A giant popliteal lipoblastoma in a 23-month-old girl: a case report

Lipoblastomas are rare benign tumors that arise from embryonic white fat and almost always occur in babies and children. Here, we report a case of a giant popliteal lipoblastoma in a 23-month-old Japanese girl...

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Clinical predictors of chronic rhinosinusitis: do the Canadian clinical practice guidelines for acute and chronic rhinosinusitis predict CT-confirmation of disease?

The diagnosis of chronic rhinosinusitis (CRS) based on clinical presentation alone remains challenging. To improve the accuracy of clinical diagnosis, the Canadian Rhinosinusitis Guidelines recommend the use o...

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A two-center, assessor-blinded, prospective trial evaluating the efficacy of a novel hypertonic draining cream for cellulite reduction: A Clinical and instrumental (Antera 3D CS) assessment

Summary

Introduction

Gynoid lipodystrophy, also known as cellulite, is a very common skin alteration representing mainly a cosmetic problem rather than a real disease. An effective treatment of cellulite has not been well established. The initial phase of cellulite is characterized by subdermal tissue edema with interstitial fluids retention. A new hypertonic topical product with draining action (HTC) containing NaCl 13%, escine, caffeine, and beta-sitosterol has been recently developed. A 28-day double-blind placebo-controlled study has shown that this cream is able to reduce thigh circumference and the thickness of adipose tissue. No data so far are available regarding an objective evaluation of skin appearance for a longer application period.

Study aim

To evaluate the clinical efficacy of 2-month HCT treatment with clinical and instrumental assessments.

Subjects and methods

In a prospective, 2-center, assessor-blinded trial 20 women (mean age 34 years) with cellulite of Grade I-III in severity were enrolled after their informed consent. HTC was applied once daily for 60 days. Primary outcomes of the trial were the evolution of thigh circumference measurements (assessed at baseline, after 1 and 2 months) and the computer-analysis of skin profilometry (ie, skin volumes) of a prespecified target area evaluated by means of Antera 3D CS digitalized images (assessed at baseline and at the end of the trial). Secondary outcome was the orange peel severity score (from 0 to 5) before and after pitch test.

Results

All subjects concluded the study period. Thigh circumference was reduced by −0.88 (right)/−1.2 cm (left) and by −1.8(right)/−2.1 (left) cm, after 30 and 60 days of treatment, respectively (P = .001, Wilcoxon test vs baseline). Antera 3D profilometry of the target zone showed a significant reduction in skin depression expressed in mm³ of −56% (from 59.7 to 26.73 mm³) after HTC application. Orange peel (no pitch test) mean (SD) score was 2.3 (1) at baseline, 2.0 (1) and 1.8 (0.8) after 1 and 2 months (P = .0031), respectively. After-pitch orange peel score was significantly reduced after treatment (from 3.3 to 2.2).

Conclusion

Once daily application of HTC for 2 months has confirmed its efficacy in the improvement of objective and subjective assessments of cellulite parameters.(Trial Number registration: ISRCTN15111614).

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Immediate effect and safety of HIFU single treatment for male subcutaneous fat reduction

Summary

Background

The increasing search for procedures for fat reduction is related to dissatisfaction with body shape. High-intensity focused ultrasound (HIFU) has been proven effective in body sculpting when used noninvasively to reduce subcutaneous fat and improve body contour.

Aims

This study aimed to evaluate the immediate effect and safety of HIFU single treatment for male localized fat and body remodeling.

Patients/Methods

Twenty-four male subjects (18 to 59 years old) with BMI ≤ 30 kg/cm² and at least 2 cm of abdominal fat received a single HIFU treatment session. Individuals were subjected to abdominal measurements before and after procedure. In addition, biochemical analyses of blood samples were performed to assess possible inflammatory effects or oxidative stress induction by the treatment.

Results

High-intensity focused ultrasound was found to be an effective treatment in reducing localized adiposities in the abdominal region. A significant decrease (0.6%) was observed in infraumbilical circumference of subjects submitted to HIFU single treatment when compared with control subjects. The laboratory parameters did not present any appreciable changes.

