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101.
Eva MF Brekke Tora S Morken Marius Wider?e Asta K H?berg Ann-Mari Brubakk Ursula Sonnewald 《Journal of cerebral blood flow and metabolism》2014,34(4):724-734
The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-13C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using 1H- and 13C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress. 相似文献
102.
Ursula C. Patel Erin L. McKissic Douglas Kasper Joseph R. Lentino Constance T. Pachucki Todd Lee Bert K. Lopansri 《International journal of clinical pharmacy》2014,36(6):1282-1289
Background Standard of care therapy (SOCT) for the treatment of methicillin susceptible staphylococcal aureus (MSSA) infections requires multiple daily infusions. Despite questionable efficacy due to high protein binding, ceftriaxone (CTX) is frequently used for treatment of MSSA at Hines VA Hospital. Objective The objective of this study was to determine clinical and microbiological outcomes in patients with MSSA bacteremia treated with CTX compared to SOCT. Setting This retrospective study was conducted at the Edward Hines, Jr. VA Hospital which is a comprehensive health care center serving the veteran population of the greater metropolitan Chicago and northwest Indiana regions and is institutionally affiliated with the Loyola University Medical Center. The Hines VA provides medical care to over 56,000 veterans and operates approximately 500 hospital beds, including acute care and nursing home beds. Method We conducted a retrospective cohort study of patients with MSSA bacteremia treated at Hines VA Hospital between January 2000 and September 2009. Patients who received either SOCT or CTX for >50 % of the treatment course and for the appropriate duration were included. Patients who were on multiple antibiotics concurrently or who received <14 days of therapy were excluded. Main outcome measure The primary outcome of this study is to compare clinical outcomes of patients with MSSA bacteremia who were treated with CTX compared to those who received standard of care agents. Results Ninety-three patients with MSSA bacteremia were included in the analysis. Fifty-one were treated with SOCT and 42 with CTX. There were no differences in microbiological cure between SOCT (94.1 %) and CTX (95.2 %) (p = 0.812). Clinical cure was similar between groups (74.5 % for SOCT, 83.3 % for CTX) (p = 0.303). CTX was used more often to treat Staphylococcus aureus bacteremia associated with osteomyelitis whereas endocarditis and central line associated infections were treated more frequently with SOCT (p = 0.01). More patients treated with CTX were managed in the ambulatory setting (64 vs. 24 %; p = <0.001). There was a trend toward a longer hospital stay with SOCT. Conclusion Clinical outcomes for MSSA bacteremia did not differ significantly between patients treated with CTX and SOCT. Findings suggest that CTX may be an alternative for outpatient management of MSSA bacteremia. 相似文献
103.
104.
Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants
105.
Inflammatory cytokines alter the hemostatic balance of endothelial cells (ECs). Alternatively spliced human tissue factor (asHTF), a soluble isoform of tissue factor (TF), has recently been detected in ECs, possibly contributing to procoagulability. Agonists regulating asHTF expression and release are yet unknown. This study examines the effect of TNF-alpha and IL-6 on the endothelial expression of both TF variants and delineates the impact of asHTF on the procoagulability of extracellular fluids. asHTF and TF mRNA were assessed by real-time PCR, and asHTF, TF, and tissue factor pathway inhibitor (TFPI) proteins by Western blot and fluorescence microscopy before and after stimulation with TNF-alpha (10 ng/mL) or IL-6 (10 ng/L). The procoagulability of cell supernatant was analyzed by a chromogenic assay with or without phospholipid vesicles. We found asHTF mRNA to be maximally increased 10 minutes after TNF-alpha and 40 minutes after IL-6 treatment (asHTF/GAPDH ratio 0.0223+/-0.0069 versus 0.0012+/-0.0006 for control, P<0.001 and 0.0022+/-0.0004 versus 0.0012+/-0.0007, P<0.05, respectively). Not only was asHTF increased, but also TFPI decreased after cytokine treatment. asHTF was found in the supernatant as early as 5 hours after TNF-alpha stimulation, supporting factor Xa generation after relipidation (6.55+/-1.13 U versus 2.99+/-0.59 U in control supernatant, P<0.00001). Removal of asHTF from supernatants by immunoprecipitation diminished its procoagulability to baseline. The soluble TF isoform expressed and released from ECs in response to inflammatory cytokines becomes procoagulant in the presence of phospholipids. Thus, asHTF released from ECs is a marker for and a contributor to imbalanced hemostasis. 相似文献
106.
