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At least 595 records · Page 33Linked to original sources
PubMed2006

Involvement of toll-like receptor 4 in the inflammatory reaction induced by hydroxyapatite particles.

Hydroxyapatite (HA) is widely used to coat metal parts in order to improve their biocompatibility. Analysis of retrieved tissues associated with failed implants, suggest that phagocytosis of HA wear debris by monocytes/macrophages might provide a potent stimulus for the release of a variety of cytokines. Phagocytosis involved a large variety of cellular receptors like toll-like receptors that results in activation of the transcriptional nuclear factor-kappaB (NF-kappaB) via a cell-signalling pathway. In the present paper, we aimed to evaluate the role of the toll-like receptor 4 (TLR4) in the production of inflammatory cytokines induced by HA particles using TLR4(+) and TLR4(-) peritoneal macrophages. We investigated the production of TNF-alpha and the activation of the nuclear transcription factor NF-kappaB. Our data clearly show for the first time that the production of TNF-alpha by macrophages exposed to HA particles was TLR4 dependent but not the activation of NF-kappaB. All these results open future therapies to reduce the inflammatory response induced by HA biomaterials.

Animals↗
PubMed2004

High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation.

BACKGROUND: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown. METHODS: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation. RESULTS: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drugs were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally, after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice. CONCLUSIONS: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.

Amitriptyline↗
PubMed2006

Serum total amylase, pancreatic amylase and lipase activities in epileptic children treated with sodium valproate monotherapy.

To investigate by a prospective, self-controlled method, whether early treatment with sodium valproate (VPA) monotherapy has some effect on serum total amylase and particularly on its pancreatic isoenzyme and lipase activities in epileptic children. Serum total amylase, pancreatic amylase and lipase activities have been evaluated in 23 epileptic children, before and at 6 and 12 months of VPA monotherapy. All children remained without clinical symptoms of pancreatitis during the period of study. Serum pancreatic amylase activities were significantly decreased at 6 and 12 months of treatment with VPA, whereas serum total amylase and lipase activities did not show any significant changes at 6 or 12 months of treatment. Non-pancreatic isoenzyme activities of amylase were significantly higher at 6 and 12 months of treatment. Three patients (13%) had slightly elevated serum total amylase levels at 6 and 12 months of treatment. There was no significant correlation of serum pancreatic amylase levels or non-pancreatic isoenzyme levels of amylase with serum VPA levels at 6 and 12 months of treatment. Non-pancreatic amylase activities, probably derived from salivary glands, may be increased in children treated with VPA monotherapy. Measurement of serum pancreatic amylase and/or serum lipase activities is indicated in patients with increased serum total amylase levels but without clinical symptoms of pancreatitis and, furthermore, in patients with symptoms suggesting dysfunction of pancreas, in order to avoid unnecessary discontinuing of VPA.

Adolescent↗
PubMed2004

Ontogenic changes of the GABAergic system in the embryonic mouse spinal cord.

Numerous studies have demonstrated an excitatory action of GABA early in development, which is likely to play a neurotrophic role. In order to better understand the role of GABA in the mouse spinal cord, we followed the evolution of GABAergic neurons over the course of development. We investigated, in the present study, the ontogeny of GABA immunoreactive (GABA-ir) cell bodies and fibers in the embryonic mouse spinal cord at brachial and lumbar levels. GABA-ir somata were first detected at embryonic day 11.5 (E11.5) exclusively at brachial level in the marginal zone. By E13.5, the number of GABAergic neurons sharply increased throughout the extent of the ventral horn both at brachial and lumbar level. Stained perikarya first appeared in the future dorsal horn at E15.5 and progressively invaded this area while they decreased in number in the presumed ventral gray matter. At E12.5, E13.5 and E15.5, we checked the possibility that ventral GABA-ir cells could belong to the motoneuronal population. Using a GABA/Islet-1/2 double labeling, we did not detect any double-stained neurons indicating that spinal motoneurons do not synthesize GABA during the course of development. GABA-ir fibers also appeared at the E11.5 stage in the presumptive lateral white matter at brachial level. At E12.5 and E13.5, GABA-ir fibers progressively invaded the ventral marginal zone and by E15.5 reached the dorsal marginal zone. At E17.5 and postnatal day 0 (P0), the number of GABA-ir fibers declined in the white matter. Finally, by P0, GABA immunoreactivity that delineated somata was mainly restricted to the dorsal gray matter and declined in intensity and extent. The ventral gray matter exhibited very few GABA-ir cell bodies at this neonatal stage of development. The significance of the migration of somatic GABA immunoreactivity from ventral to the dorsal gray matter is discussed.

