Male-sex-ratio trait in Drosophila pseudoobscura: frequency of autosomal aneuploid sperm.

Males with the SR X chromosome show the "sex-ratio" (sr) phenotype in which they produce almost entirely daughters. The few sons (about 1%) are invariably sterile X/O males and result entirely from nullo-XY sperm. The "male-sex-ratio" (msr) phenotype is a modified form of sr in which SR/Y males produce a higher frequency of sterile X/O sons. The msr trait is due to the presence of the SR X-chromosome in males which are also homozygous for one or more autosomes from the L116 strain. Here the frequency of nullo-3 and diplo-3 sperm from msr males was measured by crossing to a compound-3 strain and found to be 13.8% and 3.2%, respectively, of the total viable sperm. The sr males produced very low levels of nullo-3 sperm at a frequency not different from control X/Y males and a slightly elevated frequency of diplo-3 sperm over X/Y males. The msr males were found to have only 12% the fecundity of sr males and in matings to cause a high frequency of brown inviable eggs. These results indicate that high rates of autosomal aneuploidy are not restricted to chromosome 3 but also occur for chromosomes 2, 4 and 5. The overall frequency of autosomal aneuploid sperm is estimated to be approximately 50%. Microscopic studies of meiosis in testes from msr males indicates meiotic nondisjunction and meiotic chromosome loss are responsible for the msr phenotype. Last, microscopic studies of sperm cysts from msr males reveal high levels of spermiogenic failure.

Dysplastic tubular epithelium in "normal" kidney associated with renal cell carcinoma.

Intratubular epithelial dysplasia (IED) of the renal tubules has not been fully described in human renal cell carcinoma (RCC). This lesion has been found in male Syrian hamsters exposed to estrogens. One article reports IED in human kidney showing nephrosclerosis and RCC. We examined "normal" kidney tissue adjacent to 110 cases of RCC in an attempt to identify possible precursor lesions. There were 73 male and 37 female patients (M/F = 2:1). The ages ranged from 27 to 86 years (median 64 years). IED was identified in 30 cases. The lesions consisted of foci of crowded tubular epithelium with large, vesicular nuclei two to three times the size of nuclei of benign tubular cells with eosinophilic macronucleoli. The tubules were occasionally filled with dysplastic cells mimicking carcinoma in situ. The lesions were predominantly cortical and periglomerular. They either were subtle and focal or, less commonly, involved tubules diffusely. Eighteen of the 73 male patients (24%) had these lesions compared with 12 of 37 female patients (32%). They were more usually seen in the clear cell (21 of 66) and sarcomatoid (three of four) variants of RCC than in the oncocytic/granular cell (four of 25) or tubulopapillary (two of 14) variants. One case of collecting duct RCC showed no evidence of IED. Immunohistochemical assessment of 20 dysplastic and 20 nondysplastic lesions with their adjacent RCC for cytokeratin, vimentin, cathepsin-D, and epidermal growth factor receptors was inconclusive. Our findings suggest that IED associated with RCC might represent previously unrecognized precursor lesions along the spectrum ranging from dysplasia to frank carcinoma. The biological significance of these lesions, their preponderance in women, and the phenotypic and genotypic characteristics require further investigation.

Hepatosplenic T-cell lymphoma of alphabeta lineage in a 16-year-old boy presenting with hemolytic anemia and thrombocytopenia.

The authors report an unusual case of peripheral T-cell lymphoma in a 16-year-old boy who presented initially with jaundice, splenomegaly, anemia, and thrombocytopenia. A lymphoma was found subsequently in the spleen, which was infiltrated extensively in the red pulp by medium-sized, blastic-appearing lymphoma cells. Immunologic characterization of these cells revealed positivity for CD3, CD5, CD45RO, CD56, and T-cell intracellular antigen (TIA), and negativity for CD2, CD3, CD4, CD8, CD57, CD34, and terminal deoxynucleotidyl transferase (TdT). Conventional cytogenetic studies revealed the presence of isochromosome 7q. On follow up, this patient deteriorated rapidly, with evidence of liver and bone marrow involvement. Although the overall clinical and pathologic features of this disease were characteristic of hepatosplenic gammadelta T-cell lymphoma, the T-cell receptor of this tumor showed an immunophenotype of alphabeta not gammadelta lineage. Using the Southern blot technique, the authors demonstrated monoclonal gene rearrangement of the T-cell receptor beta-chain. Thus, they confirmed the existence of hepatosplenic alphabeta T-cell lymphoma. In view of its overall similarity to hepatosplenic gammadelta T-cell lymphoma, this unusual entity probably represents a slight biologic variation of the same disease.

