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Biomedical subjects

J E Fisher

Publications and source records attributed to J E Fisher.

At least 19 recordsLinked to original sources
PubMed2004

Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins.

Osteoporosis is associated with both atherosclerosis and vascular calcification. No mechanism yet explains the parallel progression of these diseases. Here, we demonstrate that osteoclasts (OCL) depend on lipoproteins to modulate cellular cholesterol levels and that this controls OCL formation and survival. Removal of cholesterol in OCL via high-density lipoprotein or cyclodextrin treatment dose-dependently induced apoptosis, with actin disruption, nuclear condensation and caspase-3 activation. One mechanism linked to the induction of OCL apoptosis was the cell-type-specific failure to induce HMG-CoA reductase mRNA expression, suggesting an absence of feedback regulation of de novo cholesterol biosynthesis. Furthermore, cyclodextrin treatment substantially suppressed essential M-CSF and RANKL-induced survival signaling pathways via Akt, mTOR and S6K. Consistent with these findings, cholesterol delivery via low-density lipoprotein (LDL) significantly increased OCL viability. Interestingly, OCLs from the LDL receptor (LDLR)-/- mouse exhibited reduced size and lifespan in vitro. Remarkably, LDLR+/+ OCL in lipoprotein-deficient medium phenocopied LDLR-/- OCL, while fusion and spreading of LDLR-/- OCL was rescued when cholesterol was chemically delivered during differentiation. With hyperlipidemia being associated with disease of the vascular system and bone, these findings provide novel insights into the selective lipoprotein and cholesterol dependency of the bone resorbing cell. Cell Death and Differentiation (2004) 11, S108-S118. doi:10.1038/sj.cdd.4401399 Published online 12 March 2004

Animals↗
PubMed2003

M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase.

Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFalpha, activates NF-kappaB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin (mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF- and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.

Acid Phosphatase↗
PubMed2002

Semantic clustering in verbal fluency: schizophrenic patients versus control participants.

BACKGROUND: Schizophrenic patients generate fewer words than healthy controls during verbal fluency tasks. The structure of output may explain why patients generate fewer exemplars. METHODS: Twenty-four healthy controls and 24 patients with schizophrenia participated in six, 3 min semantic fluency tasks. In a subsequent session, participants were given cards, each printed with one of their own words generated from previous fluency tasks. Participants were to sort the cards into categories (e.g. subcategories of 'animals'), thus defining their own semantic subcategories of words, and thereby eliminating experimenter assumptions about word relatedness. These clusters were matched with fluency output of each participant. The time spent searching through semantic networks within clusters and switching to other clusters when locating and producing associated words were measured. RESULTS: Patients produced fewer words and spent more time switching to words within clusters and to different clusters than controls, but otherwise response profiles were similar. Although controls returned more frequently to clusters and consequently made more switches between these clusters than patients, this group difference disappeared when the total number of words produced was covaried. CONCLUSIONS: Consistent with previous literature, patients produced fewer words and made more errors than controls. The absence of a group difference in number of different clusters or mean number of items per cluster suggests that patients are similar to controls with respect to number of ideas in their semantic network. Patients' longer between-cluster switching times indicate a general slowness that may be attributed to difficulties finding new words within a semantic field.

Adult↗
PubMed2001

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

Animals↗
PubMed2000

Patterns of MHR3 expression in the epidermis during a larval molt of the tobacco hornworm Manduca sexta.

MHR3, an ecdysone-induced transcription factor, was shown to appear in the abdominal epidermis of the tobacco hornworm Manduca sexta in a pattern-specific manner as the 20-hydroxyecdysone (20E) titer rises for the larval molt. The crochet epidermis that forms the hooked setae on the proleg is first to show MHR3 mRNA and protein followed sequentially by the spiracle, the dorsal intrasegmental annuli, the interannular regions, and finally the trichogen and tormogen cells. The protein appears in the nuclei about 8 h before the onset of cuticle formation, is present during the outgrowth of the setae, and disappears after epicuticle formation. In vitro studies showed that MHR3 mRNA induction in the crochet epidermis by 20E was more sensitive (EC(50) = 10(-6) M; 50% induction by 2 h exposure to 4 x 10(-6) M 20E) and did not require protein synthesis for maximal accumulation compared to the dorsal epidermis. The ecdysone receptor complex is present in both tissues at the outset of the molt and therefore is not a determining factor in these responses. Thus, in addition to the ecdysone receptor complex, region-specific factors govern both sensitivity and timing of responsiveness of MHR3 to 20E to ensure that this transcription factor will be present when needed for its differentiative role.

Animals↗
PubMed2000

Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist.

Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.

Animals↗
PubMed2000

Lipoblastoma: better termed infantile lipoma?

