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Biomedical subjects

S A Gross

Publications and source records attributed to S A Gross.

At least 19 recordsLinked to original sources
PubMed2006

PU.1 phosphorylation correlates with hydroquinone-induced alterations in myeloid differentiation and cytokine-dependent clonogenic response in human CD34(+) hematopoietic progenitor cells.

The transcriptional regulatory factor PU.1 is important for the regulation of a diverse group of hematopoietic and myeloid genes. Posttranslational phosphorylation of PU.1 has been demonstrated in the regulation of a variety of promoters in normal cells. In leukemia cells, differing patterns of PU.1 phosphorylation have been described among acute myelogenous leukemia (AML) subtypes. Therefore, we hypothesized that modulation of PU.1-dependent gene expression might be a molecular mediator of alterations in myeloid cell growth and differentiation that have been demonstrated to be early events in benzene-induced leukemogenesis. We found that freshly isolated human CD34(+) hematopoietic progenitor cells (HPC) exhibit multiple PU.1-DNA binding species that represent PU.1 proteins in varying degrees of phosphorylation states as determined by phosphatase treatment in combination with electrophoretic mobility shift assay (EMSA). Maturation of granulocyte and monocyte lineages is also accompanied by distinct changes in PU.1-DNA binding patterns. Experiments reveal that increasing doses of the benzene metabolite, hydroquinone (HQ) induce a time-and dose-dependent alteration in the pattern of PU.1-DNA binding in cultured human CD34(+) cells, corresponding to hyperphosphorylation of the PU.1 protein. HQ-induced alterations in PU.1-DNA binding are concomitant with a sustained immature CD34(+) phenotype and cytokine-dependent enhanced clonogenic activity in cultured human HPC. These results suggest that HQ induces a dysregulation in the external signals modulating PU.1 protein phosphorylation and this dysregulation may be an early event in the generation of benzene-induced AML.

Antigens, CD34↗
PubMed2004

Hydroquinone modulates the GM-CSF signaling pathway in TF-1 cells.

Human leukemogens, including alkylating chemotherapeutic agents and benzene, enhance granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent proliferation of human CD34+ bone marrow (BM) cells. The extracellular signal-regulated kinase (ERK) pathway plays an important role in GM-CSF-dependent proliferation and also has been implicated in the pathogenesis of acute myelogenous leukemia. Therefore, we investigated the effects of the benzene metabolite, hydroquinone (HQ), on alterations in the GM-CSF signaling pathway in TF-1 erythroleukemia cells and human CD34+ BM cells. HQ treatment in TF-1 cells results in a strong proliferative response that is dependent on ERK activation and GM-CSF production. HQ also induces ERK-dependent AP-1 activation with concomitant increased transcriptional activity of AP-1 reporter gene. However, the kinetics of ERK activation are different between rhGM-CSF and HQ in TF-1 cells: rhGM-CSF results in immediate activation of ERK, whereas HQ activation of ERK is delayed. Further, HQ and rhGM-CSF together produce an immediate increase in ERK phosphorylation, which is sustained for over 48 h. HQ also stimulates colony formation, AP-1 DNA binding and GM-CSF production in human CD34+ BM cells. These results suggest that HQ stimulates proliferation via activation of ERK/AP-1 and is at least partially mediated via the production of GM-CSF.

Antigens, CD34↗
PubMed2001

Decreased intracellular potassium levels underlie increased progesterone synthesis during ovarian follicular atresia.

More than 99% of ovarian follicles are lost by a degenerative process known as atresia, a phenomenon characterized by apoptosis of granulosa cells. Uniquely, dying granulosa cells also greatly increase their progesterone biosynthesis while reducing estrogen production. Recent studies have documented a dramatic decrease in intracellular K+ concentration during apoptosis that plays an important role in regulating apoptotic enzymes. However, it is unclear whether this ionic change affects related processes such as the change in steroidogenesis in dying granulosa cells. To explore this question, granulosa cells were cultured in hypotonic medium, which initially swells the cells. The cells respond by extruding K+, which we have documented by fluorescence spectrophotometry. The K+ efflux osmotically draws water out the cell, returning it to a near normal volume (as measured by flow cytometry). The result is a cell of normal size with a decreased intracellular K+ concentration. FSH stimulation of these cells caused an increase in progesterone biosynthesis. This response was enhanced at higher doses of FSH, although basal progesterone production was not affected, suggesting that K+ levels may affect the gonadotropin-signaling pathway. No increase in steroidogenic acute regulatory or cholesterol side-chain cleavage cytochrome P450 mRNA was detected, although cAMP production was enhanced. These results suggest that the loss of intracellular K+ by apoptotic granulosa cells greatly facilitates FSH-stimulated progesterone production.