Conclusion

This study further strengthens the current view that HIFU is an effective and safe tool for localized fat reduction.

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Subcutaneous granuloma annulare involving the scalp

Abstract

Subcutaneous granuloma annulare (SGA) is an uncommon subtype of granuloma annulare. There are few reports of this entity solely affecting the scalp. We report a case of biopsy-proven SGA in a 21-month-old boy with six asymptomatic, rock-hard scalp nodules.

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CME Accreditation Page

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Psychosocial Impact of Vascular Anomalies on Children and Their Families

Vascular anomalies are divided into tumors and malformations based on their clinical and cytologic attributes. Vascular malformations are further subcategorized as low-flow lymphatic, venous, capillary, or mixed lesions and as high-flow arteriovenous malformations. Treatment is reserved for vascular anomalies that are symptomatic or cosmetically disfiguring, and surgical and nonsurgical treatment options are widely varied with variable outcomes.

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Forthcoming Issues

Otosclerosis and Stapes Surgery

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Congenital Vascular Lesions of the Head and Neck

The number of physicians interested in the treatment of vascular anomalies has grown exponentially over the last several decades from a mere handful in the mid 1980s to several thousand today. Every year, hundreds of peer-reviewed articles are published in this field. Some of the most interesting articles have shed light on the underlying genetic and molecular bases of some of these conditions. This has led to the development of at least one group of medical therapies for some vascular lesions.

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Contents

Sujana S. Chandrasekhar

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Orthognathic Considerations of Vascular Malformations

Vascular malformations affect the craniofacial skeleton in many ways, depending on the type of the lesion and its location. The lesions may exert a mass effect and cause thinning or thickening of the bone or cause expansion from direct bony infiltration. Orthognathic surgery can be used to correct any malocclusion or open bite deformities after the soft tissues are addressed.

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Contributors

SUJANA S. CHANDRASEKHAR, MD

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Multidisciplinary Approach to Vascular Anomalies Maximizes Outcomes

The birth of a child is a glorious and simultaneously nerve-wracking event in every family. If this is the 1 in 22 children born with a vascular lesion of the head and neck (which is visible in every picture and to every visitor), the parents' concerns multiply. Will my baby bleed? Will my baby stay deformed by this lesion? Is this the tip of the iceberg of other problems? Will my baby be forced to enter chronic medical/surgical care? These are some of the questions that race through the parents' brains, even as they marvel at the wondrousness of new life.

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Copyright

Elsevier

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Classification and Pathology of Congenital and Perinatal Vascular Anomalies of the Head and Neck

Accurate histopathologic description in correlation with clinical and radiological evaluation is required for treatment of vascular anomalies, both neoplastic and malformative. It is important to examine current clinical, histologic, and immunophenotypical features that distinguish the major types of congenital and perinatal vascular anomalies affecting the head and neck. General discussions of pathogenesis and molecular diagnosis must also be taken into account. This article provides an overview of the features that distinguish the major types of congenital and perinatal vascular anomalies affecting the head and neck, and summarizes the diagnostic histopathologic criteria and nomenclature currently applied to these lesions.

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Congenital Vascular Lesions of the Head and Neck

OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA

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Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) describes the presenting manifestations of a disorder that is characterized by pathologic blood vessels. HHT is inherited as an autosomal dominant trait with variable penetrance. The abnormal vascular structures (dysplasias) can affect all the organs in the human body. The link between a physical stimulus and new lesion development has been established for mucosal trauma owing to nasal airflow turbulence, for ultraviolet exposure to the fingers, and for mechanical trauma to the dominant hand. The pressing question then is whether HHT treatment constitutes a stimulus that is sufficient to trigger new lesion development.

