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Biomedical subjects

J George

Publications and source records attributed to J George.

At least 217 records · Page 12Linked to original sources
PubMed1995

Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver.

Multivariate linear regression analysis was used to examine the influence of age, gender and environmental variables on the hepatic content of cytochromes P450 (CYP, P450) 1A2, 2C, 2E1 and 3A in 71 subjects; 21 with histologically normal livers and 50 with chronic liver disease. There was a clear negative association between age and total P450 content, NADPH-cytochrome c reductase activity and levels of 2E1 and 3A proteins. 1A2 and 2C proteins were unaltered with advancing age. Gender did not influence the expression of any of the CYP proteins. Cigarette smoking was associated with enhanced levels of 1A2, but effects of drug ingestion and alcohol consumption were not apparent in this study, probably because of case selection. It is concluded that age but not gender is a constitutional factor that influences the hepatic content of cytochrome P450 and selected CYP proteins.

Aging↗
PubMed1995

Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis.

We have recently reported that disease-specific differential alterations in the hepatic expression of xenobiotic-metabolizing cytochrome P450 (CYP P450) enzymes occur in patients with advanced liver disease. In order to determine whether the observed changes in CYP proteins are modulated at pre- or post-translational levels, we have now examined the hepatic levels of mRNA for CYPs 1A2, 2C9, 2E1 and 3A4 by solution hybridization in the same livers of 20 controls (surgical waste from histologically normal livers), 32 cases of hepatocellular and 18 of cholestatic severe chronic liver disease. CYP1A2 mRNA and CYP1A immunoreactive protein were both reduced in livers with hepatocellular and cholestatic types of cirrhosis. In contrast, CYP3A4 mRNA and protein were reduced only in livers from patients with hepatocellular diseases. For 1A2 and 3A4 there were significant correlations between mRNA species and the respective protein contents (rS1A2 = 0.74, rS3A4 = 0.64, P < 0.0001). CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of liver disease, but 2C protein was reduced only in patients with cholestatic dysfunction. The correlation between CYP2C9 mRNA and protein, was also significant (rs = 0.36, P < 0.005) but mRNA levels accounted for only 13% of the variability in protein rankings. This is probably a consequence of other CYP2C proteins apart from 2C9 being detected by the anti-2C antibody. CYP2E1 mRNA and protein were reduced in patients with cholestatic liver disease, but in hepatocellular disease the expression of only CYP2E1 mRNA was decreased. CYP2E1 mRNA was significantly correlated with CYP2E1 protein but accounted for only 18% of the variability in protein rankings (rs = 0.43, P < 0.0005). Taken collectively these data indicate that the disease-specific alterations of xenobiotic-metabolizing CYP enzymes among patients with cirrhosis is due, at least in part, to pre-translational mechanisms. The lack of a strong correlation between CYP2E1 mRNA and protein suggests that this gene, like its rat orthologue, may be subject to pre-translational as well as translational and/or post-translational regulation.

Cytochrome P-450 Enzyme System↗
PubMed1995

Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity.

LU 79553 is a novel bis-naphthalimide which is highly cytotoxic in vitro with EC50 (concentration required for 50% inhibition of growth) ranging from 2 x 10(-7) to 5 x 10(-10) M. A number of studies were conducted to examine its antitumor activity in human xenograft models. In addition, we wanted to explore the possible schedule dependency of LU 79553 cytotoxicity in these xenograft models. Complete regression of MX-1 (mammary carcinoma) xenografts was observed when LU 79553 was administered i.v. daily for 5 doses at 20 mg/kg (2 cycles starting on Days 6 and 20) or every 3 days for 2 doses at 55 mg/kg (2 cycles starting on Days 6 and 13) or every 7 days for 4 doses. Complete regression was also seen in the MX-1 model when tumors were staged at 1-2 g prior to the initiation of treatment. Regressions (complete or partial) were observed in the LX-1 (lung), CX-1 (colon), DLD (colon), and LOX (melanoma) xenograft models. A significant increase in the median survival time of OVCAR-3- (ovarian carcinoma) bearing mice was noted in LU 79553-treated animals (treated/control = 195%). The excellent activity of this compound in such a wide variety of tumor types suggests LU 79553 merits further investigation in clinical trials.

