Plasma levels in sepsis patients of annexin A1, lipoxin A4, macrophage inflammatory protein-3a, and neutrophil gelatinase-associated lipocalin

AbstractBackgroundThe relationship between the various cytokine responses that occur during sepsis remains controversial. Emerging evidence indicates that the proinflammatory and anti-inflammatory responses are regulated simultaneously from the beginning of sepsis. However, the roles of the novel anti-inflammatory mediators annexin (Anx)A1 and lipoxin (LX)A4 and the proinflammatory cytokines neutrophil gelatinase-associated lipocalin (NGAL) and macrophage inflammatory protein (MIP)-3a have been studied.MethodsIn this study, the plasma levels of AnxA1, LXA4, NGAL, MIP-3a, interleukin (IL)-8 and IL-6 in patients with sepsis were determined on admission to the intensive care unit. The patients were classified into survivors and non-survivors based on their outcome on day 28.ResultsAnxA1 and LXA4 levels were decreased in sepsis patients compared with control patients, whereas the levels of the proinflammatory cytokines MIP-3a, NGAL, IL-8, and IL-6 were elevated. Furthermore, a significantly higher level of MIP-3a was detected in nonsurviving patients compared with surviving patients (p < 0.05), whereas there were no significant differences between these two groups for the levels of the other mediators. Correlation analysis demonstrated that only NGAL level was closely correlated with the level of IL-6. Univariate analysis indicated that the levels of MIP-3a and IL-8 were independent factors associated with patient survival, but this was not confirmed by the multivariate analysis.ConclusionAnxA1 and LXA4 plasma levels were found to be decreased in sepsis patients, whereas the levels of MIP-3a and NGAL were found to be elevated. This warrants further study in order to determine the clinical implications of these changes

Isotretinoin Oil-Based Capsule Formulation Optimization

The purpose of this study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X1), hydrogenated coconut oil (X2), and soybean oil (X3). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X1X2, X1X3, and X2X3) showed more potential influence than that of the main factors (X1, X2, and X3). An optimal predicted formulation with Y10 min, Y30 min, Y60 min, and Y90 min release values of 12.3%, 36.7%, 73.6%, and 92.7% at X1, X2, and X3 of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factor f2 was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile

Highly sensitive analysis of the anti-tumor agent 1-[4-(furo[2,3-b]-quinolin-4-ylamino)phenyl]ethanone in rat plasma by high-performance liquid chromatography using electrochemical detection

Abstract A sensitive high-performance liquid chromatography method with electrochemical detection was developed for the purpose of determining the concentration of the new anti-tumor agent 1-[4-(furo[2,3-b]-quinolin-4-ylamino)phenyl]ethanone (FQPE) in rats. The plasma samples were spiked with the internal standard diclofenac and extracted using dichloromethane. A C 18 250 mm × 4 mm column was used for the separation of analyte with a mobile phase consisting of 50% acetonitrile and 50% pH 3.0 of sodium 1-pentansulfonate solution at a flow rate of 1.0 mL/min. FQPE was detected by electrochemical detector at 1.0 V and 20 nA. Intra-day and inter-day precision and accuracy were acceptable down to the limit of quantization of 1 ng/mL. The lower limit of detection (LOD) was 0.5 ng/mL. The pharmacokinetic parameters of FQPE in rats after intravenous administration of 2.1 and 4.2 mg/kg were determined. The apparent volume of distribution, half-life of elimination, and clearance showed no significant difference between the two dosages. The area under the plasma concentration time curve increased proportionally with dose. The half-life of FQPE was prolonged about 2.4-fold, compared with amsacrine

Advanced age affects the outcome-predictive power of RIFLE classification in geriatric patients with acute kidney injury