Post-transplant lymphoproliferative disorder in renal allograft recipients. Clinical experience and risk factor analysis in a single center.

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of solid organ transplantation. The University of Alberta Renal Transplant Program had not experienced a case of PTLD occurring in the early post-transplant period until March 1989. Since then, 4 patients have developed this complication. To identify the major risk factors for the recent appearance of PTLD, a retrospective analysis was carried out on 162 cadaveric renal transplants performed between July 1987 and December 1990. Four cases of polymorphic PTLD were seen. Two patients presented with fatal disseminated disease. Two others developed PTLD confined to the renal allograft; both are disease free at > 24 months of follow-up. Seventy-two (44.4%) of the cadaveric transplant recipients had received Minnesota antilymphocyte globulin (MALG) induction therapy during the study period. Twenty-four of these also received OKT3 for steroid-resistant rejection. Of the 4 patients with PTLD, 3 had received both MALG induction and OKT3; the remaining patient had received MALG induction only. The incidence of PTLD in the MALG/OKT3 group was 12.5%, which is significantly higher than that of patients receiving other immunosuppressive regimes (0.7%, P = 0.015). The incidence of PTLD was also significantly greater in the 13 patients at risk for primary EBV infection compared to the EBV seropositive patients (23.1 vs. 0.7%, P = 0.002). Only 2 seronegative patients received sequential MALG/OKT3; both developed PTLD. Thus, the population most at risk is that receiving potent antilymphocyte preparations in the setting of primary EBV infection. Allograft involvement with PTLD must be considered in the differential diagnosis of allograft dysfunction, as early diagnosis may permit the successful management of this complication.

Efficacy of lamivudine in chronic hepatitis B patients with active viral replication and decompensated cirrhosis undergoing liver transplantation.

Liver transplantation for endstage hepatitis B virus (HBV) infection has been associated with survival inferior to that of liver transplantation in other chronic liver diseases due to HBV reinfection of the graft. Lamivudine is a new nucleoside analog with potent antiviral effects against hepatitis B. Our aim was to test its efficacy when used pre- and posttransplantation in HBV-DNA positive patients with endstage liver disease. Patients received oral lamivudine 100 mg daily both pretransplant and posttransplant. Viral serology, serum and tissue HBV-DNA and liver histology were assessed sequentially. Five consecutive patients with endstage hepatitis B were entered into the trial. Serum HBV-DNA was cleared pretransplant in all patients. Three of four transplanted patients cleared HBeAg and HBsAg postoperatively, whereas all four became negative for serum HBV-DNA (dot-blot and PCR). Liver biopsies were negative for HBV-DNA by PCR in 3 of 4 cases. Lymphocytes were negative for HBV-DNA by PCR in all cases. With follow-up of 3, 14, 16, and 26 months, two patients have normal liver enzymes and normal liver histology and two have developed recurrent hepatitis B. No significant side effects were seen. This pilot study shows that lamivudine can effectively inhibit hepatitis B virus in cirrhotic patients pretransplant and posttransplant. A lamivudine resistant mutant developed in two patients. Transplant recipients with actively replicating HBV related cirrhosis may achieve a good outcome after liver transplantation using lamivudine, but viral resistance is likely to be a significant problem.

Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora.

