From the Cover: PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain

Defense of the central nervous system (CNS) against infection must be accomplished without generation of potentially injurious immune cell-mediated or off-target inflammation which could impair key functions. As the CNS is an immune-privileged compartment, inducible innate defense mechanisms endogenous to the CNS likely play an essential role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known to regulate neurodevelopment, emotion, and certain stress responses. While PACAP is known to interact with the immune system, its significance in direct defense of brain or other tissues is not established. Here, we show that our machine-learning classifier can screen for immune activity in neuropeptides, and correctly identified PACAP as an antimicrobial neuropeptide in agreement with previous experimental work. Furthermore, synchrotron X-ray scattering, antimicrobial assays, and mechanistic fingerprinting provided precise insights into how PACAP exerts antimicrobial activities vs. pathogens via multiple and synergistic mechanisms, including dysregulation of membrane integrity and energetics and activation of cell death pathways. Importantly, resident PACAP is selectively induced up to 50-fold in the brain in mouse models of Staphylococcus aureus or Candida albicans infection in vivo, without inducing immune cell infiltration. We show differential PACAP induction even in various tissues outside the CNS, and how these observed patterns of induction are consistent with the antimicrobial efficacy of PACAP measured in conditions simulating specific physiologic contexts of those tissues. Phylogenetic analysis of PACAP revealed close conservation of predicted antimicrobial properties spanning primitive invertebrates to modern mammals. Together, these findings substantiate our hypothesis that PACAP is an ancient neuro-endocrine-immune effector that defends the CNS against infection while minimizing potentially injurious neuroinflammation.

Neuropeptides enable interneuronal communication and signaling (1), mediating diverse functions ranging from endocrine stimulation and homeostatic regulation to immune signaling, pain modulation, and circadian rhythm maintenance. At present, over 100 neuropeptides are known in mammals (2). These peptides originate from neurons in the central, enteric, or peripheral nervous systems and within immune organs (3). Canonically, neuropeptides exert their biological function by binding to a cognate receptor (usually a G-coupled protein receptor [GPCR]), triggering a signal transduction pathway that leads to a functional change in the target cell (1). Neuropeptides are typically considered neurotransmitters or neurohormones, but recent work has illuminated their potential roles in modulating immune responses and neuroinflammation (4–8).Human innate and adaptive immunity have evolved via two parallel and complementary paradigms in host defense against microbial invasion: molecular and cellular. Molecular defense mediators are secreted or activated rapidly and locally to directly inhibit pathogens. Prototypic examples include host-defense peptides (HDPs), the acute-phase reactants, and the complement cascade. Cellular defense involves infiltration of professional immune phagocytes (neutrophils and macrophages) and lymphocytes into infected tissues. Cellular infiltration into the central nervous system (CNS) is a double-edged sword, given its anatomically confined space and physiologically delicate context. On one hand cellular defense may be necessary to control or clear certain pathogens. On the other hand, neutrophils and other phagocytes can cause counterproductive damage to tissue parenchyma due to production and release of reactive oxygen species and other cytotoxic constituents from phagolysosomes. Thus, molecular defenses that are rapidly deployable in immediate settings of infection to obviate the need for infiltration of potentially harmful immune cells would be of special relevance in context of the CNS.To explore putative molecular host-defense mediators within the CNS that may have both neuro- and immunomodulatory properties, we used a support vector machine (SVM) trained on HDPs (9, 10) to identify neuropeptides with potential host defense capabilities. Among the human neuropeptides identified as potential HDPs for molecular host defense of the CNS is pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is a member of the vasoactive intestinal peptide (VIP)/PACAP/secretin family (11) that regulates neurodevelopment (12), metabolism, emotion, mood, and stress responses via GPCRs (13). PACAP is known to interact with the immune system (14, 15) and modulate T helper type 1 (TH1)/TH2 cytokine production (3). Important previous work on structure activity relationships (SAR) of PACAP have also shown that it possess antimicrobial activity in vitro against a range of organisms (16–18), as well as anti-cancer activity against tumor cell lines. (Interestingly, our use of an SVM classifier that can scan different fragments of the same peptide allows us to identify antimicrobial activity in previously identified metabolites of PACAP as well^* (19)). However, host defense functions, contextual bioactivity, or pathogen-specific inducibility of PACAP or other neuropeptides regarding antimicrobial activity in vivo are not known. More specifically, the role of PACAP in the larger context of innate immunity and its in vivo relevance to antimicrobial defense of the CNS and in other tissues remains unclear, given that antimicrobial activity is strongly dependent on biochemical and physiological context (20, 21, 22). Here, we examine PACAP inducibility in response to infection in the CNS and other tissues, and whether PACAP exerts antimicrobial activity against relevant organisms in the specific biochemical context relevant to those tissues. Bioinformatic and structural analyses showed PACAP to possess almost identical structural similarity to human cathelicidin LL-37, despite having overall low sequence similarity to other known HDPs. Synchrotron X-ray scattering revealed that PACAP can induce negative Gaussian curvature (NGC) in microbial membranes, a general requirement for membrane-permeating antimicrobial processes such as pore formation, blebbing, and other membrane-perturbing events (23–25). Moreover, extending from prior work (18), antimicrobial assays and mechanistic fingerprinting analyses showed that PACAP exerts potent antimicrobial mechanisms against drug-resistant bacteria and fungi via multiple synergistic pathways, including permeabilization, disruption of cellular energetics, and activation of regulated cell death pathways. In mouse models of bacterial or fungal infection, we demonstrated that PACAP is strongly induced up to 50-fold in brain, spleen, or kidney. Further, in media simulating these tissue contexts, PACAP exerted robust microbiostatic and microbicidal efficacy. Taken together, these findings imply that PACAP is an infection-inducible, tissue-specific host-defense effector that affords rapid and contextual antimicrobial host defense in the CNS and periphery. Beyond immediate contributions to better understanding of antimicrobial defense, the present discoveries reveal specific intersections of neurological and immunological systems and establish insights into antiinfective strategies that preserve critical functions of the CNS.     

Benefits and Sustainability of a Learning Collaborative for Implementation of Treat‐to‐Target in Rheumatoid Arthritis: Results of a Cluster‐Randomized Controlled Phase II Clinical Trial

Objective

We conducted a 2‐phase randomized controlled trial of a learning collaborative to facilitate implementation of treat‐to‐target (T2T) to manage rheumatoid arthritis (RA). We found substantial improvement in implementation of T2T in phase I. Here, we report on a second 9 months (phase II), where we examined the maintenance of response in phase I and predictors of greater improvement in T2T adherence.

Methods

We recruited patients from 11 rheumatology sites and randomized them to either receive the learning collaborative during phase I or to a wait‐list control group that received the learning collaborative intervention during phase II. The outcome was change in T2T implementation score (0–100, where 100 = best) from pre‐ to postintervention. The T2T implementation score was defined as a percent of components documented in visit notes. Analyses examined the extent to which the phase‐I intervention teams sustained improvement in T2T, as well as predictors of T2T improvement.

Results

The analysis included 636 RA patients. At baseline, the mean T2T implementation score was 11% in phase I intervention sites and 13% in phase II sites. After the intervention, T2T implementation score improved to 57% in the phase I intervention sites and to 58% in the phase II sites. Intervention sites from phase I sustained the improvement during the phase II (52%). Predictors of greater T2T improvement included having only rheumatologist providers at the site, academic affiliation of the site, having fewer providers per site, and the rheumatologist provider being a trainee.

Conclusion

Improvement in T2T remained relatively stable over a postintervention period.

     

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.     

Osteoporosis knowledge,self-efficacy,and health beliefs among Chinese individuals with HIV

Summary

The worldwide uptake of FRAX is described.

Introduction

The aim of this report was to determine the usage of FRAX worldwide over a 1-year period from 1 May 2012.

Methods

The number of FRAX calculations from each country was assessed over a 1-year period and expressed as calculations per million of the population aged 50 years or more. Countries were colour coded according to usage to populate a world map.

