Genetic analysis and functional characterization of prothrombins Corpus Christi (Arg382-Cys), Dhahran (Arg271-His), and hypoprothrombinemia.

The structural abnormalities and functional characteristics of dysfunctional prothrombin variants in two new kindreds have been determined. Prothrombin Corpus Christi (family 1) was purified and found to have markedly reduced fibrinogen clotting activity, yet normal amidolytic and near-normal platelet aggregating activity. A transition (C to T) at nucleotide position 8885, present in the heterozygous form in affected family members, resulted in the substitution of Cys for Arg 382. This substitution results in the loss of a positive charge within the fibrinogen-binding exosite of thrombin, thus accounting for the observed functional defect. A heterozygous C to T transition was also present at position 19994 in other family members with a hypoprothrombinemic phenotype. This mutation results in the replacement of Gln 541 (CAA) by a premature stop codon (TAA). Prothrombin Dhahran (family 2) was found to have markedly reduced fibrinogen clotting activity, but normal amidolytic activity. Affected family members were found to have a G to A transition at nucleotide position 7312 resulting in the substitution of His for Arg 271. This substitution results in the abolition of a factor Xa cleavage site, yielding meizothrombin rather than thrombin, on activation of prothrombin Dhahran by factor Xa. All but one of the above mutations occur at CpG dinucleotides, thus further supporting the observation of a high incidence of CpG transitions in hereditary dysprothrombinemia. The significant bleeding tendencies of individuals homozygous for prothrombin Dhahran (prothrombin clotting activity 5% to 7%) contrast sharply with the absence of significant chronic bleeding in the proband expressing prothrombin Corpus Christi (prothrombin clotting activity 2%). Our findings underscore the capacity of thrombin to contribute to clinical hemostasis by mechanisms other than its fibrinogen clotting activity.

Cervical carcinoid ("argyrophil cell" carcinoma) associated with an endocervical adenocarcinoma: a light and ultrastructural study.

On microscopic examination of a cervical carcinoid removed from a 29-year-old woman, foci of endocervical adenocarcinoma in situ (AIS) and severe squamous dysplasia were present immediately adjacent to the invasive carcinoid tumor. Cells of the carcinoid tumor contained abundant intracytoplasmic argyrophilic granules and numerous neurosecretory granules (NSG) on ultrastructural study. Neoplastic cells of the endocervical AIS were devoid of argyrophilic granules and contained no NSGs. The present neoplastic process appeared similar to cases of a "mixed" type neoplasm composed of a carcinoid tumor and an adenocarcinoma, which have been reported from several areas of the body but only once previously from the cervix. The possible mechanisms accounting for such an unusual neoplastic process are discussed.

A pigmented differentiating neuroblastoma: a light and ultrastructural study.

An unusual case of a 4-year-old girl with a differentiating neuroblastoma arising in a thoracic sympathetic ganglion in which the neoplastic cells contained large amounts of melanin is described. Ultrastructural study showed the melanin granules were not associated with premelanosomes but appeared to be of lysosomal origin similar to neuromelanin seen normally in neurons of the substantia nigra and elsewhere in the central and peripheral nervous systems. The melanin in this neoplasm ws ultrastructurally distinct from that demonstrated in other types of pigmented neural crest neoplasms which have been studied ultrastructurally. The melanin in these latter neoplasms has been associated with premelanosomes and appears identical to melanin formed in epidermal melanocytes, so-called cutaneous or neural-crest-type melanin. The ultrastructural findings in this case demonstrate that neuromelanin can occur in melanotic tumors of neural crest origin, although its occurrence is much less common than that of cutaneous (neural crest) melanin.

Infusion tomography and the total body opacification effect: appraisal in the diagnosis of acute cholecystitis.

Clinical and laboratory investigations were performed to test the criteria used in infusion tomography of the gallbladder (ITGB) for the diagnosis of acute cholecystitis. The results demonstrated a 14% incidence of gallbladder wall visualization in 200 patients asymptomatic for gallbladder disease undergoing excretory urography with tomography. The animal investigation showed no significant difference (0.1 less than p less than 0.2) in radiographic results between control (n = 6) and acute cholecystitis (n = 7) groups. Serious questions are raised regarding the clinical reliability of ITGB using currently accepted diagnostic criteria.

The diagnosis and treatment of obstructive jaundice secondary to malignant lymphoma: a problem in multidisciplinary management.

Approximately 1.3% of patients with lymphoma develop obstructive jaundice secondary to lymphomatous involvement of the extrahepatic biliary system. This may occur either as an initial or as a late manifestation of disease. Clinically and radiographically the condition may mimic a variety of more common causes of obstructive jaundice. Surgical exploration may be necessary to confirm the diagnosis, but local radiotherapy would appear to be the preferred mode of treatment. Rapid progression to systemic disease occurs in the majority of patients, necessitating multidrug chemotherapy. Control of jaundice by radiotherapy is good, but long-term prognosis is poor. Supervening sepsis and gastrointestinal bleeding caused the majority of deaths, suggesting that adjunctive nutritional support, immunologic enhancement, and stress ulcer prophylaxis may be necessary if survival is to be improved.

Childhood bronchial mucoepidermoid tumors: a case report and review of the literature.

