Prenatal diagnosis of right pulmonary artery to left atrium communication.

We report a case of right pulmonary artery to left atrium communication in a fetus at 24 weeks' gestation. Fetal echocardiography showed dilatation of the left atrium and main and right pulmonary arteries. The right pulmonary artery was seen to communicate with the left atrium. Color Doppler velocimetry demonstrated high-velocity flow through the communication. The pregnancy was terminated and findings were confirmed at autopsy. The embryological and postnatal aspects of right pulmonary artery to left atrium communication are discussed.

Evaluation of antimicrobial activity of Cleome viscosa and Gmelina asiatica.

The ethanolic extracts of the leaves and flowers of Cleome viscosa and roots of Gmelina asiatica were tested for antimicrobial activity. The two plants exhibited a broad spectrum of antimicrobial activity, particularly significative against Escherichia coli , Proteus vulgaris and Pseudomonas aeruginosa. The leaf extract of C. viscosa showed moderate activity against pathogenic fungi.

Antimicrobial activity of Caesalpinia pulcherrima, Euphorbia hirta and Asystasia gangeticum.

The ethanolic extracts of the dry fruits of Caesalpinia pulcherrima, aerial parts of Euphorbia hirta and flowers of Asystasia gangeticum were tested for antimicrobial activity. The three plants exhibited a broad spectrum of antimicrobial activity, particularly against Escherichia coli (enteropathogen), Proteus vulgaris, Pseudomonas aeruginosa and Staphylococcus aureus.

Promotion by orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine.

Our earlier experiments revealed that orotic acid, a precursor for pyrimidine nucleotides, selectively stimulated the growth of carcinogen-modified liver cells to grow into enzyme-altered hepatocytes (Cancer Lett., 16: 191-196, 1982). The present study was designed to determine whether prolonged feeding of orotic acid will result in hepatocellular carcinoma in initiated rats. Accordingly, groups of rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or an equivalent volume of 0.9% sodium chloride solution 18 hr after two-thirds partial hepatectomy. After 1 week of recovery, they were continued on either the basal diet or the basal diet containing 1% orotic acid for 10 to 13 months. Some groups of rats, in addition, received a single necrogenic dose of CCl4 8 weeks following exposure to orotic acid diet. The results obtained indicated that 87.5% of initiated rats exposed to orotic acid developed hepatocellular carcinomas in 10 months and 100% in 13 months. Initiated rats exposed to orotic acid diet coupled with a single administration of CCl4 developed 100% hepatocellular carcinoma by 10 months. In contrast, the incidence of hepatocellular carcinoma in initiated rats fed basal diet alone for 13 months was 37.5%, while, in those that received CCl4 in addition, the incidence was 25% in 10 months. Interestingly, a significant number of liver cancers (29 to 36%) in the orotic acid-fed group metastasized to lungs, whereas none of the liver cancers in rats exposed to basal diet metastasized.(ABSTRACT TRUNCATED AT 250 WORDS)

Orotic acid, nucleotide-pool imbalance, and liver-tumor promotion: a possible mechanism for the mitoinhibitory effects of orotic acid in isolated rat hepatocytes.

This study was designed to determine the possible mechanism by which orotic acid exerts its mitoinhibitory effect on rat hepatocytes in primary culture. Orotic acid inhibited, dose-dependently DNA synthesis in hepatocytes induced by epidermal growth factor, transforming growth factor alpha, hepatocyte growth factor, acidic fibroblast growth factor, or plasma from rats exposed to various liver cell-proliferative stimuli, such as two-thirds partial hepatectomy, lead nitrate, cyproterone acetate, ethylene dibromide, or a diet deficient in choline. Further, orotic acid inhibited DNA synthesis even when added 24 h after the hepatocytes were primed with transforming growth factor alpha. Taken together, these results suggested that the target site may not be at the level of the growth-factor receptor and receptor-mediated early events. In a preliminary experiment, orotic acid inhibited the expression of the ribonucleoside diphosphate reductase gene. Exposure to orotic acid results in an imbalance in nucleotide pools characterized by an increase in uridine nucleotides and a decrease in adenosine nucleotides. It is hypothesized that this imbalance in nucleotide pools inhibits the expression of the ribonucleoside diphosphate reductase gene and, therefore, is a likely target for the mitoinhibitory effect of orotic acid.

