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At least 559 records · Page 31Linked to original sources
PubMed2002

The CD14+CD16+ monocytes in erysipelas are expanded and show reduced cytokine production.

In human peripheral blood the classical CD14(++)DR(+) monocytes and the pro-inflammatory CD14(+)CD16(+)DR(++) monocytes can be distinguished. In erysipelas we found strongly increased numbers of CD14(+)CD16(+) monocytes on the day of diagnosis (day 1) in 11 patients with an average of 150.5+/-76.0 cells/microl, while 1 patient had low levels (35 cells/microl, control donors 48.8+/-19.8 cells/microl). The classical monocytes were only moderately elevated in the erysipelas patients (factor 1.7 as compared to controls). Patients exhibited increased body temperature, erythrocyte sedimentation rate and increased serum levels for C-reactive protein (CRP), IL-6 and macrophage-colony-stimulating factor. Among these, body temperature and CRP showed a significant correlation to the numbers of CD14(+)CD16(+) monocytes. In 4 of 4 patients with high levels of CD14(+)CD16(+) monocytes, these levels returned to that seen in controls by day 5 of antibiotic therapy. Determination of intracellular TNF was performed by three-color immunofluorescence and flow cytometry after ex vivo stimulation with lipoteichoic acid, a typical constituent of streptococci. Here, patient CD14(+)DR(++) pro-inflammatory monocytes showed a twofold lower level of intracellular TNF. By contrast, expression of TNF was unaltered in the classical CD14(++) monocytes. These data show that in erysipelas the pro-inflammatory CD14(+)CD16(+)DR(++) monocytes are substantially expanded and selectively tolerant to stimulation by streptococcal products.

Anti-Bacterial Agents↗
PubMed2003

Feasibility and toxicity of high-dose therapy (HDT) supported by peripheral blood stem cells in elderly patients with multiple myeloma and non-Hodgkin's lymphoma: survey from a single institution.

The aim of this retrospective study was to investigate the feasibility of high-dose therapy (HDT) followed by peripheral blood stem cell transplantation (PBSCT) in elderly patients with hematological malignancies. From April 1998 to November 2001, 40 elderly patients (defined as > or =60 years) with non-Hodgkin's lymphoma (12 patients) and multiple myeloma (28 patients) were evaluated. Seven lymphoma and one myeloma patients were in complete remission (CR), 27 in partial remission (PR), two had stable disease (SD), and three progressive disease (PD). The median age was 65 years (range 60-71). Thirty-nine patients were mobilized with chemotherapy plus granulocyte-colony stimulating factor (G-CSF) and one with G-CSF alone. Patients received HDT including melphalan alone in 32 cases or combined with other drugs in six and BEAM in two. The median number of collected CD34(+) cells was 12.4 x 10(6)/kg (range 2.0-68.9). The median number of re-infused CD34(+) cells was 9.9 x 10(6)/kg (range 2.0-68.9). All patients engrafted after PBSC and the median time to neutrophil recovery (N > 500/micro l) and platelet recovery (PLT > 20,000/micro l) was 8 days (range 5-18) and 6 days (range 5-18), respectively. Nonhematological toxicity was mild and no patient died from transplant-related toxicity (TRM). Median duration of hospitalization was 18 days (range 12-24). To date, 32 patients are alive and eight died from disease progression at a median follow-up interval of 24 months. HDT supported by PBSC is a feasible procedure in selected elderly patients, and an age of more than 60 years should not be considered a contraindication for HDT.

Aged↗
PubMed2002

Spectrum of the acrocallosal syndrome.

Acrocallosal syndrome (ACS) is an autosomal recessive condition, characterized by agenesis of the corpus callosum, pre- and postaxial polydactyly, minor craniofacial anomalies, and, in most patients, severe psychomotor retardation. We here report on three patients with ACS demonstrating a spectrum from mild to severe involvement. Two patients had only mild to moderate mental retardation at the age of 2(1/2) and 4 years, respectively, with surprisingly good speech development. The third patient was severely affected and died at age 7 days because of persistent apnea. All three patients had agenesis of the corpus callosum, and large intracranial cysts, which in the third case was confirmed as a large arachnoid cyst at autopsy. Cranial cysts were also seen in 10/34 published cases of ACS. Thus, intracerebral cysts are a common finding in ACS and may serve in differentiating ACS from Greig cephalopolysyndactyly syndrome.

