AIDS-associated infections in salivary glands: autopsy survey of 60 cases.

We reviewed the autopsy findings for the submandibular glands of 60 patients with AIDS who were autopsied at the George Washington University Medical Center (Washington, DC) from 1982 to 1992. AIDS-associated infections in the submandibular glands were compared with those in the pancreas and lung. Cytomegalovirus intranuclear inclusions were found in 10 cases, and Pneumocystis carinii infection was found in one case. Disseminated mycobacterial and fungal infections were not identified in the submandibular gland, even in the presence of documented pancreatic and pulmonary infection (P < .05). Overall, the major salivary glands of patients with AIDS are less frequently involved with disseminated opportunistic infections than is either the lung or the pancreas (P < .01 and P < .001, respectively).

Antibody-facilitated macrophage killing of Trypanosoma musculi is an extracellular process as studied in several variations of an in vitro analytical system.

Antibody-facilitated macrophage (MP) destruction of Trypanosoma musculi involves ingestion and intracellular degradation of the parasites. It is likely, however, as we show here, that death of the trypanosomes is extracellular and it is the corpses that are ingested by MPs. We have utilized both peritoneal MPs and a cloned line (WLG 5) of mouse MPs to analyze the killing of T. musculi. Both types of MP were more effective when activated by interferon-gamma (IFN-gamma) rather than lipopolysaccharide (LPS). When activated by both, LPS diminished the killing activity stimulated by IFN-gamma, perhaps by changing the spectrum of lysins/toxins released by the MPs. Nitric oxide (NO) was found to be toxic for T. musculi and to be responsible, in part, for MP killing of the parasites. Although antibody and complement in concert caused lysis of T musculi, complement was not required for MP killing of the parasites. In the course of this investigation, we developed an in vitro system, involving line 5 MPs and plasma from infected mice containing resident parasites, that should prove satisfactory for detailed analyses of the mechanisms of the antibody-dependent, cell-mediated cure of T. musculi infection.

Studies with 1,1'-ethylidenebis(tryptophan), a contaminant associated with L-tryptophan implicated in the eosinophilia-myalgia syndrome.

L-Tryptophan binds to a rat liver nuclear envelope protein, and this binding is saturable, stereospecific, and of high affinity. Utilizing an in vitro assay of [3H]tryptophan binding to rat hepatic nuclear envelopes, we have previously determined that the L-tryptophan obtained from Showa Denko and which was implicated in cases of the eosinophilia-myalgia syndrome (EMS) inhibited [3H]tryptophan binding differently than did control L-tryptophan (not implicated in EMS). Therefore, in this study we investigated whether the addition of 1,1'-ethylidenebis(tryptophan) (EBT), a contaminant or impurity in L-tryptophan implicated in EMS, would have an effect. Our results indicate that EBT alone has little inhibitory binding effect compared with that of control L-tryptophan and that when EBT was added to control L-tryptophan the inhibitory binding effort was similar to that of control L-tryptophan alone. On the other hand, in vitro addition of EBT plus L-tryptophan to nuclei of cultured murine macrophages (WLG5) results in less inhibition of [3H]-tryptophan binding than does addition of L-tryptophan alone. Similar in vitro additions to nuclei of rat brain reveal little effect on binding, as was also the case for hepatic nuclear envelopes. Adding EBT to an in vitro hepatic protein synthesis system and measuring [3H]tryptophan incorporation into acid-precipitable proteins reveal that it competes similarly to that found with equimolar concentrations of unlabeled L-tryptophan. It does not affect [14C]leucine incorporation into proteins. [14C]EBT becomes incorporated in vitro into proteins (acid-precipitable), and this incorporation is diminished in the presence of equimolar concentrations of unlabeled EBT or L-tryptophan. This suggests that EBT or possibly a breakdown product becomes incorporated into proteins. Speculation as to how EBT may affect tissues in experimental animals is presented.