Animals↗
PubMed2005

Muscarinic receptor blockade attenuates reserpine-mediated Fos induction in the rat striatopallidal pathway.

Acute administration of the dopamine-depleting agent reserpine (10 mg/kg) induces Fos expression in striatopallidal neurons of intact rats-an effect that is blocked by pretreatment with the D2 agonist quinpirole (0.5 mg/kg). Systemic administration of the muscarinic antagonist scopolamine (50 mg/kg) partially attenuates reserpine-mediated striatal Fos expression. These data suggest that muscarinic receptors, either within the striatum or in extrastriatal sites, regulate D2 receptor-mediated Fos expression in rat striatopallidal neurons.

Adrenergic Uptake Inhibitors↗
PubMed2025

Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.

Recognition of specific DNA sequences by transcription factors (TFs) is a key step in transcriptional control of gene expression. While most forkhead (FH) TFs bind either an FKH (RYAAAYA) or an FHL (GACGC) recognition motif, some FHs can bind both motifs. Mechanisms that control whether an FH is monospecific vs. bispecific have remained unknown. Screening a library of 12 reference FH proteins, 61 naturally occurring missense variants including clinical variants, and 22 designed mutant FHs for DNA-binding activity using universal ("all 10-mer") protein-binding microarrays revealed non-DNA-contacting residues that control mono- vs. bispecificity. Variation in non-DNA-contacting amino acid residues of TFs is associated with human traits and may play a role in the evolution of TF DNA-binding activities and gene regulatory networks.

Humans↗
PubMed2004

Safe and efficacious prolonged use of an olive oil-based lipid emulsion (ClinOleic) in chronic intestinal failure.

BACKGROUND & AIMS: Injectable lipid emulsion is an important component of parenteral nutrition. ClinOleic is a lipid emulsion composed of olive oil (80%) and soybean oil (20%). This study evaluated the efficacy and safety of ClinOleic in adults already receiving parenteral nutrition, comparing it to their usual lipid (soybean-oil-based). METHODS: Thirteen adults dependent on home parenteral nutrition were recruited from a single hospital. ClinOleic was administered for 6 months. Two-monthly assessments were made. In addition, clinical and adverse events were recorded for 6-month periods before, during and after the study. RESULTS: Total numbers of important complications for the 6 months before, during and after the study were 13, 9 and 9, respectively. There were, respectively, 5, 3 and 2 line infections, and 2, 0 and 5 thrombotic episodes in the 3 periods. The numbers of unplanned admissions were, respectively, 8, 5 and 7, with in-patient days accounting for 3.4%, 1.5%, and 2.6% of feeding days, respectively. One patient died (pneumonia). One new case of cholecystolithiasis appeared. CONCLUSION: ClinOleic may be used as a safe alternative to standard soybean-oil-based lipid emulsions.

Adult↗
PubMed2004

Contribution of protein kinase A and protein kinase C pathways in ultraviolet B-induced IL-8 expression by human keratinocytes.

We have previously demonstrated that treatment of the human keratinocyte cell line NCTC 2544 with a UVB dose equivalent to 1h exposure (100 mJ/cm2) results in a significant increase of IL-8 production. In this study, we use specific inhibitors to investigate the role of both PKA- and PKC-mediated pathways in the regulation of UVB-induced IL-8 expression in NCTC 2544 cell line. We show here that the treatment of irradiated human keratinocytes with PKA inhibitors [H89 and PKA inhibitor (PKAi)] induced a significant decrease of IL-8 production at both mRNA and protein levels. However, the regulation of IL-8 production seems to be mediated via a cAMP-independent PKA pathway, since drugs known to enhance cAMP concentrations [PGE2, cholera toxin and dibutyryl cAMP] decrease IL-8 production in irradiated cells by down-regulating NF-kappa B activation in response to UVB radiation. Using PMA (a potent pharmacological activator of PKC) and calphostin C (a specific PKC inhibitor), we demonstrated an up-regulation of IL-8 in NCTC 2544 cells and a down-regulation of the cytokine in UVB-irradiated cells, respectively. We also observed that in our experimental conditions, staurosporine, an inhibitor of both PKC and PMA-stimulated cellular responses, does not involve PKC inhibition in irradiated cells and significantly decreased NF-kappa B activity in response to UVB radiation. Finally, we concluded that a cAMP-independent PKA activation and a PKC-associated pathway are probably involved in the regulation of UVB-induced IL-8 synthesis in human keratinocytes.