Studies on the effect of dietary orotic acid on mouse liver carcinogenesis induced by diethylnitrosamine.

The present study was designed to determine whether orotic acid, a liver tumor promoter in the rat, also promotes liver carcinogenesis in the mouse. Eight-week-old male BALB/c mice were initiated with diethylnitrosamine (90 mg/kg i.p.). One week later they were divided into 2 groups and given either a basal diet or the basal diet containing 1% orotic acid (OA). They were killed at 6 or 10 months after the administration of the carcinogen. At 6 months, no nodular lesions were seen in mice whether or not they were exposed to OA. However by 10 months 100% of mice in both groups developed hepatic nodules. OA neither shortened the latent period for the appearance of the nodular lesions not did it increase the size of the nodules. Although BALB/c mice exhibited an increase in uridine nucleotides and a decrease in adenosine nucleotides in the liver upon exposure to OA, the magnitude of the change was less compared with that seen in the rat liver. The resistance of BALB/c mouse to the tumor-promoting effects of OA may reflect in part the resistance of the mouse to OA-induced nucleotide pool imbalance.

Sequential histopathological analysis of hepatocarcinogenesis in rats during promotion with orotic acid.

In the present study, sequential histopathological changes during hepatocarcinogenesis promoted by orotic acid were examined. Male Fischer 344 rats were given 1,2-dimethylhydrazine.2HCl (100 mg/kg, i.p.) 18 h after 2/3 partial hepatectomy. After 1 week of recovery, they were divided into 2 groups; group 1 was continued on a semisynthetic basal diet while the group 2 received the basal diet containing 1% orotic acid. Rats were sacrificed after 5, 10, 20, 29, 40 and 53 weeks of promotion. Histopathological analysis indicated that emergence of hepatocellular carcinomas was preceded first by foci of morphologically and histochemically altered hepatocytes and then by the appearance of hepatocyte nodules. Clear cell foci, eosinophilic ground glass foci and gamma-glutamyltransferase positive foci were detectable after 5 weeks in initiated rats fed orotic acid. Hepatocyte nodules developed in 56% of the rats after 20 weeks of promotion, while the first hepatocellular carcinoma was observed in one rat sacrificed after 29 weeks of orotic acid promotion. Cancer incidence steadily increased with the duration of the orotic acid treatment and 59% developed hepatocellular carcinomas with 30% metastasis to lungs by 53 weeks of promotion. A relevant feature of this model is that during exposure to orotic acid no liver hyperplasia, nor bile duct or oval cell proliferation were seen and the liver architecture in the tissue surrounding focal lesions was well preserved throughout the sequence.

Induction of hepatic nodules in the rat by aristolochic acid.

Aristolochic acid (AA), used as an anti-inflammatory agent in the past, is known to be mutagenic and carcinogenic to several organs of the rat, including forestomach, renal pelvis and urinary bladder. However, despite the induction of DNA adducts in the liver, no carcinogenic potential of AA has been reported in the latter organ. The present study was based on the rationale that the lack of carcinogenicity of AA to the liver could be because this chemical may not be necrogenic at the doses examined and liver cell proliferation has been established as an essential component for initiation of liver carcinogenesis in the rat. The results indicated that AA is non-necrogenic to the rat liver. However, a single non-necrogenic dose of AA (10 mg/kg b.w., i.p.) given 18 hours after 2/3 partial hepatectomy initiated liver cell carcinogenesis. The initiated cells are promotable with 1% dietary orotic acid, a liver tumor promoter, to form glutathione-S-transferase 7-7 positive hepatic foci and nodules.

Ribonucleotide reductase: a possible target for orotic acid induced mitoinhibition in normal hepatocytes in primary culture.

