Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes.

BACKGROUND: Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. METHODS: Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. RESULTS: In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. CONCLUSIONS: Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.

Comparison of Ultrasound and MRI with Intraoperative Findings in the Diagnosis of Peroneal Tendinopathy, Tears, and Subluxation.

Suspected peroneal tendinopathy, tears, and subluxation are often confirmed preoperatively using magnetic resonance imaging (MRI) or diagnostic ultrasound (US). No study has directly compared the accuracy of these tests for the diagnosis of peroneal tendon pathology. The purpose of this study is to directly compare MRI and US to intraoperative findings in patients who underwent surgery for suspected peroneal pathology to determine the imaging diagnostic accuracy. Operative records and diagnostic images for 21 consecutive patients who had both MRI and US prior to surgery for suspected peroneal tendinopathy, tears, or subluxation were retrospectively reviewed. The results of this review are compared with the intraoperative findings to yield the sensitivity and specificity for each imaging modality. For the diagnosis of peroneal tendon tears, US was found to have a sensitivity of 88% and specificity of 100%, compared to 100% sensitivity and specificity for MRI. In the diagnosis of peroneal tendinopathy, both US and MRI had a sensitivity and specificity of 100%. In diagnosing peroneal subluxation, US was 100% sensitive compared to 66% for MRI, and both were 100% specific. In conclusion, US was found to be more effective in diagnosing peroneal subluxation and MRI was slightly more accurate in the diagnosis of peroneal tendon tears.

Public Views About Cosmetic Procedures in Riyadh, Saudi Arabia.

Background In the past decade, there has been a clear, massive increase in the number of patients undergoing cosmetic procedures in Riyadh, Saudi Arabia. This study aims to compare the demographic characteristics of patients in Riyadh undergoing cosmetic procedures. Methodology This is an analytical, observational, and cross-sectional study used to seek the public views about cosmetic procedures in Riyadh, Saudi Arabia using the snowball sampling technique. A self-administered questionnaire was distributed electronically among the target population via social media. The questionnaire was pre-tested in a pilot study of 10 individuals to ensure comprehension and ease of administration and to determine the time needed to complete it. The final adjustments were made after the pilot study. Statistical analysis was performed using SPSS Statistics version 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Results In the current study, we were able to collect the data from 600 participants, of whom females represented 527 (87.8%) of the sample. Satisfaction with their current physical appearance (370, 61.7%), financial factors (73, 12.2%), and fear of having the procedure (59, 9.8%) were the main reasons for refusing to undergo cosmetic procedures, while pleasing themselves (432, 72.1%), influence from others who have undergone cosmetic procedures (188, 31.4%), and personal dislike of one's appearance (184, 30.7%) were the main reasons for conducting cosmetic procedures. Firstly, gender showed a significant relationship with having undergone a cosmetic procedure (p-value = 0.018), with 9 (12.3%) of males and 131 (24.9%) of females reporting having undergone such a procedure. Age also played a role, with the 29-39 age group having the highest number of individuals (31.9%) who had undergone a cosmetic procedure. Conclusion This study provides valuable insights into the demographic characteristics, attitudes, and perceptions surrounding cosmetic procedures in Riyadh. The findings highlight the influence of cultural expectations, self-acceptance, social factors, and media on individuals' motivations and decision-making processes. The increasing acceptability of cosmetic interventions and the rising demand for aesthetic modifications in the locality suggest a shifting societal landscape.

The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35.

The obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy. IMPORTANCE Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.

Streptococcus pneumoniae Impairs Maturation of Human Dendritic Cells and Consequent Activation of CD4+ T Cells via Pneumolysin.