Cell Line↗
PubMed2005

Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy.

BRCA1 and BRCA2 germline mutations are associated with a strong risk of breast cancer, which may preclude breast-conserving treatment in carriers. This study examined whether mutation status influenced the rate of breast cancer recurrence following breast-conserving treatment. BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer, who had been treated with breast-conserving surgery and radiotherapy. The 131 patients with familial history were matched to 261 patients without, according to age at diagnosis and year of treatment. The follow-up of controls was at least equal to the time-interval between diagnosis and genetic testing in familial cases. Matched cohorts were compared according to rates of breast cancer recurrence as first event and contralateral breast cancer using log-rank tests. BRCA1/2 mutations were found in 20.6% patients with a family history. Nineteen patients had a BRCA1 mutation and 8 had a BRCA2 mutation. Breast cancers in mutation carriers were more often grade III (p<10-4) and oestrogen receptor negative (p=0.005) than tumours in both non-carriers and controls. Median follow-up for all 392 patients was 8.75 years. No significant differences in breast cancer recurrence as first event were seen between BRCA1/2 tumours and controls (p=0.47), carriers and non-carriers with a family history (p=0.96), or non-carriers and controls (p=0.10). On multivariate analysis, age was the most important factor significantly predicting for breast cancer recurrence. The rate of contralateral breast cancer was significantly increased in all patients with a family history: BRCA1/2 carriers versus controls (p=0.0003), non-carriers versus controls (p=0.0034) and carriers versus non-carriers (p=0.02). At a 9-year median follow-up, the rate of ipsilateral breast cancer recurrence was not higher in BRCA1 and BRCA2 mutation carriers than in non-carriers with a family history or sporadic cases. These results support the hypothesis that breast tumours in BRCA carriers are more sensitive to radiation. Therefore, breast-conserving treatment can be offered to these patients. However, longer follow-up is needed to ensure that the rate of new primary cancer in the treated breast does not increase in the long-term.

Adult↗
PubMed2004

Biphasic modulation by nitric oxide of caspase activation due to malonate injection in rat striatum.

The present study examined caspase activation and its modulation by nitric oxide (NO) in a model of oxidative stress induced by injection of malonate (3 micromol), a mitochondrial toxin, into rat striatum. Caspase-3-like enzymatic activity was maximal 6 h after malonate while NO production evaluated by its metabolites nitrites and nitrates was increased at 3 h. The neuronal NO-synthase inhibitor 7-nitroindazole reduced malonate induced-NO production by 50% at 25 mg/kg and enhanced by 32% caspase activation. This result suggests that a moderate production of NO potentiates caspase activation, an effect counterbalanced by NO itself at higher concentrations. Accordingly, complete inhibition of NO production by 7-nitroindazole at 50 mg/kg did not modify malonate-induced caspase activity. Thus NO production by the neuronal isoform of NO-synthase is not the major event leading to caspase activation due to malonate. However, NO seems to have pro- and anti-caspase effects that neutralize each other.

Animals↗
PubMed2006

Effect of sodium valproate monotherapy on serum uric acid concentrations in ambulatory epileptic children: a prospective long-term study.