The present study was designed to determine the mechanism by which orotic acid, a rat liver tumor promoter, inhibits DNA synthesis in normal hepatocytes in primary culture. Our results indicate that orotic acid inhibited the epidermal growth factor induced expression (mRNA) of both M1 and M2 subunits of ribonucleotide reductase while the expression of c-fos, c-myc, c-Ha-ras and beta-actin was not inhibited to any significant extent. These studies suggest that ribonucleotide reductase may be one target for orotic acid-induced mitoinhibition.

An earlier proliferative response of hepatocytes in gamma-glutamyl transferase positive foci to partial hepatectomy.

One of the hallmarks of initiated hepatocytes is their resistance to several hepatotoxins. This property forms the basis for their selective growth under conditions which are inhibitory to the non-initiated hepatocytes. Selective growth of initiated hepatocytes also occurs, albeit at a low level, in initiated rat liver without exposure to any known promoting regimen and/or in the absence of any known selective pressure to which initiated hepatocytes can possibly be resistant. This latter phenotypic property of initiated hepatocytes was further characterized by comparing the kinetics of response of hepatocytes in gamma-glutamyl transferase positive foci and in the surrounding liver to 2/3 partial hepatectomy both in the presence and in the absence of a promoting regimen. Male Fischer 344 rats (130-150 g) were initiated with a single dose of diethylnitrosamine and 1 week later they were placed on either a semi-synthetic basal diet or a promoting diet containing 1% orotic acid. Partial hepatectomy was performed 15 weeks after initiation and animals from both groups were killed at 12, 16, 20, 24, 30, 36, 48, 72 or 96 h after operation. Each animal received a pulse of 3H-labelled thymidine 1 h prior to killing. Autoradiographic studies revealed that hepatocytes in gamma-glutamyl transferase positive foci in the livers of rats fed the basal diet were significantly labelled at 16 h post-partial hepatectomy while surrounding hepatocytes were still virtually quiescent (LI 12.7 +/- 4.7 versus 1.2 +/- 0.5%, respectively). Higher labelling index in foci compared to the surrounding liver was also seen at 20 h post-PH (36.9 +/- 2.6 versus 21.5 +/- 2.4). Similar earlier response of hepatocytes in gamma-glutamyl transferase positive foci was also seen in initiated rats exposed to dietary orotic acid. In addition, orotic acid treatment appears to have imposed a slight delay on the entry of hepatocytes in the surrounding liver into 'S' phase and thereby enhancing the differential of growth response between these two populations.

Dietary orotic acid, a new selective growth stimulus for carcinogen altered hepatocytes in rat.

It was observed that orotic acid (OA), a precursor for pyrimidine nucleotide biosynthesis, when supplied exogenously at 1% level in the diet selectively stimulated the growth of hepatocytes modified by 1,2-dimethylhydrazine (1,2-DMH) to form gamma-glutamyltransferase (gamma-GT) (EC 2.3.2.2) positive islands. Increasing the duration of OA diet from 5 to 10 weeks resulted in an increase in the number of foci from 6 to 14/cm2. Rats that received the carcinogen and basal diet, however, developed only 1-2 foci/cm2. This unique effect of OA can be further accentuated by supplying a liver cell proliferative stimulus, such as a single necrogenic dose of CCl4.

Studies on the kinetics of expression of cell cycle dependent proto-oncogenes during mitogen-induced liver cell proliferation.

The present study was undertaken to determine the kinetics of DNA synthesis and expression of cell cycle dependent proto-oncogenes in response to two types of cell proliferative stimuli in male Wistar rat liver. The peak of DNA synthesis was approximately 24 h after a compensatory cell proliferative stimulus induced by 2/3 partial hepatectomy and approximately 36 h following a mitogenic stimulus obtained with a single dose of lead nitrate (10 micromol/100 g body wt, through femoral vein). Even though both proliferative stimuli induced the expression of c-fos, c-myc and c-Ha-ras, the extent of the increase in c-fos expression was 4- to 5-fold less in mitogen-induced cell proliferation. In addition, while the expression of c-myc, following partial hepatectomy returned to basal level by 4 h, the induced expression of c-myc persisted for up to 40 h during the lead nitrate-induced liver cell proliferation.

Stimulation of DNA synthesis by rat plasma following in vivo treatment with three liver mitogens.

