Chronic Infectious Process Research Articles

Characterization of the Macrophage Infiltrate in a Case of Xanthogranulomatous Pyelonephritis.

Xanthogranulomatous pyelonephritis (XGP) is a rare chronic infectious process of the kidney that results in diffuse destruction of the renal parenchyma [1,2]. The majority of cases of XGP occur in the setting of obstructing nephrolithiasis and are histologically characterized by the presence of lipid-laden foamy macrophages. To date, little is known regarding the molecular and functional phenotype of the infiltrating macrophages observed in cases of XGP. Human CD14+ monocytes can differentiate into macrophages and then become polarized towards two distinct phenotypes [3–5]. Classically activated (also known as M1) macrophages have the ability to secrete pro-inflammatory cytokines such as IFN-γ, IL-2, and TNF-α. Conversely, alternatively activated (also known as M2) macrophages secrete anti-inflammatory cytokines such as IL-10, IL-23, and VEGF. Characterization of the immune infiltrate in cases of XGP is necessary for understanding the pathogenesis of this disease process. Moreover, this knowledge may form the basis of future non-invasive treatment strategies for XGP. Herein, we report the phenotypic characterization of the macrophage infiltrate in a case of XGP.

COMPARATIVE CHARACTERISTIC'S OF IMMUNE STATUS OF PAT I ENTS WITH CHRONIC FORMS OF VIRAL HEPATITIS В, C, D AND HEALTHY INDIVIDUALS

Evaluate immune status in patients with chronic hepatitis (CH) depending on type of causative agent and severity of the infectious process. 232 residents of Yakutia including 127 patients with various forms of chronic hepatitis and 105 healthy individuals were examined. Relative levels of mature T-lymphocytes (CD3⁺), T-helpers (CD4⁺), T-suppressors (CD8⁺), B-lymphocytes (CD72⁺) and naturalkillers (CD16⁺) were studied by flow cytometry, as well as concentration of sera immune globulins of classes A, M and G by ELISA. In patients with chronic hepatitis of various forms, a decrease of expression of differentiating antigens - CD3⁺, CD4⁺, CD72⁺ on the surface of lymphocytes and concentration of sera immune globulins was established. In CHD patients in phase of monoreplication high activity of the infectious process is accompanied by a shift of immune regulatory index to the increase of activity of cytotoxic cells with simultaneous development of deficiency of mature functionally active T-lymphocytes. In the -group of patients with hepatitis D virus with liver cirrhosis normal concentration of sera immune globulins is retained against the decrease of the number of T-helpers and B-lymphocytes. In patients with various forms of viral hepatitis acquired immune deficiency can emerge, which is often accompanied by enhancement of NK-cell activity. The noted reduction of the number of mature functionally active T-cells, as well as main classes of sera antibodies could be con- nected with immune system load during a chronic infectious process.

Spatiotemporal Dynamics of Virus Infection Spreading in Tissues.

Virus spreading in tissues is determined by virus transport, virus multiplication in host cells and the virus-induced immune response. Cytotoxic T cells remove infected cells with a rate determined by the infection level. The intensity of the immune response has a bell-shaped dependence on the concentration of virus, i.e., it increases at low and decays at high infection levels. A combination of these effects and a time delay in the immune response determine the development of virus infection in tissues like spleen or lymph nodes. The mathematical model described in this work consists of reaction-diffusion equations with a delay. It shows that the different regimes of infection spreading like the establishment of a low level infection, a high level infection or a transition between both are determined by the initial virus load and by the intensity of the immune response. The dynamics of the model solutions include simple and composed waves, and periodic and aperiodic oscillations. The results of analytical and numerical studies of the model provide a systematic basis for a quantitative understanding and interpretation of the determinants of the infection process in target organs and tissues from the image-derived data as well as of the spatiotemporal mechanisms of viral disease pathogenesis, and have direct implications for a biopsy-based medical testing of the chronic infection processes caused by viruses, e.g. HIV, HCV and HBV.

Comparative evaluation of aggressiveness traits in staphylococcal strains from severe infections versus nasopharyngeal carriage.

