Evaluation of humoral immune response to donor HLA after implantation of cellularized versus decellularized human heart valve allografts.

We have evaluated the development of antibodies in response to donor allograft valve implant in patients who received cellularized and decellularized allografts and determined possible immunogenic epitopes considered responsible for antibodies reactivity. Serum samples from all recipients who received cellularized allografts or decellularized allografts were collected before valve replacement and at 5, 10, 30 and 90 days post-operatively and frozen until required. Tests were performed using the Luminex-based single human leukocyte antigen (HLA)-A, -B, -C and HLA-DR, -DQ antigen microsphere assay. To determine possible immunogenic epitopes, we used the HLAMatchmaker (HLAMM) software if applicable. Decellularized grafts elicited lower levels of anti-HLA class I and II antibody formation after implantation than cellularized allografts. All patients from cellularized group presented donor-specific antibodies class I and II within 3 months of observation period. In HLAMM analysis, the cellularized group had significantly higher numbers of immunogenic epitopes than decellularized group for both class I and II (p: 0.002 - cl I / p: 0.009 - cl II / p: 0.004 - cl I and II). Our findings demonstrate that the anti-HLA antibodies detected in the cellularized group were against donor HLA possible immunogenic epitopes and that in the decellularized group the anti-HLA antibodies were not against donor HLA possible immunogenic epitopes. These findings lead us to suggest that choosing sodium dodecyl sulfate decellularization process is the best alternative to decrease the immunogenicity of allograft valve transplant.

Cholinergic agonists attenuate renal ischemia-reperfusion injury in rats.

Inflammation plays a significant role in the pathophysiology of renal ischemia-reperfusion injury. Local inflammation is modulated by the brain via the vagus nerve and nicotinic acetylcholine receptors such that electrical or pharmacologic stimulation of this cholinergic anti-inflammatory pathway results in suppression of proinflammatory cytokine production. We examined the effects of cholinergic stimulation using agonists, nicotine or GTS-21, given before or after bilateral renal ischemia-reperfusion injury in rats. Pretreatment of rats with either agonist significantly attenuated renal dysfunction and tubular necrosis induced by renal ischemia. Similarly, tumor necrosis factor-alpha protein expression and leukocyte infiltration of the kidney were markedly reduced following treatment with cholinergic agonists. We found functional nicotinic acetylcholine receptors were present on rat proximal tubule epithelial cells. Cholinergic stimulation significantly decreased tubular necrosis in vagotomized rats after injury, implying an intact vagus nerve is not required for this renoprotective effect.

Reversible renal allograft dysfunction and proteinuria from nutcracker-like syndrome: a case report.

A 27-year-old Hispanic man with hypertension and renal failure was on hemodialysis for 4 years prior to receiving a living donor renal transplant from his 19-year-old sister. His serum creatinine decreased to 1.7 mg/dL at 3 weeks posttransplant with a urine protein creatinine ratio (UP) of 0.1 (g/g). Over the next 2 months, he experienced repeated episodes of allograft dysfunction with elevation of creatinine and proteinuria levels, associated with a lymphocele. Doppler studies of the allograft revealed renal vein compression. His symptoms responded to aspiration of the fluid collection, resolving completely with surgical drainage. We believe that the episodes of allograft dysfunction and proteinuria were related to recurrent lymphocele, causing a nutcracker-like syndrome.

Kappa-chain nephropathy associated with plasma cell leukemia.

A 45-year-old-woman had plasma cell leukemia (PCL) and mild renal insufficiency. Renal biopsy findings were compatible with kappa-chain nephropathy. Our case adds PCL to the list of plasma cell dyscrasias associated with kappa- and/or lambda-chain nephropathy.

PUlmonary embolism Low incidence in chronic renal failure.

The records of 2,255 autopsies performed on adults between Jan 1, 1969, and Dec 31, 1981, were reviewed for the presence of pulmonary embolism. The overall incidence was 32.3% (18.4%, microscopic; 4%, microscopic; and 9.9%, both). During this period, 95 patients with chronic renal failure (serum creatinine level, greater than 5.0 mg/dL) were identified. The incidence in this group was 9.47% (all microscopic). We conclude that pulmonary embolism is an infrequent cause of mortality in patients with chronic renal failure.

Ovarian hyperthecosis in the setting of portal hypertension.