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Outcome Measurement for Vascular Malformations of the Head and Neck

Vascular malformations are congenital anomalies of the vascular and/or lymphatic system that affect the head and neck region. The most common treatment options are sclerotherapy, laser therapy, surgery, and embolization. Because vascular malformations are variable in type, size, extent, and location, it is a challenge to select methods for evaluation of treatment outcome. Without standardized outcome reporting, it is difficult to compare and combine scientific evidence to support therapeutic decision making. Standardized collection and reporting of outcome data are the first steps toward a fair comparison between treatments. This article describes outcome measurements for vascular malformations and initiatives to improve outcome reporting.

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The Surgical Management of Infantile Hemangiomas

The surgical management of facial infantile hemangiomas presents a unique challenge. The aim of the surgeon should be to remove the hemangioma and to restore normal facial features. Each of the facial zones has its own special features and challenges. The surgeon should remember that the child started out with normal anatomy and that as the hemangioma proliferated, it displaced and thinned these normal structures and in many cases, expanded adjacent tissue. Hemangiomas do not as a rule, invade adjacent tissues as they proliferate. These facts will help in planning the various surgical approaches.

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The Management of Vascular Malformations of the Airway

Vascular malformations may affect nearly all aspects of the upper airway. Each type of malformation has a characteristic pattern of disease. These lesions may be focal or diffuse, and require directed management strategies. Physicians treating these entities should have a high level of suspicion to consider airway evaluation even in the absence of overt symptoms. However, cutaneous head and neck venous malformations or other lesions affecting the lips, oral cavity, or tongue can herald the presence of coexisting airway lesions. A multidisciplinary approach is critical in achieving comprehensive treatment.

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Infantile Hemangiomas in the Head and Neck Region

Infantile hemangiomas (IHs) are benign vascular tumors of infancy most common in the region of the head and neck. Infantile hemangiomas are common; but they are extremely heterogeneous and cause a range of complications depending on their morphology, size, or location. Medical interventions for high-risk patients include topical and systemic therapies, including oral propranolol, which has revolutionized the management of IHs over the past recent years. In the following article, the authors aim to provide a review of the natural history, pathology, complications, syndromes, and medical management of infantile hemangioma.

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Multidisciplinary Approach to the Management of Lymphatic Malformations of the Head and Neck

Lymphatic malformations (LMs) occur in 2.8 to 5 per 100,000 live births. Most involve the head and neck and they are equally common in men and women. They are developmental anomalies of unknown cause, although recent evidence suggests that an upregulation of the mammalian target of rapamycin (mTOR) pathway may be a causal factor leading to the overproduction of abnormal lymph vessels. These vessels are likely dilated lymphatic sacs sequestered from the lymphatic and venous systems. This overproduction results in the accumulation of lymph in dilated cystic spaces, which in turn results in the clinical features of an LM.

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The Role of Surgery in the Management of Infantile Hemangiomas

Surgery for the management of infantile hemangiomas has become commonplace. Surgical technique articles are plentiful; however, little has been written about the timing of surgery. Knowledge of the biology of the tumors, data from developmental psychology, and the utility of facial reconstruction provide guidelines for timing of surgical intervention.

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Congenital Vascular Tumors

Vascular tumors are benign neoplasms, which result from proliferating endothelial cells. These lesions present during infancy or childhood, may affect any location, and exhibit postnatal growth. Local complications include bleeding, tissue destruction, and pain whereas systemic sequelae include thrombocytopenia, congestive heart failure, and death. Vascular tumors should be differentiated from vascular malformations, which present at birth, have a quiescent endothelium, and grow in proportion to the child. Together, vascular tumors and malformations comprise the field of vascular anomalies.

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Etiology and Genetics of Congenital Vascular Lesions

The detection of somatic, activating genetic mutations to underlie development of vascular tumors and malformations led to a better understanding of their pathophysiology. Proteins encoded by the detected mutated genes activate the two major signaling pathways, also involved in cancer: the RAS/MAPK/ERK pathway and/or the PI3K/AKT/mTOR pathway. This gives a strong basis for studies to repurpose cancer therapeutics to patients with vascular tumors and malformations.