Despite their commensal status, staphylococci can become problematic pathogens expressing multiple and redundant virulence factors. This study aimed to evaluate aggressiveness markers comparatively in staphylococcal strains isolated from severe infections versus asymptomatic carriage in order to identify clinically relevant bacterial traits that could easily be detected in clinical practice and could be suggestive for particular host-pathogen interactions such as cyto-adhesion or biofilm formation, ultimately orienting the clinical decision-making process. We have used invitro phenotypic methods to assess adhesion to and invasion of eukaryotic cells, biofilm development, and expression of soluble virulence factors in 92 Staphylococcus spp. strains. The adhesion index, invasion capacity, biofilm formation and expression of soluble factors did not differ significantly between clinical and commensal strains. The major bacterial traits we found to be significantly more prevalent in clinical staphylococci were the aggregative adhesion pattern (P=0.012), cluster adhesion (P=0.001) and tetrad morphology (P=0.018). The aggregative adhesion pattern was correlated with higher cyto-adhesion (P<0.001), higher invasion capacity (P=0.003) and lower Carmeli scores (P=0.002). Three major bacterial traits, namely tetrad morphology, aggregative adhesion pattern, and resistance to methicillin (acronym: TAM), can be used to compute an aggressiveness score (SAS) predictive of the staphylococcal strain's virulence and capacity to initiate and develop a biofilm-driven chronic infectious process versus a fulminant acute infection, in a susceptible host.

Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by Toll-like receptors 2 and 4.

Toll-like receptors (TLRs) participate in the innate immune response and trigger the immune responses of the body. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology, characterized by an excessive autoimmune response in the body affecting the connective tissues. The disease is possibly triggered by both environmental aetiological factors and pathological organic processes such as exposure to sunlight, chronic infectious processes and genetic factors. Conversely, periodontal disease is an infectious disease caused by microorganisms in the oral cavity, resulting in a chronic inflammatory process which continuously stimulates the immune response, thus causing damage to the periodontal tissues. The expression of both TLR-2 and TLR-4 receptors are increased in both SLE and periodontal disease. Periodontitis might trigger excessive activation of immune response occurring in SLE by maintaining a high expression of TLRs, leading in turn to the acceleration of the onset and progression of autoimmune reactions. In addition, periodontal treatment is able to reduce the expression of these receptors and therefore the symptoms of SLE. Here we discuss the possible interaction between SLE and periodontitis, and suggest further studies evaluating common features in both factors that could explored, due to morbidity and mortality of SLE and the high incidence of periodontal infections around the world.

Natural sesquiterpene lactones enhance oxacillin and gentamicin effectiveness against pathogenic bacteria without antibacterial effects on beneficial lactobacilli.

This is a report on the synergistic interactions (SIs) between melampolide-type sesquiterpene lactones 1-8 from Acanthospermum hispidum DC., and oxacillin or gentamicin, against four pathogenic strains of Staphylococcus aureus and Enterococcus faecalis; two of them were multi-resistant strains obtained from chronic infectious processes. Our results showed that all associations of 1-8 with antibiotics (ATBs) are more effective than pure ATBs to control pathogenic strains of S. aureus and E. faecalis. The most relevant SIs were observed when the major lactone of A. hispidum, acanthospermal B [5], was combined with gentamicin (protein synthesis inhibitor) against an ex vivo culture of methicillin-resistant S. aureus SAR 1, displaying a significant MIC reduction in 5 (312.5 to 78.1 µg/mL), and gentamicin (120 µg/mL to 3 µg/mL). Compound 4 improved the antibiotic potency of oxacillin (cell wall synthesis inhibitor) against ampicillin-resistant E. faecalis (60 µg/mL to 1.5 µg/mL). It is important to remark that three beneficial lactobacilli were resistant to 1-8 and their mixtures with gentamicin or oxacillin in effective concentrations against pathogenic bacteria. Synergism between ATBs and phytochemicals is a therapeutically helpful concept to improve ATB efficacy and prevent resistance. The present results show that selective SIs occur between melampolides and gentamicin or oxacillin, and open a new field of research.