Animals↗
PubMed1996

Ophthalmologic manifestations of acquired immune deficiency syndrome-associated progressive multifocal leukoencephalopathy.

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is increasingly described as a late complication of the acquired immune deficiency syndrome (AIDS). The purpose of this study is to evaluate retrospectively the ophthalmologic, clinical, and investigational aspects of AIDS-associated PML. METHODS: The authors evaluated ten patients in whom ophthalmologic manifestations developed in the course of AIDS-associated PML. Findings at clinical examination and their progression over time, neuroimaging correlates, the results of pathologic investigation, and visual outcomes were reviewed. RESULTS: Progressive multifocal leukoencephalopathy was the AIDS-defining illness in six of ten patients. Homonymous visual field defects were the presenting symptom in three patients and detected in six patients overall. Occipital blindness developed in one patient. Cerebellar signs and brain stem nuclear and supranuclear palsies also were common. Confluent white matter lesions with increased intensity on T2-weighted magnetic resonance imaging were supratentorial in seven patients and infratentorial in three patients. With incomplete data, the median survival time was 3 months from PML onset. Histopathologic confirmation of PML diagnosis was available for nine of the ten patients. CONCLUSIONS: The development of progressive retrochiasmal visual field defects, supranuclear and nuclear cranial nerve palsies, or nystagmus ataxia in the relatively young patient should alert the ophthalmologist to the possibility of PML, particularly in the presence of long-tract central nervous system signs or dementia. Progressive multifocal leukoencephalopathy will often be human immunodeficiency virus associated. Human immunodeficiency virus encephalopathy, cerebral toxoplasmosis, lymphoma, and infarction need to be discriminated. Effective therapy is required urgently for this devastating disease.

AIDS Dementia Complex↗
PubMed1994

Aberrant innervational pattern in Duane's syndrome type II without globe retraction.

Using extraocular muscle electromyography we studied a patient with an adduction defect and face turn. The patient was found to have an anomalous firing pattern in the medial and lateral rectus muscles consistent with Duane's syndrome type II but globe retraction was absent. On the basis of this finding we concluded that mechanical factors appear to play a significant role in the globe retraction seen in Duane's syndrome.

Adolescent↗
PubMed1993

Necrotizing scleritis and transient myopia following strabismus surgery.

Necrotizing scleritis may occur following ocular surgery, most commonly after cataract extraction. This complication developed in a 60-year-old woman following strabismus surgery for a gaze palsy and sixth-nerve paresis following a stroke. Although an autoimmune process is present in many patients with necrotizing scleritis, none was detected in this patient. Inflammation was controlled with topical and systemic corticosteroids and ibuprofen. Good visual acuity was preserved, and improved ocular alignment was achieved. Transient myopia, not previously reported in necrotizing scleritis, was observed.

Female↗
PubMed1990

Risk of sexually transmitted disease among black adolescent crack users in Oakland and San Francisco, Calif.

Crack cocaine is a smokable form of cocaine hydrochloride that has been associated with increases in admissions to drug treatment programs, and, recently, increases in the incidence of sexually transmitted diseases (STDs) among black teenagers. In an exploratory, cross-sectional study of the prevalence of risk behaviors that would promote the dissemination of STDs (including human immunodeficiency virus) among 222 black teenaged crack users, 41% of those interviewed reported a history of an STD. A history of an STD was more likely to be reported by girls (55%) than by boys (34%) and by those who combined crack use with sexual relations (51%) than those who did not (32%). The number of risk behaviors for STDs or human immunodeficiency virus reported by respondents (including failure to use a condom in one's most recent sexual encounter, having had a history of an STD, engaging in exchanges of sex for drugs or money, combining sexual activity with drug use, and reporting five or more sexual partners per year) was evaluated using multiple regression analysis stratified by gender. For girls, a history of selling crack and the number of reported risk behaviors (R = .46); for boys who chose the description "I don't know ahead of time if I'm going to have sex--it just happens" and the number of drugs used on a daily basis were associated with the number of reported risk behaviors (R = .31). Because of the impetuous nature of some crack-related sexual activity and because 76% of respondents acknowledged that they were either "very worried" or "somewhat worried" that they might get acquired immunodeficiency syndrome, it is possible that a program of widespread distribution of condoms in neighborhoods where crack use is prevalent might make it possible for the worried, impulsive crack user to practice "safer sex."

Adolescent↗
PubMed1990

Amiodarone- and desethylamiodarone-induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes.