The normal intestinal epithelium provides a barrier relatively impermeable to luminal constituents. However, patients with inflammatory bowel disease experience enhanced intestinal permeability that correlates with the degree of injury. IL-10 gene-deficient mice were studied to determine whether increased intestinal permeability occurs as a primary defect before the onset of mucosal inflammation or is secondary to mucosal injury. At 2 weeks of age, IL-10 gene-deficient mice show an increase in ileal and colonic permeability in the absence of any histological injury. This primary permeability defect is associated with increased mucosal secretion of interferon-gamma and tumor necrosis factor-alpha, and does not involve an increase in nitric oxide synthase activity. Colonic permeability remains elevated as inflammation progresses, while ileal permeability normalizes by 6 weeks of age. IL-10 gene-deficient mice raised under germ-free conditions have no inflammation, and demonstrate normal permeability and cytokine levels. This data suggests that the intestinal permeability defect in IL-10 gene-deficient mice occurs due to a dysregulated immune response to normal enteric microflora and, furthermore, this permeability defect exists prior to the development of mucosal inflammation.

Colonic biopsy in verotoxin-induced hemorrhagic colitis and thrombotic thrombocytopenic purpura (TTP).

Sporadic cases and occasional outbreaks of hemorrhagic colitis recently have been associated with the rare Escherichia coli serotype O157:H7, which is now recognized as an important identifiable cause of bloody diarrhea in patients in whom more common gut pathogens cannot be detected. The authors report such a case in a 49-year-old woman who developed thrombotic thrombocytopenic purpura (TTP) and hemorrhagic transverse and descending colitis with a lesion having many of the features of pseudomembranous colitis. While pseudomembrane formation has been described in the hemolytic uremic syndrome (HUS), these features have not, to the authors' knowledge, been described in a patient with hemorrhagic colitis and TTP secondary to a verotoxin-producing serotype of E. coli.

Isolation and characterization of Campylobacter pyloridis from gastric biopsies.

Gastric biopsy specimens were examined microbiologically and histologically for the presence of Campylobacter pyloridis. Of 51 randomly selected patients, 22 (43%) were found to harbor C. pyloridis in the gastric mucosa. The histologic demonstration of spiral organisms observed by staining with hematoxylin and eosin correlated well with microbiologic isolation of the organisms. There was a strong association (95.5%) between C. pyloridis in the gastric mucosa and histologically defined gastritis. However, there was no obvious association between C. pyloridis and ulcers. All C. pyloridis strains isolated exhibited uniform biochemical characteristics and had almost identical protein profiles, which indicated that they belong to a relatively homogeneous group distinct from other Campylobacter species. All C. pyloridis isolates were uniformly susceptible to ampicillin, amoxicillin, cephalothin, gentamicin, kanamycin, tetracycline, coumermycin, ciprofloxacin, novobiocin, clorobiocin, and nitrofurantoin. They were moderately resistant to nalidixic acid.

Effect of diaphragm small-fiber afferent stimulation on ventilation in dogs.

Little is known regarding the role of diaphragm small-fiber afferents (groups III and IV) in the control of breathing. This study was designed to determine whether activation of these afferents with use of capsaicin affects phrenic efferent activity. Capsaicin injections into the phrenic artery were made in 10 alpha-chloralose-anesthetized dogs after each of the following procedures performed in succession: bilateral cervical vagotomy, C7 spinal cord transection, bilateral cervical dorsal rhizotomy. In six of these animals injections were also made after C2 spinal cord transection and removal of the cervical spinal cord. Injections made in the vagotomized animals were associated with apneusis followed by hyperpnea. C7 spinal transection eliminated the hyperpneic response, but the apneusis remained. Cervical dorsal rhizotomy or C2 spinal cord transection failed to abolish the apneusis in response to injection. No diaphragm response was obtained after removal of the cervical spinal cord. Experiments in three additional animals showed that capsaicin does not have a direct excitatory effect on the muscle cells of the crural diaphragm, nor does it potentiate the release of neurotransmitter in the diaphragm. The results of this study indicate that small-fiber afferents in the diaphragm have an excitatory effect on phrenic motoneurons. There is a segmental component to this reflex, since the response is observed after C2 spinal cord transection. The data also suggest that at least some of these afferents enter the spinal cord through the ventral roots.

Malignant fibrous histiocytoma of prostate gland.