Effect of 3-phenylamino-L-alanine on tryptophan binding to rat hepatic nuclear envelopes.

We have determined that the addition of 3-phenylamino-L-alanine (PAA), a recently reported contaminant in L-tryptophan implicated in the eosinophilia-myalgia syndrome, affects tryptophan binding by utilizing an in vitro measurement of 3H-tryptophan binding to hepatic nuclei or nuclear envelopes. PAA (10(-10) to 10(-4) M) diminishes the inhibitory effect of binding due to excess unlabeled L-tryptophan (10(-4) M). PAA alone has no inhibitory effect on binding. The effect of PAA on in vitro tryptophan binding is in contrast to that of another contaminant, 1,1'-ethylidenebis(tryptophan), which together with excess unlabeled L-tryptophan does not appreciably affect the binding. In vitro addition of PAA and L-tryptophan to nuclei of rat brain or of cultured murine macrophages does not affect [3H]tryptophan binding in comparison to L-tryptophan alone as is the case with hepatic nuclear envelopes. Adding PAA to an in vitro protein synthesis system and measuring [3H]tryptophan or [3H]alanine incorporation into acid-precipitable proteins reveals that it competes similarly, but somewhat less, than does equimolar concentrations of unlabeled L-tryptophan or L-alanine, respectively. This suggests that PAA or a breakdown compound becomes incorporated into proteins. Speculation as to how PAA may affect tissues in experimental animals is presented.

Effect of macrophage source and activation on susceptibility in an age-dependent model of murine hepatitis caused by a phlebovirus, Punta Toro.

The Adames strain of a bunyavirus, Punta Toro virus (PTV), is an hepatotrophic virus that has been described to produce an age-dependent lethal hepatic necrosis in 3-4 week old C57BL/6 mice, but 8 week old mice survive with minimal necrosis. The course of PTV infection in vitro in macrophages derived from these mice served as a model to study the pathogenesis of phlebovirus infection. Peripheral blood monocytes, resident or elicited peritoneal macrophages, and Kupffer cell liver macrophages, as well as hepatocytes, were able to support replication of PTV in vitro to a variable extent. Kupffer cells were the only population of macrophages, however, that expressed an age-related ability to affect viral infection and replication in vitro, suggesting that liver macrophages may have a unique modulatory effect on the occurrence and severity of PTV-induced hepatitis in mice. Whereas PTV showed minimal replication in resident peritoneal macrophages, the virus could replicate effectively in peritoneal macrophages elicited by thioglycolate. Activation of peritoneal macrophages with endotoxin resulted in a significant inhibition of intrinsic PTV replication (p less than 0.001), and a modest extrinsic inhibitory effect on PTV replication in cocultured hepatocytes. Both effects persisted in the presence of anti-interferon. These results indicate that the source and state of activation of macrophage/monocyte populations can influence the course of infection in vitro by the phlebovirus, Punta Toro, and can modulate infection in cocultured target cells.

Herpes simplex virus hepatitis in pregnancy. Two patients successfully treated with acyclovir.

Two cases of herpes simplex virus hepatitis in pregnancy are presented. Each case was characterized by extremely high serum aminotransferase levels with minimal bilirubin elevation. In both cases, liver biopsy was instrumental in arriving at the diagnosis. In addition, computed tomography showed a radiographic appearance of the liver not characteristically seen in other hepatic disorders of pregnancy. A high index of suspicion in the second case led to early recognition and treatment. Despite the presence of fulminant liver failure and evidence of herpes encephalitis in the other case, institution of therapy with acyclovir was associated with complete recovery in both patients. The present cases are compared and contrasted with the literature. The incidence of two cases within a 6-month period suggests that herpes simplex virus hepatitis in pregnancy may occur more frequently than previously reported.

Role of hepatocytes and Kupffer cells in age-dependent murine hepatitis caused by a phlebovirus, Punta Toro.

