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Biomedical subjects

A S Mills

Publications and source records attributed to A S Mills.

At least 19 recordsLinked to original sources
PubMed1995

A novel cis-acting element in a liver cytochrome P450 3A gene confers synergistic induction by glucocorticoids plus antiglucocorticoids.

The induction by dexamethasone of rat liver CYP3A1 differs from classical glucocorticoid gene regulation in part because both glucocorticoids and antiglucocorticoids such as pregnenolone 16 alpha-carbonitrile (PCN) induce CYP3A1 through transcriptional gene activation. In the present study, we transiently expressed in primary cultures of rat hepatocytes plasmids consisting of CYP3A1 5'-flanking sequences fused to a chloramphenicol acetyltransferase reporter plasmid. Deletional analysis identified a 78-base pair (bp) element located approximately 135 bp upstream of the transcriptional start site that was inducible by treatment of the cultures with dexamethasone or PCN and was induced synergistically by dexamethasone plus PCN. Nuclear extract from control rat liver protected two regions within the 78-bp sequence against digestion with DNase I. The same two regions were protected when nuclear extracts from dexamethasone-treated animals were used. Analysis of both of the "footprints" (FP1 and FP2) failed to reveal a classical sequence for the glucocorticoid-responsive element. A 33-bp element that includes FP1 sequences inserted into the chloramphenicol acetyltransferase reporter plasmid and transiently expressed in rat hepatocytes conferred a profile of dexamethasone and PCN induction similar to that of the 78-bp element. However, an Escherichia coli expressed glucocorticoid receptor protein failed to protect sequences within FP1 in DNase I footprinting experiments and failed to change its mobility in gel shift assays. Moreover, as judged by the gel shift assay, the specific protein binding to this fragment was the same whether nuclear extracts from the liver of untreated or dexamethasone-treated rats were used. We conclude that the activation of CYP3A1 gene transcription by glucocorticoids may involve proteins already bound to the controlling element in the CYP3A1 gene through a mechanism in which GR in the presence of hormone does not bind directly to CYP3A1 DNA.

Animals↗
PubMed1994

Biochemical and histologic evaluation of recurrent hepatitis C following orthotopic liver transplantation.

It is well recognized that hepatitis recurs in virtually all patients who undergo orthotopic liver transplantation for cirrhosis secondary to chronic hepatitis C (HCV). The present report describes the biochemical and histologic findings of recurrent hepatitis in 25 such patients. One patient was found to have hepatocellular carcinoma at the time of OLT and was excluded from further analysis. All post-OLT laboratory values were reviewed. Liver biopsies were performed on protocol 6, 12, 24, and 36 months following OLT. Additional biopsies were performed as necessary to evaluate abnormalities in serum liver chemistries. A total of 104 biopsies was obtained; hepatitis consistent with recurrent HCV was present in 68 (65%). Other biopsy findings included cytomegalovirus hepatitis; acute, chronic, or resolving rejection; cholestasis with or without an underlying hepatitis; steatosis, and centrilobular necrosis. Histologic hepatitis appeared in all patients within 12 months following OLT. Despite these histologic findings, serum ALT was normal for prolonged periods in over 50% of such patients. In all cases this hepatitis was mild and did not progress over a mean follow-up of 22 months (maximum 44 months), as judged by Knodell histologic activity score (mean score: 4.0 +/- 0.3). Five patients developed cholestatic jaundice, far out of proportion to the degree of histologic hepatitis. In 2 patients this was secondary to chronic rejection. The other 3 patients had drug-induced cholestasis that resolved after various medications were discontinued. HCV did not contribute to graft dysfunction in any of the 24 patients. To date, our data suggest that post-OLT hepatitis in patients with preexisting HCV is a relatively benign process. Severe cholestatic jaundice in such patients is not secondary to HCV, and should stimulate a search for other possible causes of graft dysfunction. The long-term consequences of recurrent HCV following hepatic transplantation remain to be determined.

Adult↗
PubMed1994

Hepatic lidocaine metabolism and liver histology in patients with chronic hepatitis and cirrhosis.