Oral manifestations of patients with leprosy: A disease, actually infectious but not always, still a stigma in society

Context Leprosy is a chronic granulomatous infectious disease process in humans primarily involving the skin, peripheral nerves, and nasal mucosa but capable of affecting any tissue or organ. The leprae bacilli were first observed by Hansen in 1868. Although this was the first bacterial human pathogen to be described, it continues to remain one of the least understood. Aims The aim of the study was to evaluate oral and facial manifestations in patients affected with leprosy. Materials and methods The present study was performed with an aim of reviewing oral and facial manifestations in patients suffering from leprosy. For this, 150 patients suffering from lepromatous and tuberculoid forms of leprosy were included in the study. The study was approved by the ethical committee appointed by SIBAR Institute of Dental Sciences, Guntur. Permission was also taken from asylum management and the district leprosy officer to conduct the study. All study samples were patients diagnosed with Hansen's disease by a leprologist using a bacteriological index. Results In the present study, oral and facial manifestations were observed more frequently in the lepromatous type of leprosy than in the tuberculoid form. Also, these manifestations were less pronounced in group I than in group II and were more in groups III and IV based on increased exposure to the disease process. Statistical analysis was performed using the c2 -test and P values were also found to be significant. Conclusion Present day diagnostic protocols for early detection and treatment are effective in controlling the disease and in preventing further progression with severe orofacial manifestations. A dentist should be able to recognize these manifestations and treat them under the supervision of a leprologist. Protective care must be taken in treating the disease, although it should not be held as a nightmare as was considered previously.

Bronchial arteries: anatomy, function, hypertrophy, and anomalies.

The two main sources of blood supply to the lungs and their supporting structures are the pulmonary and bronchial arteries. The bronchial arteries account for 1% of the cardiac output but can be recruited to provide additional systemic circulation to the lungs in various acquired and congenital thoracic disorders. An understanding of bronchial artery anatomy and function is important in the identification of bronchial artery dilatation and anomalies and the formulation of an appropriate differential diagnosis. Visualization of dilated bronchial arteries at imaging should alert the radiologist to obstructive disorders that affect the pulmonary circulation and prompt the exclusion of diseases that produce or are associated with pulmonary artery obstruction, including chronic infectious and/or inflammatory processes, chronic thromboembolic disease, and congenital anomalies of the thorax (eg, proximal interruption of the pulmonary artery). Conotruncal abnormalities, such as pulmonary atresia with ventricular septal defect, are associated with systemic pulmonary supply provided by aortic branches known as major aortopulmonary collaterals, which originate in the region of the bronchial arteries. Bronchial artery malformation is a rare left-to-right or left-to-left shunt characterized by an anomalous connection between a bronchial artery and a pulmonary artery or a pulmonary vein, respectively. Bronchial artery interventions can be used successfully in the treatment of hemoptysis, with a low risk of adverse events. Multidetector computed tomography helps provide a vascular road map for the interventional radiologist before bronchial artery embolization.

Molecular Pathogenesis of MALT Lymphoma.

Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT), also known as MALT lymphoma, which was first described in 1983 by Isaacson and Wright. MALT lymphomas arise at a wide range of different extranodal sites, with the highest frequency in the stomach, followed by lung, ocular adnexa, and thyroid, and with a low percentage in the small intestine. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations and missense and frameshift mutations, all pathway-related genes affecting the NF-κB signal, have been implicated in the development and progression of MALT lymphoma. However, these genetic abnormalities alone are not sufficient for malignant transformation. There is now increasing evidence suggesting that the oncogenic product of translocation cooperates with immunological stimulation in oncogenesis, that is, the association with chronic bacterial infection or autoaggressive process. This review mainly discusses MALT lymphomas in terms of their genetic aberration and association with chronic infections and summarizes recent advances in their molecular pathogenesis.

The origin and targeting of mucosa-associated lymphoid tissue lymphomas.

Extranodal mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct clinical-pathological entity that can be distinguished from other lymphomas by a number of unique features, including their location in various extranodal sites, being preceded by chronic inflammatory or infection processes; a characteristic histopathological picture; and the presence of exclusive chromosomal translocations which increase MALT1 proteolytic activity to promote constitutive NF-κB signaling and eventually drive lymphomagenesis. This review explores the major molecular and cellular events that participate in MALT lymphoma pathogenesis, focusing on gastric MALT lymphoma as a model of chronic inflammation-induced tumor development. In addition, the pivotal roles of activated MALT1 protease, its substrate TNFAIP3/A20, and the MyD88 adaptor protein in abnormally triggering downstream NF-κB pathway are overviewed. These new insights provide a mechanistic basis for using novel therapies targeting MALT1 protease or IRAK4 kinase activities. Finally, the putative cellular origin of MALT lymphomas is also discussed. Over the last decade, unraveling the biological complexity of MALT lymphomas has shed light on the fundamental cellular and molecular aspects of the disease that are to be translated into clinical diagnostics and therapy.