Amides↗
PubMed1995

Assessment of the reproductive toxicity of a complex mixture of 25 groundwater contaminants in mice and rats.

The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate contaminated groundwater supplies near hazardous waste dumps was evaluated in CD-1 Swiss mice and Sprague-Dawley rats using the reproductive assessment by continuous breeding protocol. Male and female mice and rats were exposed to MIX in the drinking water at concentrations of 1, 5, and 10% of a technically achievable stock solution. For mice, body weight and feed consumption were not affected by MIX but water consumption was decreased for both the 5 and 10% MIX groups in both F0 and F1 animals. For F0 mice, the number of live pups/litter was decreased at 10% MIX and the number of females/litter was decreased 10 and 17% at the mid and high MIX dose, respectively. Vaginal cytology was normal, as were testis weight and testicular spermatid head count. For F1 mice, fertility was unaffected, but there was a decreased number of female pups/litter (19%) and a decreased adjusted live pup weight at 10% MIX. At necropsy, cauda epididymal sperm concentration and spermatid head count were reduced (20%) in the presence of normal testis, epididymis, prostate, seminal vesicle, liver, and kidney/adrenal weight. Female estrous cyclicity was altered at 5 and 10% MIX with normal kidney/adrenal, uterus, and ovary/oviduct weight. For rats, F0 body weight and feed consumption were not affected by MIX but water consumption was decreased 10, 30, and 40% in the low-, medium-, and high-dose MIX groups, respectively, and 39% in the high-dose MIX F1 animals. Rat fertility was normal but there was a decreased number of male pups/litter (11%) and a decreased live pup weight (6%) at 10% MIX. Male and female (F1) pup weights were decreased on Postnatal Days 0, 4, 7, 14, and 21 (10% MIX) and remained lower through necropsy on Day 120 +/- 10. F1 fertility was normal but F2 pup weights were decreased (10% MIX). At necropsy, F1 (10% MIX) male body weight was decreased 16% and relative kidney, testis, epididymis, and prostate weights were increased in the presence of normal sperm concentration percentage motile sperm and percentage abnormal sperm. Estrous cyclicity was normal as were kidney/adrenal and ovary weight while female liver weight was reduced 14%. In summary, a "cocktail" of 25 chemicals commonly found in contaminated groundwater at or near hazardous waste sites was administered in drinking water at doses which resulted in severely decreased water consumption in both mice and rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Anti-actin antibodies in sera from patients with autoimmune liver diseases and patients with carcinomas by ELISA.

UNLABELLED: Smooth muscle antibodies (SMA) were initially detected in sera of patients with chronic active hepatitis (CAH). Subsequently, their presence was demonstrated in a wide variety of other diseases. SMA are a mixture of antibodies directed towards different cytoskeletal antigens. Sera with high titers of anti-actin antibodies (AAA), a subgroup of SMA, are most frequently found among patients with autoimmune chronic active hepatitis (CAH) and, to a lesser extent, among patients with primary biliary cirrhosis (PBC) and other diseases. It is therefore established that AAA are a reliable marker to autoimmune CAH. The purpose of this study was to determine the titer of AAA in sera of patients with liver, autoimmune diseases and carcinomas, using the enzyme-linked immunoabsorbent assay (ELISA) method. The results were expressed as the optical density (OD) of the examined sera divided by the OD of a sera from a healthy control (presented as percentages +/- standard deviation). Sera of 33 patients with cirrhosis, nine patients with autoimmune CAH, fifteen patients with non-autoimmune CAH, eight patients with PBC, 30 patients with Sjogren's syndrome, 60 patients with SLE, 142 patients with carcinomas of different kinds, and 34 healthy donors were examined for the presence of AAA by ELISA. Statistically significant (P < 0.003) higher titers of AAA were detected in patients with autoimmune CAH (57 +/- 23%) compared with the control group and to other groups of diseases. AAA titers in non-autoimmune CAH were not significantly higher compared to the control group. High titers of AAA were detected in 67% of the patients with autoimmune CAH, as compared with other diseases in which only up to 13% of the patients exhibited AAA positivity. CONCLUSION: existence of higher levels of AAA noted in 67% of the patients with autoimmune CAH with regard to other groups of diseases, emphasizes the value of AAA as sensitive and specific markers, capable of characterizing the patients with autoimmune chronic active hepatitis.