Recent advances in the medical and surgical treatment of chronic hepatitis and cirrhosis have made it increasingly important to develop noninvasive tests of liver function. Our study has evaluated the hepatic conversion of lidocaine to its primary metabolite monoethylglycinexylodide and compared this with liver histological findings in 225 patients with chronic hepatitis (161 with hepatitis C, 23 with hepatitis B, 21 with autoimmune hepatitis and 20 with cryptogenic hepatitis). One hundred seven (47.7%) patients had cirrhosis at the time of evaluation. A decline in monoethylglycinexylodide production was observed with worsening liver histological conditions from a mean of 81.5 +/- 7.0 ng/ml in patients with chronic persistent hepatitis to 61.2 +/- 5.5 ng/ml for chronic active hepatitis and 20.9 +/- 1.5 ng/ml in patients with cirrhosis (p < 0.05). A further stepwise decline in monoethylglycine xylodide production was observed with worsening Child class: from 25.5 +/- 2.2 ng/ml for class A patients to 8.9 +/- 1.4 ng/ml for patients with Child class C disease (p < 0.05). All patients with monoethylglycinexylodide production less than 20 ng/ml had cirrhosis confirmed on histological examination. In contrast, no relationship was observed between liver histological status and serum transaminases (AST or ALT), bilirubin, albumin and prothrombin time. Thirty-five patients underwent repeat histological evaluation and monoethylglycinexylodide testing after receiving at least 6 mo treatment for chronic hepatitis (interferon for hepatitis B and C and corticosteroids for autoimmune hepatitis). The change in monoethylglycinexylodide production observed in these patients was a linear function of the change in Knodell histological index (r = 0.73, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Collagen production by human smooth muscle cells isolated during intestinal organogenesis.

The extracellular matrix influences organogenesis by modulating cell behavior. In humans, collagen is the major matrix constituent of the adult intestinal wall and is synthesized by smooth muscle cells. The objective of the current study was to examine collagen production by fetal human intestinal smooth muscle cells isolated during intestinal morphogenesis. Techniques were developed for the isolation and culture of human fetal intestinal smooth muscle cells. The cultured cells were confirmed as muscle by immunohistochemical stains for cytoskeletal filaments and documentation of contractile behavior. In culture, these cells stained for mesenchymal and muscle cytoskeletal proteins: vimentin, actin, and desmin, and did not stain for neural or epithelial markers. The muscle cells contracted in response to acetylcholine, in contrast to human fetal dermal fibroblasts which did not contract appreciably. Collagen production was assayed by the uptake of [3H]-proline into collagenase-digestible protein. Collagen production was greatest at 11 weeks gestation, the youngest age studied. By 20 weeks gestation, collagen production had decreased to adult levels. However, when compared to another matrix-producing fetal mesenchymal cell, the dermal fibroblast, intestinal smooth muscle cells produced twice as much collagen. Collagen types were determined by polyacrylamide slab gel electrophoresis. Smooth muscle cells predominantly produced types I and III collagen alpha chains. Therefore, collagen production is a significant function of human fetal intestinal smooth muscle cells, and probably plays a major role in the development of intestinal structure. The in vitro model presented here provides a means of studying the regulation of this collagen production throughout intestinal organogenesis.

Collagen↗
PubMed1991

Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat.

The protective effect of ursodeoxycholate conjugates against bile salt hepatotoxicity was studied in chronic bile fistula rats. Taurochenodeoxycholate or taurodeoxycholate, infused intraduodenally at 24 or 16 mumols/100 g rat per hour, respectively, caused cholestasis and severe hepatocellular necrosis within 8 hours. In contrast, tauroursodeoxycholate or taurocholate at 48 mumols/100 g rat per hour were choleretic. Tauroursodeoxycholate was not hepatotoxic, whereas taurocholate produced moderate hepatocellular necrosis. Simultaneous infusion of tauroursodeoxycholate to rats receiving taurochenoxycholate or taurodeoxycholate preserved bile flow and ameliorated hepatic injury in a dose-dependent manner. Tauroursodeoxycholate protected equally by intravenous and intraduodenal routes. Intravenous glycoursodeoxycholate also was protective. The hydrophobicity index of infused bile salts correlated well with their toxicity. Concurrent administration of ursodeoxycholate conjugates did not reduce biliary recovery of intraduodenally infused [24-14C]-taurocholate. Biliary alkaline phosphatase secretion was stimulated by infusion of taurocholate, taurodeoxycholate, or taurochenodeoxycholate; simultaneous infusion of ursodeoxycholate conjugates failed to prevent this increase. We conclude that ursodeoxycholate counteracts hepatoxicity of more hydrophobic bile salts via a direct effect at the level of the liver.

Animals↗
PubMed1990

Liver transplantation in Virginia.