Influenza A Virus (IAV), Staphylococcus aureus (staphylococci), and Streptococcus pneumoniae (pneumococci) are leading viral and bacterial causes of pneumonia. Dendritic cells (DCs) are present in the lower respiratory tract. They are characterized by low expression of co-stimulatory molecules, including CD80 and CD86 and high capacity of antigen uptake. Subsequently, DCs upregulate co-stimulatory signals and cytokine secretion to effectively induce T-cell priming. Here, we investigated these processes in response to bacterial and viral single as well as coinfections using human monocyte-derived (mo)DCs. Irrespective of single or coinfections, moDCs matured in response to IAV and/or staphylococcal infections, secreted a wide range of cytokines, and activated CD4+, CD8+ as well as double-negative T cells. In contrast, pneumococcal single and coinfections impaired moDC maturation, which was characterized by low expression of CD80 and CD86, downregulated expression of CD40, and a mild cytokine release resulting in abrogated CD4+ T-cell activation. These actions were attributed to the cholesterol-dependent cytotoxin pneumolysin (Ply). Infections with a ply-deficient mutant resulted in restored moDC maturation and exclusive CD4+ T-cell activation. These findings show that Ply has important immunomodulatory functions, supporting further investigations in specific modalities of Ply-DC interplay.

Hydrogen Peroxide Is Crucial for NLRP3 Inflammasome-Mediated IL-1ß Production and Cell Death in Pneumococcal Infections of Bronchial Epithelial Cells.

Epithelial cells play a crucial role in detection of the pathogens as well as in initiation of the host immune response. Streptococcus pneumoniae (pneumococcus) is a typical colonizer of the human nasopharynx, which can disseminate to the lower respiratory tract and subsequently cause severe invasive diseases such as pneumonia, sepsis, and meningitis. Hydrogen peroxide (H2O2) is produced by pneumococci as a product of the pyruvate oxidase SpxB. However, its role as a virulence determinant in pneumococcal infections of the lower respiratory tract is not well understood. In this study, we investigated the role of pneumococcal-derived H2O2 in initiating epithelial cell death by analyzing the interplay between 2 key cell death pathways, namely, apoptosis and pyroptosis. We demonstrate that H2O2 primes as well as activates the NLRP3 inflammasome and thereby mediates IL-1ß production and release. Furthermore, we show that pneumococcal H2O2 causes cell death via the activation of both apoptotic as well as pyroptotic pathways which are mediated by the activation of caspase-3/7 and caspase-1, respectively. However, H2O2-mediated IL-1ß release itself occurs mainly via apoptosis.

Bronchial Epithelial Cells Accumulate Citrate Intracellularly in Response to Pneumococcal Hydrogen Peroxide.

Community-acquired pneumonia is an infection of the lower respiratory tract caused by various viral and bacterial pathogens, including influenza A virus (IAV), Streptococcus pneumoniae, and Staphylococcus aureus. To understand the disease pathology, it is important to delineate host metabolic responses to an infection. In this study, metabolome profiling of mono- and coinfected human bronchial epithelial cells was performed. We show that IAV and S. aureus silently survive within the cells with almost negligible effects on the host metabolome. In contrast, S. pneumoniae significantly altered various host pathways such as glycolysis, tricarboxylic acid cycle, and amino acid metabolism. Intracellular citrate accumulation was the most prominent signature of pneumococcal infections and was directly attributed to the action of pneumococci-derived hydrogen peroxide. No coinfection specific metabolome signatures were observed.

Ultrasound shear wave elastography of the anterior talofibular and calcaneofibular ligaments in healthy subjects.