Risk factors delivery of the newborns with distress

The final purpose of pregnancy and delivery is healthy newborn. 65% of fetus development takes place in the conditions of placenta hypoperfusion has an enhanceable risk of perinatal damages. Placenta dysfunction is the widest pregnancy pathology which varies from 24% to 46%.The aim of the work: to investigate risk factors of the distress onset in newborns to prevent this complication.Materials and methods: 142 case reports of delivery mothers and case reports of their newborns underwent retrospective analysis. All women were examined according to the protocols. State of newborns was assessed by Apgar scale. All infants with distress and their mothers were divided into 3 groups according randomized evaluation with Apgar scale. First group included 75 newborns with Apgar score on the first minute of 6-7 points, group II contained 46 neonates with an estimate of 4-5 points, group III consisted of 21 infants with points 3 or less. The control group included 20 infants without distress. There anamnestic, clinical-laboratory, histological and statistical methods were used in scientific work. The women’s age was from 16 to 42, the average age without reliable distinctions in all groups. The high percentage of extragenital pathology were noticed in all groups, which amounted to 36%, 45.65%, 71.45% in the comparison group - 85%. Traced deepening severity distress of increasing frequency of complications in labor: the group I childbirth complication rates were 40,00% in group II - 52,17%, in group III complication rates during labor were significantly higher - 71 and 43%, the control group it had only 15%.The average scores of Apgar on the first minute amounted to 6,76±0,13 p., 4,70±0,21 p., 2,86±0,17 p. Children with severe distress recovered significantly more active. Apgar scores increased by 1.76 p. in the III group after five minutes (p&lt;0.005) and was 4,57±0,23 p., II - at least 1,42 (6,12±0,18 p.), in the I group was only 0.38 p. (7,14±0,35 p.). Premature infants restored faster than full-term newborns. Apgar scores differed hardly in the control group on the first and fifth minute: 8,80±0,24 p. and 9,50 ± 0,26 p. The average weight of the babies in the I group was 3384,68±236,43 g, which was significantly higher (p&lt;0.001) than in the II and III groups (2510,42±187,23 g, 2234,29 69,56 g, respectively) and significantly lower (p&lt;0.05) rate control group (3852,50±196,38 g). Morphological changes in the placenta are most pronounced in severe distress - 85.71% purulent diffuse chorioamnionitis and detsiduitis with bleeding, premature the placenta aging.Conclusions:1. Risk factors for the development of fetal distress during labor are: extragenital pathology (42.96%), first childbirth (53.52%), complications of pregnancy (51.40%) (especially in the first and second trimesters, late gestosis), premature delivery (38.03%), complications during delivery (50.02%).2. The severity of the fetus at birth corresponds to more pronounced changes in the placenta in the form of local and diffuse purulent chorioamnionitis and detsiduitis, indicating a chronic infectious process, dysfunction of the placenta can cause fetal weight at birth, violation of adaptive opportunities of a fetus during labor.3. It is necessary to inspect more carefully women with infections, adequate treat revealed infections, supervise infected women in risk group of development of placentary insufficiency.