Hepatocellular dysfunction and perturbed portal hemodynamics alter steroid metabolism. Men with liver disease have gynecomastia, although women similarly affected rarely show virilization. We report a 10-yr-old girl with portal hypertension and shunting associated with precocious puberty and ovarian hyperandrogenism. This was one of premature twin girls; neither had clitoromegaly or genital ambiguity. In one child, neonatal respiratory problems led to umbilical vein catheterization with subsequent development of portal hypertension. Pubic hair was first noted at age 6 yr, breasts at 7 yr, and severe acne and clitoromegaly at 10 yr. Baseline sex hormones were elevated: androstenedione (A), 413 ng/dL; testosterone (T), 226 ng/dL; and estradiol (E2), 160 pg/mL. Liver transaminases were within the normal range, however, the coagulation profile was mildly abnormal. Cosyntropin adrenal stimulation revealed no steroidogenic defect. Dexamethasone suppression reduced A and T slightly. LH-releasing hormone stimulation produced a pubertal rise in LH and FSH. Pelvic sonography showed a large right ovary with numerous follicles. Surgical exploration revealed symmetrically enlarged ovaries with dense capsules. Histology of ovarian wedge resections showed hyperthecosis; immunohistochemistry showed stromal cells expressing steroidogenic enzymes and proteins. One month postoperatively, A and T were unchanged from baseline, whereas E2 decreased to 56 pg/mL. A single dose of depot leuprolide acetate significantly reduced T. Subsequent treatment with oral contraceptives reduced T to 50 ng/dL, and cyclical menses occurred. We conclude that precocious puberty and ovarian hyperthecosis were induced in this young girl by elevated circulating levels of sex hormones, a consequence of portasystemic shunting and impaired hepatic steroid metabolism.

Hepatitis-B-associated glomerulonephritis: pathology, pathogenesis, and clinical course.

Hepatitis-B-associated glomerulonephritis (HBGN) is a distinct entity occurring frequently in hepatitis-B-prevalent areas of the world. The disease affects both adults and children who are chronic hepatitis-B-virus (HBV) carriers with or without a history of overt liver disease. The diagnosis is established by serologic evidence of HBV antigens/antibodies, presence of an immune complex glomerulonephritis, immunohistochemical localization of 1 or more HBV antigens, and pertinent clinical history, when available. In this study we present clinicopathologic and follow-up findings in 12 patients (7 children, 5 adults) with hepatitis-B-associated glomerulonephritis. Twelve patients provided 15 renal biopsies and 1 specimen of kidney tissue, obtained at autopsy; these were examined by light microscopy, electron microscopy, and immunohistochemical methods. Membranous glomerulonephritis (MGN) with or without mesangial proliferation was noted in 7 biopsies, mesangiocapillary (membranoproliferative) glomerulonephritis (MCGN) in 5 biopsies, and proliferative glomerulonephritis with or without membranous changes in 2 biopsies. Tubulointerstitial changes were minimal except in 3 adults, in whom they were attributable to arterionephrosclerosis. Ultrastructural findings included the presence of considerable amounts of focal or diffuse granular electron-dense deposits in the glomeruli, in the subepithelial, subendothelial, and mesangial locations, occasionally destroying or replacing the lamina densa of the basement membrane. Variable mesangial proliferation was also observed, with interposition, with focal irregular reduplication of the basement membranes and rare clusters of spherical particles, probably representing viral particles in the deposits. In addition, granular deposits along tubular basement membranes were seen in 1 case. The glomerular deposits stained for 2 or more immunoglobulins, the predominant one being IgG, and variably also for complement components (C3, C4 and C1q). Hepatitis B viral antigens (HBsAg, HBcAg, HBeAg) were demonstrated using acid elution techniques in the deposits in all biopsies where frozen tissue was available, singly or in a variety of combinations and intensities. There were deposits of IgG, C3, C1q, and HBsAg along the tubular basement membranes in 1 case. Follow-up biopsies in 2 cases, 2 and 5 years apart, showed a transformation from a diffuse MGN to MCGN with segmental membranous features. Follow-up biopsy after 3 years in the third patient, who went into clinical remission, revealed partially resolving glomerular lesions. Renal lesions secondary to chronic liver disease, parasitic diseases, certain tropical nephropathies, and lupus nephritis are some of the diseases that may morphologically resemble HBGN. Recognition and differentiation of HBGN from other entities may have significant prognostic and therapeutic implications.(ABSTRACT TRUNCATED AT 400 WORDS)

Neoplastic complications of HTLV-III infection. Lymphomas and solid tumors.