Punta Toro virus (PTV) infection of C57BL/6 mice results in fulminant hepatic necrosis and death in 3-week-old susceptible mice, but survival with minimal hepatocellular necrosis in 8-week-old resistant mice. Susceptibility in 3-week-old mice is associated with an earlier rise of viral titers in liver and serum than that occurring in 8-week-old resistant mice. There is also an earlier and more rapid accumulation of infectious progeny in serum vs. liver after PTV infection in both age groups, suggesting that the virus may replicate in extrahepatic sites as well as the liver. PTV infection of isolated hepatocytes and Kupffer cells from 3- and 8-week-old mice demonstrates a significant age-related difference in the ability of these cells to support replication of PTV in vitro (P less than 0.05). The age-related difference in liver cell-PTV interaction appears to be an inherent difference in the liver cells themselves, since there are no age-related differences in viral adsorption, morphogenesis, cytopathic effect, or interferon action within these cells. Thus, age-related differences in PTV replication or dissemination at extrahepatic sites, and the ability of the virus to replicate in intrahepatic sites, may be additive factors in the expression of age-related susceptibility to PTV in C57BL/6 mice.

Expression of human immunodeficiency virus long terminal repeat in the human promonocyte cell line U937: effect of endotoxin and cytokines.

Phagocytic macrophages are known to support noncytopathic, chronic infections of human immunodeficiency virus (HIV). Regulation of viral replication in such cells with either chronic low-grade or latent HIV infection is probably influenced by both viral and cellular factors acting on the viral long terminal repeat (LTR). This study identifies naturally occurring biological response modifiers which are able to affect the HIV-LTR linked to the chloramphenicol acetyl transferase (LTR-CAT) gene in a stable transfection of the human promonocyte cell line, U937, in the absence of other viral proteins. In this model system, endotoxin lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) are able to independently stimulate expression of LTR-CAT. Granulocyte/macrophage-colony-stimulating factor can enhance the effect of TNF-alpha or LPS, but other cytokines tested had minimal or no effect on LTR-CAT. In addition to effects on cellular susceptibility and immune function, the ability of naturally occurring factors to affect HIV-LTR in its integrated state may have particular relevance to progression of active disease from latent infection.

Characterization of tumor binding by the IC-21 macrophage cell line.

The purpose of this study was to determine if the SV40-transformed murine macrophage cell line IC-21 is a suitable model to study the selective high avidity binding of tumor cells by subpopulations of activated macrophages. IC-21 macrophages bound P815, RBL5, and EL-4 murine tumor cells with high avidity, as measured by the inverted centrifugation method. Tumor binding by IC-21 macrophages was competitively inhibited by crude membrane vesicles prepared from tumor cells but not by cell membranes prepared from nontransformed splenic leukocytes, suggesting that this process was mediated by tumor-specific binding sites. IC-21 macrophages and primary cultures of pyran copolymer-elicited peritoneal macrophages demonstrated similar tumor binding avidity, kinetics, saturability, and metabolic requirements for optimal high avidity tumor binding. However, compared with primary cultures of pyran copolymer-elicited peritoneal macrophages, IC-21 macrophages bound 4-fold more tumor cells and were more homogeneous for tumor binding capability. Finally, one third of maximal tumor cell binding by IC-21 macrophages was completed within 5 min of contact with tumor, suggesting that IC-21 macrophages constitutively expressed some high avidity tumor binding sites. Their stable and homogeneous capability for binding tumor cells and their ease of growth make the IC-21 macrophage cell line a potentially valuable model for elucidating the molecular mechanisms responsible for selective high avidity tumor binding by subpopulations of activated macrophages.

Functional and structural changes in parotid glands of alcoholic cirrhotic patients.

