may initiate tissue damage.

Pathology of dysproteinemia: light chain amyloidosis, non-amyloid immunoglobulin deposition disease, cryoglobulinemia syndromes, and macroglobulinemia of Waldenström.

This review has dealt with four syndromes associated with dysproteinemia, and has emphasized studies of the tissue deposits and forms of tissue injury which occur in such patients. However, similar tissue deposits and tissue damage occasionally occur in the absence of a serum or urine paraprotein, in which case other clinical data are necessary to suggest the need for examination of tissue for Ig heavy and light chain determinants in order to provide a correct diagnosis of dysproteinemia. In such cases, one may speculate that there is a low rate of paraprotein production and secretion, in addition to tissue tropism. Some paraproteins are antibodies, in which case they may circulate and/or deposit as immune complexes, or bind to tissue antigens with immune complex formation in situ. Some paraproteins are also cryoproteins, and clues to this property can also be found in the tissue, particularly at the ultrastructural level. Thus, a wide spectrum of clinical manifestations of a B cell proliferative disorder may be associated with any of a variety of circulating paraproteins and a variety of forms of tissue deposit and injury. Consequently, the best understanding of an individual patient requires correlation of the clinical features of the disorder, the immunochemical characterization of the circulating and excreted paraproteins, and an immunohistochemical analysis of the tissue deposits and associated morphologic abnormalities. This should be correlated with histologic and immunohistologic assessment of bone marrow, looking for overt B cell neoplasia, the more difficult to define "lymphoproliferative disorders," or alterations in kappa to lambda plasma cell ratios which may correlate with the deposited material. Studies of the Ig synthesized by cultured bone marrow plasma cells, and biochemical analyses of the deposited material, have demonstrated structural abnormalities of paraproteins which may be responsible for their tissue deposition.

Visceral leishmaniasis in the acquired immunodeficiency syndrome: report of two cases.

Core biopsies of the bone marrow are indispensable in the evaluation of fever of unknown etiology in human immunodeficiency virus-positive patients. We report two patients in whom visceral leishmaniasis was diagnosed based on the typical morphology, staining characteristics, and ultrastructure of the organisms.

Glomerulonephritis in congenital cytomegalic inclusion disease.

Except for renal transplant recipients, glomerulonephritis has only very rarely been associated with renal cytomegalovirus (CMV) infection. The kidneys of five infants with congenital cytomegalic inclusion disease, including renal infection, were examined at autopsy. Two of the infants had glomerulonephritis. The younger, a 4-month-old female, had diffuse proliferative and necrotizing glomerulonephritis; virus was present in nuclei and cytoplasm of glomerular endothelial cells and, possibly, in leukocytes as well. There were no electron-dense deposits. The other infant, a 5-month-old male, had diffuse mesangial and focal segmental proliferative and sclerosing glomerulonephritis; electron-dense mesangial deposits were seen ultrastructurally. Three additional infants (a newborn male, a 2-day-old male, a 6-week-old female), all with CMV in tubules and one with a single glomerular inclusion, had only rare glomerular abnormalities, i.e., mesangial proliferation in less than 10 per cent of glomeruli (one infant) and segmental sclerosis in less than 1 per cent of glomeruli (all three infants). Thus, congenital renal CMV infection was associated with proliferative glomerulonephritis in the two infants who survived the longest. The three with shorter survival times had only minor glomerular alterations.