Abnormalities, Multiple↗
PubMed2006

Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is highly expressed in advanced ovarian cancer and is associated with aggressive histology and poor survival.

BACKGROUND: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) tumor expression is an emerging prognostic, diagnostic, and therapeutic target in early epithelial ovarian cancer (EOC). The significance of tumor overexpression of LPAAT-beta was investigated in a large number of advanced- and early-stage EOC patients. METHODS: LPAAT-beta expression was analyzed by immunohistochemistry (IHC) in 158 ovarian tumors, including 68 advanced and 90 low-stage tumors, representing all grades and histologies (including 33 borderline tumors). In advanced-stage patients, tissue from multiple sites was evaluated to assess differential expression of LPAAT-beta in local tumor and distant metastases. RESULTS: LPAAT-beta was overexpressed in 90 (57%) of all 158 ovarian tumors. Forty-nine (72%) of 68 advanced tumors overexpressed LPAAT-beta. LPAAT-beta was associated with the presence of carcinoma versus borderline histology (67% vs. 18%, P < .0001), high histologic grade [according to the Silverberg Grading Scheme] (Grade 1, 25%; Grade 2, 21%; and Grade 3, 54%; P < .0001), and with papillary-serous histology. In an analysis of the 125 carcinoma patients, LPAAT-beta increased with but was not significantly associated with advanced clinical stage (P = .1431). LPAAT-beta expression was associated with shortened progression-free survival (PFS) (5-year PFS, 32% for LPAAT-beta-positive vs. 60% for LPAAT-beta-negative; P = .0318) and decreased overall survival (OS) (5-year OS, 54% for LPAAT-beta-positive vs. 74% for LPAAT-beta-negative; P = .0173). CONCLUSIONS: LPAAT-beta is highly expressed in advanced ovarian tumors and is associated with aggressive histology and decreased PFS and OS. LPAAT-beta is an intriguing prognostic tool for the identification of high-risk EOC and a potential target for directed therapy that warrants further study.

Acyltransferases↗
PubMed2007

Phase II trial of dose-dense doxorubicin plus gemcitabine followed by paclitaxel plus carboplatin in patients with advanced urothelial carcinoma and impaired renal function.

BACKGROUND: Cisplatin-based therapy is standard in patients with advanced urothelial carcinoma but a large proportion are ineligible due to renal impairment. The safety and activity of a dose-dense carboplatin-based regimen in this patient population were explored. METHODS: Patients with advanced urothelial carcinoma who were ineligible for cisplatin were eligible based on at least 1 of the following: 1) serum creatinine >1.5 mg/dL; 2) creatinine clearance of >30 mL/min/1.73 m(2) and <60 mL/min/1.73 m(2); and/or 3) prior nephrectomy. Patients received treatment with doxorubicin plus gemcitabine every other week x 5 cycles followed by paclitaxel plus carboplatin weekly x 12 cycles. RESULTS: Twenty-five patients were treated. Myelosuppression was the major toxicity, with 28% of patients experiencing grade 3-4 neutropenia; there were only 2 (8%) episodes of febrile neutropenia. Grade > or = 3 nonhematologic toxicities were infrequent with the exception of grade > or = 3 thrombotic episodes in 4 (16%) patients. There were 5 complete responses and 9 partial responses for an overall response rate of 56% (95% confidence interval [CI]: 35%-76%). The median survival was 15 months (95% CI: 11-30). At a median follow-up for survivors of 45 months, 7 (28%) patients are disease-free. CONCLUSIONS: Dose-dense sequential chemotherapy is tolerable and active in patients with urothelial carcinoma and renal impairment. Prolonged disease-free survival is achievable in a subset of patients with primary unresectable disease or lymph-node only metastases treated with carboplatin-based therapy +/- surgical consolidation. Randomized trials are needed to define the optimal regimen in patients with advanced urothelial carcinoma and renal impairment.

Adult↗
PubMed2004

Nestin promoter/enhancer directs transgene expression to precursors of adult generated periglomerular neurons.