Microbial Impact on Hematologic Homeostasis

AbstractAbstract SCI-40During systemic infection and inflammation, immune effector cells are in high demand and are rapidly consumed at sites of need. While adaptive immune cells have high proliferative potential, innate mature immune cells are mostly postmitotic and need to be replenished from bone marrow hematopoietic stem and progenitor cells. Indeed, severe clinical infection, particularly infections challenging the innate immune response, lead to an increase in hematopoietic differentiation and throughput in bone marrow, involving subsequent differentiation stages from hematopoietic stem cells, multipotent progenitors, as well as early-lineage and late-lineage restricted hematopoietic progenitors. A fundamental question is how the increased need is sensed and translated in enhanced production and how adequate levels of response are guided. Recent research has shed light on conserved intracellular and extracellular pathogen recognition receptors, such as Toll-like receptors, that are expressed on nonhematopoietic and hematopoietic effector cells and cause activation upon ligation. This activation results in production of hematopoietic growth, survival, activation, and migration factors operating at site on effector cells, but also at remote primary hematopoietic sites to increase production upon need. Recent research by several groups, including ours, surprisingly revealed that conserved pattern-recognition receptors are also expressed on hematopoietic stem and progenitor cells in bone marrow, implying a direct effect of systemically available ligands on these cellular populations. Indeed, it has been demonstrated that, for example, ligation of Toll-like receptor 4 by its cognate agonist lipopolysaccharide can lead to divisional activation, proliferation, lineage-directed differentiation, and migration of hematopoietic stem and lineage-restricted progenitor cells, all aimed at efficient contribution to immune responses and rapid reestablishment of hematopoietic homeostasis. The relative contribution of pathogen sensing by hematopoietic and diverse nonhematopoietic cells to appropriate hematopoietic responses, as well as the subcellular translation of the signals, is the focus of ongoing research. Also to be discussed will be how chronic infectious and inflammatory processes, which are frequently associated with aging, might impinge on hematopoiesis, potentially fostering hematopoietic stem cell diseases as exhaustion or transformation. Disclosures:No relevant conflicts of interest to declare.

Fighting Fire with Fire: Is it Time to Use Probiotics to Manage Pathogenic Bacterial Diseases?

Probiotics, when considered in clinical practice, have traditionally been used for prophylaxis; however, there is growing data suggesting treatment benefits in numerous disease states. In this review, we focus on probiotics as treatment for and prevention of several acute and chronic infectious processes including Helicobacter pylori, Clostridium difficile, necrotizing enterocolitis, ventilator-associated pneumonia, vancomycin-resistant enterococci, and nonalcoholic fatty liver disease. It is inaccurate to generalize findings observed in a single probiotic species to all probiotics. This reasoning is due to the variability of colonizing abilities of native intestinal floras, probiotic or otherwise, secondary to different combinations, doses, and duration of treatments. Given these limitations, multiple animal and human studies have shown anti-inflammatory and selective antimicrobial effects of specific probiotics. Some studies suggest a role for probiotics as supplemental treatment, in combination with antibiotics, for the aforementioned disease processes. It is apparent from this review that the efficacy of probiotics is widely variable and multifaceted. More focused clinical and basic science research is necessary to better understand the treatment potential of various probiotics.

The role of the type-III secretion system of Gram-negative bacteria in the regulation of chronic infections

This review article focuses on the discussion about the role of the type III secretion system (T3SS), which was found in several Gram-negative bacteria, in the development of chronic infectious processes. The latest investigations on this issue have revealed that most severe chronic somatic diseases derive from prolonged chronic inflammation induced by various infectious agents. The T3SS may play a crucial role in the transition of an infection from an acute form to persistent one. Numerous clinical and bacteriological studies have shown that pathogenic microorganisms are persistent in a form resistant to various antibiotics. Therefore, one of the most promising goals for the development of novel antibiotics is the T3SS, which transports bacterial pathogenic factors directly into the eukaryotic cell. The functioning of the T3SS is essential for occurrence and development of both acute and chronic infectious processes.

Teaching Neuro Images : Punctuate and curvilinear enhancement peppering the pons responsive to steroids

A 48-year-old man developed progressive vertigo, ataxia, and dysarthria. MRI demonstrated gadolinium-enhancing abnormalities in the pons and cerebellar peduncles (figure, A). Further investigations excluded neurosarcoidosis, CNS lymphoma, granulomatosis, and paraneoplastic or chronic infectious processes. In particular, 2 CSF examinations revealed mildly elevated protein levels (0.73 g/L, N < 0.40 g/L) without pleocytosis, tumoral cells, or oligoclonal bands. Figure Initial T1-weighted postgadolinium brain MRI (A) Symmetric enhancement of the pons and both cerebellar peduncles, with pattern highly suggestive of a perivascular distribution. (B) Near complete resolution with corticosteroids. (C) Recurrence of the same lesions without corticosteroids. The patient was treated with IV …

