In activated macrophage, large amounts of nitric oxide (NO) are generated by inducible nitric oxide synthase (iNOS), resulting in acute or chronic inflammatory disorders. In Raw 264.7 cells ...stimulated with lipopolysaccharide (LPS) to mimic inflammation, 8-hydroxyquinoline (8HQ) inhibited the LPS-induced expression of both iNOS protein and mRNA in a parallel dose-dependent manner. 8HQ did not enhance the degradation of iNOS mRNA. To investigate the mechanism by which 8HQ inhibits iNOS gene expression, we examined the activation of MAP kinases in Raw 264.7 cells. We did not observe any significant change in the phosphorylation of MAPKs between LPS alone and LPS plus 8HQ-treated cells. Moreover, 8HQ significantly inhibited the DNA-binding activity of nuclear factor-κB (NF-κB) and CCAAT/enhancer-binding protein β (C/EBPβ), but not activator protein-1 and cAMP response element-binding protein. Taken together, these results suggest that 8HQ acts to inhibit inflammation through inhibition of NO production and iNOS expression through blockade of C/EBPβ DNA-binding activity and NF-κB activation.
Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. ...However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C-C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients. Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis.
The three proteins of the antigen 85 complex (85A, 85B, and 85C), which are major secretory products of Mycobacterium tuberculosis, were purified to homogeneity in large amounts by a combination of ...chromatography on hydroxylapatite, DEAE-Sepharose, and DEAE-Sephacel and gel filtration from M. tuberculosis culture filtrate. Then we examined the immunological reactivity of the three proteins in tuberculosis patients and healthy controls. Antibody responses to the 85B and 85A proteins in patients were significantly greater than responses to the 85C protein. In contrast, all three antigens induced significant lymphoproliferation and gamma interferon production in peripheral blood mononuclear cells from healthy tuberculin reactors.
We report in this study that an oxoiron(IV) porphyrin complex bearing electron-deficient porphyrin ligand, (TPFPP)FeIVO (TPFPP = meso-tetrakis(pentafluorophenyl)porphinato dianion), shows ...reactivities similar to those found in oxoiron(IV) porphyrin π-cation radicals. In the epoxidation of olefins by the (TPFPP)FeIVO complex, epoxides were yielded as major products; cyclohexene oxide was the sole product formed in the epoxidation of cyclohexene, and stilbenes were stereospecifically oxidized to the corresponding epoxide products. More striking results were obtained in alkane hydroxylation reactions; the hydroxylation of adamantane afforded a high degree of selectivity for tertiary C−H bonds over secondary C−H bonds, and the hydroxylation of cis-1,2-dimethylcyclohexane yielded a tertiary alcohol product with >99% retention of stereochemistry. The latter result demonstrates that an oxoiron(IV) porphyrin complex hydroxylates alkanes with a high stereospecificity. Isotope labeling studies performed with H2 18O and 18O2 in the olefin epoxidation and alkane hydroxylation reactions demonstrated that oxygen atoms in oxygenated products derived from the oxoiron(IV) porphyrin complex.
Older people with elevated blood pressure (BP) often have metabolic syndrome, a clustering of central obesity, insulin resistance, dyslipidemia, and hypertension. Exercise reduces many of these risk ...factors. This study examined whether the benefits of exercise on cardiovascular and metabolic disease risk factors are mediated by exercise-induced changes in fitness or body composition.
Randomized controlled trial, comprising 6 months of exercise training, conducted between July 1999 and November 2003. Participants included men and women (
n =115) aged 55 to 75 years with untreated systolic blood pressure (SBP) of 130 to 159 or diastolic blood pressure of (DPB) 85 to 99 mm Hg. Fitness measures included BP, lipids, lipoproteins, insulin, and glucose; peak oxygen uptake and muscle strength; and body composition measured by anthropometry, dual-energy x-ray absorptiometry, and magnetic resonance imaging.
