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Biomedical subjects

J George

Publications and source records attributed to J George.

At least 145 records · Page 8Linked to original sources
PubMed1998

Massive proteinuria as a main manifestation of primary antiphospholipid syndrome.

Renal involvement in antiphospholipid syndrome (APS) is increasingly reported. So far, massive proteinuria as the principal feature of primary APS (PAPS) has not been well documented. We describe 3 patients with PAPS and massive proteinuria. Renal biopsy was performed in all 3, and features consistent with membranous and focal segmental glomerulopathy were disclosed. These histological lesions were not yet reported in PAPS. We conclude that the spectrum of renal lesions in PAPS is diverse and that it should be considered in the differential diagnosis of patients with massive proteinuria.

Adult↗
PubMed1998

Atherosclerosis and the antiphospholipid syndrome: a link unravelled?

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to beta2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.

Animals↗
PubMed1998

Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes.

CYP3A4, the predominant cytochrome P450 expressed in human liver, is responsible for the metabolism of endogenous steroids and many drugs. On the basis of pharmacokinetic studies in patients with hormonal derangements and the effects of replacement therapy, it has been suggested that iodothyronines decrease CYP3A4-mediated drug metabolism, whereas glucocorticoids and GH enhance CYP3A4 activity. The aim of the present study, using well differentiated human hepatocytes in primary culture, was to examine directly whether hormonal factors regulate CYP3A4 gene expression. Addition of T3 to primary hepatocytes resulted in a marked reduction of CYP3A4-catalyzed testosterone 6 beta-hydroxylase activity and corresponding levels of CYP3A4 protein and messenger ribonucleic acid compared to those in untreated cells. Conversely, both dexamethasone and GH treatment substantially increased CYP3A4 gene expression. None of the hormones studied consistently altered the expression of other human cytochrome P450 genes. We conclude that iodothyronines, glucocorticoids, and GH act directly on human hepatocytes to regulate the expression of CYP3A4, and these effects appear to be exerted at a pretranslational level. Altered regulation of hepatic CYP3A4 is, therefore, likely to account for previous observations concerning the effects of endocrine diseases and hormonal treatments on human cytochrome P450-mediated drug and steroid metabolism.

Cell Survival↗
PubMed1998

Production and characterization of fusion proteins containing transferrin and nerve growth factor.

To explore the ability to use genetic fusions of transferrin as a carrier for brain targeting and delivery, a series of fusion proteins containing both human nerve growth factor (NGF) and human transferrin was produced in mammalian cells. A protein in which the hinge region from human IgG3 joined the carboxyl terminus of NGF and the amino terminus of transferrin formed a covalent homodimer, bound human transferrin receptor, and retained full NGF in PC12 cells. In contrast, proteins in which polypeptide dimerization was not induced or in which NGF was fused through its amino terminus had greatly reduced NGF activity. The ability to maintain both biologically active NGF and transferrin as part of a fusion protein may offer a novel way to deliver NGF and other neurotrophic factors to the central nervous system.

Blood-Brain Barrier↗
PubMed1998

Protective effect of curcumin, ellagic acid and bixin on radiation induced genotoxicity.

Induction of micronuclei and chromosomal aberrations produced by whole body exposure of r-radiation (1.5-3.0 Gy) in mice was found to be significantly inhibited by oral administration of natural antioxidants, curcumin (400 micro moles), ellagic acid (200 micro moles) and bixin (200 micro moles) per kilogram body weight. These antioxidants induced inhibition of micronucleated polychromatic and normochromatic erythrocytes, was comparable with alpha-tocopherol (200 micro moles) administration. Curcumin and ellagic acid were also found to significantly reduce the number of bone marrow cells with chromosomal aberrations and chromosomal fragments as effectively as alpha-tocopherol. Moreover, administration of antioxidants inhibited the DNA strand breaks produced in rat lymphocytes upon radiation as seen from the DNA unwinding studies. These results indicated that antioxidant curcumin, ellagic acid and bixin provide protection against chromosome damage produced by radiation.

Animals↗
PubMed1998

Emphysematous pyelonephritis.