Survival rates ranging from 70-80% have been documented over the past three years in liver transplant patients at the Medical College of Virginia. Survival declined in patients with numerous complications of chronic liver disease and with significant deterioration in hepatic synthetic function. Early referral was a major factor contributing to survival.

Adult↗
PubMed1989

Eosinophils in skin lesions of erythema multiforme.

To investigate the controversy regarding the presence of eosinophils in skin lesions of erythema multiforme, we undertook a retrospective clinicopathologic study of 19 recent cases that fulfilled clinical and histopathologic criteria for the disease. At least a few eosinophils were observed in 13 of 19 cases, and in four cases there were more than three per high-power field, qualifying as "tissue eosinophilia." Immunofluorescence studies in three cases with eosinophils failed to show the linear basement membrane zone fluorescence characteristic of bullous pemphigoid. Giemsa stains revealed that mast cells were present in lesions both with and without eosinophils. The only clinical features that distinguished patients with tissue eosinophilia from those without were an older age of incidence and a longer duration of disease prior to biopsy. Drugs were implicated as a causative factor in some patients both with and without eosinophils, but all four patients with tissue eosinophilia were believed to have drug-induced disease. We conclude that eosinophils do occur in skin lesions of erythema multiforme and are occasionally numerous.

Adult↗
PubMed1988

Fatal hepatic necrosis associated with parenteral gold therapy.

Two young black male patients with seronegative rheumatoid arthritis and treated with nonsteroidal antiinflammatory agents developed fulminant hepatic necrosis following the institution of parenteral gold therapy. These cases, reported from different institutions, may represent a severe form of idiosyncratic gold hepatonecrosis. Awareness of the possible association between gold therapy and severe hepatic injury may become increasingly important as oral gold preparations become widely available.

Adult↗
PubMed1988

Use of phorbol-12,13-dibutyrate as a mitogen in the cytogenetic analysis of tumors with low mitotic indexes.

Solid tumors, particularly those involving the colon, breast, and lung, are the most common tumors in humans. However, many technical difficulties exist in obtaining analyzable chromosomes from these tumors, including the inability to stimulate cell division. Phorbol-12,13-dibutyrate (PDBu) is a tumor promoter that activates a variety of cellular responses, including proliferation. Using flow cytometry, we have demonstrated that PDBu acts as a mitogen in primary cultures of colon tumor cells. Based on these results, we developed a short-term culture technique that greatly improves the yield of analyzable metaphases from colon tumors. Stimulated cultures consistently contained at least ten times more metaphases than unstimulated cultures, and chromosome morphology was improved. By modifying this technique with the addition of the calcium ionophore A23187, we have successfully obtained analyzable chromosomes from the peripheral blood of normal individuals, chronic lymphocytic leukemia patients, and a nodular small cell lymphoma patient. These results demonstrate that mitogenic stimulation by PDBu is a valuable technique in the cytogenetic analysis of colon tumors. By using PDBu alone or in combination with other agents, this technique may also be applicable to many other tumors that are difficult to karyotype because of an inability to obtain mitoses.

Calcimycin↗
PubMed1988

Effect of transmural versus nontransmural myocardial infarction on inducibility of ventricular arrhythmias during sympathetic stimulation in dogs.

Transmural myocardial infarction interrupts sympathetic nerves and denervates viable muscle distal to myocardial infarction. The effect of sympathetic stimulation on responses to programmed ventricular stimulation was studied in dogs without myocardial infarction (Group I: n = 5), with transmural anterior wall myocardial infarction (Group II: n = 6) and with nontransmural anterior wall myocardial infarction (Group III: n = 9). Ventricular effective refractory period during sympathetic stimulation decreased by 16 +/- 18, 1 +/- 2 and 12 +/- 8 ms (mean +/- SD) in viable muscle of the inferoapical left ventricle in Groups I, II and III, respectively, suggesting efferent sympathetic denervation by transmural myocardial infarction only. Sustained ventricular tachycardia or fibrillation was induced more easily during sympathetic stimulation in six of the six dogs with transmural infarction, but in only two of the nine dogs with nontransmural infarction (p less than 0.01). It is concluded that the partial sympathetic denervation produced by transmural myocardial infarction enhances the ease of induction of ventricular tachycardia and fibrillation during sympathetic stimulation. A similar mechanism may lead to increased risk for lethal arrhythmias during periods of high sympathetic tone in patients with transmural myocardial infarction.

Animals↗
PubMed1988

Immunohistology of the benign lymphoepithelial lesion in AIDS-related lymphadenopathy: a case report.