Chronic Prostatitis, Cystitis, Pyelonephritis, and Balanoposthitis in a Cat

An adult, intact male domestic shorthair presented for preputial swelling and urinary incontinence. A caudal abdominal mass was palpated. A transabdominal ultrasound examination showed severe prostatomegaly with abnormal tissue extending along the urethra. The cat was euthanized due to the owner's financial constraints and the veterinarians' suspicion of a poor long-term prognosis. Biopsies showed chronic active inflammation of the prostate, bladder, kidneys, ureters, penis, and prepuce most consistent with a chronic infectious process. Reports of feline prostatic disease of any kind are rare. Chronic prostatitis may have a more favorable prognosis than feline prostatic adenocarcinoma, currently the most commonly reported disease of the feline prostate.

In situTLR2 and TLR4 expression in a murine model of mycetoma caused byNocardia brasiliensis

Actinomycetoma caused by Nocardia brasiliensis is a common disease in tropical regions. This ailment is characterized by a localized chronic inflammation that mainly affects the lower limbs. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, inducing the production of proinflammatory mediators. The role of TLRs in the immune response against N. brasiliensis is unknown. The aim of this work was to locate and quantify in a murine model the expression of TLR2 and TLR4 in the infection site using reverse transcription-PCR and immunohistochemistry. The results showed that TLR2 expression increased in the infected tissue, whereas TLR4 expression decreased. The presence of TLR2 and TLR4 was demonstrated in different cell populations throughout the chronic infectious process. In the early stages of this process, TLR2 was expressed in neutrophils and macrophages in direct contact with the inoculum, whereas TLR4 was observed in mast cells. In the advanced stages of the infection, TLR2 was expressed in foam cells and fibroblasts and was likely associated with bacterial containment, while TLR4 was downregulated, probably resulting in an imbalance between the host immune response and the bacterial load that favoured chronic disease.

Role of BMP Signaling In the Anemia of Chronic Disease

AbstractAbstract 2043 Introduction:Anemia of chronic disease (ACD) describes anemia associated with diverse chronic inflammatory, infectious, or neoplastic processes. These conditions are frequently associated with increased circulating levels of inflammatory cytokines such as interleukin 6 (IL-6). IL-6 regulates expression of the hormone hepcidin, which inhibits the release of iron from hepatocytes, macrophages, and enterocytes into the circulation. In addition to IL-6, hepcidin gene expression is known to be transcriptionally regulated by bone morphogenetic protein (BMP) signaling. Hypothesis:We hypothesized that BMP signaling is required for the induction of hepcidin gene expression by IL-6 and plays a critical role in the pathogenesis of ACD. Methods:We used a turpentine-dependent model of ACD in mice. Mice were challenged with weekly subcutaneous injections of turpentine, which induces anemia in an IL-6 dependent manner. This model was studied to determine hepcidin gene expression and rescue ACD using BMP inhibition. Moreover, we examined hepcidin gene expression in zebrafish injected with Pseudomonas aeruginosa, and in transgenic zebrafish overexpressing human IL-6. The regulation of hepcidin gene expression was also studied in the human hepatocarcinoma cell line (HepG2). Results:Injections of mice with IL-6 (0.8 μg/g ip) increased hepatic hepcidin mRNA levels expression at 24 hours and decreased serum iron concentrations. Both effects were prevented by a small molecule BMP type I receptor kinase inhibitor, LDN-193189, or protein BMP antagonists. Weekly turpentine injections induced microcytic anemia after 3 weeks with a decrease in hemoglobin levels from 12.8±0.3 to 9.7±1.7 g/dL (*p<0.01). Concurrent treatment with LDN-193189 prevented turpentine-induced anemia and microcytosis (*p<0.01 for both). In mice challenged with turpentine for 6 weeks, treatment with LDN-193189, beginning after anemia was established at week 3, led to an increase in hemoglobin levels at week 6 (10.9±0.1 vs 9.5±0.2 g/dL, LDN193189 vs vehicle, respectively; *p<0.05).In zebrafish, microinjection with Pseudomonas aeruginosa or overexpression of human IL-6 induced hepatic hepcidin expression, an effect which was blocked by LDN-193189.Incubation of HepG2 cells with IL-6 (100 ng/ml) increased hepcidin mRNA levels 2 to 5 fold. Pretreatment with LDN-193189, or recombinant protein BMP antagonists such as noggin, abrogated the induction of hepcidin expression by IL-6. Incubation of HepG2 cells with BMP6 (2.5 to 10 ng/ml) modestly increased hepcidin mRNA levels. However, the combination of IL-6 and BMP6 synergistically increased hepcidin gene expression (*p<0.05). Conclusion:BMP signaling appears to play a critical role in the pathogenesis of anemia in a mouse ACD model. Our findings support the concept that BMP signaling is required for the induction of hepcidin gene expression by IL-6 in vitro and in vivo. Moreover, manipulation of BMP signaling represents a potentially novel therapeutic approach to the treatment of anemia associated with inflammation. Disclosures:Steinbicker:Deutsche Forschungsgemeinschaft DFG: Research Funding. Scadden:Fate Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Peterson:Massachusetts General Hospital Executive Committee on Research and NIDDK 1R01DK082971: Research Funding. Bloch:Massachusetts General Hospital Executive Committee on Research and NIDDK 1R01DK082971: Research Funding. Yu:Harvard Stem Cell Institute Seed Grant and the Howard Hughes Medical Institute Early Career Physician-Scientist Award: Honoraria, Research Funding; NHLBI 5K08HL079943: Research Funding.

