Activity of chitosan and its derivatives against Leishmania major and L. mexicana in vitro

There is an urgent need for safe, efficacious, affordable and field-adapted drugs for the treatment of cutaneous leishmaniasis which affects around 1.5 million new people worldwide annually. Chitosan, a biodegradable cationic polysaccharide, has previously been reported to have antimicrobial, anti-leishmanial and immunostimulatory activities. We investigated the in vitro activity of chitosan and several of its derivatives and showed that pH of the culture medium plays a critical role on anti-leishmanial activity of chitosan against both extracellular promastigotes and intracellular amastigotes of Leishmania major and Leishmania mexicana Chitosan and its derivatives were approximately 7-20 times more active at pH 6.5 than at pH 7.5 with high molecular weight chitosan being the most potent. High molecular weight chitosan stimulated the production of nitric oxide and reactive oxygen species by uninfected and Leishmania infected macrophages in a time and dose dependent manner at pH 6.5. Despite the in vitro activation of bone marrow macrophages by chitosan to produce nitric oxide and reactive oxygen species, we showed that the anti-leishmanial activity of chitosan was not mediated by these metabolites. Finally, we showed that rhodamine-labelled chitosan is taken up by pinocytosis and accumulates in the parasitophorous vacuole of Leishmania infected macrophages

Early administration of IL-6RA does not prevent radiation-induced lung injury in mice

<p>Abstract</p> <p>Background</p> <p>Radiation pneumonia and subsequent radiation lung fibrosis are major dose-limiting complications for patients undergoing thoracic radiotherapy. Interleukin-6 (IL-6) is a pleiotropic cytokine and plays important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate whether anti-IL-6 monoclonal receptor antibody (IL-6RA) could ameliorate radiation-induced lung injury in mice.</p> <p>Methods</p> <p>BALB/cAnNCrj mice having received thoracic irradiation of 21 Gy were injected intraperitoneally with IL-6RA (MR16-1) or control rat IgG twice, immediately and seven days after irradiation. Enzyme-linked immunosorbent assay was used to examine the plasma level of IL-6 and serum amyloid A (SAA). Lung injury was assessed by histological staining with haematoxylin and eosin or Azan, measuring lung weight, and hydroxyproline.</p> <p>Results</p> <p>The mice treated with IL-6RA did not survive significantly longer than the rat IgG control. We observed marked up-regulation of IL-6 in mice treated with IL-6RA 150 days after irradiation, whereas IL-6RA temporarily suppressed early radiation-induced increase in the IL-6 release level. Histopathologic assessment showed no differences in lung section or lung weight between mice treated with IL-6RA and control.</p> <p>Conclusions</p> <p>Our findings suggest that early treatment with IL-6RA after irradiation alone does not protect against radiation-induced lung injury.</p

Do longer consultations improve the management of psychological problems in general practice? A systematic literature review

<p>Abstract</p> <p>Background</p> <p>Psychological problems present a huge burden of illness in our community and GPs are the main providers of care. There is evidence that longer consultations in general practice are associated with improved quality of care; but this needs to be balanced against the fact that doctor time is a limited resource and longer consultations may lead to reduced access to health care.</p> <p>The aim of this research was to conduct a systematic literature review to determine whether management of psychological problems in general practice is associated with an increased consultation length and to explore whether longer consultations are associated with better health outcomes for patients with psychological problems.</p> <p>Methods</p> <p>A search was conducted on Medline (Ovid) databases up to7 June 2006. The following search terms, were used:</p> <p>general practice or primary health care (free text) or family practice (MeSH)</p> <p>AND consultation length or duration (free text) or time factors (MeSH)</p> <p>AND depression or psychological problems or depressed (free text).</p> <p>A similar search was done in Web of Science, Pubmed, Google Scholar, and Cochrane Library and no other papers were found.</p> <p>Studies were included if they contained data comparing consultation length and management or detection of psychological problems in a general practice or primary health care setting. The studies were read and categories developed to enable systematic data extraction and synthesis.</p> <p>Results</p> <p>29 papers met the inclusion criteria. Consultations with a recorded diagnosis of a psychological problem were reported to be longer than those with no recorded psychological diagnosis. It is not clear if this is related to the extra time or the consultation style. GPs reported that time pressure is a major barrier to treating depression. There was some evidence that increased consultation length is associated with more accurate diagnosis of psychological problems.</p> <p>Conclusion</p> <p>Further research is needed to elucidate the factors in longer consultations that are associated with greater detection of psychological problems, and to determine the association between the detection of psychological problems and the attitude, gender, age or training of the GP and the age, gender and socioeconomic status of the patient. These are important considerations if general practice is to deal more effectively with people with psychological problems.</p

Serum proteome analysis for profiling protein markers associated with carcinogenesis and lymph node metastasis in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC), one of the most common cancers in population with Chinese or Asian progeny, poses a serious health problem for southern China. It is unfortunate that most NPC victims have had lymph node metastasis (LNM) when first diagnosed. We believe that the 2D based serum proteome analysis can be useful in discovering new biomarkers that may aid in the diagnosis and therapy of NPC patients. To filter the tumor specific antigen markers of NPC, sera from 42 healthy volunteers, 27 non-LNM NPC patients and 37 LNM NPC patients were selected for screening study using 2D combined with MS. Pretreatment strategy, including sonication, albumin and immunoglobulin G (IgG) depletion, was adopted for screening differentially expressed proteins of low abundance in serum. By 2D image analysis and MALDI-TOF-MS identification, twenty-three protein spots were differentially expressed. Three of them were further validated in the sera using enzyme-linked immunosorbent assay (ELISA). Our research demonstrates that HSP70, sICAM-1 and SAA, confirmed with ELISA at sera and immunohistochemistry, are potential NPC metastasis-specific serum biomarkers which may be of great underlying significance in clinical detection and management of NPC

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Neutrophil responses to CRP are not dependent on polymorphism of human FcgammaRIIA (R131H).

IgG2a mediated in vitro phagocytosis is less effective for individuals homozygous for Fcgamma RIIaR131 allele and such individuals are also more susceptible to certain infections. It has been reported that CRP binds to Fcgamma RIIaR131 but not Fcgamma RIIaH131 and since Fcgamma RIIa is also a major Fc receptor on neutrophils it would be expected that normal healthy donors who did not have at least one copy of Fcgamma RIIaR131 would not respond to CRP. We examined responses reported to be dependent on FcgammaRIIa but no difference between groups was observed in CRP mediated phagocytosis of S. pneumoniae, reactive oxygen production, or IL-8 synthesis. This suggests that either neutrophil receptors other than Fcgamma RIIa are responsible for CRP mediated responses or differences in CRP binding to the forms of Fcgamma RIIa are comparatively minor