AIM OF STUDY: Most sprained lateral ankle ligaments heal uneventfully, but in some cases the ligament's elastic function is not restored, leading to chronic ankle instability. Ultrasound shear wave elastography can be used to quantify the elasticity of musculoskeletal soft tissues; it may serve as a test of ankle ligament function during healing to potentially help differentiate normal from ineffective healing. The purpose of this study was to determine baseline shear wave velocity values for the lateral ankle ligaments in healthy male subjects, and to assess inter-observer reliability. MATERIAL AND METHODS: Forty-six ankles in 23 healthy male subjects aged 20-40 years underwent shear wave elastography of the lateral ankle ligaments performed by two musculoskeletal radiologists. Each ligament was evaluated three times with the ankle relaxed by both examiners, and under stress by a single examiner. Mean shear wave velocity values were compared for each ligament by each examiner. Inter-observer agreement was evaluated. RESULTS: The mean shear wave velocity at rest for the anterior talofibular ligament was 2.09 ± 0.3 (range 1.41-3.17); and for the calcaneofibular ligament 1.99 ± 0.36 (range 1.29-2.88). Good inter-observer agreement was found for the anterior talofibular ligament and calcaneofibular ligament shear wave velocity measurements with the ankle in resting position. There was a significant difference in mean shear wave velocities between rest and stressed conditions for both anterior talofibular ligament (2.09 m/s vs 3.21 m/s; p <0.001) and calcaneofibular ligament (1.99 m/s vs 3.42 m/s; p <0.0001). CONCLUSION: Shear wave elastography shows promise as a reproducible method to quantify ankle ligament stiffness. This study reveals that shear waves velocities of the normal lateral ankle ligaments increased with applied stress compared to the resting state.

Enhanced Stability and Controlled Delivery of MOF-Encapsulated Vaccines and Their Immunogenic Response In Vivo.

Vaccines have an innate tendency to lose their structural conformation upon environmental and chemical stressors. A loss in conformation reduces the therapeutic ability to prevent the spread of a pathogen. Herein, we report an in-depth study of zeolitic imidazolate framework-8 and its ability to provide protection for a model viral vector against denaturing conditions. The immunoassay and spectroscopy analysis together demonstrate enhanced thermal and chemical stability to the conformational structure of the encapsulated viral nanoparticle. The long-term biological activity of this virus-ZIF composite was investigated in animal models to further elucidate the integrity of the encapsulated virus, the biosafety, and immunogenicity of the overall composite. Additionally, histological analysis found no observable tissue damage in the skin or vital organs in mice, following multiple subcutaneous administrations. This study shows that ZIF-based protein composites are strong candidates for improved preservation of proteinaceous drugs, are biocompatible, and are capable of controlling the release and adsorption of drugs in vivo.

Imaging of Postoperative Infection at the Knee Joint.

Postoperative infections of the knee are uncommon but may occur with joint arthroplasties, fracture fixation, or after arthroscopic procedures. The ultimate diagnosis is made by joint aspiration or tissue sampling. Joint aspiration and tissue sampling can be performed under imaging guidance or intraoperatively. Imaging is an important adjunct to clinical and laboratory findings and should start with radiographs. Cross-sectional imaging including magnetic resonance (MR) imaging, computed tomography (CT), nuclear studies, and ultrasound (US) are frequently used if the diagnosis is in doubt and to evaluate the extent of disease. We discuss the current algorithm in the diagnosis of various postoperative infections of the knee joint. The article addresses the utility of radiography, MR imaging, CT, US, and the most commonly used nuclear studies in the diagnosis of various postoperative knee infections and the imaging appearances of these infections on each of these diagnostic modalities.

Regulating the Uptake of Viral Nanoparticles in Macrophage and Cancer Cells via a pH Switch.

Controlling the uptake of nanomaterials into phagocytes is a challenging problem. We describe an approach to inhibit the cellular uptake by macrophages and HeLa cells of nanoparticles derived from bacteriophage Qß by conjugating negatively charged terminal hexanoic acid moieties onto its surface. Additionally, we show hydrazone linkers can be installed between the surface of Qß and the terminal hexanoic acid moieties, resulting in a pH-responsive conjugate that, in acidic conditions, can release the terminal hexanoic acid moiety and allow for the uptake of the Qß nanoparticle. The installation of the "pH switch" did not change the structure-function properties of the hexanoic acid moiety and the uptake of the Qß conjugates by macrophages.

Angiosarcoma treated successfully with anti-PD-1 therapy - a case report.

