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•The socio-agro-ecosystem dimension of urban horticulture can be assessed through the evaluation of individuals' perceptions of ecosystem services and their preferences for urban greenhouses.•There are correlations between ecosystem services, which presents an opportunity for integrated improvement.•The preference for greenhouses is associated with the ecosystem services they provide, indicating that people choose greenhouses based on their value for ecosystem services.

Surgery is essential for cure of early-stage non-small cell lung cancer (NSCLC). Rates of postoperative bacterial pneumonias, however, remain high, and clinical data suggests that post-operative infectious complications confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis. TLR4 recognizes gram-negative bacterium lipopolysaccharide activating the innate immune system.

CD4+Foxp3+regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREGcells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREGcell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREGcells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREGcells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREGcells. In the absence of ST2, TREGcells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+TREGover pro-inflammatory TREGcells in a Cryptococcus neoformansinfection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREGcells, ultimately dictating the dynamics of adaptive immunity to pathogens.

CD4+Foxp3+regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREGcells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREGcell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREGcells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREGcells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREGcells. In the absence of ST2, TREGcells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+TREGover pro-inflammatory TREGcells in a Cryptococcus neoformansinfection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREGcells, ultimately dictating the dynamics of adaptive immunity to pathogens.

Participation of B cells in the immune response by various antibody-independent mechanisms has recently been uncovered. B cells producing cytokines have been described for several infections and appear to regulate the adaptive immune response. B cell activation by Leishmania donovaniresults in disease exacerbation. How Leishmaniaactivates B cells is still unknown. We show that L. donovaniamastigotes activate B cells by triggering endosomal TLRs; this activation leads to the induction of various cytokines. Cytokine expression is completely abrogated in B cells from Ifnar−/−mice upon exposure to L. donovani, suggesting an involvement of IFN-I in a positive feedback loop. IFN-I also appears to enhance the expression of endosomal TLRs following exposure to L. donovani. Cell-specific ablation of endosomal TLR signaling in B cells revealed that innate B cell activation by L. donovaniis responsible for disease exacerbation through IL-10 and IFN-I production and for the promotion of hypergammaglobulinemia.

Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon-γ (IFN-γ) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology.

Urban flora is an important component of human-dominated ecosystems that links urban dwellers with nature. This study aims at compiling and analysing the alien and native vascular plant species of some selected habitats in the Srinagar city, Kashmir, India. Bi-seasonal sampling was employed and each habitat type (viz., graveyards, grasslands, orchards and wastelands) was sampled at seven different sites. The number of species recorded from graveyards was 96; from grasslands 112; 141 from orchards and 110 from wastelands. The level of invasion among habitats varied from 67.27% to 68.75%, with a mean value of 67.86%; out of clubbed species list, 64.84% were alien. Asteraceae, Poaceae, Brassicaceae and Fabaceae were the biggest families in all four habitat types. Our research shows that across habitats, alien plant species are the predominant part of their floras.

Special economic zones (SEZs) emerge as new forces driving Asian economic transformation and triggering rapid landscape fragmentation. It is imperative to map out the present and future spatial patterns of SEZs in order to understand how they undermine sustainability. Drawing from the experience of Iskandar Malaysia, one of the most successful SEZs in Southeast Asia, this study measures how biophysical and cultural landscapes are being affected by the most recent accelerated land development in the area. With aid of a hybrid model, namely the special economic zone landscape fragmentation measurement (SeLaFragment), which combines Geographic Information System (GIS), FRAGSTATS and NetLogo, the current and future fragmentation dynamics were analysed using land use data of the study area from the beginning of intensive landscape transformation in 2007 until 2010. Iskandar Malaysia’s cultural and biophysical landscapes were extensively fragmented. The analysis showed that urban built-up areas increased from 13% in 2006 to 24% in 2010. Mangrove swamps were the worst affected ecosystem as they lost 20% of their areal coverage between 2006 and 2010. The simulation of the future scenarios suggested that, in the future, fragmentation and landscape homogenisation will intensify and pose more risks to landscape quality, functions and socio-ecological services. It is obvious that rapid landscape fragmentation compromises sustainability of a wide range of ecosystems and their functions and services in and around urban areas. It is difficult to see how existing environmental strategies have been effective in addressing the emerging sustainability challenges of rapid landscape change. The best way to respond to this kind of situation in the SEZs is by focusing on holistic approach to landscape sustainability.

