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At least 127 records · Page 7Linked to original sources
PubMed2001

Post-surgical hemorrhage: formation of a "liver clot" secondary to periodontal plastic surgery.

Bleeding is a common sequela of periodontal and oral surgery. Generally, bleeding is self-limiting. Special circumstances require additional procedures to reduce or eliminate active hemorrhage. Occasionally hemorrhage can be under control when a patient is dismissed from their surgical appointment and, subsequently, the patient will experience either slow seepage of blood or extravascular clot formation. This case report describes the unique formation of a "liver clot" or "currant jelly clot" following periodontal plastic surgery. The clotting cascade and common laboratory tests to evaluate bleeding disorders are also presented.

Collagen↗
PubMedDate not supplied

A necessity for MAP kinase activation in mammalian spatial learning.

Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of protein kinases and phosphorylation of their downstream effectors plays a major role. Recent findings in our laboratory have shown a requirement for the mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to test the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperitoneally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatial learning, we administered SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platform compared with vehicle-treated controls and also failed to use a selective search strategy during subsequent probe trials in which the platform was removed. These impairments cannot be attributed to nonspecific effects of the drug during the training phase; no deficit was seen in the visible platform task, and injection of SL327 following training produced no effect on the performance of these mice in the hidden platform task. These findings indicate that the MAPK cascade is required for spatial and contextual learning in mice.

Animals↗
PubMed1992

The role of natural IgM in the hyperacute rejection of discordant heart xenografts.

The mechanism of xenograft hyperacute rejection in discordant species combinations remains controversial. The purpose of this work was to study the role of natural antibodies in the hyperacute rejection of guinea pig hearts transplanted into rats, a highly discordant combination. This study was conducted in vitro, ex vivo, and in vivo. The endothelial cells of the graft being the first targets damaged in the process of hyperacute rejection, the binding of rat natural antibodies to guinea pig endothelial cells was studied by immunofluorescence. The study was carried out in vitro on guinea pig endothelial cells in culture, and ex vivo on isolated guinea pig hearts perfused with either rat serum or immunoglobulins or immunoglobulin fragments bearing the antigen-binding site. In vitro and ex vivo, rat natural IgM were found to bind specifically to guinea pig endothelial cells, since IgM fragments bearing the antigen-binding site (Fab mu and Fab' mu) could be detected on these cells. IgM fragments were able to inhibit the fixation of native IgM molecules. In contrast, rat IgG only bound to endothelial cells through Fc portions. Thus rat natural IgM might play a role in hyperacute rejection by binding to the graft endothelial cells and triggering the complement cascade activation. In order to test the role of natural IgM in vivo, isolated guinea pig hearts were first perfused with rat Fab' mu, which inhibit the binding of IgM and are unable to activate the complement cascade. These hearts were then transplanted into Lewis rats. The rejection time of Fab' mu-perfused guinea pig hearts was prolonged compared with hearts perfused with buffer or IgG F(ab')2. Therefore, in the guinea pig to rat combination, preventing the binding of the recipient's natural IgM to the graft endothelium delays the hyperacute rejection. In addition, natural IgM are likely to play a greater role than natural IgG.

Animals↗
PubMed2000

Value of predictive genetic testing in management of hereditary non-polyposis colorectal cancer (HNPCC)

OBJECTIVE: To investigate the impact of predictive genetic testing on colonoscopic surveillance in an extended family with hereditary non-polyposis colorectal cancer (HNPCC). SETTING: Familial Bowel Cancer Service, The Royal Melbourne Hospital, Victoria. SUBJECTS: 96 people registered with the Service who were apparently unaffected members of an extended family that met the classic Amsterdam criteria for HNPCC and carried an MLH1 gene mutation (IVS9 + 3insT). INTERVENTION: Predictive genetic testing was offered in a cascade manner to at-risk family members; mutation-positive individuals were advised to have annual colonoscopic surveillance, while mutation-negative individuals were withdrawn from surveillance. MAIN OUTCOME MEASURES: Previous compliance with recommended colonoscopic surveillance; uptake and results of genetic testing; expected effect of genetic test results on number of colonoscopies over five years. RESULTS: 22 of the 96 family members (23%) were not complying with recommended surveillance. Of 48 individuals offered predictive genetic testing, 41 (85%) responded and 39 (81%) underwent testing. Seven of the 39 (18%) were positive for the family-specific mutation, and 32 (82%) were negative. The 39 tested individuals and 37 of their descendants who were registered with the screening program had undergone 70 colonoscopies in the five years before genetic testing. In the five years after testing, only 37 surveillance colonoscopies were planned (annual or two-yearly colonoscopies for the six mutation-positive individuals and five-yearly colonoscopies for four mutation-negative individuals with previously identified adenoma), an almost 50% reduction in colonoscopies. CONCLUSION: Predictive genetic testing in HNPCC families allows many individuals to be withdrawn from regular colonoscopic surveillance. It may therefore reduce costs, as well as have emotional benefits for many individuals.