Emphysematous pyelonephritis is a severe form of acute pyelonephritis, characterised by fever, abdominal pain, nausea and vomiting, associated with intraparenchymal and perirenal gas production. It is often diagnosed radiologically, by plain films of abdomen, ultrasonogram and/or CT scan and often needs surgical drainage. We report a case which could be diagnosed clinically because of extensive surgical emphysema in a diabetic patient which was successfully managed by a combined medical and surgical approach.

Anti-Bacterial Agents↗
PubMed1998

Attenuation of ECS-induced retrograde amnesia by using an herbal formulation.

Earlier research indicated the efficacy of a complex herbal formulation in the attenuation of electroconvulsive shock (ECS)-induced amnestic deficits in rats; this study sought to ascertain whether a simplified herbal formulation (Memorin; Phyto-Pharma, India) also was effective. Rats pretreated for a fortnight with Memorin (200 mg/kg/day) or vehicle were exposed to a passive-avoidance learning paradigm in a shuttle box. The next day, the rats were administered two true or sham ECSs, 5 h apart; recall of the pre-ECS learning was reassessed on the following day. ECS was found to produce significant retrograde amnesia (p < 0.002). Memorin attenuated the ECS-induced amnesia (p = 0.00003) without influencing the ECS seizure duration. The clinical implications of these findings are discussed.

Amnesia↗
PubMed1997

[Primary subclavian vein thrombosis after intensive physical exertion].

Subclavian vein thrombosis accounts for approximately 1-2% of recorded deep venous thromboses. It may be primary or secondary, and insertion of a central venous catheter is the most common cause of secondary subclavian vein thrombosis. Traumas, anatomic abnormalities and carcinoma are important additional risk factors for secondary thrombosis. Primary thrombosis of the subclavian veins is known as Paget-Schroetter syndrome. New criteria for its diagnosis include a history of increased upper extremity use prior to onset of symptoms, the presence of a venographically demonstrated thrombus and absence of any definable causes. We describe a 42-year-old woman with a history of intensive physical exertion admitted with swelling, pain and difficulty moving her arm. The diagnosis of primary subclavian vein thrombosis was established from the history of physical effort, results of Doppler ultrasound, and exclusion of other causes of subclavian vein thrombosis. This case suggests that primary subclavian vein thrombosis should be considered in young patients with subclavian vein thrombosis after exclusion of secondary disease.

Adult↗
PubMed1997

[Q fever endocarditis and bicuspid aortic valve].

Q fever is caused by the rickettsia Coxiella burnetti, an obligate intracellular bacterium acquired by inhalation of infected dust from subclinically infected animals. Q fever may be acute or chronic; the chronic form mostly presents as endocarditis. Immunocompromised states and underlying heart disease are the most important risk factors. Usually the symptoms of Q fever endocarditis are nonspecific and diagnosis is often established very late. New criteria for diagnosis include a single blood culture positive for Coxiella burnetti, positive Q fever serology and characteristic echocardiographic studies. We describe a 49-year-old man with bicuspid aortic valve admitted with fever, weight loss and a new heart murmur. The diagnosis of Q fever endocarditis was established by positive Q fever serology, and an echocardiogram showing vegetations and valvular dysfunction. This case suggests that Q fever endocarditis should be considered in patients with "sterile" endocarditis.

Aortic Valve↗
PubMed1997

Effect of the 1-(2'-deoxy-beta-D-ribofuranosyl)-3-nitropyrrole residue on the stability of DNA duplexes and triplexes.

3-Nitropyrrole (M) was introduced as a non-discriminating 'universal' base in nucleic acid duplexes by virtue of small size and a presumed tendency to stack but not hydrogen bond with canonical bases. However, the absence of thermally-induced hyperchromic changes by single-stranded deoxyoligomers in which M alternates with A or C residues shows that M does not stack strongly with A or C nearest neighbors. Yet, the insertion of a centrally located M opposite any canonical base in a duplex is sometimes even less destabilizing than that of some mismatches, and the variation in duplex stability is small. In triplexes, on the other hand, an M residue centrally located in the third strand reduces triplex stability drastically even when the X.Y target base pair is A.T or G. C in a homopurine. homopyrimidine segment. But, when the target duplex opposition is M-T and the third strand residue is T, the presence of M in the test triplet has little effect on triplex stability. Therefore, a lack of hydrogen bonding in an otherwise helix-compatible test triplet cannot be responsible for triplex destabilization when M is the third strand residue. Thus, M is non-discriminating and none-too-destabilizing in a duplex, but in a triplex it is extremely destabilizing when in the third strand.