BACKGROUND: Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%. These tumors can be found in all age groups, but are more common in older patients; with the cutaneous form most common in older white men. Combined modality therapy including surgery and radiation appears to have a better outcome than each modality alone. When metastatic, agents such as liposomal doxorubicin, paclitaxel and ifosfamide have activity but it is short-lived and not curative. Immunotherapy targeting either the PD-1 receptor or PD-L1 ligand has recently been shown to have activity in multiple cancers including melanoma, renal, and non-small lung cancer. Although these agents have been used in sarcoma therapy, their ability to treat angiosarcoma has not been reported. CASE PRESENTATION: Here we describe the case of a 63-year-old man who presented initially with angiosarcoma of the nose and received surgery for the primary. Over 4 years he had recurrent disease in the face and liver and was treated with nab-paclitaxel, surgery, and radioembolization, but continued to have progressive disease. His tumor was found to express PD-L1 and he received off-label pembrolizumab 2 mg/kg every 21 days for 13 cycles with marked shrinkage of his liver disease and no new facial lesions. Secondary to this therapy he developed hepatitis and has been treated with decreasing doses of prednisone. During the 8 months off therapy he has developed no new or progressive lesions. CONCLUSIONS: Although occasional responses to immunotherapy have been reported for sarcomas, this case report demonstrates that angiosarcoma can express PD-L1 and have a sustained response to PD-1 directed therapy.

Shear-Wave Elastography: Basic Physics and Musculoskeletal Applications.

In the past 2 decades, sonoelastography has been progressively used as a tool to help evaluate soft-tissue elasticity and add to information obtained with conventional gray-scale and Doppler ultrasonographic techniques. Recently introduced on clinical scanners, shear-wave elastography (SWE) is considered to be more objective, quantitative, and reproducible than compression sonoelastography with increasing applications to the musculoskeletal system. SWE uses an acoustic radiation force pulse sequence to generate shear waves, which propagate perpendicular to the ultrasound beam, causing transient displacements. The distribution of shear-wave velocities at each pixel is directly related to the shear modulus, an absolute measure of the tissue's elastic properties. Shear-wave images are automatically coregistered with standard B-mode images to provide quantitative color elastograms with anatomic specificity. Shear waves propagate faster through stiffer contracted tissue, as well as along the long axis of tendon and muscle. SWE has a promising role in determining the severity of disease and treatment follow-up of various musculoskeletal tissues including tendons, muscles, nerves, and ligaments. This article describes the basic ultrasound physics of SWE and its applications in the evaluation of various traumatic and pathologic conditions of the musculoskeletal system. ©RSNA, 2017.

Pediatric nevoid basal cell carcinoma syndrome.

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare, autosomal-dominant, cancer-predisposing, multisystem disorder. The clinical manifestations of NBCCS include multiple basal cell carcinomas (BCCs), odontogenic keratocysts, palmar or plantar pits, and calcification of the falx cerebri. We present a case of an 11-year-old boy with Fitzpatrick skin type V who presented with multiple facial lesions and a history of maxillary keratocysts. Skin biopsy was consistent with pigmented BCC of the right nasolabial fold. Further clinical workup revealed multiple pigmented BCCs, palmoplantar pits, and calcification of the tentorium. Genetic testing revealed a heterozygous mutation in the patched 1 gene, PTCH1, consistent with NBCCS. This case highlights the treatment considerations in pediatric cases of NBCCS in Fitzpatrick skin type V patients.

Ultrasound Evaluation of Morton Neuroma Before and After Laser Therapy.