Hepatocytes isolated from Sprague-Dawley rats were incubated with various concentrations of either amiodarone or desethylamiodarone for 0 to 96 hr. Both drugs produced a concentration-dependent increase of lactate dehydrogenase release in the culture medium, which correlated well with cell death as measured by trypan blue exclusion test. Desethylamiodarone was more toxic than amiodarone in the cultured hepatocytes. Incubation with subtoxic concentrations of either amiodarone (7.6 microM) or desethylamiodarone (8 microM) for 24 hr resulted in the development of myelinoid inclusion bodies in the hepatocytes without any excess release of lactate dehydrogenase. In experimental protocols where the hepatocytes were exposed to either amiodarone or desethylamiodarone for up to 96 hr, there was an increase in lactate dehydrogenase and the percent volume-density of multilamellar inclusion bodies with cumulative drug exposure with time. A linear correlation between hepatocyte drug concentration and multilamellar inclusion bodies was found for both amiodarone and desethylamiodarone. These results demonstrate that both amiodarone and its major metabolite, desethylamiodarone, induce lysosomal inclusions, which, under appropriate conditions, can be dissociated from cell death. Withdrawal of the drug after 24 hr exposure did not result in disappearance of the inclusion bodies from the hepatocytes for up to 96 hr of tissue culture. The concentrations at which amiodarone- or desethylamiodarone-induced electron microscopic changes and hepatotoxicity were only two to five times as high as the usual serum drug levels in patients given antiarrhythmic therapy with amiodarone.

Amiodarone↗
PubMed1990

Subcellular changes of rat myocardium after treatment with amiodarone or desethylamiodarone, studied with electron microscopy.

Amiodarone, an antiarrhythmic agent, has proven to be unique in its capability to control arrhythmias unresponsive to conventional drugs. However, its association with many undesirable side effects after chronic usage has become just as clear. Chronic clinical toxicity with amiodarone is associated with intracellular lamellar or myelinoid inclusion bodies (onionoid bodies or corpora cepiformia) in various organs (i.e. skin, cornea, lung, liver, and lymph nodes). Previous study has demonstrated formation of these inclusion bodies in canine myocardium following multiple doses of amiodarone. The present study was designed to develop a more convenient animal model, and to measure the concentration of amiodarone, as well as desethylamiodarone (its major metabolite) in this rodent model. The direct role of desethylamiodarone in formation of lamellar inclusion bodies in rat myocardium was also investigated. Amiodarone (50 mg/kg) or desethylamiodarone (25 mg/kg) was injected intraperitoneally daily for a period of 14 days. Myocardial sections revealed the presence of lamellar inclusion bodies, round or oval in appearance, in the form of laminated or concentrically arranged membranes after either amiodarone or desethylamiodarone treatment. This is the first reference to the induction of these myelinoid inclusion bodies with desethylamiodarone. Myocardial tissue concentrations of amiodarone and desethylamiodarone exceeding plasma concentrations were found in the present study and indicate the capability of these compounds to easily distribute and accumulate in the myocardium.

Amiodarone↗
PubMed1989

Amiodarone and desethylamiodarone toxicity in isolated hepatocytes in culture.

Amiodarone, a class III antiarrhythmic drug, has been found to be effective in the management of patients with life-threatening ventricular arrhythmias. Recent reports describe the presence of myelinoid inclusion bodies following amiodarone therapy in liver, myocardium, white blood cells, lung, cornea, skin, and lymph nodes; their relationship to toxicity is unclear. The exact role of desethylamiodarone, the major metabolite, of amiodarone in systemic toxicity of the parent drug is not known. Concentration-response relationships for amiodarone and desethylamiodarone were investigated by adding 1-50 micrograms/ml of the compounds of dimethyl sulfoxide (controls) to hepatocytes isolated from Sprague-Dawley rats and cultured in Leibovitz L-15 medium. Using lactate dehydrogenase release into the medium to quantitate cell death, both drugs were found to cause cell death in a concentration-dependent manner within 24 hr of incubation; this data showed desethylamiodarone to be significantly more toxic than amiodarone. In experiments with 50-micrograms/ml concentrations of amiodarone or desethylamiodarone, we found desethylamiodarone to produce a significantly greater release of lactate dehydrogenase as compared with amiodarone within 2-4 hr. Electron microscopic studies indicated the presence of myelinoid inclusion bodies at early culture stages followed by progressive swelling of mitochondria and rough endoplasmic reticula, disruption of membranes, aggregation of subcellular structures, and ultimately cell death. Ultrastructural changes occurred sooner in the hepatocytes treated with desethylamiodarone than with amiodarone. These data demonstrate that (i) desethylamiodarone is more toxic than amiodarone; (ii) acute toxicity of desethylamiodarone and amiodarone can be quantitated by lactate dehydrogenase release; (iii) both desethylamiodarone and amiodarone can induce myelinoid inclusion bodies in cultured hepatocytes; and (iv) toxicity is characterized by progressive subcellular changes leading to cell death.