The ecological processes underlying the suppressive impacts of invasive species on native species diversity, both above- and below-ground, in non-native regions are not well understood. We therefore aimed to investigate the cross-city biogeographic patterns of arbuscular mycorrhizal (AM) diversity in Conyza canadensisrhizosphere in native (North American) and non-native (Kashmir Himalayan) regions. We recovered AMF spores from rhizospheric soils of Conyzain native and non-native ranges, besides doing so from the uninvaded sites in the introduced region. DNA extracted from AMF spores was processed for cloning and PCR-RFLP of SSU rRNA gene to yield the restriction groups (RGs) followed by their sequence analysis to determine the sequence groups (SGs). The results indicated greater diversity of RGs and SGs in Conyzarhizosphere in native than in non-native sites. In the introduced region, however, the AMF diversity was more in uninvaded than in invaded sites. The species composition of AMF varied significantly between native and non-native regions and so also between invaded and uninvaded habitats. Though difference in AMF diversity between Conyzainvaded and uninvaded sites may be attributed to invasion, the role of other evolutionary factors seems likely for differences between the native and non-native regions. We suggest that the ecological processes underlying these evolutionary differences in two biogeographic regions, besides the intensity of urbanization, might play some role in these differences.

ABSTRACTThe genetic basis of natural susceptibility to progressive Cryptococcus neoformansinfection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformanssusceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2mice 35 days after C. neoformansinfection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b+dendritic cells, and CD4+cells in B6.CBA-Cnes2than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2mice. Taken together, these findings demonstrate that the Cnes2interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformansinfection.

AbstractCoxsackievirus strain B serotype 3 (CVB3)-inducedmyocarditis is an important human disease that causes permanent tissue damage and can lead to death from acute infection or long-term morbidity caused by chronic inflammation. The timing and magnitude of immune activation following CVB3 infection can mediate a positive host outcome or increase tissue pathology. To better elucidate the role of endosomal Toll-like receptor (TLR) signaling in acute CVB3 infection, we studied mice with a loss-of-function mutation, known as Letrfor ‘loss of endosomal TLR response', in Unc93b1, which is a chaperone protein for TLR3, TLR7 and TLR9. Using Unc93b1Letr/Letrmice, we determined that Unc93b1-dependent TLR activation was essential for the survival of acute CVB3-induced myocarditis. We also determined that a lack of endosomal TLR signaling was associated with a higher viral load in target organs and that it increased inflammation, necrosis and fibrosis in cardiac tissue. Loss of Unc93b1function was also associated with increased cardiac expression of Ifn-band markers of tissue injury and fibrosis including Lcn2and Serpina3nearly after CVB3 infection. These observations establish a significant role for Unc93b1in the regulation of the host inflammatory response to CVB3 infection and also reveal potential mediators of host tissue damage that merit further investigation in acute viral myocarditis.© 2015 S. Karger AG, Basel

