BCR-ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia.

The role of the BCR-ABL oncogene in the progression of chronic myeloid leukemia (CML) to blast crisis (BC) is unknown. The appearance of chromosomal aberrations in patients with CML BC has led to many attempts to elucidate a mechanism whereby BCR-ABL affects DNA damage and repair. BCR-ABL-expressing cells have been found to accumulate genetic abnormalities, but the mechanism leading to this genomic instability is controversial. In this study, we review the effects of BCR-ABL on DNA repair mechanisms, centrosomes, checkpoint activation and apoptosis. BCR-ABL has diverse effects on these mechanisms, but which of these effects are necessary for the progression of CML to BC is still unresolved.

BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold.

Earlier reports have suggested that the BCR/ABL oncogene, associated with chronic myeloid leukemia, induces a mutator phenotype; however, it is unclear whether this leads to long-term changes in chromosomes and whether the phenotype is found in primary chronic myelogeneous leukemia (CML) cells. We have addressed both these issues. BCR/ABL-expressing cell lines show an increase in DNA breaks after treatment with etoposide as compared to control cells. However, although BCR/ABL-expressing cell lines have an equivalent cell survival, they have an increase in chromosomal translocations after DNA repair as compared to control cells. This demonstrates that BCR/ABL expression decreases the fidelity of DNA repair. To see whether this is true in primary CML samples, normal CD34+ progenitor cells and CML progenitor cells were treated with etoposide. CML progenitor cells have equivalent survival but have an increase in DNA double-strand breaks (DSBs). Spectral karyotyping demonstrates new chromosomal translocations in CML cells, but not normal progenitor cells, consistent with error-prone DNA repair. Taken together, these data demonstrate that BCR/ABL enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair.

Delayed acute renal failure in post-transplant period in young children from unexplained etiology.

This report describes six young children (5 male) who developed delayed acute renal failure (DARF) in the early post-kidney-transplant (Tx) period in the absence of acute rejection (AR) or other diagnosable conditions. These young children, aged 16.5 +/- 3.1 (12-21) months [mean +/- SD, (range)] and weighing 8.5 +/- 1.7 (7.1-11.4) kg received a primary renal Tx (5 living-related donor, 1 cadaver) between 1984 and 1992. Immunosuppression included prednisone, azathioprine, and Minnesota antilymphocyte globulin (MALG, n = 5); one patient received cyclosporine and no MALG. Initially, all patients had good urine output (UO). They became systemically ill and abruptly developed diminished UO on post-operative day (POD) 6.5 +/- 1 (4-8). DARF was accompanied by fever (39.1-40.4 degrees C, n = 6), thrombocytopenia (platelets < 100,000/mm3, n = 6), leukocytosis, or leukopenia (white cell count > 20,000/mm3, n = 4 or < 1,000/mm3, n = 1). Four patients had diarrhea. Three had ascites and one was surgically explored for suspected urinary leak. None showed significant urinary obstruction by renal ultrasound. Renograms showed intact blood flow. Renal biopsy showed tubular ectasia (n = 6), vascular congestion (n = 5), focal glomerular endothelial swelling (n = 4), and capillary thrombi (n = 3). None showed AR. Five patients required dialysis for 11 +/- 4 (7-15) days. All patients survived. One patient, treated for suspected AR with the monoclonal antibody OKT3, developed shock and lost her graft on POD 12 due to vascular thrombosis. Renal functional recovery in the remaining five patients took 14 +/- 5 (6-20) days and their serum creatinine at discharge was 0.7 +/- 0.5 (0.3-1.6) mg/dl. We report DARF from undetermined etiology occurring in the first 2 weeks of renal Tx in young children. Treatment is supportive care including dialysis. Recognition of this complication will help avoid risky investigations or unnecessary treatment for rejection.

Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report.