The subventricular zone (SVZ) is a major neurogenic region in the adult brain. Cells from the SVZ give rise to two populations of olfactory bulb interneurons: the granule cells and periglomerular (PG) cells. Currently, little is known about the signaling pathways that direct these newly generated neurons to become either granule or PG neurons. In the present study, we used the nestin promoter and enhancer to direct expression of the tetracycline transactivator (tTA). We generated two independent strains of nestin-tTA transgenic animals and crossed founder mice from both lines to mice containing a tetracycline-regulated transgene (mCREB) whose expression served as a marker for the activity of the nestin-tTA transgene. mCREB expression occurred in a subset of proliferating cells in the SVZ and rostral migratory stream in both lines. Surprisingly, in both lines of nestin-tTA mice transgene expression in the olfactory bulb was limited to PG neurons and was absent from granule cells, suggesting that this nestin promoter construct differentiates between the two interneuronal populations. Transgene expression occurred in several subtypes of PG neurons, including those expressing calretinin, calbindin, GAD67, and tyrosine hydroxylase. These results suggest that a unique subset of SVZ precursor cells gives rise to PG, and not granule cells. The ability to express different transgenes within this subpopulation of neuronal precursors provides a powerful system to define the signals regulating the differentiation and survival of adult-generated neurons in the olfactory bulb.

Animals↗
PubMed2006

Expression of the glycinergic system during the course of embryonic development in the mouse spinal cord and its co-localization with GABA immunoreactivity.

To understand better the role of glycine and gamma-aminobutyric acid (GABA) in the mouse spinal cord during development, we previously described the ontogeny of GABA. Now, we present the ontogeny of glycine-immunoreactive (Gly-ir) somata and fibers, at brachial and lumbar levels, from embryonic day 11.5 (E11.5) to postnatal day 0 (P0). Spinal Gly-ir somata appeared at E12.5 in the ventral horn, with a higher density at the brachial level. They were intermingled with numerous Gly-ir fibers reaching the border of the marginal zone. By E13.5, at the brachial level, the number of Gly-ir perikarya sharply increased throughout the whole ventral horn, whereas the density of fibers declined in the marginal zone. In the dorsal horn, the first Gly-ir somata were then detected. From E13.5 to E16.5, at the brachial level, the density of Gly-ir cells remained stable in the ventral horn, and after E16.5 it decreased to reach a plateau. In the dorsal horn, the density of Gly-ir cells increased, and after E16.5 it remained stable. At the lumbar level, maximum expression was reached at E16.5 in both the ventral and dorsal horn. Finally, the co-localization of glycine and GABA was analyzed, in the ventral motor area, at E13.5, E15.5, and E17.5. The results showed that, regardless of developmental stage studied, one-third of the stained somata co-expressed GABA and glycine. Our data show that the glycinergic system matures 1 day later than the GABAergic system and follows a parallel spatiotemporal evolution, leading to a larger population of glycine cells in the ventral horn.

Animals↗
PubMed2005

Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells.

The stroma-vascular fraction (SVF) of human adipose tissue has recently been described to be composed of endothelial cells identified as CD34+/CD31+ cells, infiltrated/resident macrophages defined as CD14+/CD31+ cells, and a new cell population characterized as CD34+/CD31- cells. To elucidate the cell identity of the adipocyte precursor cells, fluorescent activating cell sorter (FACS) analyses were performed on crude SVF cultured under adipogenic conditions, i.e., serum-deprived medium containing insulin, cortisol, triiodothyronine, and supplemented with a PPARgamma agonist for the first 3 days. The progressive accumulation of lipid droplets was associated with a selective enrichment of the CD34+/CD31- cell population whereas control experiments performed in medium supplemented with 10% serum showed an overall downregulation of the three cell markers without adipogenesis. Among the different cell subsets, the CD34+/CD31- subset was the unique cell fraction able to answer to adipogenic culture conditions. Indeed, a time-dependent expression of adipocyte markers as well as acquisition of adipocyte-typical metabolic activities were observed. In parallel, the gene expression of lipogenic and lipolytic enzymes increased. The ability to differentiate into adipocytes was restricted to cells that did not express the mesenchymal stem cell marker CD105. Furthermore, the CD34+/CD31- cells did not respond to culture conditions used for hematopoietic colony assays. Taken together, the present study demonstrates that adipocyte progenitor cells, i.e., the preadipocytes, are included in the CD34+/CD31- cell fraction, which displays distinct features from the adult mesenchymal and hematopoietic stem cells.