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Distribution and molecular characterization of Acinetobacter baumannii international clone II lineage in Japan [PublishAheadOfPrint]

Multidrug-resistant (MDR) Acinetobacter spp. have been globally disseminated in association with successful clonal lineage Acinetobacter baumannii international clone II (IC II). Because the prevalence of MDR Acinetobacter spp. in Japan remains very low, we characterized all Acinetobacter spp. (n=866) from 76 hospitals between October 2012 and March 2013 to describe the entire molecular epidemiology of Acinetobacter spp. The most prevalent species was A. baumannii (n = 645; 74.5%), with A. baumannii IC II (n = 245) accounting for 28.3% of total. Meropenem-resistant isolates accounted for 2.0% (n = 17) and carried ISAba1-bla_OXA-23-like (n = 10), bla_IMP (n = 4), or ISAba1-bla_OXA-51-like (n = 3). Multilocus sequence typing of 110 representative A. baumannii revealed the considerable prevalence of domestic STs. A. baumannii IC II isolates were divided into domestic ST469 (n = 18) and globally disseminated ST208 (n = 14) and ST219 (n = 4). ST469 isolates were susceptible to more antimicrobial agents, while ST208 and ST219 overproduced intrinsic AmpC β-lactamase. A. baumannii IC II and some A. baumannii non-IC II STs (e.g. ST149 and ST246) were associated with fluoroquinolone resistance. This study revealed carbapenem-susceptible A. baumannii IC II was moderately disseminated in Japan. The low prevalence of acquired carbapenemase genes and presence of domestic STs could contribute to the low prevalence of MDR A. baumannii. A similar epidemiology might have appeared before the global dissemination of MDR epidemic lineages. In addition, fluoroquinolone resistance associated with A. baumannii IC II may provide insight into the significance of A. baumannii epidemic clones.

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Extreme drug tolerance of Mycobacterium tuberculosis in caseum [PublishAheadOfPrint]

Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence and drug tolerance are among the factors driving the long therapy duration. Assays to measure in situ drug susceptibility of Mycobacterium tuberculosis (Mtb) bacteria in pulmonary lesions are needed if we are to discover new fast acting regimens and address the global TB threat. Here we take a first step towards this goal and describe an ex vivo assay developed to measure the cidal activity of anti-TB drugs against Mtb bacilli present in cavity caseum, obtained from rabbits with active TB. We show that caseum Mtb bacilli are largely non-replicating while maintaining viability over the course of the assay, and exhibit extreme tolerance to many 1^st and 2^nd line TB drugs. Among the drugs tested, only the rifamycins fully sterilized caseum. A similar trend of phenotypic drug resistance was observed in the hypoxia and starvation induced non-replicating models, but with notable qualitative and quantitative differences: (i) caseum Mtb exhibits higher drug tolerance than non-replicating Mtb in the Wayne and Loebel models, and (ii) pyrazinamide is cidal in caseum but has no detectable activity in these classic non-replicating assays. Thus, ex vivo caseum constitutes a unique tool to evaluate drug potency against slow- or non-replicating bacilli in their native caseous environment. Intra-caseum cidal concentrations can now be related to concentrations achieved in the necrotic foci of granulomas and cavities, to establish correlations between clinical outcome and lesion-centric PK-PD parameters.

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In vitro, in silico and in vivo analysis of novel aromatic amidines against Trypanosoma cruzi [PublishAheadOfPrint]

Five bis-arylimidamides were assayed as anti-T.cruzi agents using in vitro, in silico and in vivo approaches. All were considered no PAINS, have favorable pharmacokinetic landscape, were active against trypomastigotes and intracellular forms but combined with benznidazole gave no interaction. The most selective (28SMB032) moved to in vivo led to 40% parasitemia reduction (0.1mg/kg/5 days by ip) but without mortality protection. In silico target fishing suggested DNA as main target, but ultrastructural data did not match.

