Postmortem DNA diagnosis of factor V Leiden in a neonate with systemic thrombosis and probable antithrombin deficiency.

BACKGROUND: Spontaneous neonatal thrombosis due to heritable gene defects has been reported in the past. A recently discovered defect, the factor V Leiden mutation, is the most frequent inherited risk factor for venous thrombosis. CASE: Factor V Leiden was diagnosed postmortem in a neonate who died from complications of vena caval and aortic thrombosis. Investigation into the family history revealed that the father had a record of multiple thromboses, and blood testing demonstrated that the father had antithrombin deficiency and the mother was heterozygous for factor V Leiden. Although we were unable to demonstrate directly the presence of antithrombin deficiency in the infant, we propose that a combination of the two inherited disorders was likely the cause of fatal neonatal thrombosis. CONCLUSION: The present report highlights the importance of a complete prenatal genetic analysis, including factor V Leiden testing and antithrombin measurement in families with a history of thrombotic disorders.

Diffuse renal cystic disease in children: morphologic and genetic correlations.

During a 5-year period, we evaluated seven infants and two fetuses who presented with enlarged, hyperechoic kidneys. In each, the initial clinical diagnosis was autosomal recessive polycystic kidney disease (ARPKD). Among the seven unrelated infants were three Caucasian and four African-American infants. No syndromic stigmata were evident in any of these infants. At the time of the initial evaluation, the family data were incomplete for four infants. The two fetuses were presumed to be at-risk for ARPKD based on the diagnosis in previous siblings. Renal histopathology was evaluated in all nine cases and revealed a spectrum of cystic disease ranging from ARPKD to glomerulocystic kidney disease to autosomal dominant polycystic kidney disease to diffuse cystic dysplasia. In the eight cases for whom liver histopathology was available, varying degrees of biliary dysgenesis were evident. We present a detailed analysis of the key histopathological features in each case and discuss the histopathological findings in an embryological context. In addition, we address the current role of molecular genetics in the diagnostic evaluation.

Fas ligand gene transfer to renal allografts in rats: effects on allograft survival.

BACKGROUND: Fas ligand (FasL) induces apoptosis of cells bearing its receptor Fas, and has been shown to be important in T-cell development and regulation and in immune privilege. We hypothesized that FasL expression by renal allografts might provide protection from rejection. METHODS: The murine FasL cDNA was cloned into a replication-defective adenovirus (AdV-FasL). Protein expression was confirmed by immunostaining of AdV-FasL-transduced HeLa cells. Allogeneic kidney transplants were performed between WF (RT1u) donors and Lewis (RT1) recipients. Donor kidneys were perfused in situ with saline alone (control), or 9 x 10(9) plaque-forming units of AdV-FasL. One native kidney was removed at the time of transplant and the other at 6 or 7 days. Uremic death was the endpoint, and deaths within 7 days of transplant were excluded. Transduced allografts were stained for FasL expression using a monoclonal antibody and tested for FasL mRNA production by reverse transcriptase-polymerase chain reaction and Northern blotting. RESULTS: Immunostaining of AdV-FasL-transduced allografts demonstrated efficient gene transfer lasting approximately 2 weeks, and FasL mRNA production in the AdV-FasL-transduced allografts was confirmed by Northern blotting and reverse transcriptase-polymerase chain reaction. Mean survival of animals with AdV-FasL-transduced renal allografts was 27.8 days vs. 11.6 days in control animals (P < 0.05). CONCLUSIONS: (1) Adenoviral vectors can successfully transduce rat kidneys with the FasL cDNA. (2) FasL gene transfer prolongs rat renal allograft survival.

Eosinophilic explant carditis with eosinophilia: ?Hypersensitivity to dobutamine infusion.

