Repression of SPI2 transcription by nitric oxide-producing, IFNγ-activated macrophages promotes maturation of Salmonella phagosomes

By remodeling the phagosomal membrane, the type III secretion system encoded within the Salmonella pathogenicity island-2 (SPI2) helps Salmonella thrive within professional phagocytes. We report here that nitric oxide (NO) generated by IFNγ-activated macrophages abrogates the intracellular survival advantage associated with a functional SPI2 type III secretion system. NO congeners inhibit overall expression of SPI2 effectors encoded both inside and outside the SPI2 gene cluster, reflecting a reduced transcript level of the sensor kinase SsrA that governs overall SPI2 transcription. Down-regulation of SPI2 expression in IFNγ-treated macrophages does not seem to be the result of global NO cytotoxicity, because transcription of the housekeeping rpoD sigma factor remains unchanged, whereas the expression of the hmpA-encoded, NO-metabolizing flavohemoprotein is stimulated. Because of the reduced SPI2 expression, Salmonella-containing vacuoles interact more efficiently with compartments of the late endosomal/lysosomal system in NO-producing, IFNγ-treated macrophages. These findings demonstrate that inhibition of intracellular SPI2 transcription by NO promotes the interaction of Salmonella phagosomes with the degradative compartments required for enhanced antimicrobial activity. Transcriptional repression of a type III secretion system that blocks phagolysosome biogenesis represents a novel mechanism by which NO mediates resistance of IFNγ-activated phagocytes to an intracellular pathogen

Assessment of Functional Movement Screening by Assessors of Three Different Skill Levels

In Volume 3, Issue 1 of the JSMAHS you will find Professional abstracts, as well Under Graduate student research abstracts, case reports, and critically appraised topics. Thank you for viewing this 3rd Annual OATA Special Edition

Assessment of Functional Movement Screening by Assessors of Three Different Skill Levels

In Volume 3, Issue 1 of the JSMAHS you will find Professional abstracts, as well Under Graduate student research abstracts, case reports, and critically appraised topics. Thank you for viewing this 3rd Annual OATA Special Edition

Harmonizing healthcare and other resource measures for evaluating economic costs in substance use disorder research

Background Standardization and harmonization of healthcare resource utilization data can improve evaluations of the economic impact of treating people with substance use disorder (SUD), including reductions in use of expensive hospital and emergency department (ED) services, and can ensure consistency with current cost-effectiveness and cost-benefit analysis guidelines. Methods We examined self-reported healthcare and other resource utilization data collected at baseline from three National Institute on Drug Abuse (NIDA)-funded Seek, Test, Treat, and Retain intervention studies of individuals living with/at risk for HIV with SUD. Costs were calculated by multiplying mean healthcare resource utilization measures by monetary conversion factors reflecting cost per unit of care. We normalized baseline recall timeframes to past 30 days and evaluated for missing data. Results We identified measures that are feasible and appropriate for estimating healthcare sector costs including ED visits, inpatient hospital and residential facility stays, and outpatient encounters. We also identified two self-reported measures to inform societal costs (days experiencing SUD problems, participant spending on substances). Missingness was 8% or less for all study measures and was lower for single questions measuring utilization in a recall period. Conclusions We recommend including measures representing units of service with specific recall periods (e.g., 6 months vs. lifetime), and collecting healthcare resource utilization data using single-question measures to reduce missingness

Constitutive Acid Sphingomyelinase Enhances Early and Late Macrophage Killing of Salmonella enterica Serovar Typhimurium▿

We have identified acid sphingomyelinase (ASM) as an important player in the early and late anti-Salmonella activity of macrophages. A functional ASM participated in the killing activity of macrophages against wild-type Salmonella enterica serovar Typhimurium. The role of ASM in early macrophage killing of Salmonella appears to be linked to an active NADPH phagocyte oxidase enzymatic complex, since the flavoprotein inhibitor diphenyleneiodonium not only blocked a productive respiratory burst but also abrogated the survival advantage of Salmonella in macrophages lacking ASM. Lack of ASM activity also increased the intracellular survival of an isogenic ΔspiC::FRT Salmonella strain deficient in a translocator and effector of the Salmonella pathogenicity island 2 (SPI2) type III secretion system, suggesting that the antimicrobial activity associated with ASM is manifested regardless of the SPI2 status of the bacteria. Constitutively expressed ASM is responsible for the role that this lipid-metabolizing hydrolase plays in the innate host defense of macrophages against Salmonella. Accordingly, the ASM activity and intracellular concentration and composition of ceramide, gangliosides, and neutral sphingolipids did not increase upon Salmonella infection. Salmonella triggered, nonetheless, a significant increase in the secreted fraction of ASM. Collectively, these findings have elucidated a novel role for constitutive ASM in the anti-Salmonella activity of murine macrophages