The parotid gland function and structure was studied in 30 patients with biopsy-proven alcoholic cirrhosis and in 43 age- and sex-matched alcoholic and nonalcoholic control subjects. Mean simulated parotid saliva flow rate was significantly (p less than 0.05) lower in patients with alcoholic cirrhosis as compared with alcoholic and nonalcoholic control subjects. A similar reduction was observed in mean basal parotid saliva flow rate in patients with alcoholic cirrhosis that reached statistical significance (p less than 0.05) in comparison with nonalcoholic control subjects. In addition, the concentration of sodium, bicarbonate, and total proteins in stimulated parotid saliva was significantly (p less than 0.005) lower in patients with alcoholic cirrhosis as compared with the two groups of control subjects. Sialograms in 6 patients with alcoholic cirrhosis did not reveal any obstructive lesion in the primary parotid duct or its branches. Histology of salivary tissue revealed an increase in the interstromal fatty infiltration, edema, and fibrosis without evidence of inflammatory reaction in 5 patients as compared with the control subjects. These data provide evidence for marked parotid gland dysfunction in patients with alcoholic cirrhosis presumably due to metabolic derangement and altered parotid gland structure.

Acute fatty liver of pregnancy. A reassessment based on observations in nine patients.

Acute fatty liver of pregnancy was diagnosed in nine patients over a 10-year period. Eight patients had severe hepatic dysfunction typical for this syndrome and one had subclinical disease but typical hepatic histologic findings. All patients survived with little fetal wastage; all had preeclampsia. Histologic findings included cholestasis, hepatocellular necrosis, and inflammation, as well as microvesicular fat. Histologic findings from biopsy specimens of four of seven patients were initially misinterpreted as hepatitis. This disorder may have both a broad clinical and histologic spectrum; it is probably not rare but often misdiagnosed, perhaps as viral hepatitis. The concurrence of this disorder with toxemia of pregnancy suggests that these entities may be pathophysiologically related.

Chronic liver disease following community-acquired non-A, non-B hepatitis.

Chronic non-A, non-B hepatitis occurring in an urban American population was identified in 23 patients followed for more than six months after the onset of acute hepatitis. Eight of the 23 patients subsequently developed normal aminotransferase levels a mean of 12.3 months after the onset of hepatitis. Liver biopsies were obtained from 9 of the remaining 15 patients. Eight biopsies revealed abnormalities consistent with chronic persistent hepatitis. One revealed chronic active hepatitis. The probable source of hepatitis included blood transfusions in 4%, intravenous drugs in 43%, personal contact in 4%, and no known source in 48%. Normalization of aminotransferase activity could not be predicted by initial symptoms, physical findings, or laboratory values. This study suggests that the chronic liver disease following community-acquired non-A, non-B hepatitis is frequent and may have a benign course.

Achalasia associated with squamous cell carcinoma of the esophagus: a case report.

A case of achalasia associated with squamous cell carcinoma of the esophagus is presented. Microscopic examination of the resected esophagus demonstrated abundant nerve fibers but absent ganglion cells throughout the tumor-involved segment. This finding is believed to be the cause of achalasia in this patient.

Hyperalimentation-associated jaundice: an example of a serum factor inducing cholestasis in rats.

A patient receiving total parenteral nutrition (TPN) at home following emergency resection of the small intestine was studied over a two year interval. Cholestatic jaundice developed after 6 months. A factor in serum was found to produce cholestatic changes in the bile flow of rats on intravenous infusion. Normal human serum and saline infusion did not produce this cholestasis. Endotoxin infusion in the rat produced a similar impairment in bile flow. The hypothesis was proposed that endotoxin might be an occult factor contributing to cholestasis in this case. An antiserum prepared to an endotoxin isolated from a sequestered E. coli infection in this patient, ameliorated the cholestatic effects of the patients' serum in rats. The possible role of endotoxin in the cholestasis of the TPN-induced jaundice in this patient is presented and discussed.

Vitamin A deprivation in hamsters. Correlations between tracheal epithelial morphology and serum/tissue levels of vitamin A.