BACKGROUND: The incidence of recurrence of haemolytic-uraemic syndrome (HUS) in renal allografts appears to vary by centre, with the highest rates reported from the University of Minnesota. It is possible that the high rate of HUS recurrence at this institution reflects a transplant population skewed towards patients with a form of HUS that is more likely to recur in the allograft. METHODS: This study examined whether the initial episode of HUS in the native kidneys was preceded by a diarrhoeal prodrome ('classical HUS') or not ('atypical HUS'), and evaluated transplant outcomes in 24 patients who received 36 transplants at the University of Minnesota between 31 May 1972 and 31 December 1994. RESULTS: Eighteen of the 24 patients had atypical HUS, three had classical HUS, and in three patients the presence or absence of a diarrhoeal prodrome could not be determined. Recurrent HUS, defined as microangiopathic haemolytic anaemia, thrombocytopenia, renal insufficiency, and allograft biopsy findings compatible with HUS, occurred 16 times in 14 grafts in 11 patients. Nine of these patients had atypical HUS, one had classical HUS, and in one the nature of the prodrome could not be determined. Eleven of the 14 initial recurrences took place within 2 months of transplant. Recurrence was not more frequent in patients who received cyclosporin or antilymphocyte preparations. Actuarial analysis using matched controls showed poorer graft survival in patients with a primary diagnosis of HUS (P = 0.007), due to the high frequency of graft loss in HUS patients with recurrence. CONCLUSION: Based upon these data and a review of the literature, it can be concluded that the risk of recurrence of HUS in the allograft is confined almost entirely to patients with atypical forms of HUS.

Chronic renal allograft rejection in the first 6 months posttransplant.

Between May 1, 1986 and May 31, 1992 at the University of Minnesota, we interpreted 129 renal allograft biopsy specimens (done in 48 grafts during the first 6 months posttransplant) as showing changes consistent with chronic rejection. For this retrospective analysis, we reexamined these biopsies together with clinical information to determine: (a) whether a diagnosis other than chronic rejection would have been more appropriate, (b) how early posttransplant any chronic rejection changes occurred, and (c) if the diagnosis correlated with outcome. We found that (1) chronic rejection is uncommon in the first 6 months posttransplant; it was documented in only 27 (2.4%) of 1117 renal allografts and was preceded by acute rejection in all but 3 recipients (for these 3, the first biopsy specimen showed both acute and chronic rejection). (2) Chronic vascular rejection was seen in 1 recipient as early as 1 month posttransplant; the incidence increased over time and was associated with an actual graft survival rate of only 35%. (3) The most frequent cause of arterial intimal fibrosis in the first 6 months posttransplant was arteriosclerotic nephrosclerosis (ASNS) of donor origin. Long-term graft function for recipients with ASNS was 67%. (4) Early-onset ischemia or thrombosis was seen in 14 recipients and predicted poor outcome: only 35.7% of these recipients had long-term graft function. (5) Cyclosporine (CsA) toxicity was implicated in only 3 recipients, who had mild diffuse interstitial fibrosis in association with elevated CsA levels. Other variables (including systemic hypertension, urinary tract infection, obstructive uropathy, neurogenic bladder, cobalt therapy, and recurrent disease) were not significantly associated with chronic renal lesions in the first 6 months posttransplant. A significant number of biopsies were originally interpreted as showing chronic rejection, but the diagnosis was changed upon reevaluation in conjunction with clinical data. We conclude that many factors coexist to produce chronic lesions in biopsies during the first 6 months posttransplant, so clinical correlation is needed before establishing a diagnosis of chronic rejection.

Juxtaglomerular body abnormalities in youth-onset diabetic subjects.

Abnormal microalbuminuria in insulin-dependent diabetic subjects (IDDS) is significantly associated with pre-clinical nephropathy. In youth-onset IDDS declining plasma renin activity is significantly associated with improved albumin excretion, while persistently elevated renin activity is associated with continued abnormal microalbuminuria. To determine if these changes are reflected in changes in cell count in the juxtaglomerular body and if biopsy findings correlate with abnormal microalbuminuria, renal tissue of 20 IDDS (Study IDDS) ages 16 to 31 years, evaluated concurrently for plasma renin activity and microalbuminuria, were examined by light microscopy. Biopsy or autopsy specimens from 21 normal subjects and 32 IDDS (Non-Study IDDS), ages 2 to 25, were also examined. Specimens from the majority of prepubertal and all pubertal and postpubertal Non-Study IDDS and all Study IDDS independently of status of microalbuminuria had morphologic abnormalities. Normal or mesangially expanded glomeruli were found in association with expanded juxta-glomerular bodies and increased cell number, or with sclerotic bodies and decreased cell number. Sclerosis of juxtaglomerular bodies occurred independently of glomerular sclerosis. The highest percentage of glomeruli with expanded juxtaglomerular bodies and high cell count was present in specimens of Study IDDS with the most abnormal levels of microalbuminuria. T lymphocytes, noted within juxtaglomerular bodies, were present in specimens of 62% of the 52 Study and Non-Study IDDS. Abnormalities of the juxtaglomerular body are distinctive features of renal pathology in IDDS. T lymphocytes in the endocrine juxtaglomerular body suggest the presence of an autoimmune process. Confirmatory studies are necessary.