Neoplastic disease arose in 29 of 200 patients infected with human T lymphotropic virus type III (HTLV-III) seen at a suburban hospital. Seventeen patients had Kaposi's sarcoma, one of whom also had colon carcinoma. Nine patients had lymphoproliferative disorders (seven lymphomas, one T suppressor cell chronic lymphocytic leukemia, and one multiple myeloma), including three with concomitant Kaposi's sarcoma and one with colon cancer. One other patient had colon cancer, one had a seminoma, and one had pancreatic cancer. Kaposi's sarcoma as a complication of AIDS occurred mainly in homosexuals (17 of 42 homosexuals, one of 17 drug abusers, one of five heterosexually promiscuous patients, and one of six patients who had previously received transfusions). The high-grade lymphomas did not show a predilection for any particular AIDS risk group. Three of four solid tumors arose in elderly AIDS patients. Twenty-five of 75 patients with CDC-defined AIDS had a neoplastic disorder (26 are still alive and may yet demonstrate malignancy). Few other diseases of man have been associated with as high an incidence of neoplastic transformation as occurs with HTLV-III infection.

Syndrome of severe skin disease, eosinophilia, and dermatopathic lymphadenopathy in patients with HTLV-II complicating human immunodeficiency virus infection.

Two intravenous drug users dually infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type II (HTLV-II) developed an unusual severe dermatitis characterized by progressive brawny induration, fissuring, and ulceration of the skin, with an associated CD8 cell infiltration in one patient. Both patients had persistent eosinophilia. Lymph node biopsy revealed dermatopathic lymphadenopathy, an unusual pathologic finding in HIV-1 infection but one seen in association with mycosis fungoides and other skin disorders. Two new isolates of HTLV-II virus were established from these patients and were identified as HTLV-II by Southern blotting. This type of skin disease and lymph node pathology has not been found in other intravenous drug users who have been infected with HIV-1 alone or in patients in other risk groups for HIV-1 infection. HTLV-II may play a role in this unique new disease pattern in patients infected with HIV-1.

Cellular schwannoma: a variety of schwannoma sometimes mistaken for a malignant tumor.

Fourteen cellular schwannomas, a variety of peripheral nerve sheath tumor showing a predominantly compact cellular growth, no formed cellular palisades or Verocay bodies, but the ultrastructure of schwannomas, are reported. A presumed nerve of origin was identified in three instances. The tumor had no sex predeliction; the mean age was 48. The neoplasm is usually well encapsulated and most commonly presents in the neck, posterior mediastinum, or pelvis. Because of a variety of confusing histologic features, including dense cell bundles and fascicles, storiform areas, a moderate mitotic activity and moderate nuclear atypia, six of 14 cases were mistaken for either fibrous histiocytoma, leiomyoma, malignant peripheral nerve sheath tumor, or sarcoma of uncertain type. In two instances the false impression of a malignant tumor was reinforced by clinical evidence of bony erosion and destruction. Follow-up thus far has shown the tumor to be benign.

Aggressive natural killer cell lymphoma/leukemia. A recently recognized clinicopathologic entity.

We report a comprehensive study of a case of aggressive natural killer cell lymphoma/leukemia, which is characterized by young male predominance, rapidly progressive clinical course, and presence of lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. The leukemic phase is frequently preceded by pancytopenia. The diagnostic clues are the detection of cytoplasmic granules in tumor cells on Wright-Giemsa-stained tissue imprints or smears and a selective loss of T-cell antigens. Immunophenotyping is decisive in making the final diagnosis by showing positive natural killer cell markers (CD16, CD56, and/or CD57), CD2, CD11c, and Ia, but negative CD3, T-cell receptor heterodimers, terminal deoxynucleotidyl transferase, and B-cell markers. Genotyping always shows germline configuration in both immunoglobulin and T-cell receptor genes. The unique feature in this case is its presentation as a testicular lymphoma, which has not been previously reported. Polymerase chain reaction was performed in this case but failed to detect human T-cell leukemia virus type I/II provirus. It is important to recognize this new entity as it is a highly aggressive disease with a rapidly progressive clinical course and fails to respond to any chemotherapeutic regimen available.

Localization of endothelin-1-like immunoreactivity in human placenta.