The RIFLE (risk, injury, failure, loss, and end-stage) classification is widely used to gauge the severity of acute kidney injury, but its efficacy has not been formally tested in geriatric patients. To correct this we conducted a prospective observational study in a multicenter cohort of 3931 elderly patients (65 years of age or older) who developed acute kidney injury in accordance with the RIFLE creatinine criteria after major surgery. We studied the predictive power of the RIFLE classification for in-hospital mortality and investigated the potential interaction between age and RIFLE classification. In general, the survivors were significantly younger than the nonsurvivors and more likely to have hypertension. In patients 76 years of age and younger, RIFLE-R, -I, or -F classifications were significantly associated with increased hospital mortality in a stepwise manner. There was no significant difference, however, in hospital mortality in those over 76 years of age between patients with RIFLE-R and RIFLE-I, although RIFLE-F patients had significantly higher mortality than both groups. Thus, the less severe categorizations of acute kidney injury per RIFLE classification may not truly reflect the adverse impact on elderly patients

Frequency Domain Effect of a Hysteresis Suppression System with Inverse Preisach Model Based Control

The extended Preisach model is used extensively in precision control for its ability to model and thus can be used to suppress the hysteresis phenomenon. Although an inverse model based on the classical Preisach model entails a very high level of computational complexity, recent advances in computer technology has enabled real-time implementation of such models. The extended Preisach model calculates the hysteresis action by fitting the - table in the Preisach model to a surface. One can then calculate the amount of extension and retraction simply by searching for the parameters on the surface. This paper proposes a real-time high speed implementation of a model-based hysteresis elimination control. The experimental results show that the proposed method produces a smaller tracking error with a smooth system output

Acute-on-chronic kidney injury at hospital discharge is associated with long-term dialysis and mortality

Existing chronic kidney disease (CKD) is among the most potent predictors of postoperative acute kidney injury (AKI). Here we quantified this risk in a multicenter, observational study of 9425 patients who survived to hospital discharge after major surgery. CKD was defined as a baseline estimated glomerular filtration rate <45ml/min per 1.73m2. AKI was stratified according to the maximum simplified RIFLE classification at hospitalization and unresolved AKI defined as a persistent increase in serum creatinine of more than half above the baseline or the need for dialysis at discharge. A Cox proportional hazard model showed that patients with AKI-on-CKD during hospitalization had significantly worse long-term survival over a median follow-up of 4.8 years (hazard ratio, 3.3) than patients with AKI but without CKD. The incidence of long-term dialysis was 22.4 and 0.17 per 100 person-years among patients with and without existing CKD, respectively. The adjusted hazard ratio for long-term dialysis in patients with AKI-on-CKD was 19.8 compared to patients who developed AKI without existing CKD. Furthermore, AKI-on-CKD but without kidney recovery at discharge had a worse outcome (hazard ratios of 4.6 and 213, respectively) for mortality and long-term dialysis as compared to patients without CKD or AKI. Thus, in a large cohort of postoperative patients who developed AKI, those with existing CKD were at higher risk for long-term mortality and dialysis after hospital discharge than those without. These outcomes were significantly worse in those with unresolved AKI at discharge

Serum Levels of Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor 1 Are Associated With Autonomic Dysfunction and Impaired Cerebral Autoregulation in Patients With Epilepsy

Background: Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) may regulate the autonomic nervous system (ANS) in epilepsy. The present study investigated the role of IGF-1 and BDNF in the regulation of autonomic functions and cerebral autoregulation in patients with epilepsy.Methods: A total of 57 patients with focal epilepsy and 35 healthy controls were evaluated and their sudomotor, cardiovagal, and adrenergic functions were assessed using a battery of ANS function tests, including the deep breathing, Valsalva maneuver, head-up tilting, and Q-sweat tests. Cerebral autoregulation was measured by transcranial doppler during the breath-holding test and the Valsalva maneuver. Interictal serum levels of BDNF and IGF-1 were measured with enzyme-linked immunosorbent assay kits.Results: During interictal period, reduced serum levels of BDNF and IGF-1, impaired autonomic functions, and decreased cerebral autoregulation were noted in patients with epilepsy compared with healthy controls. Reduced serum levels of BDNF correlated with age, adrenergic and sudomotor function, overall autonomic dysfunction, and the autoregulation index calculated in Phase II of the Valsalva maneuver, and showed associations with focal to bilateral tonic-clonic seizures. Reduced serum levels of IGF-1 were found to correlate with age and cardiovagal function, a parameter of cerebral autoregulation (the breath-hold index). Patients with a longer history of epilepsy, higher seizure frequency, and temporal lobe epilepsy had lower serum levels of IGF-1.Conclusions: Long-term epilepsy and severe epilepsy, particularly temporal lobe epilepsy, may perturb BDNF and IGF-1 signaling in the central autonomic system, contributing to the autonomic dysfunction and impaired cerebral autoregulation observed in patients with focal epilepsy