Assessment of Functional Movement Screening™ by Assessors of Three Different Skill Levels

• The Functional Movement Screen (FMS) is a series of 7 physical tests • FMS screens fundamental movement patterns that require mobility, stability, and motor control • FMS is comprised of deep squat (DS), hurdle step (HS), in-line lunge (IL), shoulder mobility (ShM), active straight leg raise (ASLR), trunk stability push-up (TSP), and rotary stability (RS) (Figures 1-4) • Sports medicine clinicians use FMS to assess for dysfunctional movement patterns • FMS is not intended to be a diagnostic tool • The inter-rater reliability for FMS has values ranging from 0.37 to .95 • The intra-rater reliability for FMS has values ranging from 0.76 to 0.98 • FMS was designed as a means of filling the void between pre-participation screenings and performance tests • A lack of uniform definitions for varying skill levels of FMS raters creates difficulty in the interpretation of the studies • The purpose of this study was to examine the intra- and inter-rater reliability on the FMS by novice, intermediate, & expert level rater

Miliary Histoplasmosis in a Patient with Rheumatoid Arthritis

Miliary histoplasmosis is a rare presentation that may mimic miliary tuberculosis. We report a case of miliary histoplasmosis in a 52-year-old male who was being treated with hydroxychloroquine, methotrexate, and sulfasalazine for his rheumatoid arthritis and presented to the emergency department with shortness of breath and fevers. Computed tomography (CT) chest revealed miliary pulmonary nodules. Urine Histoplasma antigen and serum Histoplasma antigen were negative; however, Coccidioides immitis complement immunofixation assay and Coccidioides IgM were positive. The patient was initiated on treatment for pulmonary coccidioidomycosis and immunosuppression was held. However, a few days later, Histoplasma capsulatum was isolated from cultures from bronchoscopy. This case highlights the difficulty in diagnosing histoplasmosis in immunocompromised patients and the importance of having a broad differential diagnosis for miliary pulmonary nodules. Tissue culture and histopathology remain the gold standard for the diagnosis of histoplasmosis. Further research needs to be conducted to determine the optimal duration of histoplasmosis treatment in immunocompromised patients

Economic benefits of substance use disorder treatment: A systematic literature review of economic evaluation studies from 2003 to 2021

The economic burden of substance use disorder (SUD) is significant, comprising costs of health care and social services, criminal justice resources, loss of productivity, and premature mortality. This study assembles and synthesizes two decades of evidence describing the benefits of SUD treatment across five main outcome domains; 1) health care utilization; 2) self-reported criminal activity by offense type; 3) criminal justice involvement collected from administrative records or self-reported; 4) productivity assessed through working hours or wages earned; and 5) social services (e.g., a day spent in transitional housing). This review included studies if they reported the monetary value of the intervention outcomes, most commonly through a cost-benefit or cost-effectiveness framework. The search included studies from 2003 to the present day as of this writing (up to October 15, 2021). Summary cost estimates were adjusted using the US Consumer Price Index (CPI) to reflect the 12-month benefits per client in USD 2021. We followed the PRISMA methodology for study selection and assessed quality using the Checklist for Health Economic Evaluation Reporting Standards (CHEERS). The databases yielded 729 studies after removing duplicates, and we ultimately selected 12 for review. Studies varied widely regarding analytical approaches, time horizons, outcome domains, and other methodological factors. Among the ten studies that found positive economic benefits, reductions in criminal activity or criminal justice costs represented the largest or second largest component of these benefits (range $621 to$193,440 per client). Consistent with previous findings, a reduction in criminal activity costs is driven by the relatively high societal cost per criminal offense, notably for violent crimes, such as aggravated assault and rape/sexual assault. Accepting the economic rationale for increased investment in SUD interventions will require recognizing that more benefits accrue to individuals by avoiding being victims of a crime than to governments through budget offsets resulting from savings in non-SUD program expenses. Future studies should explore individually tailored interventions to optimize care management, which may yield unexpected economic benefits to services utilization, and criminal activity data to estimate economic benefits across a broad range of interventions. •The greatest economic benefits over one year resulted from a reduction in criminal activity.•Alcohol use disorder interventions were associated with a decrease in healthcare utilization costs.•Reduced productivity following intervention was generally due to reduced labor force participation and lost earnings

Nitric Oxide Protects Bacteria from Aminoglycosides by Blocking the Energy-Dependent Phases of Drug Uptake▿

Our investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protect Salmonella spp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellular Salmonella against the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressed Salmonella respiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen in Salmonella, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogens Pseudomonas aeruginosa and Staphylococcus aureus. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria