Biventricular circulatory support using single-device and dual-device configurations: Initial pump characterization in simulated heart failure model.

Objective: Severe biventricular heart failure (BHF) can be remedied using a biventricular assist device (BVAD). Two devices are currently in development: a universal ventricular assist device (UVAD), which will be able to assist either the left, right, or both ventricles, and a continuous-flow total artificial heart (CFTAH), which replaces the entire heart. In this study, the in vitro hemodynamic performances of two UVADs are compared to a CFTAH acting as a BVAD. Methods: For this experiment, a biventricular mock circulatory loop utilizes two pneumatic pumps (Abiomed AB5000™, Danvers, MA, USA), in conjunction with a dual-output driver, to create heart failure (HF) conditions (left, LHF; right, RHF; biventricular, BHF). Systolic BHF for four different situations were replicated. In each situation, CFTAH and UVAD devices were installed and operated at two distinct speeds, and cannulations for ventricular and atrial connections were evaluated. Results: Both CFTAH and UVAD setups achieved our recommended hemodynamic criteria. The dual-UVAD arrangement yielded a better atrial balance to alleviate LHF and RHF. For moderate and severe BHF scenarios, CFTAH and dual UVADs both created excellent atrial pressure balance. Conversely, when CFTAH was atrial cannulated for LHF and RHF, the needed atrial pressure balance was not met. Conclusion: Comprehensive in vitro testing of two different BVAD setups exhibited self-regulation and exceptional pump performance for both (single- and dual-device) BHF support scenarios. For treating moderate and severe BHF, UVAD and CFTAH both functioned well with respect to atrial pressure regulation and cardiac output. Though, the dual-UVAD setup yielded a better atrial pressure balance in all BHF testing scenarios.

Novel intranasal vaccine targeting SARS-CoV-2 receptor binding domain to mucosal microfold cells and adjuvanted with TLR3 agonist Riboxxim™ elicits strong antibody and T-cell responses in mice.

SARS-CoV-2 continues to circulate in the human population necessitating regular booster immunization for its long-term control. Ideally, vaccines should ideally not only protect against symptomatic disease, but also prevent transmission via asymptomatic shedding and cover existing and future variants of the virus. This may ultimately only be possible through induction of potent and long-lasting immune responses in the nasopharyngeal tract, the initial entry site of SARS-CoV-2. To this end, we have designed a vaccine based on recombinantly expressed receptor binding domain (RBD) of SARS-CoV-2, fused to the C-terminus of C. perfringens enterotoxin, which is known to target Claudin-4, a matrix molecule highly expressed on mucosal microfold (M) cells of the nasal and bronchial-associated lymphoid tissues. To further enhance immune responses, the vaccine was adjuvanted with a novel toll-like receptor 3/RIG-I agonist (Riboxxim™), consisting of synthetic short double stranded RNA. Intranasal prime-boost immunization of mice induced robust mucosal and systemic anti-SARS-CoV-2 neutralizing antibody responses against SARS-CoV-2 strains Wuhan-Hu-1, and several variants (B.1.351/beta, B.1.1.7/alpha, B.1.617.2/delta), as well as systemic T-cell responses. A combination vaccine with M-cell targeted recombinant HA1 from an H1N1 G4 influenza strain also induced mucosal and systemic antibodies against influenza. Taken together, the data show that development of an intranasal SARS-CoV-2 vaccine based on recombinant RBD adjuvanted with a TLR3 agonist is feasible, also as a combination vaccine against influenza.

PLGA Particles in Immunotherapy.

Poly(lactic-co-glycolic acid) (PLGA) particles are a widely used and extensively studied drug delivery system. The favorable properties of PLGA such as good bioavailability, controlled release, and an excellent safety profile due to the biodegradable polymer backbone qualified PLGA particles for approval by the authorities for the application as a drug delivery platform in humas. In recent years, immunotherapy has been established as a potent treatment option for a variety of diseases. However, immunomodulating drugs rely on targeted delivery to specific immune cell subsets and are often rapidly eliminated from the system. Loading of PLGA particles with drugs for immunotherapy can protect the therapeutic compounds from premature degradation, direct the drug delivery to specific tissues or cells, and ensure sustained and controlled drug release. These properties present PLGA particles as an ideal platform for immunotherapy. Here, we review recent advances of particulate PLGA delivery systems in the application for immunotherapy in the fields of allergy, autoimmunity, infectious diseases, and cancer.

Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition.

New treatment options to battle hormone-refractory prostate carcinoma (PC) are a pressing medical need. Chronic inflammation has been implicated in PC etiology. The pro-inflammatory cytokines IL-6, IL-23 and IL-17 are key mediators to promote growth of PC. Here, we evaluate the potential of immunoproteasome inhibition for anti-inflammatory and direct anti-tumorigenic therapy of PC. The anti-tumor effect of immunoproteasome inhibitor ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in castration-resistant (CR)PC after castration. Inhibition of the immunoproteasome subunit LMP7 induced apoptotic cell death in PC cell lines. In TRAMP mice, ONX 0914-treatment resulted in significant inhibition of PC growth with a decreased frequency of malignant prostatic lesions and inhibition of metastasis formation. The number of immunosuppressive myeloid cells in PC was greatly reduced in response to ONX 0914. Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising drug target for the treatment of PC.

Evaluation of centrifugal blood pump performances for biventricular support in the virtual simulation model.

BACKGROUND: Despite the advances in the left ventricular assist device (LVAD), there are still situations that require a biventricular assist device (BVAD) system. The purpose of this study was to explore and compare the system performance interactions with the HeartMate3 (HM3) and HeartWare (HVAD) in a BVAD configuration using the virtual mock loop (VML) simulation tool. METHODS: The VML simulation tool is an in silico implementation of a lumped parameter model of the cardiovascular system with mechanical circulatory support. Patients with ejection fractions of 60%, 20%, and 15% were simulated in VML, and the HVAD and HM3 in a BVAD with ventricular cannulation were applied to simulated conditions. Pump speeds that restored baseline normal hemodynamics were determined. To determine the optimal speeds for BVAD, the left and right arterial pressures (LAP, RAP) were plotted. RESULTS: In the HVAD, LAP and RAP are balanced at 11 mm Hg with LVAD 3500 rpm, right ventricular assist device (RVAD) 2200 rpm; at 13 mm Hg with LVAD 3000 rpm, RVAD 1700 rpm; and at 14 mm Hg with LVAD 2500 rpm, RVAD 1300 rpm. For the HM3, at 8 mm Hg with LVAD 7000 rpm, RVAD 5000 rpm; at 9 mm Hg with LVAD 6000 rpm, RVAD 4300 rpm; and at 9.5 mm Hg with LVAD 5000 rpm, RVAD 3500 rpm. CONCLUSION: The RVAD/LVAD speed ratios required for atrial balance were approximately 0.6 for the HVAD and 0.7 for the HM3. However, the HVAD required RVAD speeds below its range of operation.

PLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy.

With emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.

An Unusual Case of Solitary Osteochondroma of the Iliac Wing.

INTRODUCTION: Osteochondromas represent one of the most common bone tumors accounting for 8% of all bone tumors. While most osteochondromas arise in the metaphysis of long bones, osteochondromas have been reported in atypical locations such as the scapula, metatarsals, and the pelvic region. Osteochondromas are capable of growing large enough to cause mass effects and can undergo malignant transformation, stressing the clinical importance of recognizing these tumors. Case Presentation. In this case, we present an 18-year-old skeletally mature Caucasian male with a symptomatic osteochondroma arising from the iliac wing. The osteochondroma increased in size since he reached skeletal maturity. This resulted in a mass effect that interfered with activities of daily living, including clothing wear and symptomatic impaction on hard surfaces. CONCLUSION: The majority of osteochondromas arise from the metaphysis of long bones, but case reports have shown that osteochondromas presenting in atypical locations such as the pelvis do occur. In the case of our patient, his asymptomatic pelvic tumor grew to the extent that it was causing interference with activities of daily living. Surgical excision of his tumor proved to be curative, and there was no recurrence at 6 months after excision. Osteochondromas in this region are capable of growing large enough to cause sexual dysfunction. Clinical suspicion must be high to properly diagnose osteochondromas in atypical locations. All providers, particularly those in primary care, should be aware of these locations as patients with symptomatic mass lesions will likely initially present here.

Modeling of Virtual Mechanical Circulatory Hemodynamics for Biventricular Heart Failure Support.

OBJECTIVE: In this study, a mechanical circulatory support simulation tool was used to investigate the application of a unique device with two centrifugal pumps and one motor for the biventricular assist device (BVAD) support application. Several conditions-including a range of combined left and right systolic heart failure severities, aortic and pulmonary valve regurgitation, and combinations of high and low systemic and pulmonary vascular resistances-were considered in the simulation matrix. Relative advantages and limitations of using the device in BVAD applications are discussed. METHODS: The simulated BVAD pump was based on the Cleveland Clinic pediatric continuous-flow total artificial heart (P-CFTAH), which is currently under development. Different combined disease states (n = 10) were evaluated to model the interaction with the BVAD, considering combinations of normal heart, moderate failure and severe systolic failure of the left and right ventricles, regurgitation of the aortic and pulmonary valves and combinations of vascular resistance. The virtual mock loop simulation tool (MATLAB; MathWorks®, Natick, MA) simulates the hemodynamics at the pump ports using a lumped-parameter model for systemic/pulmonary circulation characteristic inputs (values for impedance, systolic and diastolic ventricular compliance, beat rate, and blood volume), and characteristics of the cardiac chambers and valves. RESULTS: Simulation results showed that this single-pump BVAD can provide regulated support of up to 5 L/min over a range of combined heart failure states and is suitable for smaller adult and pediatric support. However, good self-regulation of the atrial pressure difference was not maintained with the introduction of aortic valve regurgitation or high systemic vascular resistance when combined with low pulmonary vascular resistance. CONCLUSIONS: This initial in silico study demonstrated that use of the P-CFTAH as a BVAD supports cardiac output and arterial pressure in biventricular heart failure conditions. A similar but larger device would be required for a large adult patient who needs more than 5 L/min of support.

A simulation tool for mechanical circulatory support device interaction with diseased states.

We have created a simulation model to investigate the interactions between a variety of mechanical circulatory support (MCS) devices and the circulatory system with various simulated patient conditions and disease states. The present simulation accommodates a family of continuous-flow MCS devices under various stages of consideration or development at our institution. This article describes the mathematical core of the in silico simulation system and shows examples of simulation output imitating various disease states and of selected in vitro and clinical data from the literature.

Analysis of Cleveland Clinic continuous-flow total artificial heart performance using the Virtual Mock Loop: Comparison with an in vivo study.

The Virtual Mock Loop (VML) is a mathematical model designed to simulate mechanism of the human cardiovascular system interacting with mechanical circulatory support devices. Here, we aimed to mimic the hemodynamic performance of Cleveland Clinic's self-regulating continuous-flow total artificial heart (CFTAH) via VML and evaluate the accuracy of the VML compared with an in vivo acute animal study. The VML reproduced 124 hemodynamic conditions from three acute in vivo experiments in calves. Systemic/pulmonary vascular resistances, pump rotational speed, pulsatility, and pulse rate were set for the VML from in vivo data. We compared outputs (pump flow, left and right pump pressure rises, and atrial pressure difference) between the two systems. The pump performance curves all fell in the designed range. There was a strong correlation between the VML and the in vivo study in the left pump flow (r2 = 0.84) and pressure rise (r2 = 0.80), and a moderate correlation in right pressure rise (r2 = 0.52) and atrial pressure difference (r2 = 0.59). Although there is room for improvement in simulating right-sided pump performance of self-regulating CFTAH, the VML acceptably simulated the hemodynamics observed in an in vivo study. These results indicate that pump flow and pressure rise can be estimated from vascular resistances and pump settings.

Harnessing Dendritic Cells for Poly (D,L-lactide-co-glycolide) Microspheres (PLGA MS)-Mediated Anti-tumor Therapy.

With emerging success in fighting off cancer, chronic infections, and autoimmune diseases, immunotherapy has become a promising therapeutic approach compared to conventional therapies such as surgery, chemotherapy, radiation therapy, or immunosuppressive medication. Despite the advancement of monoclonal antibody therapy against immune checkpoints, the development of safe and efficient cancer vaccine formulations still remains a pressing medical need. Anti-tumor immunotherapy requires the induction of antigen-specific CD8+ cytotoxic T lymphocyte (CTL) responses which recognize and specifically destroy tumor cells. Due to the crucial role of dendritic cells (DCs) in initiating anti-tumor immunity, targeting tumor antigens to DCs has become auspicious in modern vaccine research. Over the last two decades, micron- or nanometer-sized particulate delivery systems encapsulating tumor antigens and immunostimulatory molecules into biodegradable polymers have shown great promise for the induction of potent, specific and long-lasting anti-tumor responses in vivo. Enhanced vaccine efficiency of the polymeric micro/nanoparticles has been attributed to controlled and continuous release of encapsulated antigens, efficient targeting of antigen presenting cells (APCs) such as DCs and subsequent induction of CTL immunity. Poly (D, L-lactide-co-glycolide) (PLGA), as one of these polymers, has been extensively studied for the design and development of particulate antigen delivery systems in cancer therapy. This review provides an overview of the current state of research on the application of PLGA microspheres (PLGA MS) as anti-tumor cancer vaccines in activating and potentiating immune responses attempting to highlight their potential in the development of cancer therapeutics.

Simulated Performance of the Cleveland Clinic Continuous-Flow Total Artificial Heart Using the Virtual Mock Loop.

Our new Virtual Mock Loop (VML) is a mathematical model designed to simulate the human cardiovascular system and gauge performance of mechanical circulatory support devices. We aimed to mimic the hemodynamic performance of Cleveland Clinic's self-regulating continuous-flow total artificial heart (CFTAH) via VML and evaluate VML's accuracy versus bench data from our standard mock circulatory loop. The VML reproduced 23 hemodynamic conditions. Systemic/pulmonary vascular resistances and pump rotational speed were set for VML from bench test data. We compared outputs (pump flow, left/right pump pressure rise, normalized pump performance, and atrial pressure difference) of the two methods. Data from pump flow and left pump pressure rise were similar, but right pump pressure rise slightly differed. Left pump normalized pump performance curves were similar. Right pump VML results were within the same performance range indicated by bench tests. The plots of atrial pressure differences of VML versus bench-test data were similar, but slightly differed in the midrange of systemic/pulmonary gradients. Virtual Mock Loop successfully reproduced results from our mock circulatory loop of CFTAH test conditions. The CFTAH's self-regulation feature of right pump performance was also calculated effectively. We foresee using versions of the VML for training, simulating physiologic cardiac conditions, and patient monitoring.

Use of a Mechanical Circulatory Support Simulation to Study Pump Interactions With the Variable Hemodynamic Environment.

The Virtual Mock Loop, a versatile virtual mock circulation loop, was developed using a lumped-parameter model of the mechanically assisted human circulatory system. Inputs allow specification of a variety of continuous-flow pumps (left, right, or biventricular assist devices) and a total artificial heart that can self-regulate between left and right pump outputs. Hemodynamic inputs were simplified using a disease-based input panel, allowing selection of a combination of cardiovascular disease states, including systolic and diastolic heart failure, stenosis, and/or regurgitation in each of the four valves, and high to low systemic and pulmonary vascular resistance values. The menu-driven output includes a summary of hemodynamic parameters and graphical output of selected flows, pressures, and volumes in the heart's four chambers as well as in the pulmonary artery and aorta. New tools to augment experimental research on implantable heart-assist devices and to increase our understanding of patient-specific pump interactions are in high demand. The purpose of this ongoing study is to demonstrate the use of a system analysis computer simulation to explore and better comprehend the interactions of mechanical circulatory support pumps with a more extensive combination of patient-specific or simulation conditions than can be established by practical experimentation. Usability is an important factor in constructing computer models for research purposes, and among our primary objectives in creating this simulation model were to make it as portable and useful as possible outside the lab environment, by people not involved in the creation of its operational software.

Human IgE mAbs define variability in commercial Aspergillus extract allergen composition.

Sensitization to Aspergillus species is associated with allergic respiratory diseases. Allergen immunotherapy with nonstandardized Aspergillus extracts is commonly used as therapy in these patients. Unfortunately, no method exists to measure the relevant allergen protein content in diagnostic and therapeutic extracts. Thus, there is a critical need for Aspergillus extract standardization. We hypothesized that development of Aspergillus-specific human IgE mAbs would allow for the characterization of the relevant human allergenic epitopes among currently available commercial Aspergillus fumigatus extracts. Patients with allergic bronchopulmonary mycosis were recruited from Vanderbilt University Medical Center. IgE antibody-secreting B cells were grown and immortalized using human hybridoma techniques first described here. Twenty-six human Aspergillus-reactive IgE mAbs were used as capture and detection reagents to characterize the Aspergillus allergen content of commercial extracts. We found extreme variability in the specificity and quantity of their protein targets. Just 4 mAbs reacted with all available extracts, and only 1 of 4 extracts contained the major allergen Asp f 1. This degree of variability will almost certainly affect the efficacy of these reagents when used in diagnosis and treatment. Human IgE mAbs represent an innovative tool for the evaluation of relevant human allergenic epitopes, which may assist in future development and long-term standardization of mold extracts.

Amycomicin is a potent and specific antibiotic discovered with a targeted interaction screen.

The rapid emergence of antibiotic-resistant pathogenic bacteria has accelerated the search for new antibiotics. Many clinically used antibacterials were discovered through culturing a single microbial species under nutrient-rich conditions, but in the environment, bacteria constantly encounter poor nutrient conditions and interact with neighboring microbial species. In an effort to recapitulate this environment, we generated a nine-strain actinomycete community and used 16S rDNA sequencing to deconvolute the stochastic production of antimicrobial activity that was not observed from any of the axenic cultures. We subsequently simplified the community to just two strains and identified Amycolatopsis sp. AA4 as the producing strain and Streptomyces coelicolor M145 as an inducing strain. Bioassay-guided isolation identified amycomicin (AMY), a highly modified fatty acid containing an epoxide isonitrile warhead as a potent and specific inhibitor of Staphylococcus aureus Amycomicin targets an essential enzyme (FabH) in fatty acid biosynthesis and reduces S. aureus infection in a mouse skin-infection model. The discovery of AMY demonstrates the utility of screening complex communities against specific targets to discover small-molecule antibiotics.

Antibacterial photosensitization through activation of coproporphyrinogen oxidase.

Gram-positive bacteria cause the majority of skin and soft tissue infections (SSTIs), resulting in the most common reason for clinic visits in the United States. Recently, it was discovered that Gram-positive pathogens use a unique heme biosynthesis pathway, which implicates this pathway as a target for development of antibacterial therapies. We report here the identification of a small-molecule activator of coproporphyrinogen oxidase (CgoX) from Gram-positive bacteria, an enzyme essential for heme biosynthesis. Activation of CgoX induces accumulation of coproporphyrin III and leads to photosensitization of Gram-positive pathogens. In combination with light, CgoX activation reduces bacterial burden in murine models of SSTI. Thus, small-molecule activation of CgoX represents an effective strategy for the development of light-based antimicrobial therapies.

Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract.

UNLABELLED: Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. IMPORTANCE: The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into significant ramifications for bacterial persistence and disease severity. While many studies have demonstrated that modifications of the LPS lipid A moiety modulate the extent of Toll-like receptor 4 (TLR4) activation, our studies implicate the O-antigen sugar moiety as another potential rheostat for the modulation of proinflammatory cytokine production.

The interleukin-17 receptor B subunit is essential for the Th2 response to Helicobacter pylori, but not for control of bacterial burden.

Helicobacter pylori infection leads to an inflammatory response in 100% of infected individuals. The inflammatory cells which are recruited to the gastric mucosa during infection produce several pro- and anti-inflammatory cytokines including several cytokines in the interleukin-17 family. The anti-inflammatory cytokine, interleukin 25 (IL-25, also known as IL-17E), signals through a receptor, which is a heterotrimeric receptor comprised of two IL-17 receptor A subunits and an IL-17 receptor B subunit. Previous studies in our laboratory demonstrated that IL-17RA is required to control infection with Helicobacter pylori in the mouse model. Moreover, the absence of IL-17 receptor A leads to a significant B cell infiltrate and a remarkable increase in lymphoid follicle formation in response to infection compared to infection in wild-type mice. We hypothesized that IL-25, which requires both IL-17 receptor A and IL-17 receptor B for signaling, may play a role in control of inflammation in the mouse model of Helicobacter pylori infection. IL-17 receptor B deficient mice, IL-17 receptor A deficient mice and wild-type mice were infected with Helicobacter pylori (strains SS1 and PMSS1). At several time points H. pylori-infected mice were sacrificed to investigate their ability to control infection and inflammation. Moreover, the effects of IL-17 receptor B deficiency on T helper cytokine expression and H. pylori- specific serum antibody responses were measured. IL-17 receptor B-/- mice (unlike IL-17 receptor A-/- mice) exhibited similar or modest changes in gastric colonization, inflammation, and Th1 and Th17 helper cytokine responses to wild-type mice infected with Helicobacter pylori. However, H. pylori-infected IL-17 receptor B-/- mice have reduced expression of IL-4 and lower serum IgG1 and IgG2a levels compared to infected IL-17 receptor A-/- and wild-type mice. These data indicate that signaling through the IL-17 receptor B subunit is not necessary for control of Helicobacter pylori in our model.

New paradigms of urinary tract infections: Implications for patient management.

Urinary tract infections (UTIs) represent one of the most commonly acquired diseases among the general population as well as hospital in-patients, yet remain difficult to effectively and consistently treat. High rates of recurrence, anatomic abnormalities, and functional disturbances of the urinary tract all contribute to the difficulty in management of these infections. However, recent advances reveal important molecular and genetic factors that contribute to bacterial invasion and persistence in the urinary tract, particularly for the most common causative agent, uropathogenic Escherichia coli. Recent studies using animal models of experimental UTIs have recently provided mechanistic insight into the clinical observations that question the effectiveness of antibiotic therapy in treatment. Ultimately, continuing research will be necessary to identify the best targets for effective treatment of this costly and widespread infectious disease.

IL-23 Contributes to Control of Chronic Helicobacter Pylori Infection and the Development of T Helper Responses in a Mouse Model.

The immune response to Helicobacter pylori involves a mixed T helper-1, T helper-2, and T helper-17 response. It has been suggested that T helper cells contribute to the gastric inflammatory response during infection, and that T helper 1 (Th1) and T helper 17 (Th17) subsets may be required for control of H. pylori colonization in the stomach. The relative contributions of these subsets to gastritis and control of infection are still under investigation. IL-23 plays a role in stabilizing and expanding Th17 cell cytokine expression. Expression of IL-23, which is induced in dendritic cells and macrophages following co-culture with H. pylori, has also been reported to increase during H. pylori infection in humans and animal models. To investigate the role of IL-23 in H. pylori, we infected IL-23p19 deficient mice (IL-23-/-) and wild-type littermates with H. pylori strain SS1. At various time points post-infection, we assessed colonization, gastric inflammation, and cytokine profiles in the gastric tissue. Specifically, H. pylori-infected IL-23-/- mice have higher levels of H. pylori in their stomachs, significantly less chronic gastritis, and reduced expression of IL-17 and IFNγ compared to H. pylori-infected wild-type mice. While many of these differences were significant, the H. pylori infected IL-23-/- had mild increases in our measurements of disease severity. Our results indicate that IL-23 plays a role in the activation of the immune response and induction of gastritis in response to H. pylori by contributing to the control of infection and severity of gastritis.