BACKGROUND: Eosinophilic carditis with peripheral eosinophilia has been observed in a number of clinical situations. This report describes this association in patients undergoing heart transplantation and offers a possible explanation. METHODS: The clinical records and explanted hearts of 31 consecutive patients who received primary orthotopic heart transplants were reviewed. Clinical features particularly analyzed included the following: age, cardiac status and assistance devices, catheterizations, medical or surgical disorders including parasites, tryptophane exposure, medications, and peripheral blood counts. Pathologic features particularly studied included the following: dilatation and hypertrophy, fibrosis, mural thrombi, carditis, eosinophils, myocardial necrosis, vasculitis, valvular disease, and coronary artery disease. Prior endomyocardial biopsy specimens were also reviewed. RESULTS: Seven patients had eosinophilic carditis compatible with hypersensitivity carditis. Eight had eosinophilia. All patients with carditis received intravenous dobutamine (Dobutrex solution) continuously for more than 1 month immediately preceding transplantation. All patients with eosinophilia received intravenous dobutamine continuously for 15 days or longer and exhibited eosinophilia only during dobutamine therapy with the exception of one patient in whom eosinophilia was observed 8 days after cessation of 8 days of therapy. Among 13 patients who received dobutamine for more than a month immediately before transplantation, nine had eosinophilic carditis, peripheral eosinophilia, or both. CONCLUSIONS: Prolonged continuous intravenous administration of dobutamine was associated with eosinophilic carditis and eosinophilia. No other clinical factor with a relationship to either eosinophilia or carditis was identified. The responsible agent may have been a preservative in the dobutamine solution, sodium bisulfite.

Diffuse mesangial sclerosis in a fetus.

An 18-week fetus was born following termination of pregnancy by prostaglandin induction. Pregnancy was terminated because of elevated maternal serum alpha-fetoprotein and ultrasonographic evidence of severe oligohydramnios, intrauterine growth retardation, non-visualization of the bladder, dolichocephaly and possible mild hydrocephalus. Pathologic examination disclosed diffuse mesangial sclerosis and histologic evidence of the nephrotic syndrome. To our knowledge this is the first reported example of ante-natal diffuse mesangial sclerosis; of fetal congenital nephrosis other than Finnish type; and of fetal congenital nephrosis with prominent glomerular lesions.

Renal allografts in cystinosis and mesangial demography.

Twenty-four biopsies of generally cadaveric renal allografts from 20 patients with cystinosis were examined by light, polarization, phase contrast and electron microscopy. Cystine crystals, or cytoplasmic crystalline spaces compatible with cystine, were observed in interstitial cells in 23 of the 24 biopsies and in glomeruli in six. Among the six, crystalline spaces were identified by electron microscopy in cells compatible with macrophages in the mesangium in two, and, in one of the latter, dark, presumably cystine-containing cells were also present in the mesangium. On the premise that cystine-containing cells derive from the host, these findings support the thesis that in man cells of the mononuclear phagocyte system of extrarenal origin may exist in the mesangium. However, in comparison with infiltration of the interstitium, infiltration of the glomerulus by macrophages from extrarenal sources is scant, as studied under conditions of renal transplantation.

Dark cells of cystinosis: occurrence in renal allografts.

Twenty-four biopsies of renal allografts, generally cadaveric, from 20 patients with cystinosis were examined by light, polarization, phase contrast, and electron microscopy. The unusual dark cells previously reported in the native kidneys and livers of patients with cystinosis were observed in 12 of the 24 biopsies. The cells were present in the interstitium in all of these 12 biopsies, in glomeruli in one biopsy, and in the tubular lumen in two biopsies. They were evident by light and electron microscopy in stained and unstained ultrathin sections, and could be discerned solely in Epon sections. The dark appearance resulted from the presence of dark, fine granular material in the cytoplasm and nucleus and in cytoplasmic inclusions. The cells were judged to be macrophages. They were present as early as 3 months following transplantation and bore no relationship to interstitial crystals or inflammation. The dark cells have two important implications: cystine storage may not be limited to lysosomes, and dark cells are a morphologic alternative to the traditional identifying configuration of cystine in tissues, namely crystals.

47,XXX chromosome constitution, ovarian dysgenesis, and genito-urinary malformation.

We describe the second known reported fetus with 47,XXX chromosome constitution and ovarian dysgenesis, in this instance with an unusual urinary tract malformation, nonimmune fetal ascites and meconium peritonitis.

DMSO potentiates aminonucleoside of puromycin nephrosis in rats.

Dimethyl sulphoxide (DMSO), 3 g/kg body weight, administered daily by the intraperitoneal route, potentiated the proteinuria and formation of tubular casts in aminonucleoside of puromycin (PA) induced nephrosis in Sprague-Dawley rats. The effect was evident at 4 as well as 8-9 days following PA administration. In the absence of PA, DMSO did not induce proteinuria or cast formation. The mechanism by which DMSO enhanced proteinuria and cast formation is not known.