Karachi, a city of unique terrain and moderate tropical climate, is home to several mosquito species. The geographical distribution and density of these species may vary within the city, owing to their interaction with an ever-increasing population and urban settings. As a consequence, the prevalence of vector-borne diseases is unpredictable within the geographical limits of Karachi city. In this spatiotemporal study, 1,156 mosquito samples were collected from 50 study sites with unique ecological characteristics within the city and a taxonomical exercise was conducted to investigate different vector species thriving in different months and seasons of the year. The main genera of mosquitoes were identified and categorized using a pictorial key based on the standard guidelines of the Walter Reed Biosystematics Unit, substantiated with ancillary literature. Three important genera were found in Karachi: Anopheles, Aedesand Culex. Important subgenera were subsequently identified, based on their susceptibility to major vector-borne diseases. January had the highest concentration of adult mosquitoes, as the colder weather conditions were suitable for breeding. May recorded the lowest number, owing to excessively hot weather when most of the breeding pockets had dried out; less vegetation (in pre-monsoon conditions) prevented mosquito growth. Slum areas showed an abundance of malaria and dengue vectors, owing to poor hygiene conditions caused by open sewage drains. Hence, a major precaution is to raise awareness among people about mosquito-borne diseases. The breeding habitats of these vectors should be studied using geospatial technologies to improve spatial and temporal coverage.

Breuste J., Schnellinger J., Qureshi S., Faggi A.: Urban ecosystem services on the local level: Urban green spaces as providers. Ekologia (Bratislava), Vol. 32, No. 3, p. 209-304, 2013. Ecosystem services are provided at different spatial and service/functional scales. The local level is the basic unit for ecosystem services, especially when it comes to the human dimension of urban landscapes. These services are provided by green elements (patches) or basic complex ecosystems (green areas) which differ from their neighbourhoods through their structures and functions. This study reviews the generally available knowledge on urban green functions and services at the site level and explains them by using own studies in five different cities in three different continents related to distinct ecosystem services. This allows the development of a methodology to evaluate and compare ecosystem services at the site level. The methodology is based at two levels, patch and green space, and includes the relationship with the surrounding green and built-up space. Different urban green space types are characterized by their internal structures of vegetation, size, shape and location in relation to at least a semi-quantitative scaling of their urban ecosystem services. The evaluated urban green spaces are public urban green spaces. The urban ecosystem services assessed include climate regulation, biodiversity, nature experience, recreation and health. The actual urban challenges, such as land use change, adaptation to climate change, demographic change and urban cultural diversity, demand a systematic and very concrete monitoring of urban ecosystem services at the site level.

ABSTRACTGenetic factors that regulate the pathogenesis of pneumonia caused by the fungus Cryptococcus neoformansare poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection with C. neoformansATCC 24067. The aim of the present study was to characterize the inflammatory response of C3H/HeN mice following C. neoformanspulmonary infection and to identify genetic loci that regulate host defense. Following cryptococcal infection, C3H/HeN mice demonstrated a Th2 immune response with heightened airway and tissue eosinophilia, goblet cell metaplasia, and significantly higher lung interleukin-5 (IL-5) and IL-13 protein expression relative to CBA/J mice. Conversely, CBA/J mice exhibited greater airway and tissue neutrophilia that was associated with significantly higher pulmonary expression of gamma interferon, CXCL10, and IL-17 proteins than C3H/HeN mice. Using the fungal burden at 4 weeks postinfection as a phenotype, genome-wide quantitative trait locus (QTL) analysis among 435 segregating (C3H/HeN × CBA/J)F2 (C3HCBAF2) hybrids identified two significant QTLs on chromosomes 1 (Cnes4) and 9 (Cnes5) that control susceptibility to cryptococcal pneumonia in an additive manner. Susceptible C3H/HeN mice carry a resistance allele at Cnes4and a susceptibility allele at Cnes5. These studies reveal additional genetic complexity of the host response to C. neoformansthat is associated with divergent patterns of pulmonary inflammation.