Actins↗
PubMed1995

A comparison of hospital policies for measles, mumps, and rubella infection control in Los Angeles County, 1989 and 1992.

BACKGROUND: A survey was conducted in 1992 in Los Angeles County, California, to assess changes since an earlier survey in 1989 in the numbers of acute care hospitals that had established policies on measles, mumps, and rubella infection control and the extent to which these policies were implemented. METHODS: A questionnaire inquiring about measles, mumps, and rubella infection control was sent to ICPs of 133 acute care hospitals in Los Angeles County. The results were compared with those of a similar survey conducted in 1989. The increase in the number of hospitals with such policies between 1989 and 1992 was analyzed. RESULTS: In 1989, 29 (28%), 9 (9%), and 65 (64%) of the 102 respondent hospitals had measles, mumps, and rubella infection control policies, respectively. Larger proportions of the 95 respondent hospitals in 1992 had measles (56, 59%), mumps (15, 16%), and rubella (69, 73%) infection control policies. CONCLUSIONS: The number of hospitals with infection control policies for measles, mumps, and rubella increased from 1989 to 1992. Efficiency and scope of such policies varied, however, and could be improved by making the policies mandatory, requiring written documentation of employee immunity, and extending policies to cover all employees. The most dramatic increase was in the number of hospitals with infection control policies for measles; this increase may have been caused by the 1987 to 1989 measles epidemic in Los Angeles County, by increased awareness of the Immunization Practices Advisory Committee recommendations, or by increased sensitivity to the issue of infection control triggered by the 1989 survey.

California↗
PubMed1995

Cloning of the mgtE Mg2+ transporter from Providencia stuartii and the distribution of mgtE in gram-negative and gram-positive bacteria.

The MM281 strain of Salmonella typhimurium possesses mutations in each of its three Mg2+ transport systems, requires 100 mM Mg2+ for growth, and was used to screen a genomic library from the gram-negative bacterium Providencia stuartii for clones that could restore the ability to grow without Mg2+ supplementation. The clones obtained also conferred sensitivity to Co2+, a phenotype similar to that seen with the S. typhimurium corA Mg2+ transport gene. The sequence of the cloned P. stuartii DNA revealed the presence of a single open reading frame, which was shown to express a protein with a gel molecular mass of 37 kDa in agreement with the deduced size of 34 kDa. Despite a phenotype similar to that of corA and the close phylogenetic relationship between P. stuartii and S. typhimurium, this new putative Mg2+ transporter lacks similarity to the CorA Mg2+ transporter and is instead homologous to MgtE, a newly discovered Mg2+ transport protein from the gram-positive bacterium Bacillus firmus OF4. The distribution of mgtE in bacteria was studied by Southern blot hybridization to PCR amplification products. In contrast to the ubiquity of the corA gene, which encodes the dominant constitutive Mg2+ influx system of bacteria, mgtE has a much more limited phylogenetic distribution.

Amino Acid Sequence↗
PubMed1995

Bilateral emphysematous pyelonephritis responding to nonsurgical management.

Bilateral emphysematous pyelonephritis is a rare condition, with only 14 cases reported in the English literature. It carries a bad prognosis, surgical management being the recommended mode of therapy. We report a case of bilateral emphysematous pyelonephritis in a 50-year-old diabetic lady which was successfully managed using antibiotics alone.