Amiodarone↗
PubMed1988

Histochemical localization of prostaglandin-synthetase in the salivary glands of Praomys (Mastomys) natalensis.

The cellular distribution of prostaglandin-synthetase was studied in the salivary glands of Praomys (Mastomys) natalensis. Only the epithelial cells of the ducts showed discrete prostaglandin-synthetase activity, whereas the acini and the stroma gave completely negative results in all three salivary glands of both sexes. The presence of exogenous substrates was not required for the reaction, since identical results are observed following incubation with and without arachidonic acid. The localization of prostaglandin synthetase in the ductal epithelia of Praomys salivary glands is related to a possible regulatory role of the prostaglandins on the reabsorptive activity of the ductal cells.

Animals↗
PubMed1988

The prostate in pregnant and non-pregnant Praomys (Mastomys) Natalensis at the subcellular level.

The prostate of the pregnant Praomys appears more active than that of the non-pregnant Praomys. At the light microscopic level, the most obvious features are heightening of secretory cells and increased secretory product in acinar lumina. Apparent at the electron microscopic level are an increase and dilation of the rough endoplasmic reticulum, numerous scattered secretion granules, and a dilated Golgi apparatus. Therefore, stimulation of the gland is evident upon cytological evaluation and this increased activity may be due to the direct or indirect effects of androgenic stimulation.

Animals↗
PubMed1987

Magnetic resonance imaging of optic tract involvement in multiple sclerosis.

We studied two cases of optic tract involvement in multiple sclerosis with documentation by magnetic resonance imaging. In one, incongruous homonymous hemianopsia was accompanied by a decrease in visual acuity in one eye from chiasmal involvement. In the other, the involvement was restricted to the optic tract and the homonymous hemianoptic visual field defect was nearly congruous.

Adult↗
PubMed1987

Comparative morphology of the prostate in adult male and female Praomys (Mastomys) Natalensis studied with electron microscopy.

Comparative study at the cellular and subcellular levels of the adult male and female prostates of a unique species of rodent--Praomys (Mastomys) Natalensis--was made. The female possesses a well-developed prostate throughout life that may be considered homologous to the ventral prostatic lobe in the male Praomys. Histologically, only small differences exist to indicate that the female prostate is somewhat less active than the male (less secretion and the presence of fewer supranuclear light areas in the female than in the male prostate). At the electron microscopic level, within the female prostatic cells, there is less rough endoplasmic reticulum, and the number of secretory granules is lower than in the male. The arrangement of the cells, the organization of the subcellular structures, and the mode of secretion in both female and male prostates, however, are similar.

Animals↗
PubMed1986

Amiodarone-associated changes in human neutrophils.

Amiodarone and its major metabolite, desethylamiodarone, were measured in the plasma, white blood cells (WBCs) and red blood cells (RBCs) of 14 patients receiving chronic amiodarone therapy. The mean plasma concentrations (+/- standard error of the mean) of amiodarone and desethylamiodarone were 2.4 +/- 0.6 and 1.6 +/- 0.4 microgram/ml, respectively. The drug level in the WBCs was 62 +/- 12 micrograms/g protein during the early loading phase and 106 +/- 33 micrograms/g protein during maintenance phase of amiodarone therapy. Desethylamiodarone concentration in the WBCs was 42 +/- 18 and 190 +/- 33 micrograms/g protein during the loading and maintenance phases, respectively. Although a trend in WBC to plasma concentration was seen, there was no linear correlation between these levels. In 1 patient with severe neuropathy, biopsy of the nerve and muscle showed high concentrations of both amiodarone and desethylamiodarone. Although there was a decrease in tissue drug levels, proportionately high tissue:plasma drug levels were detected at the time of necropsy approximately 6.5 months after amiodarone was discontinued in this patient. Neutrophils from all patients receiving chronic amiodarone therapy showed multiple myelin-like polymorphic inclusion bodies (onionoid bodies) upon electron microscopic examination. Our observations suggest that WBC drug concentrations and electron microscopic changes may provide a means of correlating tissue concentrations and of following patients receiving chronic amiodarone therapy.

Amiodarone↗