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2.  Dr Pat Manson and the way forward 
doi:10.3399/bjgp12X658421
PMCID: PMC3481509  PMID: 23211172
3.  AN HONOURABLE MAN 
doi:10.3399/bjgp12X641564
PMCID: PMC3338046
4.  Book reviews 
doi:10.3399/bjgp11X593938
PMCID: PMC3162162
5.  Professor Ian Richardson 
doi:10.3399/bjgp11X561438
PMCID: PMC3047335
6.  STRUCTURAL CHARACTERISATION OF THE LEISHMANIA MAJOR ORTHOLOGUES OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) 
Leishmania major, an intracellular parasitic protozoon that infects, differentiates and replicates within macrophages, encodes two closely related MIF-like proteins, which have only ~20% amino acid identity with mammalian MIF. Recombinant L. major MIF1 and MIF2 have been expressed and the structures, resolved by X-ray crystallography, show a trimeric ring architecture similar to mammalian MIF but with some structurally distinct features. LmjMIF1, but not LmjMIF2, has tautomerase activity, indicating that the LmjMIFs have evolved potentially different biological roles. This is further demonstrated by the differential life cycle expression of the proteins. LmjMIF2 is found in all life cycle stages whereas LmjMIF1 is found exclusively in amastigotes, the intracellular stage responsible for mammalian disease. The findings are consistent with parasite MIFs modulating or circumventing the host macrophage response and thereby promoting parasite survival, however analysis of the L. braziliensis genome showed that this species lacks intact MIF genes - highlighting that MIF is not a virulence factor in all species of Leishmania.
doi:10.1016/j.bbrc.2009.01.030
PMCID: PMC3242041  PMID: 19187777
7.  Sustainable primary care 
doi:10.3399/bjgp10X539452
PMCID: PMC2965988
10.  Leishmania inhibitor of serine peptidase prevents TLR4 activation by neutrophil elastase promoting parasite survival in murine macrophages 
Leishmania major is a protozoan parasite that causes skin ulcerations in cutaneous leishmaniasis. In the mammalian host, the parasite resides in professional phagocytes and has evolved to avoid killing by macrophages. We identified L. major genes encoding inhibitors of serine peptidases, ISPs, which are orthologues of bacterial ecotins and found that ISP2 inhibits trypsin-fold S1A family peptidases. Here we show that L. major mutants deficient in ISP2 and ISP3 (Δisp2/3) trigger higher phagocytosis by macrophages through a combined action of the complement type-3 receptor (CR3), toll-like receptor 4 (TLR4) and unregulated activity of neutrophil elastase (NE), leading to parasite killing. While all three components are required to mediate enhanced parasite uptake, only TLR4 and NE are necessary to promote parasite killing after infection. We found that the production of superoxide by macrophages in the absence of ISP2 is the main mechanism controlling the intracellular infection. Furthermore, we show that NE modulates macrophage infection in vivo, and that the lack of ISP leads to reduced parasite burdens at later stages of the infection. Our findings support the hypothesis that ISPs function to prevent the activation of TLR4 by NE during the Leishmania-macrophage interaction in order to promote parasite survival and growth.
doi:10.4049/jimmunol.1002175
PMCID: PMC3119636  PMID: 21098233
12.  Doctors urged to take up challenge of climate change 
BMJ : British Medical Journal  2008;336(7639):298-299.
doi:10.1136/bmj.39482.626632.DB
PMCID: PMC2234549
14.  Travelling in Palestine 
doi:10.3399/bjgp09X420662
PMCID: PMC2673161  PMID: 19401019
15.  Stories from Palestine and Israel 
doi:10.3399/bjgp09X420158
PMCID: PMC2648927  PMID: 19275843
16.  Why nuclear disarmament is a medical issue 
BMJ : British Medical Journal  2007;334(7590):426.
doi:10.1136/bmj.39129.668681.94
PMCID: PMC1804198
18.  Mum and me 
doi:10.3399/bjgp08X319585
PMCID: PMC2441523
19.  Climate change … what can we do? 
doi:10.3399/bjgp08X280056
PMCID: PMC2277135  PMID: 18387251
20.  Influence of parasite encoded inhibitors of serine peptidases in early infection of macrophages with Leishmania major 
Cellular Microbiology  2009;11(1):106-120.
Ecotin is a potent inhibitor of family S1A serine peptidases, enzymes lacking in the protozoan parasite Leishmania major. Nevertheless, L. major has three ecotin-like genes, termed inhibitor of serine peptidase (ISP). ISP1 is expressed in vector-borne procyclic and metacyclic promastigotes, whereas ISP2 is also expressed in the mammalian amastigote stage. Recombinant ISP2 inhibited neutrophil elastase, trypsin and chymotrypsin with Kis between 7.7 and 83 nM. L. major ISP2–ISP3 double null mutants (Δisp2/3) were created. These grew normally as promastigotes, but were internalized by macrophages more efficiently than wild-type parasites due to the upregulation of phagocytosis by a mechanism dependent on serine peptidase activity. Δisp2/3 promastigotes transformed to amastigotes, but failed to divide for 48 h. Intracellular multiplication of Δisp2/3 was similar to wild-type parasites when serine peptidase inhibitors were present, suggesting that defective intracellular growth results from the lack of serine peptidase inhibition during promastigote uptake. Δisp2/3 mutants were more infective than wild-type parasites to BALB/c mice at the early stages of infection, but became equivalent as the infection progressed. These data support the hypothesis that ISPs of L. major target host serine peptidases and influence the early stages of infection of the mammalian host.
doi:10.1111/j.1462-5822.2008.01243.x
PMCID: PMC2659362  PMID: 19016791
23.  Bodies at the Edinburgh Festival 
PMCID: PMC1920736  PMID: 17007723

Results 1-25 (43)