Pulmonary neuroendocrine cells in pediatric lung disease: alterations in airway structure in infants with bronchopulmonary dysplasia.

Despite four decades of investigation, the function of pulmonary neuroendocrine cells (NEC) remains unclear. Since NEC secretory products may influence airway growth or differentiation or alter airway smooth muscle tone, increased numbers of NEC seen in bronchopulmonary dysplasia (BPD) may be partially responsible for the genesis of the structural and pathophysiological alterations seen in this disease state. Changes in airway structure were studied in six infants dying with BPD and six conceptional age-matched control infants dying of noncardiopulmonary disease. Changes in bombesin-, calcitonin-, and serotonin-immunoreactive NEC were quantified in lung specimens from three infants who died at 2 months of age with severe BPD and three conceptional age-matched controls. There were no differences in either bronchiolar or bronchial airway epithelial areas, but significant increases in bronchiolar (1.8-fold) (P < 0.001) and especially bronchial smooth muscle (2.5-fold) (P < 0.001) were documented in infants with BPD. Few bombesin-, calcitonin-, and serotonin-immunoreactive cells were identified in cartilaginous airways; however, there was a clear increase in the total number of bronchiolar immunoreactive cells in infants with severe BPD (28.5 +/- 11.2 cells/mm airway epithelium) compared to control infants (4.5 +/- 4.9) (P < 0.05). Our results confirm that airway wall composition does change in BPD, but there is either no or an inverse correlation between NEC number and airway epithelial and smooth muscle areas and cell numbers. The role of NEC secretory products in airway smooth muscle growth and function requires further investigation.

Disseminated malignant histiocytosis in a golden retriever: clinicopathologic, ultrastructural, and immunohistochemical findings.

Diagnosis of malignant histiocytosis (MH), a disorder characterized by systemic proliferation of morphologically atypical histiocytes and their precursors, in an 8-year-old neutered female Golden Retriever was based on light and electron microscopic and immunohistochemical findings. Clinically, the dog presented with unilateral forelimb lameness. Eight days after surgical exploration of a swollen brachium, the dog developed sudden onset of posterior paresis, fecal and urinary incontinence, and a flaccid tail. Necropsy revealed infiltrative and nodular lesions in the right forelimb and regional lymph nodes, thoracic and abdominal cavities, and lumbar epidural space. Gross lesions were not found in the lungs or integument. Histopathologic examination showed infiltrates of atypical histiocytes in skeletal muscle, joint, and regional lymph nodes of the right forelimb; intercostal muscle; lung; liver; spleen; pancreas; kidneys; and spinal dura. Most tumor infiltrates were nodular and composed of loosely aggregated cells that were 10-30 microns in diameter with abundant eosinophilic to foamy cytoplasm, had central or eccentric nuclei, and were periodic acid-Schiff negative. Many binucleated cells, multinucleated giant cells, and mitotic figures were seen. Tumor cells contained phagocytosed erythrocytes, mononuclear cells, and some leukocytes. Ultrastructural features of tumor cells included cytoplasmic lipid droplets, lysosomes, and phagolysosomes. Immunohistochemical studies on paraffin-embedded sections showed positive reactivity to human T-cell Ag (clone UCHL-1) and for lysozyme, alpha-1-antitrypsin, and cathespin B. Polyclonal intracellular immunoglobulin reactivity and lectin binding (peanut, soybean, and wheat germ agglutinins and concanavalin A) were also demonstrated. Criteria for diagnosis of malignant histiocytic tumors and differential diagnosis are discussed.

Bannayan-Riley-Ruvalcaba syndrome.

Here we report on 12 affected members of a family with Bannayan-Riley-Ruvalcaba syndrome. We present clinical evidence of overlap between Bannayan-Zonana syndrome. Riley-Smith syndrome, and Ruvalcaba-Myhre syndrome in this autosomal dominantly inherited condition. We expand the phenotypic spectrum to include Hashimoto thyroiditis, which occurred in 7 of our cases. Finally, we discuss the relationship between the syndrome and juvenile polyposis of infancy.

