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Biomedical subjects

D George

Publications and source records attributed to D George.

At least 73 records · Page 4Linked to original sources
PubMed1993

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke.

OBJECTIVE: To study and describe a large family with the tRNA Leu(UUR) point mutation at position 3243 in mitochondrial DNA, which is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. DESIGN: Survey; case series. SETTING: University hospital inpatient and outpatient neurology department. PATIENTS: Twelve patients from three generations in a family carrying the tRNA Leu(UUR) point mutation at position 3243 were studied. INTERVENTIONS: Clinical evaluation, muscle biopsy, and mitochondrial DNA point mutation quantitation of the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes in muscle and blood. MAIN OUTCOME MEASURE: Correlation between clinical, pathologic, and genotypic features. RESULTS: Family members had various combinations of sensorineural hearing loss, retinal pigmentary degeneration, migraine, hypothalamic hypogonadism, and mild myopathy. Only one member had a strokelike episode at the age of 46 years. This patient had the highest point mutation percentage. CONCLUSION: This report suggests that this point mutation may not be associated with stroke in all families and that whether patients develop stroke may depend on the percentage of mutant mitochondrial DNA and its tissue distribution.

Adult↗
PubMed1993

Double-outlet single ventricle and an abdominal vascular mass: in utero diagnosis with pathological confirmation.

A fetal echocardiographic scan was performed when routine prenatal ultrasound screening failed to identify four cardiac chambers. The scan showed a single ventricle with an associated circoid varicosity. Because of these anomalies, amniocentesis was suggested and trisomy 18 confirmed. The presence of major cardiac structural anomaly should prompt careful and specific review of all fetal anatomy to screen for syndrome identification and consideration of amniocentesis.

Abnormalities, Multiple↗
PubMed1993

Maternal/congenital syphilis in a large tertiary-care urban hospital.

Among the women delivering a total of 9,591 infants in 1990 at Hutzel Hospital in Detroit, 148 had positive results in the rapid plasma reagin (RPR) and fluorescent treponemal antibody-absorption tests for syphilis. This group included primarily young, black, multigravid women with a history of crack cocaine use. RPR titers ranged from 1:1 to 1:256 among the 103 mothers not treated or inadequately treated for syphilis. Two mothers with very low RPR titers (1:2) delivered a stillborn infant and an infant with a reaction in the cerebrospinal fluid Venereal Disease Research Laboratory (CSF-VDRL) test, respectively. Seventy-five percent of the infants born to untreated or inadequately treated women had asymptomatic congenital syphilis. The remaining 25% were stillborn (6 infants) or had clinical features of congenital syphilis (3 infants), a reactive CSF-VDRL test (11 infants), or radiological evidence of periostitis or metaphysitis (6 infants). Abnormalities were documented in the placentas from 11 live births and one stillbirth. The resurgence of congenital syphilis highlights the need for better diagnostic tests and for studies that will determine optimal therapy for mother and infant.

Adult↗
PubMed1993

Combination therapy in experimental invasive aspergillosis.

Combination antifungal therapy was assessed in an immunosuppressed rabbit model of invasive aspergillosis. Treatment with fluconazole, amphotericin B, or a combination of both significantly prolonged survival of animals lethally challenged with Aspergillus fumigatus. High-dose amphotericin B was the most effective therapy for invasive aspergillosis. Although no antagonism was seen when fluconazole was given prophylactically or therapeutically in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B. Animals given a sublethal challenge of A. fumigatus had lower mortality rates when given amphotericin B, fluconazole as treatment or prophylaxis, or various combination therapies. Only animals treated with flucytosine had mortality rates comparable to those of controls. No antagonism was observed with combinations of fluconazole and amphotericin B, flucytosine and amphotericin B, or fluconazole and flucytosine. These observations provide evidence that fluconazole, flucytosine, and amphotericin B used in various combinations are not antagonistic and may provide some insight into the treatment of invasive aspergillosis in humans.

Amphotericin B↗
PubMed1993

Differential seasonal regulation of melatonin receptor density in the pars tuberalis and the suprachiasmatic nuclei: a study in the hedgehog (Erinaceus europaeus, L.).