Adult↗
PubMed2003

Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test.

It is generally accepted that the phospholipase-A2-cyclooxygenase-prostanoids-cascade mediates spinal sensitization and hyperalgesia. However, some observations are not in line with this hypothesis. The aim of the present work was to investigate whether different components of this cascade exhibit nociceptive or antinociceptive effects in the rat formalin test. Intrathecal (i.th.) injection of prostaglandin E2 (PGE2) induced a dose-dependent antinociceptive effect on the formalin-induced nociception. Furthermore, thimerosal, which inhibits the reacylation of arachidonic acid thereby enhancing arachidonic acid levels, had an antinociceptive effect rather than the expected pronociceptive effect when given i.th. While the phospholipase A2 inhibitor methyl arachidonyl fluorophosphonate (MAFP; i.th.) had a significant antinociceptive effect, its analogue palmitoyl trifluoromethyl ketone (PTFMK; i.th.) had no significant effect on the formalin-induced nociception. However, MAFP, but not PTFMK, showed a cannabinoid CB1 agonistic effect as shown by the inhibition of electrically evoked contractions of the vas deferens isolated from CB1 wild-type mice but not of that from CB1 knockout mice. The antinociceptive effect of MAFP was completely reversed by the CB1 receptor antagonist AM-251 (i.th.), thus attributing such effect to its CB1 agonistic effect. Moreover, the antinociceptive effect of the cyclooxygenase inhibitor, flurbiprofen (i.th.) was reversed by the co-administration of AM-251, but not by PGE2. Finally. the combination of phenylmethylsulfonyl fluoride (PMSF; intraperitoneal), which inhibits the degradation of anandamide through the inhibition of fatty acid amidohydrolase, with thimerosal (i.th.) produced a profound CB1-dependent antinociception. The present results show that endocannabinoids play a major role in mediating flurbiprofen-induced antinociception at the spinal level.

Analgesics↗
PubMed1999

Trophic cascades in a complex terrestrial community.

To test for direct and indirect effects of a top predator on three lower trophic levels, we conducted two multiyear predator addition experiments in a tropical wet forest. Periodic additions of a top predator (predatory clerid beetle) to a wet forest understory shrub caused a reduction in the predatory beetle's prey (a predatory ant), increased herbivory, and reduced leaf area of the plant. These effects occurred whether beetles were added to naturally occurring shrubs or to reproductive fragments, suggesting fitness effects of top predators through three trophic levels. A correlational study showed that trophic effects of top predators also cascaded to nearby conspecifics in the forest understory. We use trends from understory plant surveys to suggest mechanisms by which these cascades could ultimately affect species diversity in the local plant community.

Journal Article↗
PubMed1998

Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics.

Delayed effects for pharmacodynamic responses can be observed for many signal transduction processes. Three approaches are summarized in this report to describe such effects caused by cascading steps: stochastic process model, gamma distribution function, and transit compartment model. The gamma distribution function, a probability density function of the waiting time for the final step in a stochastic process model, is a function of time with two variables: number of compartments N, and the expected number of compartments occurring per unit time k. The parameter k is equal to 1/tau, where tau is the mean transit time in the stochastic process model. Effects of N and k on the gamma distribution function were examined. The transit compartment model can link the pharmacokinetic profile of the tested compound, receptor occupancy, and cascade steps for the signal transduction process. Time delays are described by numbers of steps, the mean transit time tau, and the amplification or suppression of the process as characterized by a power coefficient gamma. The effects of N, tau, and gamma on signal transduction profiles are shown. The gamma distribution function can be utilized to estimate N and k values when the final response profile is available, but it is less flexible than transit compartments when dose-response relationships, receptor dynamics, and efficiency of the transduction process are of concern. The transit compartment model is useful in pharmacokinetic/pharmacodynamic modeling to describe precursor/product relationships in signal transduction process.

Animals↗
PubMed2003

Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis.