The present study was undertaken to determine the effect of two different types of liver cell proliferative stimuli, namely compensatory regeneration and direct hyperplasia on DNA synthesis of normal and preneoplastic isolated hepatocytes. Platelet-poor plasma (PPP) isolated from male Wistar rats treated with three different hepato-mitogens, lead nitrate (LN), cyproterone acetate (CPA) and ethylene dibromide (EDB), or subjected to surgical partial hepatectomy (PH), was tested for its ability to stimulate DNA synthesis in normal and preneoplastic hepatocytes in primary cultures. Induction of DNA synthesis was detected as early as 30 min after CPA, EDB and PH administration and persisted up to 5 days after the LN administration. In addition, hepatocytes isolated from preneoplastic liver nodules were also able to respond in culture to the DNA synthesis stimulus induced by these factors.

Effect of beta-carotene on the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase in rat liver.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), is a rate-limiting enzyme in the biosynthesis of not only cholesterol but also a variety of non-sterol isoprenoids. It is subjected to multivalent feedback suppression by transcriptional and post-transcriptional control mechanisms mediated by sterols and non-sterol substances. In the present study, the effect of a plant isoprenoid, beta-carotene, on the expression of HMG-CoA reductase in rat liver was investigated. In control rats the hepatic levels of mRNA transcripts of HMG-CoA reductase increased following 2/3 partial hepatectomy with two peaks, one at 8 h and the other at 24 h. Administration of the carotenoid (70 mg/kg, given every alternate day for 3 consecutive weeks) partially inhibited the increase in the transcript level with a 50% reduction at 8 h and 30% reduction at 24 h post partial hepatectomy. Nuclear run-off assays with nuclei isolated from the resting liver and from livers of control rats and rats exposed to beta-carotene for 3 consecutive weeks and killed 8 h after partial hepatectomy indicated that beta-carotene did not inhibit the rate of transcription of HMG-CoA reductase gene. These observations suggest that beta-carotene regulates the expression of HMG-CoA reductase by some post-transcriptional mechanisms.

Effect of PSC 833, a potent inhibitor of P-glycoprotein, on the growth of astrocytoma cells in vitro.

Malignant astrocytomas have been found to express P-glycoprotein (Pgp, mdr1 gene product). It was hypothesized that in addition to conferring multidrug resistance, Pgp is intimately associated with the development of astrocytomas. Accordingly, we studied the effect of PSC 833 (PSC, Novartis), a potent inhibitor of Pgp, on the growth of Pgp-expressing astrocytoma cells. The results showed that in all the cell lines tested, PSC (10-60 microM) inhibited the growth as well as induced cell death. Cells exposed to PSC exhibited DNA ladder characteristic of apoptosis. PSC-induced cell death could be reversed by Z-VAD-fmk, a general caspase inhibitor, indicating that PSC-induced cell death was characteristic of caspase-mediated apoptosis. These results suggest a novel therapeutic strategy in the treatment of malignant astrocytomas by inhibitors of Pgp.

Cervical vascular injuries: a trauma center experience.

BACKGROUND: We analyzed 76 patients with cervical vascular injuries from penetrating neck trauma (n = 528) between 1977 and 1990 at a level I trauma center to evaluate the role of angiography in diagnosis and management and to assess the course and outcome of these patients. METHODS: Patients who were hemodynamically unstable underwent immediate surgical exploration. Stable patients were subjected to diagnostic investigation. Angiography was routinely performed to diagnose vascular injury in zones I and III and zone II if the trajectory was in the vicinity of major vessels. Therapeutic embolization was performed when possible at angiography; all other vascular injuries were treated surgically. RESULTS: Thirteen patients (2.5%) died of penetrating neck trauma, in 12 of whom hemorrhage was the contributing factor (12/76; 15.8% of patients with vascular injury). In nine patients who were hemodynamically stable vascular injury was diagnosed by angiography: 5 (6.8%) of 73 in zone I and 3 (5.4%) of 56 in zone III, four of whom underwent therapeutic embolic occlusion of the injured vessel. Injuries to vertebral and subclavian arteries and subclavian and innominate veins were often multiple, causing exsanguination and death (6.8% in zone I). In three patients with no preoperative neurologic deficit, the internal carotid artery was ligated without complication; in all other patients injury to the common carotid or internal carotid artery was repaired, in six of them with polytetrafluoroethylene grafts. CONCLUSIONS: Selective management of penetrating neck trauma should include routine angiography in zones I and III. Injuries to the common and internal carotid arteries should be repaired. The internal carotid artery may be ligated in the absence of preoperative neurologic deficit. Arterial injuries in the neck can be repaired with polytetrafluoroethylene grafts.