Adipose Tissue↗
PubMed2003

Two-treatment comparison based on joint toxicity and efficacy ordered alternatives in cancer trials.

The primary goal of anticancer treatments is to attain efficacy, however toxicity could affect the course of the therapy. Methods have been proposed for comparing two treatments on the basis of the joint distribution for safety and efficacy outcomes, but they do not take into account the cumulative doses of drugs (chemotherapy) or radiation (radiotherapy) received by each patient. Moreover, these methods assume a parametric form for the joint distribution. In this paper we define a multi-dimensional parameter including toxicity and efficacy outcomes and the dose at which one, none or both occur. Each patient is classified into an ordered category depending on the order of occurrence of these two criteria: the sooner the patient benefits from efficacy and/or the later he/she experiences toxicity, the better is the treatment. We then apply likelihood ratio tests with ordered alternatives. This procedure requires constrained maximum likelihood estimation via isotonic regression. A large set of simulations compares the proposed tests to other more usual tests and the results show a good power and a satisfactory type I error control. Our approach is illustrated with a multi-centre randomized clinical trial involving patients with metastatic non-seminomatous germ cell tumours.

Antineoplastic Agents↗
PubMed2004

Alteration of hippocampal cell proliferation in mice lacking the beta 2 subunit of the neuronal nicotinic acetylcholine receptor.

Adult hippocampal neurogenesis declines with age in parallel with decreased performance on a variety of hippocampal-dependent tasks. We measured the rate of cellular proliferation in the hippocampus of mice lacking the beta 2-subunit of the nicotinic acetylcholine receptor (beta 2-/- mice) at three ages: young adult (3 months old), fully adult (7-10 months old), and aged (22-24 months old). Consistent with previous studies, we observed an age-related decline in hippocampal proliferation in both groups. However, in fully adult beta 2-/- mice a 43% reduction of granule cell proliferation was detected compared to age-matched controls. This was accompanied by a significant decrease in dentate gyrus area/section and the length of the granule cell layer in beta 2-/- mice. These alterations were not the result of a change in plasma corticosterone levels or expression of the neurotrophic factor BDNF in the dentate gyrus, two known regulators of hippocampal cell proliferation. Similarly, there was no increase in gliosis, abnormal myelination, or apoptotic cell death in the beta 2-/- animals, although there was a significant shift in the location of apoptotic cells in the dentate gyrus indicative of a change in neuronal survival. These results suggest that the beta 2-subunit containing nicotinic acetylcholine receptors play an important role in regulating cell proliferation in the hippocampus and that endogenous acetylcholine may act to oppose the negative effects of normal aging and stress on cellular proliferation.

Aging↗
PubMed2005

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.

Animals↗
PubMed2002

A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein.

P-glycoprotein (P-gp) is a multidrug transporter responsible for resistance to anticancer chemotherapy and physiologically involved in absorption, distribution, and excretion of a large number of hydrophobic xenobiotics. P-gp exhibits both an ATPase activity correlated with its drug transport function and a basal ATPase activity in the absence of any drug. We have developed a high-throughput screening test to detect specific interactions between drugs and P-gp. We took into account the existence of multiple binding sites on P-gp to propose and validate an optimized strategy, based on the modulation of the basal ATPase activity of P-gp and of the ATPase activity stimulated by three reference substrates (verapamil, vinblastine, and progesterone). The ATPase activity measurements were performed on P-gp-containing membrane vesicles from actinomycin-D-selected hamster DC-3F lung fibroblasts by a spectrophotometric method based on continuous monitoring of ADP formation, regenerated in ATP by a coupled enzyme system. This assay may be performed on 96- or 384-well microtiter plates. When applying this ATPase assay to 41 compounds known from the literature for their interaction with P-gp, 95% of them were found to be positive, whereas only 78% were positive when considering solely the modulation of the basal activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Relative contribution of NF-kappaB and AP-1 in the modulation by curcumin and pyrrolidine dithiocarbamate of the UVB-induced cytokine expression by keratinocytes.