De novo hemolytic uremic syndrome following renal transplantation.

We report a case of complete recovery of renal function in a patient with de novo hemolytic uremic syndrome (HUS) following renal transplantation. This 3-year-old girl had none of the factors known to contribute to the development of HUS in transplant recipients. This case illustrates the usefulness of renal biopsy in the accurate diagnosis and management of dysfunction in the allograft following renal transplantation.

Wilms tumor and the VATER association.

We describe an infant with the VATER association in whom a Wilms tumor was noted when she was 5 months old. The lower pole tumor arose near the pelvis and grew into an adjacent calix producing a cystic and solid mass with numerous papillary projections resembling sarcoma botryoides. Histopathologically, the tumor was a classical Wilms tumor but it was unusual in that the papillary projections of the tumor were covered by intestinal-like epithelium, which was interpreted as metaplastic urothelium. The margins were free of tumor and the patient is being treated according to the National Wilms Tumor Study Protocol for stage I lesions. She is currently without evidence of recurrence.

Congenital adrenal hypoplasia and selective absence of pituitary luteinizing hormone: a new autosomal recessive syndrome.

Congenital hypoplasia of the adrenal glands (CHA) is a rare condition, particularly in the absence of a central nervous system (CNS) anomaly. Two major types of CHA have been described in the setting of an apparently normal CNS and pituitary: a cytomegalic type usually with X-linked recessive inheritance and a miniature adult type that, when hereditary, is an autosomal recessive trait. Glycerol kinase deficiency (GKD) is an X-linked recessive trait, and it may be associated with CHA and adrenal insufficiency, presumably because of deletion of adjacent X-linked loci. We report on three sibling infants, one male and two females, with normal CNS and lethal CHA of the miniature adult type, selective absence of pituitary LH; two of the infants also had glycerol kinase (GK) activity that was decreased but not in the GKD range. Restriction fragment length polymorphism (RFLP) analysis of X chromosome markers located at Xp21-p22 was carried out on the maternal grandfather, both parents, two of three affected infants, and a living normal brother. The results excluded the X-linked type of this disorder associated with GKD in this family. Autosomal recessive inheritance is most likely.

De novo focal glomerulosclerosis after kidney transplantation.

A transplanted kidney in a patient developed focal and segmental glomerulosclerosis, associated with severe systemic hypertension, proteinuria, progressive azotemia, and allograft hypertrophy. A pediatric kidney with two main arteries was used, and occlusion of the artery supplying the upper pole resulted in infarction of this portion of the allograft. Because other known factors predisposing to focal sclerosis were absent, it is postulated that renal hemodynamic changes associated with reduction in functioning renal mass, attended by striking stimuli for renal hypertrophy, resulted in progressive damage. The implications of these concepts are discussed in relation to the progression of renal diseases.

Cellular antigens in nephroblastoma: identification with monoclonal antibodies which recognize hemopoietic cells.

The correlation between expression of differentiation antigens and morphogenesis was examined in 11 human nephroblastomas using monoclonal antibodies which recognize both hemopoietic and renal cells. Analysis of frozen tissue sections by indirect immunofluorescence revealed that blastema cells and some tubules were recognized by BA-1 and OKB2, which identify unstimulated B cells and granulocytes. Stroma, some tubules, and focal blastema were recognized by BA-2, which identifies a 24-kDa antigen on leukemic cells and platelets. Mature epithelium in glomerular bodies was identified by C3bR and J5, which recognize CR1 and the common acute lymphoblastic leukemia antigen, respectively. Tissue sections from a clear cell sarcoma and a mesoblastic nephroma were notably reactive only with BA-2. These observations demonstrate that the relationship between antigen expression and morphology in nephroblastomas is similar to that observed in fetal kidney and suggest that expression of these cell surface antigens may have a role in morphogenesis.

Direct hyperbilirubinemia and hepatic fibrosis: a new presentation of Jeune syndrome (asphyxiating thoracic dystrophy).