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A prospective trial on the use of trough concentration versus area under the curve (AUC) to determine therapeutic vancomycin dosing [PublishAheadOfPrint]

We hypothesized that dosing vancomycin to achieve trough concentrations >15 mg/L overdoses many adults compared to AUC-guided dosing. We conducted a 3-year, prospective study of vancomycin dosing, plasma concentrations, and outcomes. In year 1, non-study clinicians targeted trough concentrations of 10-20 mg/L (infection dependent) and controlled dosing. In years 2 and 3, the study team controlled vancomycin dosing with the BestDose Bayesian software to achieve a daily, steady-state AUC:MIC≥400, with maximum AUC 800 mg*h/L, regardless of trough concentration. For Bayesian estimation of AUCs, we used trough samples in years 1-2 and optimally timed samples in year 3. We enrolled 252 adults ≥18 years old with ≥1 available vancomycin concentration. Only 19% of all trough concentrations were therapeutic vs. 70% of AUCs (P<0.0001). After enrollment, median trough concentrations by year were 14.4, 9.7, and 10.9 mg/L (P=0.005), with 36%, 7%, and 6% over 15 mg/L (P<0.0001). Bayesian AUC-guided dosing in years 2 and 3 was associated with fewer additional blood samples per subject (3.6, 2.0, 2.4, P=0.003), shorter therapy (8.2, 5.4, 4.7 days, P=0.03), and reduced nephrotoxicity (8%, 0% and 2%, P=0.01). Among nephrotoxic patients, the median inpatient stay was 20 vs. 6 days (P=0.002). There was no difference in efficacy by year, with 42% having microbiologically proven infections. Compared to trough concentration targets, AUC-guided, Bayesian-assisted vancomycin dosing was associated with decreased nephrotoxicity, reduced per-patient blood sampling, and shorter length of therapy, without compromising efficacy. These benefits have the potential for substantial cost savings.

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Mutations in Genes Encoding Penicillin-Binding Proteins and Efflux Pumps Play a Role in {beta}-Lactam Resistance in Helicobacter cinaedi [PublishAheadOfPrint]

β-Lactams are often used to treat Helicobacter cinaedi infections; however, the mechanism underlying β-lactam resistance is unknown. In this study, we investigated β-lactam resistance in a H. cinaedi strain, MRY12-0051 (MIC of AMX and CRO: 32 and 128 μg/ml; obtained from human feces). Based on a comparative whole genome analysis of MRY12-0051 and the CRO-susceptible H. cinaedi strain MRY08-1234 (MIC of AMX and CRO: 1 and 4 μg/ml; obtained from human blood), we identified five mutations in genes encoding penicillin-binding proteins (PBPs), including two in pbpA, one in pbp2, and two in ftsI. Transformation and penicillin-binding assays indicated that CRO resistance was mainly associated with mutations in pbpA; mutations in ftsI also led to increased resistance to AMX. Knocking out cmeB and cmeD, which encode resistance-nodulation-division-type efflux pump components, in H. cinaedi type strain CCUG18818 (AMX MIC: 4--8 μg/ml) resulted in an 8- and 64-fold decrease, respectively, in the AMX MIC. Hence, MICs of AMX in H. cinaedi become similar to those of H. pylori isolates in the absence of cmeD. In conclusion, the difference in susceptibility to β-lactams between H. pylori and H. cinaedi is explained by differences in efflux pump components. Mutations in pbpA are the primary determinant of high resistance to β-lactams in H. cinaedi.

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Role of smeU1VWU2X Operon in the Alleviation of Oxidative Stresses and the Occurrence of Sulfamethoxazole/trimethoprim-resistant Mutants in Stenotrophomonas maltophilia [PublishAheadOfPrint]