Adenine↗
PubMed1997

[Ischemic hepatitis in congestive heart failure after an episode of hypotension].

Ischemic hepatitis can occur as an acute episode in advanced congestive heart failure (CHF). The mechanism is massive necrosis of the central lobules resulting from acute hypoxia when low cardiac output further reduces oxygen supply, aggravating underlying congestion due to poor venous outflow. We describe a 70-year-old woman with congestive heart failure for 7 years who was admitted with jaundice, vomiting, abdominal pain and oliguria after an episode of hypotension. The diagnosis of ischemic hepatitis was established by a documented episode of severe hypotension, followed by elevation of serum transaminases, a rise in serum bilirubin and LDH levels, prolonged prothrombin time and acute renal failure. Other causes of acute hepatitis, such as a virus or drugs were excluded, and improved liver and renal function followed hemodynamic stabilization. We conclude that ischemic hepatitis should be considered whenever acute hepatitis follows a recent episode of systemic hypotension, especially in the context of concomitant CHF.

Aged↗
PubMed1997

Chromophore-modified bis-naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]isoquinoline-1,3-diones.

The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitumor agents that consist of two chromophores bridged by an alkylamino linker. In the present study we have explored the effect produced by the presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with different polyamine chains on cellular cytotoxicity. Bis-dibenz[de,h]isoquinoline-1,3-diones with the bridge (CH2)2-NH-(CH2)n-NH-(CH2)2, where n = 2-5, showed optimum cytotoxicity with IC50's around 10 nM. Compound 16, which has the (CH2)2-NH-(CH2)3-NH-(CH2)2 bridge, altered DNA mobility and topoisomerase I and II activity at approximately 5 microM. When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.

1-Naphthylamine↗
PubMed1997

Mutagenic, carcinogenic and cocarcinogenic activity of cashewnut shell liquid.

The petroleum ether extract of cashewnut shell (Anacardium occidentale) was tested for its mutagenic, carcinogenic and cocarcinogenic potency. Mutagenicity tests using Salmonella typhimurium (Ame's test) Strains TA 1535, TA 100 and TA 98 showed that cashewnut shell liquid is non-mutagenic up to a concentration of 0.003% (in 0.1 ml DMSO) with and without metabolic activation (S 9 mixture). Carcinogenicity testing using murine (female Swiss albino mice) two stage skin tumourigenesis model revealed that cashewnut shell liquid has no tumour initiating potency at a concentration of 10% (in 0.2 ml acetone) while it may act as weak promoter (P < 0.05) at a concentration of 5% (in 0.2 ml acetone). Testing for cocarcinogenic potency of cashewnut shell liquid (2% and 5% in 0.2 ml acetone) demonstrated that it has no cocarcinogenic potency on mouse skin tumour model when applied along with 2 x 10(-6)% benzo(a)pyrene in acetone up to a period of 20 weeks.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Subcutaneous T-cell lymphoma in a patient with rheumatoid arthritis not treated with cytotoxic agents.

This case report describes an 81-year-old patient with prolonged rheumatoid arthritis (RA), which was complicated by the occurrence of a subcutaneous T-cell lymphoma. During the course of his illness the patient had not been treated with disease-modifying agents (i.e. cytotoxic agents), but only symptomatically with anti-inflammatory drugs. This finding demonstrates a previously undescribed association between RA and a rare from of subcutaneous T-cell lymphoma, which may add more information to the controversial issue of emergence of malignancy in RA.

Aged↗
PubMed1997

Time-dependent expression of cytochrome P450 genes in primary cultures of well-differentiated human hepatocytes.