Lipoblastoma is a rare adipose tumor occurring exclusively in childhood. There have been no reports of metastases, making the designation "blastoma" confusing, since this term is usually reserved for malignant tumors. Two recent cases treated at our institution confirm its benign nature. In addition, a review of the literature supports the idea that the tumor may more accurately be described as an "infantile lipoma". Infantile lipoma better reflects many of the tumor's characteristics such as, its early occurrence, it's ability to mature into a simple lipoma, it's cellular composition of mainly mature adipocytes, and its benign course. Although lipoblastoma is an uncommonly encountered tumor, making an effort to change its name to infantile lipoma will result in a more a accurate term that will facilitate treatment.

Abdominal Neoplasms↗
PubMed2000

In vivo effects of bisphosphonates on the osteoclast mevalonate pathway.

Estrogen deficiency is a leading cause of osteoporosis associated with increased osteoclastic bone resorption. In vitro studies indicate that the clinically used nitrogen-containing bisphosphonates (N-BPs) such as alendronate (ALN), risedronate (RIS) and ibandronate (IBA) suppress bone resorption via inhibition of the mevalonate pathway enzyme farnesyl diphosphate (FPP) synthase in osteoclasts (Ocs). The object of this study was to test the hypothesis that N-BPs inhibit the mevalonate pathway of Ocs in vivo. The mevalonate pathway enzyme hydroxymethyl-glutaryl-coenzyme A reductase (HMGR), is modulated by feedback inhibition from downstream metabolites. We therefore evaluated the in vivo expression of HMGR in Ocs from animals treated with BP. The N-BPs, ALN, IBA and RIS, selectively suppressed HMGR expression in up to 85% of rat tibia osteoclasts, after 48 hr treatment. Etidronate and clodronate, bisphosphonates that do not inhibit FPP synthase, were without effect. Simvastatin treatment opposed ALN reduction of HMGR expression, suggesting regulation by a metabolite(s) between mevalonate and FPP. These data provide the first in vivo evidence for N-BP effects on the mevalonate pathway in osteoclasts, and strongly support the hypothesis that N-BPs act via this mechanism.

Alendronate↗
PubMed2000

Characteristics of empirically supported treatments.

This study presents a survey of general characteristics of empirically supported treatments (ESTs) identified by the American Psychological Association Division 12 Task Force on the Promotion and Dissemination of Psychological Procedures. Results indicate that the ESTs share the following characteristics: they involve skill building, have a specific problem focus, incorporate continuous assessment of client progress, and involve brief treatment contact, requiring 20 or fewer sessions. Traditional assessment methods, such as intelligence testing, projectives, and objective personality tests such as the MMPI-2, are rarely used in these treatments. Although it is recognized that these findings are in part an artifact of sociological factors present in contemporary psychotherapy development and research, the findings may also serve as a heuristic aid in the development of therapies.

Behavior Therapy↗
PubMed1999

Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro.

Nitrogen-containing bisphosphonates were shown to cause macrophage apoptosis by inhibiting enzymes in the biosynthetic pathway leading from mevalonate to cholesterol. This study suggests that, in osteoclasts, geranylgeranyl diphosphate, the substrate for prenylation of most GTP binding proteins, is likely to be the crucial intermediate affected by these bisphosphonates. We report that murine osteoclast formation in culture is inhibited by both lovastatin, an inhibitor of hydroxymethylglutaryl CoA reductase, and alendronate. Lovastatin effects are blocked fully by mevalonate and less effectively by geranylgeraniol whereas alendronate effects are blocked partially by mevalonate and more effectively by geranylgeraniol. Alendronate inhibition of bone resorption in mouse calvaria also is blocked by mevalonate whereas clodronate inhibition is not. Furthermore, rabbit osteoclast formation and activity also are inhibited by lovastatin and alendronate. The lovastatin effects are prevented by mevalonate or geranylgeraniol, and alendronate effects are prevented by geranylgeraniol. Farnesol and squalene are without effect. Signaling studies show that lovastatin and alendronate activate in purified osteoclasts a 34-kDa kinase. Lovastatin-mediated activation is blocked by mevalonate and geranylgeraniol whereas alendronate activation is blocked by geranylgeraniol. Together, these findings support the hypothesis that alendronate, acting directly on osteoclasts, inhibits a rate-limiting step in the cholesterol biosynthesis pathway, essential for osteoclast function. This inhibition is prevented by exogenous geranylgeraniol, probably required for prenylation of GTP binding proteins that control cytoskeletal reorganization, vesicular fusion, and apoptosis, processes involved in osteoclast activation and survival.

Alendronate↗
PubMed1998

High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange.