Overexpression of resistance-nodulation-division (RND)-type efflux pumps is an important mechanism for bacteria to combat antimicrobials. RND efflux pumps are also critical for bacterial physiology such as oxidative stress tolerance. Stenotrophomonas maltophilia, a multi-drug resistant opportunistic pathogen, harbors eight RND-type efflux pump operons. Of them, smeU1VWU2X operon is unique for its possession of two additional genes, smeU1 and smeU2, which encode proteins of short-chain dehydrogenase/reductase (SDR) family. Overexpression of the SmeVWX pump is known to contribute to the acquired resistance to chloramphenicol, quinolone, and tetracycline; however, SmeU1 and SmeU2 are little involved in this phenotype. In this article, we further linked smeU1VWU2X operon to oxidative stress alleviation and sulfamethoxazole/trimethoprim (SXT)-resistant mutants occurrence. SmeU1VWU2X operon was inducibly expressed upon the challenge of menadione (MD), plumbagin (PL), and hydrogen peroxide (H₂O₂), verified by chromosomal smeU1VWU2X-xylE transcriptional fusion construct and quantitative real-time PCR (qRT-PCR). The MD-mediated smeU1VWU2X upexpression was totally dependent on SoxR, partially relied on SmeRv, but was less relevant to OxyR. SmeRv, but not SoxR and OxyR, played a regulatory role in the H₂O₂-mediated smeU1VWU2X upexpression. The significance of smeU1VWU2X upexpression was investigated in respect of oxidative stress alleviation and SXT-resistant mutants occurrence. Overexpression of smeU1VWU2X operon contributed to the alleviation of MD-mediated oxidative stress. Of the encoded proteins, SmeVWX pump and SmeU2, rather than SmeU1, participated in the MD tolerance. Furthermore, we also demonstrated that MD-mediated expression of smeU1VWU2X operon decreased SXT resistance frequency when S. maltophilia was grown in the reactive oxygen species (ROS)-rich environment.

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Polymyxin B and ZTI-01 (fosfomycin for injection) against KPC-producing Klebsiella pneumoniae: Evaluation of activity and emergence of resistance [PublishAheadOfPrint]

ZTI-01 (fosfomycin for injection) is a broad spectrum antibiotic with a novel mechanism of action and is currently under development in the USA for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multi-drug resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing K. pneumoniae and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MICPMB: 0.5mg/L, MICFOF: 32mg/L) and BRKP67 (MICPMB: 8mg/L, MICFOF: 32mg/L) at initial inoculum of 10⁷ CFU/mL were evaluated over 168h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5mg/kg loading dose as a 2h infusion followed by 1.5mg/kg q12h as a 1h infusion) and fosfomycin (6g q6h as a 1h or 3h infusion) regimens alone and in combination. Population analysis profiles (PAPs), and MIC testing were performed to assess emergence of resistance. Polymyxin B or fosfomycin monotherapy was ineffective and selected for resistance by 24h. Polymyxin B plus fosfomycin 1h infusion demonstrated sustained bactericidal activity by 4h with undetectable colony counts beyond 144h. Polymyxin B plus fosfomycin 3h infusion demonstrated bactericidal activity at 4h followed by regrowth similar to control by 144h. PAPs revealed resistant subpopulations by 120h. The combination of polymyxin B and fosfomycin 1h infusion is a promising treatment option for KPC-producing K. pneumoniae and suppresses the emergence of resistance. Further evaluation of novel dosing strategies is warranted to optimize therapy.

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Epidemiology of carbapenem-resistant Enterobacteriaceae infections: report from China CRE Network [PublishAheadOfPrint]