PURPOSE: Hyperuricemia has been shown to be related to cardiovascular morbidity and mortality. There is controversial data about the effect of sodium valproate (VPA) monotherapy on serum uric acid concentrations. The purpose of this study was to investigate by a long-term, prospective method, whether treatment with VPA monotherapy may alter serum uric acid concentrations and liver function tests in ambulatory epileptic children. MATERIAL AND METHODS: Serum uric acid concentrations were determined in 28 ambulatory epileptic children before and at 6, 12 and 24 months of VPA monotherapy. Serum concentrations of biochemical markers of liver and renal function, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (gamma-GT) and creatinine (Cr) were also measured before and at 6, 12 and 24 months of VPA monotherapy. Serum VPA concentrations remained within the therapeutic range (50-100 mg/L) during the period of study. RESULTS: No statistically significant changes in serum uric acid concentrations were found at 6, 12 or 24 months of treatment. Serum ALT concentrations were significantly increased at 6 and 12 months of treatment, AST concentrations at 6 and 12 months of treatment and LDH concentrations at 12 months of treatment. CONCLUSIONS: VPA monotherapy does not have a significant effect on serum uric acid concentrations in ambulatory epileptic children. Further studies are needed to definitively address whether it would be useful for physicians to routinely check for elevated serum uric acid levels in children treated with VPA.

Adolescent↗
PubMed2006

Early and persistent increase in serum lipoprotein (a) concentrations in epileptic children treated with carbamazepine and sodium valproate monotherapy.

PURPOSE: The aim of this study was to investigate by a prospective, self-controlled method, whether treatment with carbamazepine (CBZ) and sodium valproate (VPA) monotherapy may alter serum lipoprotein (a) [Lp(a)] concentrations in epileptic children. METHODS: Serum Lp(a) concentrations have been determined in 18 epileptic children before and at 6, 12 and 24 months of treatment with CBZ monotherapy and in 30 epileptic children before and at 6, 12 and 24 months of treatment with VPA monotherapy. Serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoproteins A-I and B concentrations and serum concentrations of biochemical markers of liver and renal function were also measured in the study participants. RESULTS: Serum Lp(a) concentrations were significantly increased at 6, 12 and 24 months of CBZ and VPA monotherapy. There were no significant correlations between serum Lp(a) and serum lipids, lipoproteins, apolipoproteins, concentrations of biochemical markers of liver and renal function or antiepileptic-drugs concentrations. CONCLUSIONS: Children who receive CBZ or VPA monotherapy may have significant and persistent increase in serum lipoprotein (a) concentrations, occuring early in the course of therapy. It may be useful to measure serum Lp(a) concentrations routinely in epileptic children taking these antiepileptic drugs, especially in those that are already at higher atherosclerotic risk.

Adolescent↗
PubMed2006

Protein kinase PKC delta and c-Abl are required for mitochondrial apoptosis induction by genotoxic stress in the absence of p53, p73 and Fas receptor.

Doxorubicin, cis-diamminedichloroplatinum (II) and 5-fluorouracil used in chemotherapy induce apoptosis in Hep3B cells in the absence of p53, p73, and functional Fas. Since mediators remain unknown, the requirement of PKC delta (PKCdelta) and c-Abl was investigated. Suppression of c-Abl or PKCdelta expression using SiRNAs impaired PARP cleavage, Gleevec and/or rottlerin inhibited the induction of the subG1 phase and the increase of reactive oxygen species level. Co-precipitations and phosphorylations to mitochondria of c-Abl, PKCdelta and Bcl-X(L/s) were induced. A depolarization of the mitochondrial membrane and activations of caspase-2 and -9 were observed. We propose that, in the absence of p53, p73 and Fas, genotoxic drugs could require both PKCdelta and c-Abl to induce apoptosis through the mitochondrial pathway.

Apoptosis↗
PubMed2005

High sensitivity enzyme-linked immunosorbent assay (ELISA) method for measuring protein carbonyl in samples with low amounts of protein.