Partial liquid ventilation using conventional ventilatory schemes improves lung function in animal models of respiratory failure. We examined the feasibility of high-frequency partial liquid ventilation in the preterm lamb with respiratory distress syndrome and evaluated its effect on pulmonary and systemic hemodynamics. Seventeen lambs were studied in three groups: high-frequency gas ventilation (Gas group), high-frequency partial liquid ventilation (Liquid group), and high-frequency partial liquid ventilation with hypoxia-hypercarbia (Liquid-Hypoxia group). High-frequency partial liquid ventilation increased oxygenation compared with high-frequency gas ventilation over 5 h (arterial oxygen tension 253 +/- 21.3 vs. 17 +/- 1.8 Torr; P < 0.001). Pulmonary vascular resistance decreased 78% (P < 0.001), pulmonary blood flow increased fivefold (P < 0.001), and aortic pressure was maintained (P < 0.01) in the Liquid group, in contrast to progressive hypoxemia, hypercarbia, and shock in the Gas group. Central venous pressure did not change. The Liquid-Hypoxia group was similar to the Gas group. We conclude that high-frequency partial liquid ventilation improves gas exchange and stabilizes pulmonary and systemic hemodynamics compared with high-frequency gas ventilation. The stabilization appears to be due in large part to improvement in gas exchange.

Animals↗
PubMed1998

The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats.

Integrins that bind RGD (arginine-glycine-aspartic acid) containing peptides, especially the vitronectin receptor alpha(v)beta3, have been implicated in the regulation of osteoclast function. Echistatin, an RGD-containing snake venom peptide with high affinity for beta3 integrins, as well as nonpeptide RGD mimetics, were shown to inhibit osteoclastic bone resorption in vitro and in vivo. To evaluate the role of RGD-binding integrins in bone metabolism, we examined by several methods the effects of echistatin on ovariectomy (OVX)-induced bone loss in mice and rats. First, we confirmed that echistatin binds in vitro with high affinity (Kd, 0.5 nM) to alpha(v)beta3 integrin purified from human placenta and established a competitive binding assay to measure echistatin concentrations in serum. We find that echistatin infused for 2 or 4 weeks at 0.36 microg/h x g body weight (approximately 50 nmol/day x mouse) completely prevents OVX-induced cancellous bone loss in the distal femora of ovariectomized mice. Echistatin has no effect on uterine weight, body weight, and femoral length changes induced by OVX, nor does it cause any apparent changes in major organs other than bone. In OVX rats, echistatin infusion at 0.26 microg/h x g for 4 weeks effectively prevents bone loss, evaluated by dual energy x-ray absorptiometry of the femur, by femoral ash weight, and by bone histomorphometry of the proximal tibia. At effective serum concentrations of 20-30 nM, measured at the end of the infusion period, echistatin maintains histomorphometric indices of bone turnover at control levels but does not decrease osteoclast surface. In conclusion, these results provide in vivo evidence, at the level of bone histology, that RGD-binding integrins, probably alpha(v)beta3, play a rate-limiting role in osteoclastic bone resorption and suggest a therapeutic potential for integrin ligands in the suppression of bone loss.

Animals↗
PubMed1997

Gestational diabetes mellitus in women receiving beta-adrenergics and corticosteroids for threatened preterm delivery.

OBJECTIVE: To determine whether the incidence of gestational diabetes mellitus (GDM) is increased in patients receiving corticosteroids with or without beta-adrenergic agents for threatened preterm delivery. METHODS: We reviewed the laboratory records of 3396 patients undergoing screening (1-hour glucose) and diagnostic testing (3-hour glucose tolerance test [GTT]) for GDM over 2 years. Patients with antepartum admissions during which they received corticosteroids with or without beta-adrenergic agents for threatened preterm delivery were compared with a control group during the same period. Differences between the study and control groups were analyzed using chi 2, Student t test, or Fisher exact test where appropriate. P < .05 was considered significant. RESULTS: Fifty patients in the study group were compared with 1985 control patients. The remaining 1361 patients failed to meet inclusion criteria. The overall incidence of diagnosed GDM was significantly greater in the corticosteroid-beta-adrenergic agents study group, in which five (23.8%) of 21 patients screened had abnormal 3-hour GTT results, compared with 79 (4.0%) of 1985 controls (P = .001). One-hour glucose screening test results were abnormal in 60% of the study group compared with 25% of the controls (P < .001). CONCLUSION: Patients treated with beta-adrenergic agents and corticosteroids for threatened preterm delivery are at a significantly increased risk for developing GDM. The high rate of abnormal results in response to the 1-hour glucose screen suggests that this test is of limited value in patients exposed to these medications.

Adrenergic beta-Agonists↗
PubMed1996

Behavioral effects of prenatal exposure to pulsed-wave ultrasound in unanesthetized rats.