Carbapenem-resistant Enterobacteriaceae (CRE) infection is highly endemic in China, but estimates of infection burden are lacking. We established incidence of CRE infection from a multicenter study that covered 25 tertiary hospitals in 14 provinces. CRE cases defined as carbapenem non-susceptible C. freundii, E. coli, E. cloacae, or K. pneumoniae infections during January to December 2015 were collected and reviewed from medical records. Antimicrobial susceptibility testing and carbapenemase genes identification were performed. Among 664 CRE cases, most were caused by K. pneumoniae (73.9%), followed by E. coli (16.6%), and E. cloacae (7.1%). The overall CRE infection incidence per 10,000 discharges was 4.0, and differed significantly by region, with the highest in Jiangsu (14.97), and the lowest in Qinghai (0.34). 83.8% of patients had underlying co-morbidities; the median age was 62 years (range, 45–74) and 450 (67.8%) were male. Lower respiratory tract infections (65.4%) were most common, followed by urinary-tract infection (16.6%), intra-abdominal infection (7.7%), and bacteremia (7.7%). The overall hospital mortality rate was 33.5%. All isolates showed non-susceptibility to carbapenems and cephalosporins. Susceptibility rate of Polymyxin B was >90%. Tigecycline demonstrated higher susceptibility rate against E. coli, compared with K. pneumoniae (90.9% vs. 40.2%). Of 155 clinical isolates analyzed, 89% produced carbapenemases with a majority of isolates producing KPC (50%) and/or NDM (33.5%)-type beta-lactamases among K. pneumoniae and E. coli. Incidence of CRE infection in China was 4.0 per 10,000 discharges. The patient-based disease burden in tertiary hospitals in China is severe, suggesting an urgent need to enhance infection control.

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Chemogenomic profiling of the fungal pathogen Candida albicans [PublishAheadOfPrint]

There are currently a small number of classes of antifungal drugs, and these drugs are known to target a very limited set of cellular functions. We derived a set of approximately 900 non-essential, transactivator-defective disruption strains from the tetracycline regulated GRACE strain collection of the fungal pathogen Candida albicans. This strain set was screened against classic antifungal drugs to identify gene inactivations that conferred either enhanced sensitivity or increased resistance to the compounds. We examined two azoles, fluconazole and posaconazole; two echinochandins, caspofungin and anidulafungin; as well as the polyene amphotericin B. Overall, the chemogenomic profiles within drug classes were highly similar, but there was little overlap between classes, suggesting the different drug classes were interacting with discrete networks of genes in C. albicans. We also tested two pyridine amides, designated GPI-LY7 and GPI-C107; these drugs gave very similar profiles that were distinct from the echinochandins, azoles or polyenes, supporting the idea they target a distinct cellular function. Intriguingly, where these gene sets can be compared to genetic disruptions conferring drug sensitivity in other fungi, we find very little correspondence in genes. Thus even though the drug targets are the same in the different species, the specific genetic profiles that can lead to drug sensitivity are distinct. This implies that chemogenomic screens in one organism may be poorly predictive of the profiles found in other organisms, and that drug sensitivity and resistance profiles can differ significantly among organisms even when the apparent target of the drug is the same.

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PA5470 Counteracts Antimicrobial Effect of Azithromycin by Releasing Stalled Ribosome in Pseudomonas aeruginosa [PublishAheadOfPrint]

Pseudomonas aeruginosa causes various acute and chronic infections in human. Treatment with azithromycin (AZM) has been shown to benefit patients with chronic P. aeruginosa infections. By binding to the exit tunnel of 50S ribosome, AZM causes ribosome stalling and depletion of intracellular tRNA pool. It has been shown that AZM is able to kill stationary-phase P. aeruginosa cells and repress quorum sensing regulated virulence factors as well as swarming motility. In P. aeruginosa, PA5470 encodes a putative peptide chain release factor, whose expression is highly induced by macrolide antibiotics. However, its function remains unknown. Here we found that overexpression of PA5470 increased bacterial tolerance against AZM and alleviated the repression of swarming motility. Ribosome pull-down assays revealed that PA5470 contributes to the release of ribosome stalled by the AZM. We further demonstrate that overexpression of PA5470 counteracts AZM mediated repression on the translation of the quorum sensing regulator RhlR. Overall, our results revealed a novel role of PA5470 in bacterial response to AZM.