Cefuroxime↗
PubMed1995

Prenatal diagnosis of partial trisomy through in situ hybridization on amniocytes with whole chromosome and centromere-specific DNA probes. A case report.

BACKGROUND: DNA probes specific for whole chromosomes or portions of chromosomes can provide important information to aid the clinician in managing pregnancy and the geneticist in relaying accurate recurrence risk information to the patient. CASE: In this case, sonography was ordered because of a low fundal height in a 29-year-old primigravida at 35 weeks' gestational age; it revealed major fetal anomalies. A small supernumerary marker was seen in some cultured amniocytes. Metaphase spreads were analyzed by means of fluorescence in situ hybridization using a centromere probe specific for chromosome 22 and a whole chromosome probe for the 11 chromosome. In situ hybridization showed that the marker chromosome was a derivative of chromosome 22 with 11q material attached near the centromere. The fetal karyotype was 47,XY,+der(22) t(11;22)(q23.3;q11.2)mat. The mother was later found to be a balanced translocation carrier. CONCLUSION: It was possible to offer rapid prenatal diagnosis for this family using interphase analysis with the 22 centromere probe. The patient had chorionic villus sampling, and DNA probes were used to analyze cells directly from the biopsy. The signal representing the supernumerary marker was not observed. Karyotype analysis later showed that the fetus was normal but a translocation carrier. This report illustrates that rapid in situ hybridization can provide important information in known cases of translocation carriers.

Adult↗
PubMed1995

The occurrence of thromboembolic events following airplane flights--'the economy class syndrome'.

The occurrence of thromboembolic phenomena following long-distant airplane flights is well characterized in the literature. However, it seems that despite being repeatedly described, the recognition of its implications by the medical services at the airports is still insufficient. We describe two cases: the first presented with a clinical picture consistent with the diagnosis of pulmonary embolus validated by a lung perfusion-ventilation scan, and the second, with deep vein thrombosis in his left femoral vein. Both patients were diagnosed several days after a prolonged airway flight. The purpose of this article is to draw attention to the thromboembolic phenomena known to be associated with airplane flights, provide possible mechanisms to account for their envolvement, and emphasize the measures that should be taken to prevent their occurrence.

Aged↗
PubMed1995

The role of p53 mutations in bilateral breast carcinoma.

Mutations of the tumor suppressor gene p53 have been implicated in certain familial cases of breast cancer. We examined a series of 38 cases of nonfamilial bilateral breast cancer using antibodies CM1 and DO7 to p53 wild-type and mutant protein (Novocastra Laboratories) by the avidin-biotin-peroxidase complex method. The two antibodies reacted similarly. Mutant p53 protein was detected in 17 of 76 (22%) tumors but in only 3 of 38 (8%) paired tumors. There were no significant differences in p53 expression between synchronous (< 12 mos) and metachronous tumors (29% vs 17%, P = 0.09) or between first and second tumors (14% vs 26%, P = 0.29). Mutant p53 was detected bilaterally in one metachronous and two synchronous cases, which were amplified and sequenced and two synchronous cases, which were amplified and sequenced by polymerase chain reaction and single strand confirmation polymorphism. One synchronous case showed a bilateral mutation in exon 2-3; the other had a bilateral mutation in exon 8-9. In the metachronous case, a mutation could be demonstrated in only one breast. Analysis of all tumors demonstrated that when p53 protein is overexpressed in the first tumor, there is a 60% probability of overexpression in the second, whereas if absent from the first, it is unlikely to be present in the second. These data suggest that p53 mutations do not play a major role in the pathogenesis of bilateral disease in most women.

Adult↗
PubMed1995

Metastatic cervical carcinoma presenting as psoas abscess and osteoblastic and lytic bony metastases.