We report a case of a benign lymphoepithelial lesion of the parotid gland in a patient with progressive generalized lymphadenopathy (PGL) related to human immunodeficiency virus. Serologic studies and immunoperoxidase studies for lymphocyte subsets, which have not previously been reported in this lesion, suggest involvement of an intraparotid lymph node by PGL rather than Sjogren's syndrome.

AIDS-Related Complex↗
PubMed1988

Cutaneous cytomegalovirus infection in a liver transplant patient. Diagnosis by in situ DNA hybridization.

A 39-year-old woman who had cryptogenic cirrhosis and who had received two liver transplants developed necrotic skin lesions over the chest, upper arms, and thighs. Biopsy showed enlarged endothelial cells with intranuclear and intracytoplasmic inclusions characteristic of cytomegalovirus (CMV) infection. However, a few multinucleated gaint cells were observed beneath a necrotic epidermis. This, combined with the clinical presentation, suggested to infectious disease consultants an infection with herpes simplex virus. Using the immunoperoxidase technique, inclusions stained positively with antibody to CMV and showed a negative reaction for herpes simplex antigen. In situ hybridization using biotinylated DNA probes on formalin-fixed, paraffin-embedded tissue sections confirmed the diagnosis of CMV infection and failed to substantiate infection with herpes simplex virus. Subsequently, blood cultures became positive for CMV. The early recognition of CMV infection in the skin permitted institution of antiviral therapy with gancyclovir. Specific skin lesions of CMV infection are likely to be encountered with increasing frequency among immunosuppressed patients. Lesions may be vesicular, and epidermal multinucleated giant cells can occasionally be identified. In situ hybridization is a technique that is readily adaptable to surgical pathology laboratories and permits both a rapid, specific diagnosis and the early institution of appropriate therapy.

Adult↗
PubMed1987

Allergic fungal sinusitis due to Curvularia lunata.

The clinical and pathologic features of allergic fungal sinusitis caused by Curvularia lunata, as seen in two patients, are described. The findings are identical to those of allergic aspergillus sinusitis. Patients have allergies, nasal polyposis, and, occasionally, eosinophilia. Radiographs show opacification of multiple sinuses without bone destruction. Surgical specimens consist of polyps and inspissated, mucoid material. Diagnostic microscopic features, termed "allergic mucin," include eosinophils, numerous Charcot-Leyden crystals, and hyphae embedded in pools of mucus. The recognition of allergic mucin may be impeded by extensive degranulation and fragmentation of the eosinophils. In addition, the fragments of mucin exhibit large, poorly stained central areas, probably due to incomplete penetration by the fixative. Eosinophils are easier to recognize in well-fixed areas. Electron microscopy, though not of diagnostic necessity, confirms the eosinophilic nature of the infiltrate. It is important that surgical pathologists recognize this distinctive clinicopathologic entity and recommend appropriate cultures.

Adolescent↗
PubMed1987

The impact of an educational workshop on colorectal screening practices.

Since its establishment in 1983, the Virginia Colorectal Cancer Control Project has emphasized the importance of routine screening of asymptomatic adults for colorectal cancer. This has been accomplished through educational workshops that are offered to primary care physicians. These workshops provide didactic information on current concepts in screening and individualized instruction on the use of the flexible sigmoidoscope. Eleven workshops have been conducted since the fall of 1984. During the spring of 1986, a survey was mailed to workshop participants to determine whether changes had occurred in their screening practices. A total of 115 physicians responded to the survey. Prior to the workshop, 86 physicians performed the digital rectal examination; now 100 do. Prior to the workshop, 68 physicians performed the fecal occult blood test; now 89 do. Prior to the workshop, 34 physicians used a flexible scope; now 71 do. Participants found the workshop to be extremely effective in providing individualized instruction.

Colorectal Neoplasms↗
PubMed1986

Beta-chain human chorionic gonadotropin-producing leiomyosarcoma of the small intestine.

A 22-year-old patient with primary leiomyosarcoma of the small bowel presented with symptoms including nausea and vomiting, a symptom complex similar to hyperemesis gravidarum in the pregnant female. She was found to have elevated levels of serum beta-HCG which were localized to the leiomyosarcoma cells utilizing an immunoperoxidase staining technique. Thus, this patient presents evidence that beta-HCG may be produced by sarcoma cells and, therefore, that beta-HCG may be used as a tumor marker in some sarcoma patients.

Adult↗