Jeune syndrome (asphyxiating thoracic dystrophy) is an autosomal recessive skeletal dysplasia with multisystem involvement. The disorder is usually considered lethal, with death resulting from respiratory insufficiency during infancy, or from renal failure during childhood. Hepatic dysfunction, diagnosed on the basis of direct hyperbilirubinemia and hepatic fibrosis, led to early diagnosis of Jeune syndrome in a newborn infant. Review of the literature indicates that the specific pathologic lesion (biliary dysgenesis with portal fibrosis and bile duct proliferation) has been observed as an incidental finding at autopsy, but that clinically significant liver dysfunction has not been appreciated as an important manifestation in this disorder. The characteristic histopathologic abnormality has been present in every patient studied, and may advance during infancy; in contrast, clinical liver dysfunction resolves over the first few months of life. Whereas many patients with Jeune syndrome die early, several have survived into adolescence, suggesting that aggressive treatment is appropriate, especially for those with minimal respiratory and renal involvement. Longitudinal evaluation of liver function and pathology in these survivors is needed to define the long-term prognosis.

Systemic amyloidosis complicating cystic fibrosis. A retrospective pathologic study.

A retrospective autopsy study during 1957 to 1983 of patients with clinically documented cystic fibrosis (CF) who were at least 15 years old at the time of death (33 patients) revealed that 11 (33%) had amyloid deposits in multiple organs. The spleen, liver, and kidneys were the principally affected organs, with microscopic deposits mainly restricted to blood vessels. Only one patient had overt clinical manifestations of organ dysfunction secondary to the presence of amyloid. No differences were noted between the groups with (11 patients) and without (22 patients) amyloidosis with respect to age at diagnosis of CF; number, severity, and types of infections; and longevity. Our data demonstrate that amyloidosis is more common in patients with CF than previously reported, and this purported increase parallels the longer life span of these patients. Those patients who are older than 15 years of age constitute the particular group at risk, and they should be evaluated for amyloidosis if unusual clinical findings emerge to suggest it. Clinically evident amyloidosis is uncommon, however, in patients with CF and amyloid deposits at this time. It is likely that clinically relevant amyloidosis will become more of a complicating factor in the future as the life span of these patients continues to increase.

de la Chapelle dysplasia.

Since the description by de la Chapelle and colleagues of two sibs with a unique skeletal dysplasia, two additional cases have occurred, one in the original Finnish family and one sporadic patient born to unrelated parents of Belgian descent. The original Finnish family has later had a fourth child, a normal daughter who was found to be unaffected upon radiographic examination in the 19th week of gestation. These additional findings are compatible with recessive inheritance. Physical features common to these four patients include cleft palate, small thorax, moderately severe micromelia with small hands, and equinovarus deformity. In each case, the ulnae and fibulae were reduced to an almost triangular osseous remnant. Other long bones were short and bowed. Neonatal death occurred in all cases and may be attributed to a consistent triad of respiratory tract malformations: laryngeal stenosis, tracheobronchomalacia, and pulmonary hypoplasia. Clinical and radiographic features are sufficiently unique to distinguish de la Chapelle dysplasia from other disorders in the spectrum of neonatal lethal osteochondrodysplasias. Lacunar halos were identified as a distinctive histopathologic feature also observed in achondrogenesis but not in several other skeletal dysplasias.

Secondary (AA) amyloidosis in cystic fibrosis. A report of three cases.

The authors report the pathologic features of three cases of amyloidosis associated with cystic fibrosis. Renal biopsy led to the diagnosis (case 1) or suspicion (case 2) of amyloidosis in patients who were 23 and 21 years old, respectively. The third patient died at age 22 years, and amyloidosis was not discovered until autopsy. Immunohistochemical staining and potassium-permanganate pretreatment of histologic sections in all three cases provided evidence that the amyloid seen in these patients is of the secondary (AA) type. Congo red staining in each case and electron microscopy in case 1 confirmed the initial diagnosis of amyloidosis. A markedly elevated serum amyloid A protein (160 micrograms/mL; normal less than 1 microgram/mL) in case 1 indicated the presence of large quantities of the precursor protein from which the AA fibrils of secondary amyloid are derived. The kidneys, spleen, and liver contained amyloid deposits in autopsy material from all three cases. Involvement of other organs by amyloid was variable. Review of autopsy material in Boston from 23 additional cystic fibrosis patients with long-term survival did not reveal any evidence of amyloidosis. It appears that secondary amyloidosis is emerging as a significant, although rare, complication of cystic fibrosis as greater numbers of these patients survive into adulthood.