Antoniak S Boltzen U Riad A Kallwellis-Opara A Rohde M Dörner A Tschöpe C Noutsias M Pauschinger M Schultheiss HP Rauch U 《Journal of molecular and cellular cardiology》2008,45(1):118-126
We investigated the effects of viral infection on Tissue Factor (TF) expression and activity in mice within the myocardium to understand increased thrombosis during myocarditis. Mice were infected with coxsackie virus B3 (CVB3) and the hearts were collected at day 4, 8 and 28 post infection (p.i.). Myocardial TF expression and cellular activity as well as plasma activity were analyzed from CVB3 infected mice by Western blot, chromogenic Factor Xa generation assay, in situ staining for active TF and immunohistochemistry. In addition to TF expression, hemodynamic parameters were measured during the time course of infection. Furthermore, we analyzed myocardial tissues from patients with suspected inflammatory cardiomyopathy. TF protein expression was maximally 5-fold elevated 8 days p.i. in mice and remained increased on day 28 p.i. (P < 0.001 vs. non-infected controls). Alterations in TF expression were associated with fibrin deposits within the myocardium. The TF pathway inhibitor protein expression in the myocardium was not altered during myocarditis. Active cellular TF co-localized with CD3 positive cells and VCAM-1 positive endothelial cells in the myocardium. The TF expression was positively correlated with the amount of infiltrating CD3 and Mac3 positive cells (Spearman-Rho ρ = 0.749 P < 0.0001 for CD3+ and ρ = 0.775 P < 0.0001 for Mac3+; N = 35). Increased myocardial TF expression was associated with a 2-fold elevated plasma activity (P < 0.05 vs. non-infected controls). In the human hearts, the TF expression correlated postively with an endothelial cell activation marker (ρ = 0.523 P < 0.0001 for CD62E; N = 54). Viral myocarditis is a hypercoagulative state which is associated with increased myocardial TF expression and activity. Upregulation of TF contributes to a systemic activation of the coagulation cascade. 相似文献
107.
Calcium lability of cytoplasmic microtubules and its modulation by microtubule-associated proteins 总被引:31,自引:0,他引:31
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Manfred Schliwa Ursula Euteneuer Jeannette Chloe Bulinski Jonathan G. Izant 《Proceedings of the National Academy of Sciences of the United States of America》1981,78(2):1037-1041
Detergent-extracted BSC-1 monkey cells have been used as a model system to study the Ca2+ sensitivity of in vivo polymerized microtubules under in vitro conditions. The effects of various experimental treatments were observed by immunofluorescence microscopy. Whereas microtubules are completely stable at Ca2+ concentrations below 1 μM, Ca2+ at greater than 1-4 μM induces microtubule disassembly that begins in the cell periphery and proceeds towards the cell center. At concentrations of up to 500 μM, both the pattern and time course of disassembly are not markedly altered, suggesting that, within this concentration range, Ca2+ effects are catalytic rather than stoichiometric. Higher (millimolar) Ca2+ concentration results in rapid destruction of microtubules. Of other divalent cations, only Sr2+ has a slight depolymerizing effect, whereas millimolar Ba2+, Mg2+, or Mn2+ is ineffective. Disassembly induced by micromolar Ca2+ is inhibited by pharmacological agents known to bind to calmodulin and inhibit its function, suggesting that calmodulin mediates Ca2+ effects. Both the addition of exogenous brain microtubule-associated proteins (MAPs) after lysis and the retention of endogenous cellular MAPs normally extracted during the lysis step stabilize microtubules against the depolymerizing effect of micromolar Ca2+. The results indicate that, in this model system, microtubules are sensitive to physiological Ca2+ concentrations and that this sensitivity may be conferred by calmodulin associated with the microtubules. MAPs appear to have a modulating effect on microtubular Ca2+ sensitivity and thus may function as a discriminating factor in cellular functions performed by calmodulin. It is hypothesized that Ca2+-stimulated microtubule disassembly depends on the relative amount of MAPs. 相似文献
108.
CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis 总被引:1,自引:0,他引:1
Mason U Aldrich J Breedveld F Davis CB Elliott M Jackson M Jorgensen C Keystone E Levy R Tesser J Totoritis M Truneh A Weisman M Wiesenhutter C Yocum D Zhu J 《The Journal of rheumatology》2002,29(2):220-229
OBJECTIVE: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies. METHODS: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-na?ve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)].The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment. RESULTS: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab. CONCLUSION: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response. 相似文献
109.
Chinn S Jarvis D Melotti R Luczynska C Ackermann-Liebrich U Antó JM Cerveri I de Marco R Gislason T Heinrich J Janson C Künzli N Leynaert B Neukirch F Schouten J Sunyer J Svanes C Vermeire P Wjst M Burney P 《Lancet》2005,365(9471):1629-35; discussion 1600-1
110.
Borck G Topaloglu AK Korsch E Martiné U Wildhardt G Onenli-Mungan N Yuksel B Aumann U Koch G Ozer G Pfäffle R Scherberg NH Refetoff S Pohlenz J 《The Journal of clinical endocrinology and metabolism》2004,89(8):4136-4141
Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G--> A) in the TSHbeta gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHbeta locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHbeta mutation is among the more common TSHbeta gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal. 相似文献