IL-10 Blocks the Development of Resistance to Re-Infection with Schistosoma mansoni

Despite effective chemotherapy to treat schistosome infections, re-infection rates are extremely high. Resistance to reinfection can develop, however it typically takes several years following numerous rounds of treatment and re-infection, and often develops in only a small cohort of individuals. Using a well-established and highly permissive mouse model, we investigated whether immunoregulatory mechanisms influence the development of resistance. Following Praziquantel (PZQ) treatment of S. mansoni infected mice we observed a significant and mixed anti-worm response, characterized by Th1, Th2 and Th17 responses. Despite the elevated anti-worm response in PBMC's, liver, spleen and mesenteric lymph nodes, this did not confer any protection from a secondary challenge infection. Because a significant increase in IL-10-producing CD4+CD44+CD25+GITR+ lymphocytes was observed, we hypothesised that IL-10 was obstructing the development of resistance. Blockade of IL-10 combined with PZQ treatment afforded a greater than 50% reduction in parasite establishment during reinfection, compared to PZQ treatment alone, indicating that IL-10 obstructs the development of acquired resistance. Markedly enhanced Th1, Th2 and Th17 responses, worm-specific IgG1, IgG2b and IgE and circulating eosinophils characterized the protection. This study demonstrates that blocking IL-10 signalling during PZQ treatment can facilitate the development of protective immunity and provide a highly effective strategy to protect against reinfection with S. mansoni

An effective nonchemical treatment for head lice: A lot of hot air. American academy of pediatrics

ABSTRACT OBJECTIVES. Head lice (Pediculus humanus capitis) are a major irritant to children and their parents around the world. Each year millions of children are infested with head lice, a condition known as pediculosis, which is responsible for tens of millions of lost school days. Head lice have evolved resistance to many of the currently used pediculicides; therefore, an effective new treatment for head lice is needed. In this study we examined the effectiveness of several methods that use hot air to kill head lice and their eggs. METHODS. We tested 6 different treatment methods on a total of 169 infested individuals. Each method delivers hot air to the scalp in a different way. We evaluated how well these methods kill lice and their eggs in situ. We also performed follow-up inspections to evaluate whether the sixth, most successful, method can cure head louse infestations. RESULTS. All 6 methods resulted in high egg mortality (Ն88%), but they showed more-variable success in killing hatched lice. The most successful method, which used a custom-built machine called the LouseBuster, resulted in nearly 100% mortality of eggs and 80% mortality of hatched lice. The LouseBuster was effective in killing lice and their eggs when operated at a comfortable temperature, slightly cooler than a standard blow-dryer. Virtually all subjects were cured of head lice when examined 1 week after treatment with the LouseBuster. There were no adverse effects of treatment. CONCLUSIONS. Our findings demonstrate that one 30-minute application of hot air has the potential to eradicate head lice infestations. In summary, hot air is an effective, safe treatment and one to which lice are unlikely to evolve resistance. www.pediatrics.org/cg

Active Site Rearrangement of the 2-Hydrazinopyridine Adduct in Escherichia coli Amine Oxidase to an Azo Copper(II) Chelate Form: A Key Role for Tyrosine 369 in Controlling the Mobility of the TPQ-2HP Adduct.

Adduct I (λmax at ∼430 nm) formed in the reaction of 2-hydrazinopyridine (2HP) and the TPQ cofactor of wild-type Escherichia coli copper amine oxidase (WT-ECAO) is stable at neutral pH, 25 °C, but slowly converts to another spectroscopically distinct species with a λmax at ∼530 nm (adduct II) at pH 9.1. The conversion was accelerated either by incubation of the reaction mixture at 60 °C or by increasing the pH (>13). The active site base mutant forms of ECAO (D383N and D383E) showed spectral changes similar to WT when incubated at 60 °C. By contrast, in the Y369F mutant adduct I was not stable at pH 7, 25 °C, and gradually converted to adduct II, and this rate of conversion was faster at pH 9. To identify the nature of adduct II, we have studied the effects of pH and divalent cations on the UV−vis and resonance Raman spectroscopic properties of the model compound of adduct I (2). Strikingly, it was found that addition of Cu2+ to 2 at pH 7 gave a product (3) that exhibited almost identical spectroscopic signatures to adduct II. The X-ray crystal structure of 3 shows that it is the copper-coordinated form of 2, where the +2 charge of copper is neutralized by a double deprotonation of 2. These results led to the proposal that adduct II in the enzyme is TPQ−2HP that has migrated onto the active site Cu2+. The X-ray crystal structure of Y369F adduct II confirmed this assignment. Resonance Raman and EPR spectroscopy showed that adduct II in WT-ECAO is identical to that seen in Y369F. This study clearly demonstrates that the hydrogen-bonding interaction between O4 of TPQ and the conserved Tyr (Y369) is important in controlling the position and orientation of TPQ in the catalytic cycle, including optimal orientation for reactivity with substrate amines