We examined the distribution of endothelin-1-like immunoreactivity in human placenta, using the immunoperoxidase technique. A specific polyclonal antibody to endothelin-1 was raised in rabbits, which recognized endothelin-1 and its precursor molecule, big endothelin. Immunoperoxidase staining revealed that endothelin-1-like immunoreactivity was widely distributed in the placenta. Endothelin-1-like immunoreactivity was present in endothelial cells of capillaries of the microvilli and in small- and medium-sized arteries and veins. The distribution of endothelin-1-like immunoreactivity was similar to the distribution of Factor VIII-related antigen, which stains endothelial cells. The nature of endothelin in the human placenta was further examined with cultured umbilical vein endothelial cells. Endothelial cells released endothelin-like material into the culture medium. The amount of endothelin-like material varied directly with time of incubation and the amount of fetal calf serum in the culture medium. Fractionation of the endothelin-1-like material by reversed-phase high-performance liquid chromatography (HPLC) and quantitation by radioimmunoassay (RIA) revealed that endothelin-like immunoreactivity co-eluted with endothelin-1 but not with big endothelin-1. We conclude that endothelin-1-like immunoreactivity is widely distributed in vascular endothelium of the human placenta. These data are compatible with a role for endothelin as an autocrine or paracrine modulator of vascular tone in the human placenta.

Renal cell carcinoma with X;1 translocation in a child with Klinefelter syndrome.

Klinefelter syndrome (KS) is a sex chromosome abnormality occurring in 1 in 1,000 males. An association with leukemia, germ cell tumor, and male breast cancer has been suggested in KS. Such information is important for professionals caring for KS patients as the condition is frequently not clinically recognizable until after puberty. We report on a renal cell carcinoma (RCC) in a 10-year-old boy with KS. He developed intermittent hematuria at age 10 years and was diagnosed with a right kidney mass, which on pathology was identified as RCC. In addition, he was known to have learning disabilities and language delays. Analysis of peripheral blood chromosomes showed a 47,XXY karyotype while analysis of tumor cells demonstrated clonal abnormalities including a translocation between chromosomes X and 1, designated 47,XXYc,t(X;1)(p11.2;q21)[6]/47,XXYc,t(X;1),r(Xp)[2]/46,X XYc,-X,t(X;1)[7]. Renal cell carcinoma is rare in childhood and is not previously reported in KS. The oncogenetic significance of the chromosomal regions involved in this translocation is discussed in relation to the congenital abnormality of the patient.

Systemic lupus erythematosus complicated by thrombotic microangiopathy.

Seven patients with systemic lupus erythematosus (SLE) or SLE-like disease developed thrombotic microangiopathy. Prominent features of their acute illnesses were microangiopathic hemolytic anemia (7), thrombocytopenia (7), fever (1), nervous system disease (4), and renal dysfunction (5). Laboratory data were significant for antinuclear antibody (ANA) (7), DNA (5), low C3 level (3), low C4 level (2), antiphospholipid antibody (6), schistocytes (7), and lactate dehydrogenase > 500 (7). All seven patients received treatment that initially included steroids but later included cyclophosphamide (4), plasma infusion (1), plasmapheresis (5), intravenous gamma-globulin (2), anti-platelet agents (2), or vincristine (3). Six patients improved, and one patient expired during treatment. Of the six patients who survived this complication, three expired within the year following their acute illnesses. Histology, available in two cases, showed vascular changes consistent with a microangiopathic process. We conclude that the spectrum of vascular diseases in SLE extends beyond vasculitis to include noninflammatory vascular processes that can cause equally devastating complications.

Metastatic malignant mesothelioma presenting as colonic polyps.

A 66-year-old male engineer diagnosed with malignant pleural mesothelioma 4 years previously had thoracotomy, radiotherapy, and chemotherapy. He was followed regularly with chest computed tomography (CT) scan and had been asymptomatic. During one of his physical examinations, routine sigmoidoscopy showed incidental colonic polyps which were biopsied. Subsequently, recurrence of pleural mesothelioma and peritoneal involvement by mesothelioma was documented. Two of the polyps showed metastatic malignant mesothelioma in the lamina propia which strongly resembled adenocarcinoma histologically causing difficulty in making definitive diagnosis. Review of the literature disclosed no previously documented similar occurrence. This case shows the importance of clinical history and ancillary laboratory procedures such as immunohistochemistry and electron microscopy to avoid diagnostic pitfalls.

Histiocyte-rich B-cell lymphoma.