A total of 51 men and 53 women completed the trial. Exercise significantly increased aerobic and muscle fitness, lean mass, and high-density lipoprotein cholesterol and reduced total and abdominal fat. DBP was reduced more among exercisers. There were no associations among changes in fitness with risk factors. Reductions in total body and abdominal fat and increases in leanness, largely independent of weight loss, were associated with improved SBP, DBP, total cholesterol, very low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and insulin sensitivity. At baseline, 42.3% of participants had metabolic syndrome. At 6 months, nine exercisers (17.7%) and eight controls (15.1%) no longer had metabolic syndrome, whereas four controls (7.6%) and no exercisers developed it (
p =0.06).
Although exercise improved fitness, the reductions in total and abdominal fatness and increase in leanness were more strongly associated with favorable changes in risk factors for cardiovascular disease and diabetes, including those that constitute metabolic syndrome.
Calcineurin inhibitors used in kidney transplantation for immunosuppression have adverse effects that may contribute to nephrotoxicity and increased cardiovascular risk profile. Fish oils are rich in ...very long chain omega-3 fatty acids, which may reduce nephrotoxicity by improving endothelial function and reduce rejection rates through their immuno-modulatory effects. They may also modify the cardiovascular risk profile. Hence, fish oils may potentially prolong graft survival and reduce cardiovascular mortality.
To assess the benefits and harms of fish oil supplementation on kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library, issue 2 2005), MEDLINE (1966-April 2005) and EMBASE (1980-April 2005).
All randomised controlled trials (RCTs) and quasi-RCTs of fish oils in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. RCTs of fish oil versus statins were included.
Data was extracted and the quality of studies assessed by two authors, with differences resolved by discussion with a third independent author. Dichotomous outcomes were reported as relative risk (RR) and continuous outcome measures were reported as the mean difference (MD) with 95% confidence intervals using the random effects model. Heterogeneity was assessed using a Chi(2) test on n-1 degrees of freedom and the I(2) statistic. Data not suitable for pooling were tabulated and described.
Sixteen studies (733 patients) were suitable for analysis. Fish oil did not significantly affect patient or graft survival, acute rejection rates, calcineurin inhibitor toxicity or renal function, when compared to placebo. Fish oil treatment was associated with a lower diastolic blood pressure (MD 4.5 mmHg; P = 0.004) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (MD 0.12 mmol/L; P = 0.01) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out.
There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve renal function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.
Prolonged hospitalisation not only increases cost, it is also associated with other complications. Length of stay (LOS) is one of the indicators that reflect total cost of care during ...hospitalisation. So, it is of paramount importance to find out why elderly patients overstay in acute care hospitals and address these issues proactively. Since no local data is available, a study was planned to ascertain reasons why the discharging of elderly patients from hospital is delayed and whether these reasons are avoidable.
Long-stay patients were defined as those whose LOS had notably exceeded the average LOS for the Diagnosis Related Group (DRG), based on principal admitting diagnosis. A separate analysis showed that the specialty-specific long-stay marker for geriatric medicine was 28 days, so casenote review was done for all patients with LOS of more than 28 days who were discharged from geriatric medicine service of an acute care hospital during a 1-year study period. Information was collected on demographic profile, functional and cognitive status, past medical and social history, admitting medical diagnoses, discharge limiting and delaying factors.
During the study period, 150 patients stayed over 28 days and 137 casenotes were available for review. The mean age of the patients was 84 years, 55.5% were female, 77.4% were Chinese, mean abbreviated mental test (AMT) score was 3 and mean modified Barthel's score was 11. The commonest primary diagnosis was sepsis followed by neurological problems, falls-related complication and cardiovascular diseases. The 2 most common discharge limiting factors (the final event which resulted in delay in discharge) were social issues (54, 39.4%) and sepsis (47, 34.3%). Of 47 patients with sepsis, 37 (78.7%) were nosocomial infection. Urinary tract infection and pneumonia were the 2 most common nosocomial infections. The 4 most common factors contributing to delayed discharge (various problems that surfaced throughout the hospital stay) were sepsis (94, 68.6%), deconditioning (65, 47.4%), social issues (52, 38.0%) and cardiovascular disorders (37, 27.0%).
Elderly patients are more prone to hospitalisation-related complications like nosocomial infection and deconditioning leading to prolonged hospital stay. Early interventions can reduce these complications. Early identification of social issues and prompt discharge planning should be done to avoid delay in discharge.
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