Prenatal diagnosis of cystinosis utilizing chorionic villus sampling.

The prenatal diagnosis of cystinosis is currently based on the increased amount of free-cystine present in amniotic fluid cells. Amniocyte cultures must be grown for at least 2 weeks to obtain sufficient cells for such measurements. Thus, the diagnosis cannot be made until close to 20 weeks gestational age by this method. We report a case in which chorionic villi were used for direct cystine measurement resulting in the in utero diagnosis of cystinosis at 9 weeks gestational age. The diagnosis was confirmed by the study of cultured chorionic villus cells, and of the 10-week abortus.

Bilateral pulmonary agenesis and microphthalmia.

We describe a stillborn boy with bilateral pulmonary agenesis associated with bilateral microphthalmia. The diagnosis defied antenatal ultrasonography and M-mode echocardiography. There were associated absence of bronchi, pleural cavities, pulmonary arteries, and veins; overriding of the aorta with high ventricular septal defect; a nodular vestige of the main pulmonary artery; and eventration of the left hemidiaphragm. The brain was normal to gross examination. Karyotype was 46,XY. Bilateral pulmonary agenesis is rare, this being only the third known case associated with deficiency of ocular tissue and the first such case in conjunction with a brain of normal gross structure. The cause is unknown.

Effect of adrenalectomy on the pancreas of db/db mice.

Adrenalectomy has been performed in the diabetic mouse and the islet immunohistochemistry studied. Adrenalectomy restored blood glucose to normal. Mean islet size of diabetic animals was larger than that of either adrenalectomized diabetic animals or of lean controls. Adrenalectomy restored the immunohistochemical appearance of the islets to normal when examined with anti-insulin, anti-glucagon and anti-somatostatin antisera.

Fetal gonadoblastoid testicular dysplasia.

The case of a 950-g male infant born at 28 weeks of gestation with bilateral gonadoblastoma-like testicular lesions who lived for one hour is presented. The infant had a 46, XY karyotype and multiple congenital anomalies.

The pancreas in the degu.

Unique alpha-cell crystals, a herpes-like virus, islet amyloidosis, and immunohistochemical reactions of islets are compared in the rodent, Octodon degus, in animals with ordinary and high circulating glucose levels. Results suggest that crystals, virus, and amyloid are independent of blood sugar and bear no obvious relation to one another, although each is more common in older than in young animals. The crystals do not react with anti-glucagon. In the presence of high blood glucose, qualitative histochemical studies demonstrated diminished islet insulin and an unusual reaction with anti-somatostatin: (1) paucity of the usual cells that stain darkly for somatostatin and (2) striking staining of intermediate hue in most islet cells and in (3) multitudes of cell nests in exocrine parenchyma. The intermediate staining reaction may represent a visible demonstration of the paracrine phenomenon.

Focal renal cortical necrosis associated with zomepirac.

Anaphylactoid shock, disseminated intravascular coagulation, and anuric renal failure requiring dialysis occurred in a patient receiving zomepirac sodium for toothache. Although renal function showed gradual improvement after seven days of anuria, the recovery was slow and incomplete. Renal biopsy three weeks after the onset of renal failure revealed evidence of focal renal cortical necrosis. Association of zomepirac administration with renal cortical necrosis is not known to have been previously demonstrated. This observation adds another dimension to the previously reported renal complications of nonsteroidal anti-inflammatory agents, especially zomepirac. The proportions of lymphocyte subsets, as defined with monoclonal antibodies, and the proliferative response to mitogens were normal. The patient's lymphocytes showed no proliferative response to zomepirac. Serum complement components and immunoglobulin levels were within normal limits, and radioallergosorbent testing gave negative results. The mechanism of anaphylactoid reaction to zomepirac in this case, therefore, remains unclear.

Hereditary nephritis (Alport's syndrome)-1983.

In the 81 years that have passed since the first description of the pedigree ultimately augmented by Alport, and in the 56 years since the latter description, insight into the pathogenesis of lethal familial hematuria has been limited. Work during the past decade has focused on the antigenic and chemical composition of the glomerular basement membrane. It is ever more likely that lethal familial hematuria of Alport type is a genetically heterogeneous phenotype.