A 60-year-old Chinese lady presented with a left flank mass and weight loss. Plain films showed a sclerotic L1 vertebral body, osteopenic L2 and L3 vertebral bodies and loss of left psoas outline. However initially unrevealed history of previous carcinoma of the cervix caused confusion as to the aetiology of a sclerotic vertebral body associated with an left flank collection. Psoas abscess with adjacent bony osteomyelitis was initially suspected. The left flank mass turned out to be an infected necrotic large metastatic lymph node compressing the lower pole of the left kidney. The sclerotic and osteopenic vertebral bodies represented an unusual presentation of bony cervical carcinoma metastases.

Bone Diseases, Metabolic↗
PubMed1995

Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease.

To determine whether cytochrome P450 proteins were differentially altered in severe chronic liver diseases, we examined 50 livers removed at liver transplantation from patients with end-stage cirrhosis, including 18 with and 32 without cholestasis, and compared the results with 21 histologically normal livers. NADPH-cytochrome c reductase activities were unaltered in microsomes from cirrhotic livers. Total cytochrome P450 content was significantly reduced. The catalytic activities of four xenobiotic-metabolizing P450s and the level of the corresponding proteins were differentially altered. Thus, P450 3A-supported testosterone 6 beta-hydroxylase activity and 3A protein appeared to be reduced, but only in the subgroup without cholestasis was this change significant. In contrast, 2E1 and the related N,N-dimethylnitrosamine N-demethylase activity were clearly reduced in livers from patients with cholestatic forms of cirrhosis but appeared not to be changed in other cirrhotic livers. Similarly, P450 2C protein was reduced only in patients with severe chronic cholestasis. Finally, P450 1A2 and 1A2-supported ethoxyresorufin O-deethylase activity were significantly reduced in hepatic microsomes from patients with both types of advanced liver disease. In summary, these data demonstrate that cytochrome P450 proteins are selectively altered in severe chronic liver disease, some being profoundly decreased, others less so or not at all. Our results also suggest that there may be different patterns of altered hepatic P450 expression according to the presence or absence of cholestasis in patients with cirrhosis severe enough to require transplantation.

Adolescent↗
PubMed1994

Amplification and overexpression of HER-2/neu in carcinomas of the salivary gland: correlation with poor prognosis.

There are few reliable prognostic markers of biological aggressiveness for head and neck carcinomas in general. For salivary gland carcinomas, anatomic location, tumor size, histological grade, and extent of disease involvement are considered to be clinically important risk factors for recurrent disease. Molecular genetic alterations in salivary gland carcinomas have not been characterized, and tumor cell proteins have not been shown to be prognostically significant. Here a cohort of mucoepidermoid carcinomas of the major (parotid and submandibular) salivary glands are analyzed for a molecular genetic alteration, HER-2/neu gene amplification, and gene amplification and expression results are compared with long-term clinical follow-up information. Archival tissues resected from 58 patients with mucoepidermoid carcinoma of salivary glands were evaluated for HER-2/neu gene amplification by fluorescence in situ hybridization and for gene expression by immunohistochemistry in a blinded fashion. Clinical follow-up information was compared with the results of these analyses to determine whether there were significant associations. Overexpression, identified as membrane immunostaining by immunohistochemistry, was observed in 22 of 58 (38%) mucoepidermoid carcinomas. Gene amplification, characterized by fluorescence in situ hybridization, was observed in 12 (21%) cases. Eleven of the 12 cases with gene amplification were also immunostained for HER-2/neu. Both gene amplification (P = 0.0001, P < 0.0001) and immunostaining (P < 0.0001, P < 0.0001) were correlated with shorter disease-free interval and poorer overall patient survival, respectively. Multivariate analysis showed that HER-2/neu immunostaining and amplification were markers of poor prognosis independent of histopathological grade, tumor size, and involvement of regional lymph nodes. HER-2/neu is amplified and/or overexpressed in approximately one-third of mucoepidermoid carcinomas of salivary glands. Amplification and/or overexpression appears to be an independent marker of poor prognosis in mucoepidermoid carcinomas of the salivary glands as it is in carcinomas of the breast, ovary, and endometrium.

Adolescent↗