The English language medical literature does not contain any definitive reports of malignant fibrous histiocytoma (MFH) arising in the prostate gland. A case of prostatic MFH is described, characterized by rapid local tumor progression and pulmonary metastases. The histologic diagnosis was supported by immunohistochemical and electron microscopic studies.

Synergistic interaction between an H2-receptor antagonist and enprostil on 24-hour intragastric pH, serum gastrin concentration, and tissue immunoperoxidase staining for gastrin, somatostatin, and serotonin in a patient with metastatic gastrinoma.

A 56-year-old woman newly diagnosed as having Zollinger-Ellison syndrome due to a metastatic gastrinoma underwent 24-hour intragastric pH monitoring, serum gastrin (total, G-17 and G-34) measurements, and immunoperoxidase staining of duodenal, antral, and gastric body biopsies for gastrin, somatostatin, and serotonin. Determinations were made while the patient was given different doses of ranitidine, enprostil (a synthetic orally administered prostaglandin E2), or ranitidine plus enprostil. Following are the findings from this single-patient study: Intragastric pH was persistently low but varied in response to food when the patient was given ranitidine. Immunocytochemical staining of antral biopsies obtained before the patient was treated revealed a reduced number of cells containing G-17 and G-34 but an increase in the antral somatostatin-containing D-cells. Treatment with 35 micrograms of enprostil BID plus 300 mg of ranitidine BID for two and 11 weeks was associated with an increased number of duodenal G-cells, a decrease in antral D-cells, and a decrease in the number of antral serotonin-containing cells. Enprostil in a dosage of 35 or 70 micrograms BID had no effect on intragastric pH, but when enprostil was given in combination with ranitidine, postprandial and nocturnal intragastric alkalinity was accentuated along with a return of duodenal and antral G-cells and a loss of the antral D-cell hyperplasia. Optimal pH control was achieved with 300 mg of ranitidine BID; more frequent dosing with ranitidine did not further increase intragastric pH. Both the total serum gastrin concentration and G-17 levels fluctuated in response to meals. The serum concentrations of total gastrin, G-17, and G-34 were reduced with enprostil and with ranitidine.

Enprostil reduces G-cell hyperplasia and hypergastrinemia in duodenal ulcer.

A 42-year-old man with a 26-year history of duodenal ulcer volunteered for a 24-hour intragastric pH monitoring study, at which time his fasting gastrin concentration was found to be elevated. Secretin injection decreased the serum gastrin concentration. When not on treatment his total gastrin, gastrin-17 (G-17), and gastrin-34 (G-34) response to a protein-containing breakfast was marked. Immunocytochemical staining of antral biopsies showed hyperplasia of gastrin-containing cells, more pronounced for G-17 than for G-34. Cimetidine or cimetidine plus pirenzepine increased 24-hour intragastric pH, whereas pirenzepine alone rendered the gastric contents more acidic, particularly overnight. The total serum gastrin concentrations increased after meals and were unaffected by cimetidine or pirenzepine; enprostil, however, reduced the postprandial increase in total gastrin, G-34, and G-17. After six weeks of treatment with enprostil, the number of cells containing G-17 and G-34 was reduced. The findings show that G-cell hyperplasia may occur in the presence of a normal fasting serum gastrin concentration; fasting serum gastrin concentrations may fluctuate widely over time; the food-stimulated increase in G-17 was greater than that for G-34, and is associated with more pronounced antral hyperplasia for G-17 and G-34; and enprostil blunts the postprandial increase in G-17, G-34, and total gastrin. These observations suggest that enprostil may reduce G-cell hyperplasia and hypergastrinemia.

Ecology of depression in late childhood and early adolescence: a profile of daily states and activities.

This study investigated daily states and time use patterns associated with depression. Four hundred eighty-three 5th to 9th graders reported on their experience when signalled by pagers at random times. Depressed youth reported more negative affect and social emotions, lower psychological investment, lower energy, and greater variability in affect. These differences were weaker for 5th and 6th graders, suggesting that self-reported feeling states are a poor indicator of depression prior to adolescence. No differences were found in the daily activities of depressed youths nor in the amount of time spent alone, but depressed youths experienced other people as less friendly and more often reported wanting to be alone, especially when with their families. They also spent less time in public places and more time in their bedrooms. Finally, depressed boys, but not girls, spent much less time with friends, particularly of the same sex, suggesting that social isolation is more strongly associated with depression for boys.

