Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.

The roles of liver, kidney, and gut in maintaining fuel homeostasis were studied in 28 patients with severe hepatic cirrhosis, 25 of whom had alcohol-induced cirrhosis. Hepatic, portal, and renal blood flow rates were measured and combined with substrate concentration differences across liver, gut, and kidney to calculate the net flux of free fatty acids, ketone bodies, triglycerides, and glucose with selected glucose precursors, including glycerol, lactate, pyruvate, and amino acids. Data from the catheterization studies were related to hepatic histology, glycogen content, and activities of gluconeogenic enzymes and compared with data obtained from control patients. The effects of food deprivation on net flux of fuels across the liver, gut, and kidney were assessed after overnight and after 3d of fasting. Activities of gluconeogenic enzymes were normal, but hepatic glycogen content was diminished in cirrhotic livers, probably as a consequence of extensive hepatic fibrosis. Extrahepatic splanchnic tissues (gut) had only a small influence on total splanchnic flux rates of carbohydrates, lipids and, amino acids. In cirrhotic patients, there was no mean renal glucose contribution to the bloodstream after an overnight or after a 3-d fast. After an overnight fast hepatic glucose production in patients with cirrhosis was diminished as a result of low-rate glycogenolysis. Hepatic gluconeogenesis and ketogenesis were increased. This pattern of hepatic metabolism mimics that seen in "normal" patients after more advanced stages of starvation. After 3 d of starvation, patients with hepatic cirrhosis have hepatic gluconeogenic and ketogenic profiles comparable to those of normal patients undergoing starvation of similar duration. Nevertheless, the total number of caloric equivalents derived from ketone bodies plus glucose corrected for recycled lactate and pyruvate added to the bloodstream by the cirrhotic livers that could be terminally oxidized by peripheral tissues was less than the contributions made by the normal livers, both after and overnight and after a 3-d fast.

Paramagnetic pyrophosphate. Preliminary studies on magnetic resonance contrast enhancement of acute myocardial infarction.

Ferric pyrophosphate (Fe-PyP) was investigated in an animal model of acute myocardial infarction for its potential to provide contrast enhancement of the peri-infarct zone using magnetic resonance (MR) imaging. Radiotracer studies compared the biodistribution of soluble 59Fe-PyP with 99mTc-PyP in excised tissue samples. Preferential localization of 59Fe-PyP in the peri-infarct zone was found to be similar to 99mTc-PyP. The ratio (percent dose/gram of tissue) at the edge of the infarct to normal tissue was 1.30 +/- 0.16 and 1.44 +/- 0.33 for 99mTc-PyP and 59Fe-PyP, respectively. In initial studies with high doses of the contrast agent, gated T1-weighted MR images of animals with 48-hour-old infarcts were obtained at 15-minute intervals after injection of Fe-PyP at a dose of 350 mg/kg. Contrast enhancement of the infarct zone was observed in all studies and was maximal 15-30 minutes after injection. Signal intensity ratios (infarct/normal) increased from a baseline 1.31 +/- 0.22 to a peak 1.90 +/- 0.57. Studies were then performed with smaller amounts of Fe-PyP. Images obtained with 50 mg/kg Fe-PyP showed contrast enhancement beginning at 60 minutes. Toxicology studies showed primarily respiratory effects, which became significant at doses of 190 mg/kg. These preliminary studies suggest that Fe-PyP potentially could serve as an MR contrast agent to localize and size acute myocardial infarcts; however, its clinical use may be limited by potential toxicity and dose limitations.

Nephrogenic metaplasia of the ureter.

We present what, to our knowledge, is the first reported case of nephrogenic metaplasia of the ureter. Nephrogenic metaplasia involves the transitional epithelium of the urinary tract and results in the formation of epithelial tubules, which are histologically similar to renal tubules. Special stains demonstrated both intracellular and intraluminal mucin. Ultrastructurally, the lesion consisted of epithelial cells with sparse microvilli and a thick basal lamina. The criteria for diagnosis and differentiation from carcinoma are discussed.