The purpose of this study was to define nebulization conditions providing delivery of aerosols of EPI-hNE4, an inhibitor of human neutrophil elastase (HNE). EPI-hNE4 was nebulized with Pari LC Star and tested at three concentrations (2.5, 5, and 10 mg/mL). The inhaled mass was measured over 15 min. Particle size distribution was measured by cascade impaction. The effect was also tested of mixing EPI-hNE4 with a (99m)Tc human serum albumin (HSA) tracer on the aerodynamic properties of the aerosol. The inhibitory activity of EPI-hNE4 after nebulization was assessed on purified HNE. The inhaled mass was 32.3 +/- 3.5% (mean +/- SD) after 10 min and 44.2 +/- 3.8% (mean +/- SD) after 15 min. Mass median aerodynamic diameter ranged between 1.2 and 1.8 microm. The (99m)Tc HSA EPI-hNE4 aerosol was similar in terms of particle size distribution (y = 1.0338x - 0.003, r = 0.83). (99m)Tc activity was predictive of EPI-hNE4 mass distribution (y = 1.0278x - 1.6991, r = 0.89). The inhibitory capacity of aerosolized samples remained unchanged after up to 10 min of nebulization. EPI-hNE4 can be nebulized efficiently without decrease in its activity. Mixing this inhibitor with (99m)Tc HSA should allow quantification of its deposition in CF patients.

Administration, Inhalation↗
PubMed1999

Insulin stimulates ecdysteroid production through a conserved signaling cascade in the mosquito Aedes aegypti.

Selective activators and inhibitors of insulin signaling cascades in mammalian cells were tested for their effects on insulin stimulated steroidogenesis by ovaries of Aedes aegypti. Bovine insulin in the concentration range of 1.7 microM to 85 microM stimulated ecdysteroidogenesis in vitro. Pervanadate, an inhibitor of tyrosine kinase phosphatase, stimulated ecdysteroid production at concentrations of 250 microM to 1 microM. Okidaic acid, a serine/threonine phosphatase inhibitor, stimulated steroidogenesis with an ED50 of 77.39 nM. A selective inhibitor of tyrosine kinase activity, HNMPA-(AM3), inhibited ecdysteroid production with an IC50 of 14.2 microM. Two selective inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY294002, inhibited ecdysteroid production at low concentrations (IC50 = 1.6 nM and 30 nM, respectively). These concentrations are similar to those inhibiting insulin action in mammalian cells. A selective inhibitor of mitogen-activated protein kinase, PD098059, had no effect on ecdysteroid production even up to 100 microM. Thus, insulin stimulation of ecdysteroid production by ovaries in vitro appears to be controlled by the tyrosine kinase activity of the mosquito insulin receptor and the signaling cascade involving phosphatidylinositol 3-kinase and protein kinase B.

Aedes↗
PubMed1998

Comparison of beta-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer's disease patients: amorphic plaques and cytoskeletal changes occur independently.

Alzheimer's disease is characterized neuropathologically by senile plaques and cytoskeletal changes. It has been proposed that amorphic plaques would locally induce anterograde propagation of cytoskeletal changes in consecutive neurons followed by amorphic plaque deposition at their axonal terminals. The Alzheimer changes would spread in this way along neural pathways. To test the 'primary amyloid anatomical cascade hypothesis', Congo red staining, beta-protein/A4 (Abeta) antiserum and Alz-50, which recognizes cytoskeletal changes, were applied to the hypothalamus and adjoining brain areas of five Alzheimer's disease patients of 40-90 years of age and five age- and sex-matched controls. The results showed that (1) virtually all Abeta plaques in the hypothalamus were of the Congo red-negative amorphic type; (2) amorphic plaques and Alz-50-stained cytokeletal changes were observed not only in all Alzheimer's disease patients but also in a non-demented, 90-year-old control subject; (3) the density of amorphic plaques in the hypothalamus was unrelated to the duration of the dementia; (4) the density of amorphic plaques was unrelated to that of Alz-50-stained cytoskeletal changes; (5) double-labeling with anti-Abeta and Alz-50 did not show an evident topical relationship between amorphic plaque deposition and the occurrence of cytoskeletal changes; and (6) the distribution of Abeta and Alz-50 staining in five brain areas, for which essential anatomical information is available, did not support the primary amyloid anatomical cascade hypothesis. Amorphic plaques and cytoskeletal changes rather occur independently.

Adult↗
PubMedDate not supplied

Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.