Using quantitative autoradiography, we have studied the seasonal changes of high affinity melatonin receptor density in both the SCN and PT of the hedgehog, a seasonal breeder and an hibernator. Animals in 3 different physiological states were studied: sexually active animals, and sexually inactive animals during the hibernation period, being then either euthermic or hypothermic. In sexually active animals, Bmax were 75.8 +/- 7.1 fmol/mg protein in PT and 9.1 +/- 0.5 fmol/mg protein in SCN; and Kd values were: 94 +/- 22 pM in the PT and 101 +/- 15 pM in the SCN. This specific binding was strongly decreased in the PT of sexually inactive animals. Moreover, this decrease was significantly stronger in hypothermic than in euthermic hedgehogs. Saturation studies and Scatchard analysis revealed that the observed decrease in the PT resulted from change in the Bmax but not in the Kd, Bmax values being respectively 56.4 +/- 5.9 and 29.5 +/- 1.9 fmol/mg protein in euthermic and hypothermic sexually at rest animals. In none of the different physiological states, did the density of melatonin receptors of the SCN show any changes, Bmax values being respectively 9.8 +/- 0.5 and 9.8 +/- 0.4 fmol/mg protein in euthermic and hypothermic sexually at rest animals. This shows for the first time a tissue-specific regulation of melatonin receptor density occurring in the PT but not in the SCN. Furthermore, this decrease of binding in the PT is correlated with both sexual inactivity and hibernation period. This strongly suggests that the mediation of the photoperiodic effect on seasonal functions like seasonal hypothermia and reproduction involves an effect of melatonin on the PT rather than on the SCN.

Animals↗
PubMed1992

The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.

A cellular phosphoprotein with an apparent molecular mass of 90 kd (p90) that forms a complex with both mutant and wild-type p53 protein has been characterized, purified, and identified. The protein was identified as a product of the murine double minute 2 gene (mdm-2). The mdm-2 gene enhances the tumorigenic potential of cells when it is overexpressed and encodes a putative transcription factor. To determine if mdm-2 could modulate p53 transactivation, a p53-responsive element from the muscle creatine kinase gene was employed. A wild-type p53-expressing plasmid enhanced the expression of the p53-responsive element when cotransfected into cells that contain no endogenous p53. When a cosmid expressing mdm-2 was transfected with this p53-expressing plasmid, the transactivation of the p53-responsive element was inhibited. Thus, a product of the mdm-2 oncogene forms a tight complex with the p53 protein, and the mdm-2 oncogene can inhibit p53-mediated transactivation.

Amino Acid Sequence↗
PubMed1992

Animal models: usefulness for studies of fungal pathogenesis and drug efficacy in aspergillosis.

This review describes our experience during the past 8 years with an immunocompromised rabbit model of invasive aspergillosis. We have used the model to evaluate the efficacy of a variety of antifungal therapies, including amphotericin B-deoxycholate, a liposomal amphotericin B preparation, some of the newer azoles (i.e., fluconazole, saperconazole, and the experimental compound SCH 39304), and combination therapy with amphotericin B-deoxycholate plus fluconazole. The model provides a rigorous test of efficacy when animals receive a lethal challenge; permits studies of the kinetics of aspergillar antigenemia in response to therapy with each antifungal agent or regimen; allows comparison of the relation of antigenemia to the extent of disease in target organs; and is useful in correlating the timing of antifungal therapy with the success of treatment. These observations in our animal model may provide some insight into the treatment of invasive aspergillosis in humans.

Animals↗
PubMed1992

Microbiological efficacy and pharmacokinetics of prophylactic antibiotics in liver transplant patients.

The pharmacokinetics of perioperative systemic antibiotics and the microbiological effectiveness of oral nonabsorbable antibiotics started immediately prior to surgery were studied in 18 adult patients undergoing liver transplantation. All patients received cefotaxime, 2 g intravenously, at 6-h intervals during surgery and then at 8-h intervals thereafter for 48 h; eight patients also received ampicillin at the same dose and schedule. This regimen produced levels of antibiotics in blood that appeared appropriate for prophylaxis. The first dose peak (68 +/- 18 micrograms/ml) and trough (6.9 +/- 4.7 micrograms/ml) levels of cefotaxime in serum and the first dose peak (73 +/- 22 micrograms/ml) and trough (4.1 +/- 2.3 micrograms/ml) levels of ampicillin in serum, which were assayed by high-performance liquid chromatography, were similar to levels reported in normal volunteers, despite mean intraoperative blood loss of 3.3 liters and fluid replacement of 21 liters. On postoperative days 1 and 2, the levels of cefotaxime and ampicillin were maintained at or above 0.9 and 1.3 micrograms/ml, respectively, with little accumulation. By random assignment, 8 patients received systemic antibiotics alone and 10 patients received systemic antibiotics plus a 3-week regimen of oral nonabsorbable antibiotics (gentamicin, polymyxin E, and nystatin) beginning when a donor liver was procured. Pre- and postoperative cultures of rectum, throat, and gastric aspirate samples showed persistence of aerobic gram-negative bacilli for the first 2 postoperative weeks in about half of the patients in each group. Failure of the regimen of oral nonabsorbable antibiotics to supplement cefotaxime in eradicating aerobic gram-negative bacilli from stools probably results from impaired peristalsis during and after surgery and warrants earlier initiation of the regimen.