The effects of vitamin A deprivation on the tracheal epithelium of young hamsters were investigated. Colchicine was administered 6 h prior to death to induce metaphase arrest, thus making it possible to quantify the mitotic rates of basal cells and secretory (mucous) cells in the epithelium. Blood samples were taken from all hamsters, and liver samples from some, in order to measure serum and tissue levels of vitamin A. Age-matched controls were compared with the following groups of hamsters maintained on a vitamin A deficient diet: pre weight plateau animals (those gaining weight), weight plateau-early weight loss animals (those maintaining approximately the same weight for 3 or 4 days, followed in some cases by a loss of weight for 3 or 4 days), and prolonged weight loss animals (those showing a loss of weight for 5 or more days). Four week old hamsters in a pre weight plateau had undetectable amounts of vitamin A in their livers and declining levels in their serum, whereas 4 1/2 week old hamsters still gaining weight had barely detectable levels of vitamin A in their serum. Nevertheless, the tracheal epithelium of these animals was not different from controls in appearance, proportions of different cell types, mitotic rates of secretory and basal cells, or in the number of cells per millimeter of basement membrane (cell density). Vitamin A was undetectable in the serum and livers of hamsters in the weight plateau-early weight loss stage. At this time the tracheal epithelium showed minimal morphological change, with small focal areas of epidermoid metaplasia in some animals. The tracheas of animals in early weight loss were smaller than tracheas in the control group, and there was a trend towards an increase in the number of epithelial cells per millimeter basement membrane. Cell types in the minimally changed epithelium appeared nearly normal, but there was an increase in the proportion of basal cells, and an absence (or near absence) of division in both basal and secretory cells. Tracheal rings from hamsters in the prolonged weight loss stage were lined by a cornifying metaplastic epidermoid epithelium. Our findings demonstrate that barely detectable levels of vitamin A in the serum are sufficient to maintain normal growth and differentiation of hamster tracheal epithelium (late pre weight plateau stage). When vitamin A serum levels fall below detectable limits the animals enter the weight plateau-early weight loss stage. This stage is accompanied by an inhibition of tracheal epithelial cell growth, although nearly normal cellular differentiation is maintained.(ABSTRACT TRUNCATED AT 400 WORDS)

Prevalence and natural history of distal common bile duct stenosis in alcoholic pancreatitis.

Distal common bile duct stenosis was observed in 16 (9%) of 170 alcoholic patients admitted to a Veterans Administration Medical Center in the last five years. The following clinical and biochemical features were significantly more common (P less than 0.05) among the 16 patients with common bile duct stenosis than in 154 without: jaundice, cholangitis, hyperbilirubinemia, alkaline phosphatasemia, pancreatic calcification, and malabsorption. Surgical decompression of biliary tree was necessitated in 13 of 16 cases due to obstructive jaundice in seven, cholangitis in four, portal fibrosis in one, and persistent abdominal pain in one. The mean (+/- SE) time interval between initial serum alkaline phosphatase elevation and surgical intervention was 308 +/- 108 days. Liver histology in eight cases was remarkable for portal fibrosis in seven and biliary cirrhosis in one. These data suggest that distal common bile duct stenosis is a progressive lesion which is quite prevalent in patients with advanced pancreatic disease of alcoholic etiology.

Liver ultrastructure in mitochondrial urea cycle enzyme deficiencies and comparison with Reye's syndrome.

The liver ultrastructural findings in two girls with partial carbamyl phosphate synthetase I (CPS) deficiency and their heterozygote parents and two siblings with ornithine transcarbamylase (OTC) deficiency are described. Liver ultrastructure in the four patients with inherited deficiencies of urea cycle enzymes showed minimal alterations with essentially normal mitochondria when biopsy was performed during periods of good control of their hyperammonemia. Mitochondrial ultrastructure was also essentially normal in the heterozygotes for carbamyl phosphate synthetase I deficiency. These findings are in contrast to the marked alterations in mitochondrial ultrastructure found in the study of two cases of Reye's syndrome in which severe depression of ornithine transcarbamylase and carbamyl phosphate synthetase I activities was noted.