Management of non-Hodgkin lymphomas arising at extranodal sites

Primary extranodal lymphomas are relatively rare non-Hodgkin lymphoma presentations with either no or only "minor" nodal involvement along with a clinically "dominant" extranodal component, to which primary treatment must often be directed. Clinical presentations depend largely on the localization and are similar to those of other malignancies affecting that specific organ. In addition to the histological subtype, the primary organ of origin represents the most significant prognostic factor due to differences in natural history and, mainly, in management strategies related to organ-specific problems. In principle, as for primary nodal disease, treatment strategies depends on the patient's clinical conditions, the extent and/or location of the disease, and the histological type. In general, for stage I and II disease with low tumor burden, local therapy is a relevant option both for cure and local control. In advanced stage disease, systemic chemoimmunotherapy is usually required. Localizations with particularly poor survival are the enteropathy-type T-cell lymphoma, the primary testicular diffuse large B-cell lymphoma, and the primary CNS Lymphoma. However, recent studies have shown that site-tailored treatment strategies in testis and brain lymphoma may result in a significant outcome improvement. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common indolent subtype. This lymphoma usually arises in mucosal sites where lymphocytes are not normally present and where a lymphoid infiltration is acquired in response to either chronic infectious conditions or autoimmune processes: Helicobacter pylori gastritis, Hashimoto's thyroiditis, Sjögren syndrome. Indeed, a pathogenetic link between gastric MALT lymphoma and H. pylori is strongly suggested by the regression of gastric MALT lymphoma (in approx. 75% of cases) after antibiotic eradication of the microorganism.

The distributed genome hypothesis as a rubric for understanding evolution in situ during chronic bacterial biofilm infectious processes.

Most chronic infectious disease processes associated with bacteria are characterized by the formation of a biofilm that provides for bacterial attachment to the host tissue or the implanted medical device. The biofilm protects the bacteria from the host's adaptive immune response as well as predation by phagocytic cells. However, the most insidious aspect of biofilm biology from the host's point of view is that the biofilm provides an ideal setting for bacterial horizontal gene transfer (HGT). HGT provides for large-scale genome content changes in situ during the chronic infectious process. Obviously, for HGT processes to result in the reassortment of alleles and genes among bacterial strains, the infection must be polyclonal (polymicrobial) in nature. In this review, we marshal the evidence that all of the factors are present in biofilm infections to support HGT that results in the ongoing production of novel strains with unique combinations of genic characteristics and that the continual production of large numbers of novel, but related bacterial strains leads to persistence. This concept of an infecting population of bacteria undergoing mutagenesis to produce a 'cloud' of similar strains to confuse and overwhelm the host's immune system parallels genetic diversity strategies used by viral and parasitic pathogens.