Adult↗
PubMed1992

Saperconazole therapy in a rabbit model of invasive aspergillosis.

The efficacy of orally and intravenously administered saperconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral saperconazole at dosages of 5, 10, and 15 mg/kg of body weight per day improved survival compared with that of controls. In addition, saperconazole at 10 and 15 mg/kg/day reduced the tissue burden and reduced levels of circulating antigen, which correlated with increasing dosages of saperconazole. Intravenous saperconazole produced levels in serum more than 10-fold that of oral therapy. Intravenous saperconazole not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues compared with those of controls and was as effective as amphotericin B in these studies. Saperconazole was effective in the treatment of experimental invasive aspergillosis and demonstrates the potential of the newer azoles in therapy for invasive aspergillosis.

Administration, Oral↗
PubMed1992

Effect of thrombin inhibition on the dynamics of thrombolysis and on platelet function during thrombolytic therapy.

To evaluate the effect of thrombin on the dynamics of thrombolysis, we infused rabbits with heparin or hirudin alone or in conjunction with tissue-type plasminogen activator (t-PA) and monitored the kinetics of fibrinolysis and changes in ex vivo platelet aggregation responses over time. Both heparin and hirudin enhanced total fibrinolysis in an ex vivo arteriovenous shunt preparation: 82 +/- 2% and 79 +/- 2%, respectively, compared with 51 +/- 8% for t-PA alone (P less than 0.05) and 50 +/- 4% for t-PA plus aspirin (p less than 0.05). Heparin coadministered with t-PA significantly reduced the half-time for clot lysis compared with t-PA alone (p less than 0.05), whereas hirudin coadministered with t-PA significantly reduced the half-time for clot lysis compared with that for t-PA alone, t-PA plus aspirin, and t-PA plus heparin (5.5 +/- 0.6 versus 12.1 +/- 2.0 versus 12.6 +/- 2.2 versus 10.0 +/- 0.8 minutes, respectively; p less than 0.05). Both heparin and hirudin prevented the increase in ADP-induced platelet aggregation normally seen with t-PA alone (p less than 0.01 by t test; p less than 0.05 by two-way analysis of variance). These data demonstrate that selective, antithrombin III-independent thrombin inhibitors can enhance the efficacy of thrombolysis by modulating the dynamics of the process and preventing platelet activation associated with plasminogen activator therapy.

Animals↗
PubMed1992

Potentiation of epidermal growth factor-induced differentiation of cultured human placental cells by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) potentiates epidermal growth factor (EGF)-stimulated placental lactogen (hPL) secretion by cultured placental cells. In this study we have examined the effects of EGF and IGF-I, alone or in combination, on the differentiation of placental cells in culture and correlated this differentiation with hPL secretion. Addition of EGF (10 ng/mL) or IGF-I (100 ng/mL) alone in serum-free medium was associated with enlargement of the BhCG-positive (differentiated cytotrophoblast marker) mononucleated trophoblast cells. Concomitant addition of IGF-I and EGF resulted in more marked enlargement of the BhCG-positive cells, aggregation of the enlarged cells, and early syncytiotrophoblast formation. Measurement of hPL in the medium revealed that the stimulatory effect (P less than 0.05) of EGF on hPL secretion by total placental cells was proportional to the stimulatory effect of EGF on cell differentiation, as revealed by the obliteration of its stimulatory effect on hPL by BhCG-positive cells. The augmented stimulatory effect of EGF on hPL secretion by all cells in the presence of IGF-I was decreased (P less than 0.05) when expressed per number of human chorionic gonadotropin (BhCG)-positive cells. The dose-response curves of hPL stimulation by IGF-I in the presence of EGF revealed that the decreased effect of IGF-I on hPL secretion by BhCG-positive-staining cells was due to the difference in magnitude (approximately 1.5 times) of stimulation of BhCG staining of and hPL secretion by the cells. These results extend our previous suggestion that IGF-I in placenta, in addition to its effect on hPL secretion, affects cell differentiation; however, the two effects may not be interdependent.