Differential baseline and response profile to IFN-γ gene transduction of IL-6/IL-6 receptor-α secretion discriminate primary tumors versus bone marrow metastases of nasopharyngeal carcinomas in culture

<p>Abstract</p> <p>Background</p> <p>Understanding of immunobiology of bone marrow metastases (designated BM-NPC) <it>versus </it>primary tumors (P-NPC) of the nasopharynx is far from complete. The aim of this study was to determine if there would be differences between cultured P-NPCs and BM-NPCs with respect to (i) constitutive IL-6 and the IL-6 receptor gp80 subunit (IL-6Rα) levels in the spent media of nontransduced cells, and (ii) IL-6 and IL-6Rα levels in the spent media of cells transduced with a retroviral vector containing the <it>IFN-γ </it>gene.</p> <p>Methods</p> <p>A panel of NPC cell lines were transduced with the <it>IFN-γ </it>gene through a retroviral vector. Four clonal sublines were isolated <it>via </it>limiting dilution methods. Cytofluorometric analysis was performed for the detection of cell surface antigens of HLA class I, HLA class II and ICAM-1. ELISA was used to assay for IFN-γ, IL-6 and IL-6Rα in the spent media of cultured cell lines.</p> <p>Results</p> <p>Our results showed that in day 3 culture supernatants, low levels of soluble IL-6 were detected in 5/5 cultured tumors derived from P-NPCs, while much higher constitutive levels of IL-6 were detected in 3/3 metastasis-derived NPC cell lines including one originated from ascites; the difference was significant (<it>p </it>= 0.025). An inverse relationship was found between IL-6Rα and IL-6 in their release levels in cultured P-NPCs and metastasis-derived NPCs. In <it>IFN-γ</it>-transduced-P-NPCs, IL-6 production increased and yet IL-6Rα decreased substantially, as compared to nontransduced counterparts. At variance with P-NPC cells, the respective ongoing IL-6 and IL-6Rα release patterns of BM-NPC cells were not impeded as much following <it>IFN-γ </it>transduction. These observations were confirmed by extended kinetic studies with representative NPC cell lines and clonal sublines. The latter observation with the clonal sublines also indicates that selection for high IL-6 or low IL-6Rα producing subpopulations did not occur as a result of <it>IFN-γ</it>-transduction process. P-NPCs, which secreted constitutively only marginal levels of IFN-γ (8.4 ~ 10.5 pg/ml), could be enhanced to produce higher levels of IFN-γ (6.8- to 10.3-fold increase) after <it>IFN-γ </it>transduction. Unlike P-NPCs, BM-NPCs spontaneously released IFN-γ at moderate levels (83.8 ~ 100.7 pg/ml), which were enhanced by 1.3- to 2.2-fold in the spent media of their <it>IFN-γ</it>-transduced counterparts.</p> <p>Conclusion</p> <p>Our results showed that cultured P-NPCs and BM-NPCs could be distinguished from one another on the basis of their differential baseline secretion pattern of IFN-γ, IL-6 and IL-6Rα, and their differential response profiles to <it>IFN-γ </it>gene transfer of the production of these three soluble molecules. These results suggest that the IL-6 and IFN-γ pathways in a background of genetic instability be involved in the acquisition of metastatic behaviour in BM-NPCs.</p