This is the second report of histiocyte-rich B-cell lymphoma and the first case analyzed by flow cytometry and cytogenetic study. The immunophenotype determined by flow cytometry was that of a B-cell antigen-positive, surface immunoglobulin-negative B-cell lymphoma with 79% CD11c positive histiocytes. The lymphoid cells were composed of 76% neoplastic B-cells and 24% reactive T-cells. Immunohistochemical staining showed large numbers of histiocytes positive for CD68 and lysozyme in the lymph node and the bone marrow. Neoplastic lymphoid cells were positive for CD20, CD45, CD74 and CDw75. The monoclonality of the tumor cells was established by the evidence of rearrangements of the heavy chain and kappa light chain genes and a complex clonal cytogenetic abnormalities including t(8;14)(q11;q32). The tumor cells were large, pleomorphic lymphoid cells and showed no features resembling those of the L/H cells of Hodgkin's disease as previously reported. The rapidly progressive clinical course in the present case is consistent with the clinical features shown in the original study. The histiocytic component in this tumor is presumably recruited by a lymphokine with the nature of a growth factor from the tumor cells that may also be responsible for the rapid proliferation of the tumor cells and the aggressive clinical course. This entity merits special recognition because it leads to a predictable poor prognosis and because of its potential of being misdiagnosed as true histiocytic lymphoma.

The clonal origin of two cell populations in Richter's syndrome.

A case of Richter's syndrome was studied by morphology, immunohistochemistry, flow cytometry, and immunoglobulin gene rearrangement. Flow cytometric study clearly demonstrated two monoclonal populations. The use of double staining with CD 5/CD 19 antibodies accompanied by two-color flow cytometric analysis clearly defined the chronic lymphocytic leukemia population and separated it from the lymphoma population. Immunoglobulin heavy-chain gene analysis of blood and lymph node specimens revealed nonidentical as well as identical nongermline bands in these two populations. However, light-chain gene analysis demonstrated that both populations shared a common clonal origin. This result underscores the unreliability of using heavy chain genotype alone to identify clonal origin. Since post-rearrangement deletion, point mutation, and heavy chain switching occur in heavy chain genes, but are seldom seen in light chain genes, it is important to analyze both heavy and light chain genes to conclusively determine clonal origin.

Islet cell hyperplasia: an unusual cause of hypoglycemia in an adult.

This is a case presentation of a 32-year-old man with a one year history of symptomatic hypoglycemia and documented elevations of his fasting plasma insulin to glucose ratio, caused by islet cell hyperplasia. Islet cell hyperplasia is a common cause of hypoglycemia in the pediatric population, but is very rare in adults. As in the pediatric group, adults should be treated with subtotal (75-85%) resection of the pancreas and with diazoxide for symptomatic recurrence of hypoglycemia. We suggest that the term islet cell hyperplasia is preferred to designate a diffuse proliferation of endocrine cells that may express itself with different morphologic patterns, varying from case to case. Islet cell hyperplasia, therefore, comprises nesidioblastosis, endocrine cell budding from ductal structures, as well as islet and islet cell hypertrophy, septal islets, islet dysplasia, and adenomatosis. Immunohistochemistry is a valuable method for the demonstration of the polymorphic hormonal content of the proliferated islet cells. We propose that the term nesidioblastosis, previously used to describe some similar cases, should be avoided because of confusion about its definition.

Flow cytometry of peritoneal washings in gynecologic neoplasia.

A prospective, double blind study was initiated to compare flow cytometry to cytopathology in detecting malignant cells within peritoneal washings. Deoxyribonucleic acid (DNA) histograms were generated using 4',6-diamidino-2-phenylindole (DAPI) as a DNA fluorochrome. Evaluation of these data revealed a correlation of 84.5% with the cytologic findings. Two specimens demonstrated euploidy in the presence of cytologically malignant cells (false negative), 28 of 128 specimens (21.8%) manifested aneuploidy with negative cytologic findings (false positive). Further evaluation of this latter subgroup revealed 22 of the 28 to possess unequivocal histologic evidence of malignancy, thus yielding an actual false positive rate of 4.7%. This preliminary study demonstrates that flow cytometry is a highly sensitive, accurate, and analytic method for the detection of malignant cells within peritoneal washings and that it may augment the cytologic examination. However, additional comparative studies are necessary to conclusively demonstrate its apparent diagnostic potential.

Renal involvement in patients with hepatosplenic Schistosomiasis mansoni.

In a prospective study of renal involvement in 100 consecutively hospitalized patients with hepatosplenic schistosomiasis mansoni, 15 exhibited persistent proteinuria of varying degree, which in 6 instances was accompanied by hypertension. Nine patients had the nephrotic syndrome. The most common glomerular lesion in this group was membrano-proliferative glomerulonephritis. Surgical biospy obtained during splenectomy in 15 patients without clinical evidence of renal involvement showed glomerular lesions in 6 instances. Focal proliferative glomerulonephritis was the most common lesion in this group. The detection of silent glomerular lesions in patients with Schistosoma mansoni infection suggests that the glomerular alterations may precede clinical manifestations of renal disease.