The effect of cytosine-arabinoside treatment on the overexpression of c-myc protooncogene in a case of prolymphocytic leukemia.

An unusually high level of expression of the c-myc protooncogene was observed in peripheral blood lymphocytes of a patient with prolymphocytic leukemia (atypical chronic lymphocytic leukemia). The overexpression of c-myc could not be attributed to a high level of proliferating activity of the leukemic cells in the blood. Treatment with cytosine-arabinoside at high doses abolished this altered expression of c-myc and resulted in a twofold increase in the expression of a gene sequence encoding the invariant gamma-chain of class II histocompatibility antigens, preferentially expressed in resting B lymphocytes. These observations suggest that the leukemic cells may have been arrested in the cell cycle outside the G0 phase. Our findings demonstrate that growth-regulated genes can be useful molecular markers of diseases with altered mechanisms of cellular proliferation.

Malignant myoepithelioma of the parotid gland: case report and review of the literature.

A 62-year-old male with a myoepithelioma of the right parotid gland was treated with surgical excision followed by adjuvant radiation therapy. Prior to the completion of radiation therapy, the patient developed progressive disease at local, regional, and distant metastatic sites. Combined modality treatment with radiation and chemotherapy resulted in a significant but transient shrinkage of the tumours at all sites. The patient succumbed to metastatic disease 212 days following the diagnostic biopsy. This case illustrates several of the distinctive clinical and pathological characteristics of this rare tumour.

Crescents in diabetic glomerulopathy. Incidence and clinical significance.

Crescents, defined as any proliferative or fibrous space occupying reaction of the parietal layer of Bowman's capsule, occur as a regular and integral feature of the glomerular changes of diabetes mellitus. The frequency of crescents and adhesions to the capsule increases with increasing total severity of diabetic glomerular and vascular disease in glomeruli with mild-moderate diffuse glomerulosclerosis (GS), severe diffuse GS, and nodular GA. The high frequency (greater than 90 per cent) of crescents and adhesions in glomeruli with exudative lesions is unrelated to over-all severity of diabetic renal disease. The 8.73 per cent of glomeruli with exudative lesions had 45 per cent of the total crescents observed. The mechanism of crescent formation in diabetes is probably similar to the proposed pathogenesis of crescents in other renal diseases. The underlying injury in the glomerular capillaries in diabetes is mainly the "exudative lesion." The percentage of diabetic glomeruli with crescents correlated better with blood urea nitrogen and creatinine that did the percentage of end stage glomeruli (a measure of severity of vascular disease), the percentage of diabetic glomeruli with severe diffuse GS, the percentage of diabetic glomeruli with nodular GS, or the percentage of diabetic glomeruli with exudative lesions. The percentage of diabetic glomeruli with crescents correlated better with severity of vascular disease than did any of the other diabetic glomerular changes. No correlation existed between incidence of crescents and "capsular drops."

Basaloid squamous cell carcinoma of floor of mouth.