The present experiment examined the developmental neurotoxicity of pulsed-wave (pw) ultrasound in rats, using an exposure system designed to eliminate restraint or anesthesia from the exposure conditions. Pregnant Sprague-Dawley CD rats trained to remain immobile in a water-filled ultrasound exposure tank were scanned with 3-MHz pw ultrasound at spatial peak temporal average intensities (ISPTA) of 0, 2, 20, or 30 W/cm2 on embryonic days 4-20 for approximately 10 min/day. The data showed that such insonation produced no adverse effects on maternal weight gain or reproductive outcome, nor on the postnatal growth or survival of the offspring. No exposure-related alterations in behavioral development were observed in the offspring of rats scanned with pw ultrasound during gestation. In addition, there was no consistent evidence of an ultrasound-associated change in the adult offspring behaviors tested; i.e., no treatment effects were found on measures of locomotor activity, water maze learning, and acoustic startle reactivity. An effect on tactile startle was observed on some trials in the low exposure group male offspring, but this effect was neither dose dependent nor consistent with any other finding. Overall, these results indicate that the neurobehavioral development of rats was not altered by prenatal exposure to pw ultrasound at ISPTA levels of up to 30 W/cm2.

Animals↗
PubMed1996

Perfluorocarbon-associated gas exchange improves oxygenation, lung mechanics, and survival in a model of adult respiratory distress syndrome.

OBJECTIVE: To compare the effectiveness of perfluorocarbon-associated gas exchange to volume controlled positive pressure breathing in supporting gas exchange, lung mechanics, and survival in an acute lung injury model. DESIGN: A prospective, randomized study. SETTING: A university medical school laboratory approved for animal research. SUBJECTS: Neonatal piglets. INTERVENTIONS: Eighteen piglets were randomized to receive perfluorcarbon-associated gas exchange with perflubron (n=10) or volume controlled continuous positive pressure breathing (n=8) after acute lung injury was induced by oleic acid infusion (0.15 mL/kg iv). MEASUREMENTS AND MAIN RESULTS: Arterial and venous blood gases, hemodynamics, and lung mechanics were measured every 15 mins during a 3-hr study period. All animals developed a metabolic and a respiratory acidosis during the infusion of oleic acid. Following randomization, the volume controlled positive pressure breathing group developed a profound acidosis (p<.05), while pH did not change in the perfluorocarbon-associated gas exchange group. Within 15 mins of initiating perfluorocarbon-associated gas exchange, oxygenation increased from a PaO2 of 52 +/- 12 torr (6.92 +/- 1.60 kPa) to 151 +/- 93 torr (20.0 +/- 12.4 kPa) and continued to improve throughout the study (p<.05). Animals that received volume controlled positive pressure breathing remained hypoxic with no appreciable change in PaO2. Although both groups developed hypercarbia during oleic acid infusion, PaCO2, steadily increased over time in the control group (p<.01). Static lung compliance significantly increased postrandomization (60 mins) in the animals supported by perflurocarbon-associated gas exchange (p<.05), whereas it remained unchanged over time in the volume controlled positive pressure breathing group. However, survival was significantly higher in the perfluorocarbon-associated gas exchange group with eight (80%) of ten animals surviving the entire study period. Only two (25%) of the eight animals in the volume controlled positive pressure breathing group were alive at the end of the study period (log-rank statistic, p=.013). CONCLUSIONS: Perflurocarbon-associated gas exchange enhanced gas exchange, pulmonary mechanics, and survival in this model of acute lung injury.

Animals↗
PubMed1996

Oncogene expression in patients with familial polyposis coli/Gardner's syndrome.

We evaluated whether c-myc and ras P-21 oncogene expression could identify familial polyposis coli/Gardner's syndrome patients at risk for colon cancer. Monoclonal antibodies recognizing c-myc and ras P-21 proteins were used in immunohistochemistry to stain 26 paraffin-embedded tissue specimens collected over 12 years from 5 familial polyposis coli/Gardner's syndrome patients at various stages of their disease. Differences in staining intensity between specimens were noted with each of the two tissues markers; however, c-myc showed also a distinct cellular staining pattern in patients with advanced histologic features. The c-myc oncogene exhibited strong homogeneous cytoplasmic staining in all adenocarcinoma specimens; weak cytoplasmic staining was found in normal biopsies and in 5/10 familial polyposis coli/Gardner's syndrome specimens in the early stage of disease. In contrast, a heterogeneous staining pattern with a strong supranuclear and weak nuclear and cytoplasmic staining was demonstrated in specimens with advanced histologic features of familial polyposis coli/ Gardner's syndrome and also in postoperative ileal specimens. Anti-ras P-21 antibody, on the other hand, demonstrated a homogeneous cytoplasmic staining pattern in all specimens. We feel that the c-myc oncogene expression, in distinction to that of ras P-21, has potential as a genetic tissue marker to distinguish early from more progressive disease.

Adenocarcinoma↗