A bronchial mucoepidermoid tumor in a 13-year-old female was studied by light and electron microscopy. This is the seventh reported case of this rare bronchial neoplasm in a person less than 16 years of age and the only case, in any age group, which has been studied ultrastructurally. All reported cases of bronchial mucoepidermoid tumors in childhood have been histologically of the low grade (well differentiated) variety with a benign clinical course. Although there are histological features which distinguish this lesion from the even rarer bronchial mucous gland adenoma, the clinical features and biological potential of the two lesions in this age group appear to be identical. The optimal surgical therapy for bronchial mucoepidermoid tumors and mucous gland adenomas, when occurring in children, is identical. There must be total removal of either lesion with the sacrifice of as little normal lung as possible. When technically possible, a sleeve resection of the involved bronchus is recommended; however, in most cases, the location of the lesion requires a lobectomy for complete removal.

Primary oat cell carcinoma of the larynx: a case report and review of the literature.

A case of an extrapulmonary oat cell carcinoma arising in the larynx of a 45-year-old male is described. Ultrastructural study demonstrated numerous neurosecretory granules in the tumor cells identical to those described in oat cell carcinomas of the lung. Primary oat cell carcinomas of the larynx are highly malignant neoplasms. Of six previously reported acceptable cases of this rare entity, with adequate followup, all but one has died of tumor within 14 months of diagnosis. The present patient is alive without evidence of tumor 15 months following diagnosis. Aggressive therapy consisting of a combination of surgery, radiation therapy and systemic chemotherapy was utilized in this case. The use of such aggressive combination therapy appears indicated in cases of primary oat cell carcinoma of the larynx if improved survival is to be achieved.

Malignant histiocytosis occurring in patients with acute lymphocytic leukemia.

Five cases of malignant histiocytosis (MH) in patients being treated for acute lymphocytic leukemia (ALL) have been previously reported. Two additional cases are described here, all known cases are reviewed, and the phenomenon is discussed. The most tenable explanation for this phenomenon appears to be that ALL and MH may have been interrelated in these patients with both diseases originating from a common stem cell.

Treatment of autologous immune complex glomerulonephritis with vasoactive amine antagonists.

AIC nephritis produced in rats by a single injection of FxIA in CFA was treated by agents with known antihistamine and antiserotonin activity. The effect of this drug regimen in altering the deposition of Ag-Ab complexes in the glomerulus was assessed by light, immunofluorescent, and electron microscopy. The vasoactive amine antagonists Chlortrimeton, Vistaril, Azatadine, and Sansert, when given singly or in combinations which completely abrogated histamine and serotonin-induced skin wheal formation, were unsuccessful at reducing apparent glomerular deposition of the circulating immune complexes of AIC nephritis.

Pulmonary venoocclusive disease: case report and review of the literature.

A fatal case of pulmonary venoocclusive disease in a 4-year-old boy is reported, with emphasis on the radiologic features of this condition. The disease is characterized by fibrous intimal obliteration of the lumina of small pulmonary veins and venules leading to severe secondary pulmonary arterial hypertension. The clinical picture is usually indistinguishable from that of other forms of pulmonary arterial hypertnesion, but radiologic features of postcapillary pulmonary hypertension, in conjunction with a normal venoocclusive disease. The diagnosis is definitively established by lung biopsy.

Glomerulonephritis mediated by antibody to glomerular basement membrane. Immunological, clinical, and histopathological characteristics.

A prospective study was undertaken to establish the incidence of glomerular basement membrane (GBM) antibody-mediated glomerulonephritis and its histopathological characteristics in a clinical group of patients presenting with renal disease. Biopsies from 43 of 409 consecutive patients technically satisfactory for direct immunofluorescent (IF) examination had diffuse and generalized linear localization of host immunoglobulin (Ig); two other badly scarred kidneys tested negative to IF although GBM antibodies were eluted. Confirmatory evidence of GBM antibody-mediated disease in these patients came from whole kidney or biopsy elutions (15 patients), serologic assays for circulating GBM antibodies by indirect IF (9 of 38 patients), radioimmunoassay (26 of 34), and hemagglutination (31 of 32). Although sera were not tested from six patients, circulating antibodies were demonstrated by some test in 36 of 39 of the remainder. Histologically, half of the patients had minor and nonspecific glomerular abnormalities or mild focal proliferative glomerulonephritis. More severely involved kidneys had focal necrotizing (17%), rapidly progressive (7%), and chronic, usually sclerosing, glomerulonephritis (27%). Clinical courses of these patients comparably were quite variable, ranging from indolent microhematuria and/or gross hematuric bouts to progressive renal failure; nephrotic syndrome was observed in 11 patients. GBM antibody-mediated glomerulonephritis may be a relatively mild disease with apparently stable renal function, although 16 patients have experienced functional deterioration, and 11 have progressed to dialysis, renal transplantation, or death.

Immunopathologic findings in idiopathic renal hematuria.

Eighty patients had idiopathic renal hematuria and normal renal function. Renal biopsy showed minimal changes or focal glomerulonephritis in two thirds of the patients. The remainder exhibited diffuse proliferative glomerulonephritis and included nine patients with segmental glomerular sclerosis. Electron microscopy disclosed alterations of the capillary loop in 23 biopsy specimens and electron-dense deposits in 11. Immunofluorescent microscopy identified glomerular-bound immunoglobulins, C3, or fibrinogen in 58% in a generalized distribution. IgG was the immunoglobulin seen most commonly. IgA and IgM were present in 14 and 13 biopsy specimens, respectively. These findings suggest that idiopathic renal hematuria is a clinical syndrome rather than a single disease with varying underlying renal findings. Both immunologic and nonimmunologic mechanisms may be involved, and the prognosis is favorable even in patients followed up for 11 years.