Case report: mesenteric mixed haemangioma and lymphangioma; report of a case with 10 year follow-up after radiation treatment.

A patient with massive mixed haemangioma and lymphangioma of the mesentery first presented in childhood with ascites which subsided spontaneously and, subsequently, at 21 years of age, presented with gastrointestinal bleeding. At laparotomy, the lesion was found to involve 90% of the mesentery and was unresectable due to its bulk. Hence he was treated by radiotherapy (15 Gy/15 fractions/3 weeks followed by a boost of 5 Gy/4 fractions/4 days). He responded to the treatment. 10 years later he again experienced mild gastrointestinal bleeding which subsided spontaneously. This case illustrates the efficacy of radiotherapy in massive mesenteric haemolymphangiomas. Review of the literature revealed that surgical excision, embolization, and radiotherapy have been used in the treatment of haemangiomas and lymphangiomas. In unresectable cases, radiotherapy has a definite role in the management. A variety of doses has been employed in the literature. No definite dose-response relationship was identified.

Graft-versus-host disease after liver transplantation complicated by systemic aspergillosis with pancarditis.

Graft-versus-host disease after liver transplantation complicated by systemic aspergillosis with pancarditis. Can J Gastroenterol 2000;14(7):637-640. Acute graft-versus-host disease (GVHD) is a common complication after bone marrow transplantation, with characteristic rash and diarrhea being the most common features. After liver transplantation, however, this phenomenon is very rare. Most transplant patients are on a variety of medications, including immunosuppressants; therefore, the differential diagnosis of skin rash or diarrhea is broad. A 37-year-old man who underwent liver transplantation for primary biliary cirrhosis, and developed a rash and watery diarrhea, is presented. Skin and colonic biopsies confirmed acute GVHD. A pulse of intravenous steroids was given. The skin rash improved, but he developed pancytopenia. His course was complicated by central line infection, jugular and subclavian vein thrombosis, pseudomembranous colitis, recurrent bacteremia, cholestasis on total parenteral nutrition and cytomegalovirus infection. After the onset of pleuritic chest pain and clinical sepsis, spiral computed tomography scan of his chest and abdomen revealed septic infarcts in multiple organs. Despite empirical treatment with amphotericin B, he died of multiorgan dysfunction syndrome within 72 h. Autopsy revealed systemic aspergillosis with pancarditis, endocardial vegetations, and septic pulmonary, splenic, hepatic and renal infarcts. The pathogenesis and experience with this rare, but often fatal, complication of liver transplantation are reviewed. In contrast to GVHD after bone marrow transplantation, pancytopenia is common and liver dysfunction is rare. One should have a high level of suspicion in the liver transplant recipient presenting with rash and/or diarrhea.

Hemorrhagic intestinal Henoch-Schonlein purpura complicated by cytomegalovirus infection.

A 54-year-old man on hemodialysis for acute chronic renal failure and on corticosteroids for Henoch-Schonlein purpura developed massive hematochezia. After extensive clinical investigation, an ileal bleeding site was identified and surgically removed. Pathological examination of the diseased bowel segment revealed an extensive vasculitis with mucosal ulceration attributable to Henoch-Schonlein purpura as well as florid cytomegalovirus infection.

Immunocytochemical and morphometric studies of gastrin-, somatostatin- and serotonin-producing cells in the stomach and duodenum of patients with acid peptic disorders.