Animal models that simulate various aspects of human brain aging are an essential step in the development of interventions to manage cognitive dysfunction in the elderly. Over the past several years we have been studying cognition and neuropathology in the aged-canine (dog). Like humans, canines naturally accumulate deposits of beta-amyloid (Abeta) in the brain with age. Further, canines and humans share the same Abeta sequence and also first show deposits of the longer Abeta1-42 species followed by the deposition of Abeta1-40. Aged canines like humans also show increased oxidative damage. As a function of age, canines show impaired learning and memory on tasks similar to those used in aged primates and humans. The extent of Abeta deposition correlates with the severity of cognitive dysfunction in canines. To test the hypothesis that a cascade of mechanisms centered on oxidative damage and Abeta results in cognitive dysfunction we have evaluated the cognitive effects of an antioxidant diet in aged canines. The diet resulted in a significant improvement in the ability of aged but not young animals to acquire progressively more difficult learning tasks (e.g. oddity discrimination learning). The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies.

Aging↗
PubMed2002

Predicting the quality of powders for inhalation from surface energy and area.

PURPOSE: To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. METHODS: Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler (GlaxoSmithKline) or Handihaler (Boehringer Ingelheim). RESULTS: In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R2 value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. CONCLUSIONS: A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.

Administration, Inhalation↗
PubMed2000

Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro.

The melanoma differentiation-associated gene-7 (mda-7), cloned from a human melanoma cell line H0-1, is known to induce tumor cell-selective growth inhibition in breast cancer cells in vitro and loss of tumorigenicity ex vivo. Yet, the mechanisms underlying these effects are still unknown. Therefore, we investigated these mechanisms on the molecular level in human non-small cell lung carcinoma (NSCLC) cells in vitro. Overexpression of mda-7 protein by Ad-mda-7 significantly suppressed proliferation and induced G2/M cell cycle arrest in wild-type p53 (A549, H460), and p53-null (H1299) non-small cell lung cancer cell lines, but not in normal human lung fibroblast (NHLF) cells. p53, Bax, and Bak protein expression was up-regulated in wild-type p53 tumor cell lines, but not in p53-null cells, suggesting that an intact p53 pathway was required for Bax and Bak induction. However, in all three cancer cell lines tested, activation of the caspase cascade and cleavage of poly(ADP-ribose) polymerase (PARP) appeared to be independent of the p53 mutational status. Together, these results suggest that apoptosis may be induced via multiple pathways by Ad-mda-7 in lung cancer cells and that Ad-mda-7 has the potential to become a novel therapeutic for clinical cancer gene therapy. Gene Therapy (2000) 7, 2051-2057.

Adenoviridae↗
PubMed1988

Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa.

Based on the observation that high levels of renin and angiotensin II (Ang II) are found in the adrenal zona glomerulosa (ZG), it has been postulated that Ang II is formed intracellularly by the renin-converting enzyme cascade in this tissue. To test this hypothesis, we examined renin-angiotensin system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (IR-Ang II) were observed in vesicular fractions but were not colocalized. In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang II-containing vesicular fractions. These data do not support the hypothesis that Ang II is formed intracellularly within the renin-containing vesicles of the ZG. Rather, since modulatable renin release from adrenal ZG slices was observed and renin activity was found in dense vesicular fractions (33-39% sucrose), it is likely that Ang II formation in the ZG is extracellular and initiated by the release of vesicular renin. Receptor-mediated endocytosis and subsequent degradation of Ang II in ZG lysosomes have been shown by others. The presence of IR-Ang II in light vesicular fractions (15% sucrose) and the finding of a high correlation between ZG IR-Ang II and Ang II receptor levels suggest that the primary occurrence of this peptide in the ZG is by receptor-mediated endocytosis. In ZG lysosomal fractions 125I-labeled Ang II was degraded to 125I-labeled des-[Phe8]Ang II. Since Ang II antibodies do not recognize des-[Phe8]Ang II, these findings explain why IR-Ang II in the ZG is due predominantly to Ang II and not to its C-terminal immunoreactive fragments.

Adrenal Cortex↗
PubMed2000

Functional expression of O-linked GlcNAc transferase. Domain structure and substrate specificity.