Results

Over the index year, there were estimated to be 2,391,639 calculations sourced from 173 counties. Uptake was high in North America, the Antipodes and most countries of Europe; intermediate in Latin America and the Middle East; and very low in Africa and much of South East Asia.

Conclusions

It is expected that the comparative data will encourage the development of new FRAX models and the uptake of FRAX into assessment guidelines.     

High Frequency of Serum Chromium Deficiency and Association of Chromium with Triglyceride and Cholesterol Concentrations in Patients Awaiting Bariatric Surgery

Background

To our knowledge, the frequency of serum chromium deficiency in patients awaiting bariatric surgery has not been determined. This study was designed to assess chromium concentration and its association with glycemic levels and lipid profile in patients prior to bariatric surgery.

Methods

This study recruited 73 candidates for bariatric surgery between March and September 2012. Their sociodemographic, anthropometric, and biochemical data were collected.

Results

Of the 73 patients, 55 (75.3 %) were women (75.34 %). Mean patient age was 37.20?±?9.92 years, and mean body mass index was 47.48 kg/m² (range, 43.59 to 52.50 kg/m²). Chromium deficiency was observed in 64 patients (87.7 %). Correlation analysis showed significant negative relationships between chromium concentration and BMI and zinc concentration and a significant positive relationship between chromium and glycated hemoglobin. Multiple linear regression analysis showed that serum chromium concentration was significantly associated with total cholesterol (β?=?0.171, p?=?0.048) and triglyceride (β?=??0.181, p?=?0.039) concentrations.

Conclusions

Serum chromium deficiency is frequent in candidates for bariatric surgery and is associated with total cholesterol and triglyceride concentrations. Early nutritional interventions are needed to reduce nutritional deficiencies and improve the lipid profile of these patients.     

Effects of host-directed therapies on the pathology of tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has co-evolved with the human immune system and utilizes multiple strategies to persist within infected cells, to hijack several immune mechanisms, and to cause severe pathology and tissue damage in the host. This delays the efficacy of current antibiotic therapy and contributes to the evolution of multi-drug-resistant strains. These challenges led to the development of the novel approach in TB treatment that involves therapeutic targeting of host immune response to control disease pathogenesis and pathogen growth, namely, host-directed therapies (HDTs). Such HDT approaches can (1) enhance the effect of antibiotics, (2) shorten treatment duration for any clinical form of TB, (3) promote development of immunological memory that could protect against relapse, and (4) ameliorate the immunopathology including matrix destruction and fibrosis associated with TB. In this review we discuss TB-HDT candidates shown to be of clinical relevance that thus could be developed to reduce pathology, tissue damage, and subsequent impairment of pulmonary function. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Wettability and Surface Roughness Analysis of Laser Surface Texturing of AISI 430 Stainless Steel

Due to its wide applicability in industry, devising microstructures on the surface of materials can be easily implemented and automated in technological processes. Laser Surface Texturing (LST) is applied to modify the chemical composition, morphology, and roughness of surfaces (wettability), cleaning (remove contaminants), reducing internal stresses of metals (hardening, tempering), surface energy (polymers, metals), increasing the adhesion (hybrid joining, bioengineering) and decreasing the growth of pathogenic bacteria (bioengineering). This paper is a continuation and extension of our previous studies in laser-assisted texturing of surfaces. Three different patterns (crater array-type C, two ellipses at 90° overlapping with its mirror-type B and 3 concentric octagons-type A) were applied with a nanosecond pulsed laser (active medium Nd: Fiber Diode-pumped) on the surface of a ferritic stainless steel (AISI 430). Micro texturing the surface of a material can modify its wettability behavior. A hydrophobic surface (contact angle greater than 90°) was obtained with different variations depending on the parameters. The analysis performed in this research (surface roughness, wettability) is critical for assessing the surface functionality, characteristics and properties of the stainless steel surface after the LST process. The values of the surface roughness and the contact angle are directly proportional to the number of repetitions and inversely proportional to the speed. Recommendations for the use of different texturing pattern designs are also made.     

Compound heterozygosity in the GALC gene in a late onset Iranian patient with spastic paraparesis,peripheral neuropathy and leukoencephalopathy

Neurological Sciences -