We sought to establish an in vitro system to study the regulation of highly differentiated hepatocellular functions, and specifically the time-dependent expression of four cytochrome P450 (P450) genes at the messenger RNA (mRNA) and protein levels. When seeded onto matrigel, hepatocytes could be maintained for 8 days in media that were free of serum and hormones (except for insulin). Cells retained a spherical phenotype; they secreted albumin and not alpha-fetoprotein; and the cellular RNA/DNA ratio rose progressively in culture. The isolation procedure and the duration of culture affected expression of specific P450s differently. CYP1A2, CYP2C9, and CYP2E1 mRNAs were not altered by cell isolation, and levels of CYP1A2 and CYP2C9 mRNA were also maintained for 8 days in culture, whereas CYP2E1 mRNA declined to 9% of values in fresh hepatocytes by day 8. CYP3A4 mRNA content was considerably decreased in freshly isolated hepatocytes compared with normal liver, and expression of this gene during the course of culture was more variable than that of the other P450s. Use of Williams' E medium considerably enhanced accumulation of CYP3A4 mRNA, compared with modified Waymouth 752/1 medium, but had a detrimental effect on levels of the other P450 mRNAs. Despite high levels of expression at the mRNA level, the microsomal protein contents of CYP1A2, CYP2C9, CYP2E1, and CYP3A4 declined progressively during the course of culture; this decline was most rapid for CYP3A4. These results confirm the potential of primary cultures of well-differentiated human hepatocytes for studies of P450 gene regulation in humans, but they also demonstrate that culture conditions are variables that must be carefully controlled when examining liver-specific gene expression in vitro. In particular, time in culture may variably affect expression of P450 enzyme changes at both the mRNA and protein levels.

Cell Differentiation↗
PubMed1997

Mechanism for maintenance of high breast tumor estradiol concentrations in the absence of ovarian function: role of very high affinity tissue uptake.

Breast tumors from postmenopausal women contain levels of estradiol similar to those in premenopausal patients even though serum estradiol levels fall by an order of magnitude upon cessation of ovarian function. The present study sought to examine enhanced uptake from plasma as one potential mechanism for maintenance of high tissue estradiol levels in postmenopausal patients. Accordingly, we used osmotic minipumps to continuously infuse estradiol (E2) at rates producing serum concentrations ranging from pre- to postmenopausal levels for two weeks to oophorectomized Sprague-Dawley rats bearing nitrosomethylurea-induced mammary tumors. We then measured E2 concentrations in various tissues and sera and reasoned that tissue affinities for estradiol could be directly calculated from in vivo measurements by adapting Scatchard analysis to steroid infusion data. Using this method, we demonstrated a very high affinity estradiol binding component with a Kd two orders of magnitude higher (i.e., 0.35 x 10(-12) M) than determined with standard in vitro techniques. A second estradiol binding component with the expected Kd of 1 x 10(-10) M was also present. Estradiol bound to both classes of binding sites could be 98% displaced with diethylstilbestrol within a 6-hr period. In vivo steroid binding off-times calculated from log-linear slopes averaged approximately 60 min. These data demonstrated that the actual E2 binding affinity in target tissues in vivo, especially at low estrogen concentrations, is much higher than usually estimated from standard, in vitro estrogen receptor assays. These observations provide one mechanism to explain why estradiol concentrations remain high in breast cancer tissue from postmenopausal women and consequently can stimulate tumor proliferation.

Animals↗
PubMed1997

Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS).

Ox-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to foam cell formation. APS is characterized by repeated venous and arterial thromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence of antibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospholipids bear structural resemblance to LDL, and several studies have indeed proved that aPL display cross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized and native forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice. Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinical picture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, native LDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL were found to exhibit a significantly more severe form of the disease in comparison with native LDL- and PBS-infused mice, expressed by lower platelet counts (261,000/mm3, 535,000/mm3 and 455,000/mm3, respectively), longer activated partial thromboplastin time (aPTT) (99 +/- 12 s, 63 +/- 8 s and 74 +/- 8 s, respectively) and higher fetal resorption rates (72.7%, 34.4% and 32.6%, respectively). The results of this study show that Ox-LDL, compared with native LDL, aggravates the clinical manifestations of experimental APS and suggest that cross-reactivity of Ox-LDL with phospholipids may provide a pathogenic explanation for this effect.

Animals↗