ABSTRACTGenetically regulated mechanisms of host defense against Cryptococcus neoformansinfection are not well understood. In this study, pulmonary infection with the moderately virulent C. neoformansstrain 24067 was used to compare the host resistance phenotype of C57BL/6J with that of inbred mouse strain SJL/J. At 7 days or later after infection, C57BL/6J mice exhibited a significantly greater fungal burden in the lungs than SJL/J mice. Characterization of the pulmonary innate immune response at 3 h after cryptococcal infection revealed that resistant SJL/J mice exhibited significantly higher neutrophilia, with elevated levels of inflammatory cytokine tumor necrosis factor alpha (TNF-α) and keratinocyte-derived chemokine (KC)/CXCL1 in the airways, as well as increased whole-lung mRNA expression of chemokines KC/CXCL1, MIP-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, and MCP-1/CCL2 and cytokines interleukin 1β (IL-1β) and IL-1Ra. At 7 and 14 days after infection, SJL/J mice maintained significantly higher levels of TNF-α and KC/CXCL1 in the airways and exhibited a Th1 response characterized by elevated levels of lung gamma interferon (IFN-γ) and IL-12/IL-23p40, while C57BL/6J mice exhibited Th2 immunity as defined by eosinophilia and IL-4 production. Alveolar and resident peritoneal macrophages from SJL/J mice also secreted significantly greater amounts of TNF-α and KC/CXCL1 following in vitro stimulation with C. neoformans. Intracellular signaling analysis demonstrated that TNF-α and KC/CXCL1 production was regulated by NF-κB and phosphatidylinositol 3 kinase in both strains; however, SJL/J macrophages exhibited heightened and prolonged activation in response to C. neoformansinfection compared to that of C57BL/6J. Taken together, these data demonstrate that an enhanced innate immune response against pulmonary C. neoformansinfection in SJL/J mice is associated with natural resistance to progressive infection.

Genetically regulated mechanisms of host defense against Cryptococcus neoformans infection are not well understood. In this study, pulmonary infection with the moderately virulent C. neoformans strain 24067 was used to compare the host resistance phenotype of C57BL/6J with that of inbred mouse strain SJL/J. At 7 days or later after infection, C57BL/6J mice exhibited a significantly greater fungal burden in the lungs than SJL/J mice. Characterization of the pulmonary innate immune response at 3 h after cryptococcal infection revealed that resistant SJL/J mice exhibited significantly higher neutrophilia, with elevated levels of inflammatory cytokine tumor necrosis factor alpha (TNF-) and keratinocyte-derived chemokine (KC)/CXCL1 in the airways, as well as increased whole-lung mRNA expression of chemokines KC/CXCL1, MIP-1/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, and MCP-1/CCL2 and cytokines interleukin 1β (IL-1β) and IL-1Ra. At 7 and 14 days after infection, SJL/J mice maintained significantly higher levels of TNF- and KC/CXCL1 in the airways and exhibited a Th1 response characterized by elevated levels of lung gamma interferon (IFN-) and IL-12/IL-23p40, while C57BL/6J mice exhibited Th2 immunity as defined by eosinophilia and IL-4 production. Alveolar and resident peritoneal macrophages from SJL/J mice also secreted significantly greater amounts of TNF- and KC/CXCL1 following in vitro stimulation with C. neoformans. Intracellular signaling analysis demonstrated that TNF- and KC/CXCL1 production was regulated by NF-B and phosphatidylinositol 3 kinase in both strains; however, SJL/J macrophages exhibited heightened and prolonged activation in response to C. neoformans infection compared to that of C57BL/6J. Taken together, these data demonstrate that an enhanced innate immune response against pulmonary C. neoformans infection in SJL/J mice is associated with natural resistance to progressive infection.