Cell Differentiation↗
PubMed1992

Measurement of free radicals from smoke inhalation and oxygen exposure by spin trapping and ESR spectroscopy.

Research in smoke inhalation has established that free radicals are produced from gases released during combustion and these species impair lung function. Using spin traps and their adducts in an animal model free radicals were measured. Various hyperbaric oxygen regimens were tested in an attempt to attenuate pulmonary damage caused by free radical reactions. Our data demonstrated that persistent oxygen- and carbon-centered free radicals are detectable in intravascular fluids after smoke inhalation. The smoke inhalation model showed however, clearing of spin trap adducts one hour after smoke exposure. Other researchers have found that when 100% oxygen is given at 1 atmosphere absolute (ATA) for 1 h, free radicals were not detectable. However, oxygen given at 2.5 ATA does produce detectable free radicals. With continued exposure at this pressure, the levels of free radicals increase for up to 60 min. This study suggests that the level of free radical induced oxygen toxicity may be a function of oxygen pressure and duration of oxygen exposure.

Animals↗
PubMed1991

Trisomy 8 in primary esthesioneuroblastoma.

Esthesioneuroblastoma is a rare malignancy believed to be derived from neuroectodermal stem cells within the olfactory epithelium. We have obtained the karyotype of a primary esthesioneuroblastoma following brief (7-day) in vitro culture, and have determined that the only observable cytogenetic anomaly is the presence of an additional chromosome 8. Previously, the karyotypes of two cell lines established from metastatic esthesioneuroblastomas have been reported to contain the equivalent of three copies of chromosome 8, in addition to other chromosomal aberrations, including the reciprocal translocation, t(11;22)(q24;q12). Examination of the cytogenetic literature suggests that an extra copy of chromosome 8 is a common occurrence in undifferentiated small round cell tumors frequently observed to carry the t(11;22), including esthesioneuroblastoma, Ewing's sarcoma, peripheral neuroepithelioma, Askin's tumor, and rhabdomyosarcoma. These data, combined with our report of a small round cell tumor with the karyotype 47,XY, +8, indicate that trisomy 8 may be a common phenomenon in these tumors, and may also provide some sort of selective advantage to these tumor types.

Chromosome Aberrations↗
PubMed1991

The role of fluconazole in the early treatment and prophylaxis of experimental invasive aspergillosis.

The efficacy of fluconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with fluconazole at 60 or 120 mg/kg/day was begun 24 h after lethal challenge and compared to that with amphotericin B at 1.5 mg/kg/day. Fluconazole reduced mortality compared with that in untreated controls and at 120 mg/kg/day reduced the tissue burden of A. fumigatus 10- to 100-fold in liver, kidney, and lung. However, amphotericin B was more effective in sterilizing tissues. Both fluconazole and amphotericin B dramatically decreased or eliminated circulating aspergillus antigen. Prophylaxis with fluconazole, begun 48 h before sublethal challenge, sterilized liver and kidney tissues and significantly reduced the tissue burden in lung. Early treatment with fluconazole reduced mortality and reduced antigenemia but did not sterilize tissues. Fluconazole prophylaxis at these doses prevented dissemination of invasive aspergillosis. Fluconazole was shown to have activity in the early treatment and prophylaxis of experimental invasive aspergillosis.

Animals↗
PubMed1991

Efficacy of SCH 39304 in treatment of experimental invasive aspergillosis.

The efficacy of SCH 39304 (SCH) against Aspergillus fumigatus was assessed with an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with SCH at 10 or 15 mg/kg of body weight per day was begun 24 h after lethal challenge and compared with therapy with amphotericin B at 1.5 mg/kg/day. Compared with untreated controls, SCH reduced mortality and also reduced the tissue burden of A. fumigatus 100- to 1,000-fold in liver, kidney, and lung tissues. SCH at 15 mg/kg/day and amphotericin B eliminated A. fumigatus in liver, kidney, and lung tissues. In addition, both dosages of SCH significantly eliminated the organism from brain tissues, compared with controls. Both SCH and amphotericin B decreased or eliminated circulating aspergillus antigen. These results show that new azoles can be as effective as amphotericin B in eradicating the organism from tissues and offer promise in improving the treatment of invasive aspergillosis.

Amphotericin B↗