BACKGROUND: Only five cases of basaloid squamous cell carcinoma (BSCC), a rare tumor of head and neck, have been reported to involve the floor of mouth. METHODS: Clinicopathologic and immunohistochemical features of eight BSCC of floor of mouth were studied to evaluate the significance of the basaloid features. RESULTS: Five patients were male and three were female. Their mean age was 52 years (range, 39-59). At presentation, one patient was diagnosed with Stage II disease, four were diagnosed with Stage III disease, and three were diagnosed with Stage IV disease. Aside from typical squamous differentiation, each patient had a component of basaloid cells arranged in irregular nests, cords, or pseudoglandular spaces with a brisk mitotic rate, myxoid stroma, and marked tendency for perineural invasion. A panel of immunostains yielded the following results: keratin, +8/8; carcinoembryonic antigen, +3/8; and S-100, chromogranin, and neuron-specific enolase were negative. Mucin stains were negative in all cases. Ultrastructural characterization of three BSCC revealed squamous differentiation of the basaloid cells and a peculiar basal membrane-like material in between them. No neurosecretory granules were present. Seven patients underwent surgery; six of them were also treated with postoperative radiation therapy. In two cases, chemotherapy was added at recurrence. One nonresectable patient received radiation and chemotherapy. At the last follow-up, five patients were dead of disease within 13 months from the diagnosis. One patient died of an unknown cause. Two patients were still alive at the time of this report, 4 and 2 months after treatment. Seven patients had recurrent disease. The authors compared these data with a control group of patients with conventional squamous cell carcinoma (SCC). CONCLUSIONS: The authors' results indicate that BSCC of floor of mouth is an aggressive variant of SCC and is prognostically worse than the conventional SCC, regardless of the grade of the latter.

Cell cycle analysis of human peripheral blood T lymphocytes in long-term culture.

We have studied the cell cycle of resting T lymphocytes from long-term (LT) cultures following stimulation with phytohemagglutinin (PHA) and recombinant Interleukin 2 (IL-2). We examined the kinetics of entry into S phase by autoradiography, the accumulation of cellular RNA by microfluorometric techniques, and ultrastructural morphology by electron microscopy. In addition, we examined the expression at the mRNA level of six cell cycle-dependent growth-regulated genes (c-fos, c-myc, KC-1, JE-3, vimentin, and histone H3). We show that T lymphocytes of LT cultures respond differently to mitogenic stimulation than the T lymphocytes of freshly isolated peripheral blood mononuclear cell cultures. At the ultrastructural, biochemical, and molecular levels, resting T lymphocytes of LT cultures can be distinguished from physiological (G0) lymphocytes of peripheral blood.

The renal disease of thoracic asphyxiant dystrophy.

In those children with thoracic asphyxiant dystrophy, a genetically determined disorder, who survive infancy, the development of renal disease may be life-threatening. This report will present data obtained in six patients from three families which deals with the renal abnormalities in thoracic asphyxiant dystrophy. Both functional and anatomic abnormalities are described. Abnormalities in solute transport in the proximal tubule may be the earliest sign of renal dysfunction in this syndrome. Early glomerular changes may be more important than previously recognized. Finally, the various phenotypic expressions of this disorder are considered.

Pathology of the glomerulus in sickle cell anemia with and without nephrotic syndrome.

Glomeruli from 6 cases of sickle cell disease (SS) with the nephrotic syndrome (NS) were compared histologically and quantitatively with glomeruli from 9 cases of SS, 10 cases of sickle cell trait (SCT), 4 cases of other hemoglobinopathies, all without NS, and normal controls. Five of 6 patients with SS and NS had extensive reduplication of their glomerular basement membranes and mild mesangial proliferation. Similar but milder lesions occurred in SS without NS but not in SCT or controls. Incidental renal disease occurred in 1 patient with SS and NS. Nephrotic syndrome was probably secondary to effects of sickle cell disease. Glomeruli in SS were significantly larger (>70%) than in SCT and controls. Mean total glomerular area per unit area of cortex in SS with normal BUN significantly exceeded that of SCT, which, in turn, was significantly greater than that of controls. Mechanisms for the histologic lesions and hypertrophy of the glomeruli were suggested.

Neuroblastoma as a prominent component of a mixed germ cell tumor of testis.