OBJECTIVE: The objective of our study was to retrospectively assess for differences in imaging appearances of Morton neuromas before and after laser therapy using diagnostic ultrasound (US). MATERIALS AND METHODS: A retrospective review was performed to identify patients who underwent US imaging to evaluate for Morton neuroma during the study period (June 1, 2013-July 1, 2014); of the 42 patients identified, 21 underwent US evaluations before and after laser therapy. US reports and images were reviewed and correlated with clinical history. The final study group consisted of 21 patients who had a total of 31 Morton neuromas evaluated using US after treatment. A retrospective review was then performed to characterize the appearances of these lesions before and after therapy followed by an analysis of variables. RESULTS: Retrospective US review of 31 pretreatment Morton neuromas showed fusiform, heterogeneously hypoechoic masses with well-defined borders in most cases and that pain was reported when transducer pressure was applied in 97% (30/31) of cases. After treatment, lesions showed ill-defined borders (23/31), and pain with application of transducer pressure was either significantly decreased or absent (29/31); these findings were concordant with the clinical findings. Both of these characteristics were statistically significant (p < 0.0001). In addition, more Morton neuromas occurred in the second intermetatarsal space than in the third intermetatarsal space (p < 0.0001). CONCLUSION: US may be used to identify posttreatment changes after laser therapy of Morton neuromas. Posttreatment changes include ill-defined borders and less pain or the absence of pain with the application of transducer pressure. These criteria may be applied in future clinical studies evaluating the efficacy of laser therapy for Morton neuroma.

Normal Magnetic Resonance Imaging Anatomy of the Capsular Ligamentous Supporting Structures of the Knee.

Recognition of the normal magnetic resonance (MR) imaging appearances of the capsular ligaments of the knee is of great importance. These ligaments contribute to stability of the knee joint and are frequently injured. In this article, we describe the normal MR imaging anatomy of the capsular ligaments of the knee including the lateral and medial collateral ligamentous complexes, the extensor mechanism, and the supporting ligamentous structures of the proximal tibiofibular joint. Normal MR imaging findings and important anatomic variants of the neurovascular structures of the knee are also described.

The Collateral Ligaments and Posterolateral Corner: What Radiologists Should Know.

Ligamentous and tendinous structures of the posterolateral corner of the knee provide important static and dynamic stability to the knee joint and act in conjunction with anterior and posterior cruciate ligaments. Injuries of these structures are not uncommon. Failure to treat posterolateral corner injuries leads to posterolateral instability of the knee and subsequently poor outcome of cruciate ligament reconstructions. Currently, MRI is the diagnostic modality of choice in the evaluation of posterolateral corner injuries of the knee. We review normal MR imaging anatomy of the complex anatomical structures of the posterolateral corner of the knee, their biomechanical function, injuries, and current treatment options.

High-Resolution US of Rheumatologic Diseases.

For the past 15 years, high-resolution ultrasonography (US) is being routinely and increasingly used for initial evaluation and treatment follow-up of rheumatologic diseases. This imaging technique is performed by using high-frequency linear transducers and has proved to be a powerful diagnostic tool in evaluation of articular erosions, simple and complex joint and bursal effusions, tendon sheath effusions, and synovitis, with results comparable to those of magnetic resonance imaging, excluding detection of bone marrow edema. Crystal deposition diseases including gouty arthropathy and calcium pyrophosphate deposition disease (CPPD) have characteristic appearances at US, enabling differentiation between these two diseases and from inflammatory arthropathies. Enthesopathy, which frequently accompanies psoriatic and reactive arthritis, also has a characteristic appearance at high-resolution US, distinguishing these two entities from other inflammatory and metabolic arthropathies. The presence of Doppler signal in examined joints, bursae, and tendon sheaths indicates active synovitis. Microbubble echo contrast agents augment detection of tissue vascularity and may act in the future as a drug delivery vehicle. Frequently, joint, tendon sheath, and bursal fluid aspirations and therapeutic injections are performed under US guidance. The authors describe the high-resolution US technique including gray-scale, color or power Doppler, and contrast agent-enhanced US that is used in evaluation of rheumatologic diseases of the wrist and hand and the ankle and foot in their routine clinical practice. This article demonstrates imaging findings of normal joints, rheumatoid arthritis, gouty arthritis, CPPD, psoriatic and reactive arthritis, and osteoarthritis.