Following ultraviolet B treatment, expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 by NCTC 2544 keratinocyte cell line was significantly enhanced both at the mRNA and protein level. The UVB also increased the IL-10 steady-state mRNAs level. Radiation-induced cytokine overexpression was accompanied by NF-kappaB and AP-1 transcription factors activation as assessed by electrophoretic mobility shift assays. To investigate in keratinocytes the relative contributions of those transcription factors on UVB-mediated cytokine induction, cell cultures were supplemented with curcumin and pyrrolidine dithiocarbamate (PDTC), agents known to modulate NF-kappaB and AP-1 activation. Both compounds significantly inhibited NF-kappaB activation by UVB, but AP-1 activation was unaffected by curcumin while PDTC further stimulated its activation. In parallel, curcumin decreased, in a dose-dependent manner, the UVB-mediated overexpression of all three pro-inflammatory cytokines and only exhibited a moderate enhancing influence on IL-10 expression. In turn, the inhibitory influence of PDTC on radiation-induced TNF-alpha and IL-6 expression is much lower and in contrast to curcumin, it stimulated IL-8. Taken together, our data indicated that control of proinflammatory cytokine expression induced by UVB in keratinocytes required the selective inhibition of NF-kappaB activation. Simultaneous AP-1 activation by agents like PDTC might, partially or totally, depending on cytokine-type, counterbalanced the inhibitory effect exerted on UVB-induced NF-kappaB activation in keratinocytes.

Base Sequence↗
PubMed1958

[Time agnosia].

Explore the source record for details and available documents.

Agnosia↗
PubMed2005

Improvement in Tc-99m HMPAO brain SPECT findings during donepezil therapy in a patient with pure akinesia.

A 58-year-old man presented with a history of disturbance in initiating gait. His history revealed meningoencephalitis five years prior to admission. Neurological examination included gait disturbance as difficulty in initiation and a hesitating speech with many freezing episodes and micrographia Magnetic resonance imaging (MRI) showed diffuse hyperintensity of frontal subcortical white matter on T2 weighted images. He was diagnosed with PA. L-Dopa up to the dosages of 1000 mg/ day and selegiline 10 mg/day were given. First brain SPECT using technetium-99m labeled D,L-hexamethylpropylene amine oxime (Tc-99m HMPAO) was performed when he was taking L-dopa and selegiline. In visual evaluation, hypoperfusion in bilateral frontoparietal cortex was seen (Fig. 2). Treatment with L-dopa and selegiline produced no benefit. Donepezil 10 mg/day was begun. This therapy regimen resulted in dramatic clinical improvement within several days that was confirmed by blinded raters who watched the patient's video recordings. During this response second brain perfusion SPECT study was repeated during donepezil therapy. Markedly increased perfusion in bilateral frontoparietal cortex was observed. This is the first case of PA to develop possibly after an episode of bacterial pneumococcal meningoencephalitis and who responded to donepezil as documented by changes in clinical findings and Tc-99m HMPAO brain SPECT studies.

Alexia, Pure↗
PubMed2006

Medium-term methionine supplementation increases plasma homocysteine but not ADMA and improves blood pressure control in rats fed a diet rich in protein and adequate in folate and choline.

BACKGROUND: Hyperhomocysteinemia (HHcy) is associated with cardiovascular risk, possibly because it increases asymmetric dimethyl-arginine (ADMA), but the general association remains unclear and may vary with nutritional and physiological conditions. AIM OF THE STUDY: We aimed to monitor the effect of methionine supplementation, and subsequent HHcy, on plasma ADMA and hemodynamics in the context of a diet rich in protein and adequate in folic acid and choline. METHODS: For 6 weeks, rats were fed a 29% protein diet supplemented (M) or not (C) with 8 g/kg L: -methionine. Blood pressure and plasma amino acids, including homocysteine and ADMA, were measured throughout the experiment and additional parameters, including in vivo hemodynamic response to acetylcholine, were measured at week 5-6. RESULTS: As compared to the C diet, the M diet induced a marked HHcy during the first 3 weeks, which lessened at week 5. In contrast, plasma ADMA stayed similar in the C and M diet. Paradoxically, M rats had lower mean and diastolic blood pressure values over the experiment, together with a lower left ventricular mass at week 6, when compared with C rats. No difference was observed between groups regarding vascular reactivity and plasma NOx at week 6. CONCLUSIONS: In a context of a diet rich in protein and adequate in methyl donors, rats exhibit a complex adaptation to the medium-term methionine supplementation, with improvement in blood pressure control despite marked HHcy. The lack of increase in plasma ADMA may account for the absence of detrimental effects of HHcy on hemodynamics.

Adaptation, Physiological↗