BACKGROUND: Primitive neuroectodermal tissue in teratomas of testis has been reported in the literature. A mixed germ cell tumor of testis with a prominent neuroblastoma component dictating the clinical behavior was found to be unique. METHODS: Tissue sections were stained with hematoxylin and eosin, and immunohistochemical, ultrastructural, cytogenetic, and flow cytometric analyses were performed on the primitive neuroectodermal component of the testicular mass. Follow-up results at 2.5 years are included. RESULTS: The microscopic findings on hematoxylin and eosin slides showed cells composing the majority of the neoplasm to have features of neuroblastoma. The immunohistochemical stains showed positivity for neuron-specific enolase in the cells comprising the neuroblastoma, and transmission electron microscopic study corroborated these findings by demonstrating microtubules and rare membrane-limited, dense-core granules in the cytoplasm. Flow cytometry showed a hypertetraploid population with a large aneuploid DNA content. Cytogenetics revealed a hypertriploid modal number of 74 chromosomes. The clinical features were dictated by the neuroblastoma component in a fashion similar to that of adult neuroblastomas and responded to the chemotherapeutic regimen designed for treating neuroblastoma. CONCLUSIONS: The neuroblastoma component proved to be more aggressive than the other elements of this neoplasm. This finding suggests that mixed germ cell tumors showing a large neuroblastoma component should be treated promptly and aggressively with chemotherapy.

Quantitative morphometry of glomerulonephritis with crescents. Diagnostic and predictive value.

Histologic patterns in the glomerular tufts in "Glomerulonephritis with many crescents" take three main forms: (1) compression and sclerosis of glomeruli, (2) necrotizing glomerulitis, and (3) proliferation with or without exudation. In the third group, histologic differentiation between patients with poststreptococcal glomerulonephritis with many crescents (AGN) and those with nonstreptococcal rapidly progressive glomerulonephritis (RPGN) may be impossible. In a retrospective study, quantitative morphometry of glomeruli effectively separated three patients with AGN from two patients with RPGN after the usual histologic and electron microscopic observations had failed. Parameters studied were areas of tufts and crescents and total number of cells and granulocytes in tufts and crescents. Surface areas of tufts and crescents were separately determined by photographing glomeruli, projecting and tracing outlines of tufts and crescents, and cutting out and weighing the tracings. The cell density of glomerular tufts (cell per 1000-sq. mum. area) was significantly greater in AGN than in RPGN when either total cell densities (17.64 plus or minus 0.41 versus 13.63 plus or minus 0.30) or total cells minus granulocytes (16.39 plus or minus 0.50 versus 12.99 plus or minus 0.52) were compared. The cell density in the tufts was 120 and 70 per cent greater than controls in AGN and RPGN, respectively. Exudation of inflammatory cells is contributory but not the major cause of hypercellularity in AGN. Follow-up studies with biopsies showed marked resolution in two of three patients with AGN, with normal blood urea nitrogen levels and focal scarring in the third, whereas the two patients with RPGN had either extensive scarring and reduced renal function or required chronic hemodialysis.

Mineralocorticoid and glucocorticoid receptor steroid binding and localization in colonic cells.

In rat colon epithelium glucocorticoids and mineralocorticoids regulate Na transport by binding to distinct receptors and stimulating different pathways. The distribution and intracellular localization of mineralocorticoid (MR) and glucocorticoid (GR) receptors in colonic Na-absorbing surface cells and Cl-secreting crypt cells is unknown. Surface and crypt cells were sequentially isolated from rat distal colon by EDTA chelation and mechanical dissociation. Cell viability was confirmed by trypan blue exclusion and low rates of 2',7'-bis(2-carboxyethyl)-5(6)-carboxylfluorescein leak. Histologic examination, alkaline phosphatase activity, and rates of [3H]leucine incorporation confirmed separation of surface from crypt cells. Scatchard analysis of [3H]aldosterone and [3H]triamcinolone acetonide binding demonstrated that the number of MR decreased from 7,228 +/- 1,067 in surface to 2,299 +/- 434 receptors/cell in crypt cells, whereas the number of GR increased from 20,857 +/- 4,241 in surface to 58,598 +/- 8,207 receptors/cell in crypt cells. The dissociation constants were 2.8 +/- 0.4 nM for the MR and 12 +/- 3 nM for the GR. Indirect immunofluorescence using the specific anti-MR antibody hMRsN and the anti-GR antibody BuGR-2 demonstrated that both unliganded receptors were cytoplasmic and translocated to the nucleus after hormone binding. These data indicate that both surface and crypt cells are potentially responsive to mineralocorticoids and glucocorticoids and that both the MR and GR require hormone for nuclear translocation.