Helical computed tomography in differentiating appendicitis and acute gynecologic conditions.

OBJECTIVE: To determine the accuracy and effect of helical computed tomography (CT) in women clinically suspected of having either appendicitis or an acute gynecologic condition. METHODS: One hundred consecutive nonpregnant women suspected of having appendicitis or an acute gynecologic condition prospectively had helical CT. Interpretations were correlated with surgical and pathologic findings (41 cases) and clinical follow-up for at least 2 months (59 cases). The accuracy for confirming or excluding both appendicitis and acute gynecologic conditions was determined. The effect on patient care was determined by comparing pre-CT plans with actual treatment. RESULTS: Thirty-two women had appendicitis, 15 had acute gynecologic conditions, 27 had other specific diagnoses, and 26 had nonspecific abdominal pain. For diagnosing appendicitis or acute gynecologic conditions, CT had 100% and 87% sensitivity, 97% and 100% specificity, 94% and 100% positive predictive value, 100% and 98% negative predictive value, and 98% and 98% accuracy, respectively. After CT was done, 36 planned hospital admissions, 25 planned hospital observations, and six planned appendectomies were deferred; six women had alternative surgical procedures on the basis of CT results. One patient had an unnecessary appendectomy on the basis of CT findings. CONCLUSION: Helical CT is an excellent imaging option for differentiating appendicitis from most acute gynecologic conditions.

Helical CT and three-dimensional CT of facial and orbital injury.

Knowledge of the regions of the face and their buttresses and knowledge of the types of facial injuries frequently encountered simplifies the diagnostic task. The indications for CT include detection of suspected fractures and preoperative planning. The cost of facial CT to the hospital has declined and is little different than the cost of plain films. CT may become the screening modality of choice depending on the cost structure at any given hospital.

Helical CT of appendicitis and diverticulitis.

The clinical diagnosis of appendicitis and diverticulitis remains challenging. Clinical diagnosis alone can lead to unnecessary hospitalizations and surgeries, prolonged periods of hospital observation, and delays prior to necessary medical or surgical treatment. Helical CT combined with recently reported techniques for imaging appendicitis and diverticulitis offers rapid and accurate confirmation or exclusion of these entities as well as identification of alternative conditions that can clinically mimic them. More routine use of helical CT holds great promise for improving patient care and lowering hospital resource use in patients with clinically suspected appendicitis and diverticulitis.

Misdiagnosis of primary epiploic appendagitis.

BACKGROUND: The authors determined the radiological misdiagnosis rate of primary epiploic appendagitis (PEA) and its impact on patient management and hospital resource use. METHODS: A total of 660 computed tomography scans performed for clinically suspected diverticulitis (348 cases) or appendicitis (312 cases) were reviewed for cases meeting strict radiological criteria for PEA. Retrospective interpretations were compared with radiological reports. Medical records and hospital cost data were reviewed to estimate impact on patient management and resource use. RESULTS: Eleven scans (2%) met criteria for PEA. Seven scans were initially misdiagnosed as diverticulitis (6 patients) or appendicitis (1 patient). All misdiagnosed patients were hospitalized (mean 4.3 days); 6 received antibiotic therapy. Average cost per patient was $4,117. Four scans were initially correctly diagnosed as PEA. One patient was hospitalized (1 day); none received antibiotic therapy. Average cost per patient was $1,205. CONCLUSIONS: Radiological misdiagnosis of PEA leads to unnecessary hospitalization, medical treatment, and overuse of hospital resources.