The oxidative modification of proteins has been shown to play a major role in a number of pathological processes. One such modification is the addition of the carbonyl groups to the amino acid residue in proteins. For the measurement of the carbonyl groups in low concentration protein samples, we have modified the ELISA (enzyme-linked immunosorbent assay) method that was developed by Buss et al. [Buss, I. H; Chan, T. P.; Sluis, K. B.; Domigan, N. M.; Winterbourn, C. C. Protein carbonyl measurement by a sensitive ELISA method. Free Radic. Biol. Med.23:361-366; 1997 ]. In the modified method, protein samples diluted in phosphate-buffered saline were adsorbed to wells of an ELISA plate and then reacted with dinitrophenylhydrazine (DNPH). The protein-conjugated DNPH was probed by a commercial anti-DNPH antibody, and then a second antibody conjugated with horseradish peroxidase was added for quantification. The method was calibrated using oxidized albumin, and required only 5 mug protein. This obviated the need to concentrate protein in experimental and clinical samples with low amounts of protein. In addition the effect of TCA on carbonyl measurement is eliminated. The standard curve was linear in the range of 0-3.36 nmol carbonyls/mg protein, which is the range within which clinical samples fell. The results correlated well with the colorimetric carbonyl assay. The method was used to analyze the amount of protein carbonyl in aqueous humor and diluted plasma samples.

Calibration↗
PubMed2006

Endogenous and exogenous cyclicity and temperament in bipolar disorder: review, new data and hypotheses.

In this special issue dedicated to Falret and the French contributions to the concept of cyclicity in manic depressive illness, we begin with a historical overview of the development of the concept of cyclicity and its fundamental significance in manic-depressive illness and we underscore how the concept fell into neglect only to reemerge in recent years. We then look at the intimate relationship between mania and depression. The hypothesis of the primacy of mania is discussed. The thesis is presented, supported by the examination of 100 consecutive index manias, that in most cases mania is triggered by external factors acting upon hyperthymic patients, determining an exogenous cyclicity. On the other hand, in BPII patients the temperamental mood instability (cyclothymia) is an inherent and decisive factor in determining the cyclic autonomous course of the disorder. Finally, a new distinction of Bipolar Disorders, based on premorbid temperament and course of the illness, is considered.

Bipolar Disorder↗
PubMed2005

hMutS alpha is protected from ubiquitin-proteasome-dependent degradation by atypical protein kinase C zeta phosphorylation.

The hMutS alpha (hMSH2-hMSH6) protein heterodimer plays a critical role in the detection of DNA mispairs in the mismatch repair (MMR) process. We recently reported that hMutS alpha proteins were degraded by the ubiquitin-proteasome pathway in a cell-type-dependent manner, indicating that one or several regulator(s) may interfere with hMutS alpha protein ubiquitination and degradation. On the other hand, we and others have shown that protein kinase C (PKC) is involved as a positive regulator of MMR activity. Here, we provide evidence that the atypical PKC zeta regulates ubiquitination, degradation, and levels of hMutS alpha proteins. Using both PKC zeta-transfected U937 and PKC zeta siRNA-transfected MRC-5 cell lines, we found that PKC zeta protein expression was correlated with that of hMutS alpha as well as with MMR activity, but was inversely correlated with hMutS alpha protein ubiquitination and degradation. Interestingly, PKC zeta interacts with hMSH2 and hMSH6 proteins and phosphorylates both. Moreover, in an in vitro assay PKCzeta mediates phosphorylation events decreasing hMutS alpha protein degradation via the ubiquitin-proteasome pathway. Altogether, our results indicate that PKC zeta modulates hMutS alpha stability and protein levels, and suggest a role for PKC zeta in genome stability by regulating MMR activity.

Antimetabolites, Antineoplastic↗
PubMed2003

Neuro-inflammatory risk factors for treatment failure in "early second stage" sleeping sickness patients treated with pentamidine.

In a clinical trial on efficacy of Pentamidine in second stage Trypanosoma brucei gambiense patients with </=20 cells/microl in cerebrospinal fluid (CSF), 43% of treatment failures were observed. We hypothesised that unsuccessful treatment was caused by uncured brain infection. The relationship between treatment outcome and CSF cell count, protein concentration, presence of trypanosomes, the intrathecal immune response, and CSF total IgM and trypanosome specific antibodies detected by LATEX/IgM and LATEX/T.b. gambiense card agglutination tests was examined. Cell counts of 11-20 cells/microl, intrathecal IgM synthesis, CSF end-titres in LATEX/IgM >/=4 and LATEX/T.b. gambiense positive CSF, were associated with treatment failure. Detection of intrathecal IgM synthesis is valuable for assessment of brain involvement and treatment decision.

Adolescent↗