Effects of intravenous versus intraatrial administration of doxorubicin on the function and structure of the heart.

To evaluate the relationship of toxicity of doxorubicin to route of administration, we studied 21 mongrel dogs which were randomly assigned to one of three groups: 1) a control group undergoing intraatrial indwelling catheter placement but no drug therapy; 2) an IV group receiving weekly doxorubicin by peripheral IV bolus administration; and 3) a catheter group receiving weekly doxorubicin through an indwelling intraatrial catheter. After 8 weeks all dogs were evaluated hemodynamically and then sacrificed. Sections of right ventricle were evaluated by light and electron microscopy. Although no hemodynamic alterations were found in any of the three groups, significant ultrastructural damage consistent with doxorubicin cardiac toxicity was demonstrable in four of the six evaluable catheter dogs receiving intraatrial doxorubicin, but in none of the other 13 dogs evaluated. This finding suggests that the intraatrial administration of doxorubicin may lead to cardiac toxicity at a lower cumulative dose than noted with peripheral IV administration.

Combined liver-kidney transplantation in a child with primary hyperoxaluria.

A 3.5-year-old boy presented with end-stage renal disease and bilateral nephrocalcinosis. Renal biopsy demonstrated marked parenchymal calcium oxalate deposition and a diagnosis of primary hyperoxaluria (PH) was made. Following 2 years of hemodialysis he received two renal allografts which were lost at 7 and 11 months, respectively, due to biopsy-proven recurrent oxalosis. Combined liver-kidney transplantation was then performed, after which renal and hepatic function initially stabilized. The patient died on the 28th postoperative day, of infectious complications and progressive respiratory insufficiency. However, comparisons between the patterns of urinary oxalate excretion noted after the isolated renal and liver-kidney transplants indicated that, following the latter, successful biochemical correction of the enzyme defect responsible for type 1 PH had occurred.

Successful heart transplantation in recipients with recent preoperative pulmonary emboli.

Acute pulmonary embolus (less than 6 weeks old) has been considered an absolute contraindication to heart transplantation for fear of the potential problems of lung abscess, empyema, bronchopleural fistula, and systemic sepsis in an immunosuppressed patient. It is difficult to adhere to this principle because 30% to 50% of patients with dilated cardiomyopathy may have an acute pulmonary embolus and would be excluded from transplantation. Several centers have considered such patients for heart transplantation if they are young, on maximal medical therapy, and in extremis. The surgical management of the postoperative pulmonary problems can include bronchoscopy, antibiotics, surgical drainage, decortication, and pulmonary resection with or without muscle flaps. We describe our approach to two such patients who were managed successfully with lobectomies and latissimus dorsi muscle flaps to seal the bronchus and fill the pleural space.

Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy.

Five patients with carcinoma developed thrombotic microangiopathy (characterized by renal insufficiency, microangiopathic hemolytic anemia, and usually thrombocytopenia) after treatment with cisplatin, bleomycin, and a vinca alkaloid. One patient had thrombotic thrombocytopenic purpura, three the hemolytic-uremic syndrome, and one an apparent forme fruste of one of these disorders. Histologic examination of the renal tissue showed evidence of intravascular coagulation, primarily affecting the small arteries, arterioles, and glomeruli. Because each patient was tumor-free or had only a small tumor at the onset of this syndrome, the thrombotic microangiopathy may have been induced by chemotherapy. Diagnosis of this potentially fatal complication may be delayed or missed if renal tissue or the peripheral blood smear is not examined, because renal failure may be ascribed to cisplatin nephrotoxicity and the anemia and thrombocytopenia to drug-induced bone marrow suppression.