Gastric and duodenal biopsies from 90 patients with various acid peptic disorders-reflux esophagitis (n = 24), gastric ulcer (n = 13), duodenal ulcer (n = 47) and nonulcer dyspepsia (n = 6)-were examined. Seven patients with minimal dyspeptic symptoms and an endoscopically and histologically normal stomach and duodenum served as controls. Immunoperoxidase staining for gastrin-producing G cells, somatostatin-producing D cells and serotonin-producing EC cells was carried out on fundic, antral and duodenal biopsies, and was quantified using a Zeiss MOP Videoplan using the peroxidase-antiperoxidase technique of Sternberger. In the gastric antrum, a G:D:EC cell ratio of approximately 1.6:1:1-was observed. In the duodenum the corresponding ratio was 1:1:2.4. No significant differences were observed within any of the major diagnostic categories. Patient age, sex, duration of symptoms, smoking habits, alcohol consumption and nonsteroidal anti-inflammatory drug use had no effect on endocrine cell densities. Reduced G cell density in the descending duodenum was observed in the presence of mild duodenitis in four patients. In four patients with evidence of antral intestinal metaplastic changes, a significant increase in duodenal G cell densities was found. These results suggest that a change in the number of G, D or EC cells does not play a primary role in the pathophysiology of acid peptic disorders in the majority of patients.

Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity.

Azathioprine is a drug commonly used for the treatment of inflammatory bowel disease, organ transplantation and various autoimmune diseases. Hepatotoxicity is a rare, but important complication of this drug. The cases reported to date can be grouped into three syndromes: hypersensitivity; idiosyncratic cholestatic reaction; and presumed endothelial cell injury with resultant raised portal pressures, venoocclusive disease or peliosis hepatis. The components of azathioprine, 6-mercaptopurine and the imidazole group, may play different roles in the pathogenesis of hepatotoxicity. The strong association with male sex, and perhaps with human leukocyte antigen type, suggests a genetic predisposition of unknown type. Many of the symptoms of hepatotoxicity, such as nausea, abdominal pain and diarrhea, can be nonspecific and can be confused with a flare-up of inflammatory bowel disease. As well, the subtype resulting in portal hypertension can occur without biochemical abnormalities. A 63-year-old man with Crohn's disease who is presented developed the rare idiosyncratic form of azathioprine hepatotoxicity, but also had a severe disabling steroid myopathy, peripheral neuropathy, resultant deep venous thrombosis and pulmonary embolism related to immobility, and a nosocomial pneumonia. His jaundice and liver enzyme levels improved markedly on withdrawal of the drug, returning to almost normal in five weeks. Treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle. Understanding the risks of treatment is the first important step. There must be a low threshold for obtaining liver function tests, especially in men, and alertness to the need to discontinue the drug or perform a liver biopsy should patients on azathioprine develop liver biochemical abnormalities, unexplained hepatomegaly or signs of portal hypertension.

Periarterial fibrosis in the spleen in idiopathic thrombocytopenic purpura.

The characteristic splenic lesion of idiopathic thrombocytopenic purpura (ITP) is said to be enlargement of the Malpighian bodies with the appearance of prominent germinal centers. Twenty-seven spleens therapeutically removed for ITP and 15 control spleens removed for trauma were reviewed. Lymphoid hyperplasia with germinal center formation was found more frequently in spleens with ITP than in the control spleens. In two of the spleens removed for ITP, a peculiar lesion was observed, which consisted of concentric layers of hyalinized material surrounding small arterioles, similar to the vascular "onionskinning" that commonly occurs in the spleens of patients with systemic lupus erythematosus. The clinical histories and laboratory data of these patients did not establish a diagnosis of systemic lupus erythematosus at the time of presentation.

Clear-cell epithelial neoplasms of the large intestine.

We report four cases of primary clear-cell adenoma and adenocarcinoma of the large intestine. The neoplasms grossly resembled ordinary colonic adenomas and adenocarcinomas but microscopically were composed of uniform cells with optically clear cytoplasm. Mucin stains were negative, and the clear nature of the cytoplasm was due to glycogen accumulation. Areas of transition between normal colonic epithelial constituents and the clear-cell lesion were observed. Three of the four cases stained strongly positively for carcinoembryonic antigen. These lesions are apt to give rise to considerable diagnostic confusion and, in particular, resemble metastatic renal cell carcinoma. The usual strong positive carcinoembryonic antigen reaction is helpful in establishing this diagnosis.