O-GlcNAc transferase (OGT) modifies nuclear pore proteins and transcription factors. In Arabidopsis, the OGT homolog participates in the gibberellin signaling pathway. We and others have proposed that mammalian OGT is the terminal step in a glucose-sensitive signal transduction pathway that becomes disregulated in insulin resistance. To facilitate mutational analysis of OGT in the absence of competing endogenous activity, we expressed the 103-kDa human OGT in Escherichia coli. Kinetic parameters for the purified recombinant enzyme (K(m) = 1.2 microM for Nup 62; K(m) = 0.5 microM for UDP-GlcNAc) are nearly identical to purified mammalian OGT. Deletions in the highly conserved C terminus result in a complete loss of activity. The N-terminal tetratricopeptide repeat domain is required for optimal recognition of substrates. Removal of the first three tetratricopeptide repeats greatly reduces the O-GlcNAc addition to macromolecular substrates. However, this altered enzyme retains full activity against appropriate synthetic peptides. Autoglycosylation of OGT is augmented when the first six tetratricopeptide repeats are removed showing that these repeats are not required for catalysis. Given its proposed role in modulating insulin action, OGT may modify kinases involved in this signaling cascade. Among the many kinases tested, OGT glycosylates glycogen synthase kinase-3 and casein kinase II, two enzymes critical in the regulation of glycogen synthesis.

Casein Kinase II↗
PubMed2002

Effect of cage vs. floor litter environments on the pulmonary hypertensive response to intravenous endotoxin and on blood-gas values in broilers.

Intravenous endotoxin has been shown to trigger a delayed pulmonary hypertensive response that varies widely in magnitude and duration among individual broilers. It was proposed that this individual variability may reflect immunological differences acquired during previous respiratory challenges that might have subsequently altered the endotoxin-initiated biochemical cascade. In Experiment 1, we tested the hypothesis that, when compared with broilers reared in clean stainless steel cages (Cage group), broilers reared on floor litter (Floor group) should experience a greater respiratory challenge and therefore may consistently exhibit a more enhanced pulmonary hypertensive response to intravenous endotoxin. Birds in the Cage group were grown in stainless steel cages at a low density (72 birds/8 m2 chamber), and fecal and dander materials were removed daily. Birds in the Floor group were reared on wood-shavings litter at a higher density (110 birds/8 m2 chamber). Pulmonary and systemic mean arterial pressures and blood-gas values were evaluated prior to and following the intravenous administration of 1 mg Salmonella typhimurium endotoxin. Broilers in the Floor and Cage groups exhibited pulmonary hypertensive responses to endotoxin that were very similar in terms of time of onset, duration, and magnitude, as well as variability in the response among individuals. Systemic hypotension also developed similarly in both groups following endotoxin injection. Blood-gas values indicated that the partial pressure of CO2 and the HCO3- concentration in arterial blood were higher (P < 0.05) in the Floor group than in the Cage group prior to and subsequent to the endotoxin injection. In Experiment 2, we reevaluated the effect of a dirty vs. a clean environment on blood-gas values using a different strain of broilers, and confirmed the negative impact of floor rearing on blood-gas values. We conclude that broilers reared on the floor inhaled litter dust and noxious fumes, which impaired pulmonary gas exchange and increased the arterial partial pressure of CO2 when compared with broilers reared in clean stainless steel cages. Nevertheless, the pulmonary hypertensive response to endotoxin did not differ between broilers reared on the floor and those in cages.

Animal Husbandry↗
PubMed2000

Intramucosal pH and endotoxin and cytokine release in severe acute pancreatitis.

It has been postulated that in severely ill patients splanchnic hypoperfusion may cause endotoxin release from the gut, and this leakage of endotoxin into the circulation can trigger the cascade of inflammatory cytokines. We tested this hypothesis in 9 patients with acute severe pancreatitis by monitoring gastric intramucosal pH (pHi) as measure of splanchnic hypoperfusion at 12-h intervals trying to correlate it to endotoxin and cytokine release. Only 3 of 59 samples, obtained from 3 patients contained circulating endotoxin. Thirteen of 15 plasma samples drawn at pHi <7.20 did not contain endotoxin. The pHi was significantly lower in patients who subsequently developed 3 or more organ failures (P = 0.0017, analysis of variance). Although endotoxemia was only occasionally found, most patients had measurable interleukin 1beta (IL-1beta), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10) in their plasma. Concentrations of IL-6, IL-8, and IL-10 on admission correlated to degree of organ dysfunction as measured by the multiple organ system failure score (P = 0.035, r = 0.74; P = 0.010, r = 0.91; P = 0.021, r = 0.82, respectively). In conclusion, patients with acute, severe pancreatitis often have splanchnic hypoperfusion and produce a wide array of cytokines despite a rare occurrence of endotoxemia.

APACHE↗