Immunologically active molecules such as cytokines and chemokines have been implicated in skeletal muscle weakness during sepsis as well as recovery from muscle injury. In sepsis, Toll-like receptors (TLRs) act as key sentinel molecules of the innate immune system. Here we determined skeletal muscle cell responses of two prototypical CC and CXC chemokine genes (monocyte chemoattractant protein 1 [MCP-1] and KC, respectively), to stimulation with specific TLR ligands. In addition, we examined whether NF-κB and calcineurin signaling are involved in these responses. Differentiated myotubes and intact whole muscles expressed TLR2, TLR4, TLR5, and TLR9. Stimulation with ligands for TLR2 (peptidoglycan) or TLR4 (LPS) elicited robust and equivalent levels of MCP-1 and KC mRNA expression, whereas stimulation of TLR5 (by flagellin) required gamma interferon priming to induce similar effects. Although both TLR2 and TLR4 ligands activated the NF-κB pathway, NF-κB reporter activity was approximately 20-fold greater after TLR4 stimulation than after TLR2 stimulation. Inhibitory effects of NF-κB blockade on TLR-mediated chemokine gene expression, by either pharmacological (pyrrolidine dithiocarbamate) or molecular (IKK{szligbeta} dominant-negative transfection) methods, were also more pronounced during TLR4 stimulation. In contrast, inhibitory effects on TLR-mediated chemokine expression of calcineurin blockade (by FK506) were greater for TLR2 than for TLR4 stimulation. MCP-1 and KC mRNA levels also demonstrated differential responses to NF-κB and calcineurin blockade during stimulation with specific TLR ligands. We conclude that skeletal muscle cells differentially utilize the NF-κB and calcineurin pathways in a TLR-specific manner to enable complex regulation of CC and CXC chemokine gene expression.

ABSTRACTImmunologically active molecules such as cytokines and chemokines have been implicated in skeletal muscle weakness during sepsis as well as recovery from muscle injury. In sepsis, Toll-like receptors (TLRs) act as key sentinel molecules of the innate immune system. Here we determined skeletal muscle cell responses of two prototypical CC and CXC chemokine genes (monocyte chemoattractant protein 1 [MCP-1] and KC, respectively), to stimulation with specific TLR ligands. In addition, we examined whether NF-κB and calcineurin signaling are involved in these responses. Differentiated myotubes and intact whole muscles expressed TLR2, TLR4, TLR5, and TLR9. Stimulation with ligands for TLR2 (peptidoglycan) or TLR4 (LPS) elicited robust and equivalent levels of MCP-1 and KC mRNA expression, whereas stimulation of TLR5 (by flagellin) required gamma interferon priming to induce similar effects. Although both TLR2 and TLR4 ligands activated the NF-κB pathway, NF-κB reporter activity was approximately 20-fold greater after TLR4 stimulation than after TLR2 stimulation. Inhibitory effects of NF-κB blockade on TLR-mediated chemokine gene expression, by either pharmacological (pyrrolidine dithiocarbamate) or molecular (IKKβ dominant-negative transfection) methods, were also more pronounced during TLR4 stimulation. In contrast, inhibitory effects on TLR-mediated chemokine expression of calcineurin blockade (by FK506) were greater for TLR2 than for TLR4 stimulation. MCP-1 and KC mRNA levels also demonstrated differential responses to NF-κB and calcineurin blockade during stimulation with specific TLR ligands. We conclude that skeletal muscle cells differentially utilize the NF-κB and calcineurin pathways in a TLR-specific manner to enable complex regulation of CC and CXC chemokine gene expression.

Gram-negative bacterial lipopolysaccharide evokes a protective inflammatory response in the normal host. Through genetic analysis of mutant mice, the gene encoding Toll-like receptor 4 (Tlr4) was recently identified as a critical component of this host defense mechanism. Tlr4is a member of an ancient gene family that regulates antimicrobial host defense in plants, invertebrates and mammals.

Abstract.: The GATA family of zinc finger proteins are transcriptional regulators with critical functions in lineage differentiation and embryonic development. Based on structural and expression pattern comparisons, the GATA proteins have been subdivided into two groups. The first subgroup consists of GATA-1, -2, and -3, which are all highly expressed in the hematopoietic system, whereas GATA-4, -5, and -6 are present essentially in the heart and gut. We have isolated and functionally characterized the rat GATA-5 cDNA, which encodes a 45-kDa protein with 71%, 73%, and 97% homology to its amphibian, avian, and murine homologs, respectively. Northern blot analysis showed that rat GATA-5 is expressed in a dynamic pattern during embryonic and postnatal development. In the midgestation embryo, GATA-5 transcripts are most abundant in the heart and decrease dramatically in the postnatal heart; in contrast, GATA-5 expression is upregulated in the lung and gut during postnatal development. Functional studies with recombinant GATA-4, -5, and -6 proteins show that GATA-5 has preferential affinity for a subset of GATA elements found on cardiac promoters and differentially activate cardiac gene transcription. Structure-function analysis revealed the presence of an activation domain within the carboxy terminal region of GATA-5 that is essential for transcriptional regulation of target promoters. Linkage analysis localized Gata5 to distal mouse Chromosome (Chr) 2 in a conserved linkage group with genes localized to rat Chr 3q43 and human Chr 20q13.2-q13.3. The results suggest that GATA-5 may have specific downstream targets and that GATA-4, -5, and -6 can only partially substitute for each other in cardiogenesis. Thus, Gata5 probably plays a specialized evolutionary conserved role in cardiac development.

TheLpslocus on mouse chromosome 4 controls host responsiveness to lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria. The C3H/HeJ inbred mouse strain is characterized by a mutantLpsallele (Lpsd) that renders it hyporesponsive to LPS and naturally tolerant of its lethal effects. To identify theLpsgene by a positional cloning strategy, we have generated a high-resolution linkage map of the chromosomal region surrounding this locus. We have analyzed a total of 1604 backcross mice from a preexisting interspecific backcross panel of 259 (Mus spretus× C57BL/6J)F1 × C57BL/6J and two novel panels of 597 (DBA/2J × C3H/HeJ)F1 × C3H/HeJ and 748 (C57BL/6J × C3H/HeJ)F1 × C3H/HeJ segregating atLps.A total of 50 DNA markers have been mapped in a 11.8-cM span overlapping theLpslocus. This positions theLpslocus within a 1.1-cM interval, flanked proximally by a large cluster of markers, including three known genes (Cd30l, Hxb,andAmbp), and distally by two microsatellite markers (D4Mit7/D4Mit178). The localization of theLpslocus is several centimorgans proximal to that previously assigned.

Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinflammatory state in the infected host. Genetic regulation of this response has been localized to the Lps locus on mouse chromosome 4, through study of the C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr mice are homozygous for a mutant Lps allele (Lpsd/d) that confers hyporesponsiveness to LPS challenge, and therefore exhibit natural tolerance to its lethal effects. Genetic and physical mapping of 1,345 backcross progeny segregating this mutant phenotype confined Lps to a 0.9-cM interval spanning 1.7 Mb. Three transcription units were identified within the candidate interval, including Toll-like receptor 4 (Tlr4), part of a protein family with members that have been implicated in LPS-induced cell signaling. C3H/HeJ mice have a point mutation within the coding region of the Tlr4 gene, resulting in a nonconservative substitution of a highly conserved proline by histidine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4. Identification of distinct mutations involving the same gene at the Lps locus in two different hyporesponsive inbred mouse strains strongly supports the hypothesis that altered Tlr4 function is responsible for endotoxin tolerance.

The fourth reported case of candidal epididymo-orchitis in the literature and the first reported case successfully cured with only low dose amphotericin B is described. A 75-year-old male with chronic myelogenous leukemia presented with acute testicular and epididymal swelling and pain. Subsequent investigations suggested the diagnosis of epididymo-orchitis due to Candida albicans. This was successfully treated with intravenous amphotericin B (total dose of 500 mg). Based on the three previous case reports and the current case several characteristic features that increased the suspicion of this entity were identified. These features include an immunocompromised state, candiduria, specific epididymal ultrasonographic appearance, as well as typical clinical features of epididymo-orchitis.