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Limited Effect of Later-generation Fluoroquinolones in the Treatment of Ofloxacin-resistant and Moxifloxacin-susceptible Multidrug-resistant Tuberculosis [PublishAheadOfPrint]

Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant/moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used in all patients. Overall, 171 patients (82%) had ofloxacin-susceptible/moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group) and 37 (18%) had ofloxacin-resistant/moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a previous history of MDR-TB treatment (P < 0.001) and cavitary lesions on chest radiography (P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have drug resistance to pyrazinamide (P = 0.003), streptomycin (P = 0.015), prothionamide (P < 0.001), and para-aminosalicylic acid (P < 0.001). Favorable outcomes were more frequently achieved in the ofloxacin-susceptible group than in the ofloxacin-resistant group [91% (156/171) vs. 57% (21/37), respectively; P < 0.001]. In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval = 1.55-18.53) times more likely than the ofloxacin-resistant group (P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, favorable treatment outcomes for ofloxacin-resistant MDR-TB were significantly lower than for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more aggressive therapies may be needed for ofloxacin-resistant MDR-TB.

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The Trypanocidal Effect of Novel Quinolines: In vitro And In vivo Studies [PublishAheadOfPrint]

The therapy for Human African Trypanosomiasis and Chagas Disease, caused by Trypanosoma brucei and Trypanosoma cruzi respectively, are limited providing minimal therapeutic options for the millions of individuals living in very poor communities. The effect of ten novel quinolines are evaluated herein through in silico and by phenotypic studies using in vitro and in vivo models. ADMET properties revealed that most molecules did not infringe Lipinski's rules, which is a prediction of good oral absorption. They showed good probability of CaCo₂ permeability and for human intestinal absorption, low probability of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T.cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole —Bz), except DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191 and DB2217), displaying EC₅₀ <3 μM (<4-fold than Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes showing EC₅₀ values ranging from 0.6 to 0.1 μM. All quinolines were also in vitro highly active on African trypanosomes showing EC₅₀ values ≤ 0.25 μM. The most potent and highly selective candidates for each parasite species were tested in vivo models. Results for DB2186 were promising in mice with T.cruzi and T.brucei infection, reaching 70 % reduction of the parasitemia load and it cured 2 of 4 mice, respectively. DB2217 was in vivo also active and cured all 4 mice (100% cure rate) with T.brucei infection.

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Pharmacodynamics of the Long Acting Echinocandin, CD101, in the Neutropenic Invasive Candidiasis Murine Model Using an Extended Interval Dosing Design [PublishAheadOfPrint]

Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans making it possible to design once-weekly dosing strategies. The current study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select C. albicans (n=4), C. glabrata (n=3), and C. parapsilosis (n=3) strains. The CD101 MIC ranged from 0.03 -- 1 mg/L. Plasma pharmacokinetic measurements were performed from uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 -- 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days at which time organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The PK/PD index AUC/MIC correlated well with efficacy (R² 0.74 -- 0.93). The median stasis 24-h free drug AUC/MIC targets were: C. albicans 2.92, C. glabrata 0.07, and C. parapsilosis 2.61. The PK/PD targets for 1-log₁₀ kill endpoint were 2-4--fold higher. Interestingly, the aforementioned PK/PD targets were numerically lower for all three species compared to other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

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Presence of mcr-3 variant in Aeromonas caviae, Proteus mirabilis, and Escherichia coli from one domestic duck [PublishAheadOfPrint]

The rapid rise and dissemination of MDR bacteria is a major threat to public health worldwide, and has narrowed the treatment options for infections caused by these bacteria (1)....

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Concentrations of cefuroxime in brain tissue of neurointensive care patients [PublishAheadOfPrint]

Introduction Effective concentrations of antibiotics in brain tissue are essential for antimicrobial therapy of brain infections. However, data concerning cerebral penetration properties of antibiotics for treatment or prophylaxis of central nervous system infections are rare.

Methods Six patients suffering subarachnoid hemorrhage and requiring cerebral microdialysis for neurochemical monitoring were included in this study. Free interstitial concentrations of cefuroxime after intravenous application of 1500 mg were measured by microdialysis in brain tissue as well as in plasma at steady-state (n=6) or after single-dose administration (n=1).

Resultsx At steady-state free area under the concentration-time curve from 0 to 24 hours (AUC_0-24) –values of 389.0±210.3 mg/L*h and 131.4±72.8 mg/L*h were achieved for plasma and brain, respectively, resulting in a brain tissue penetration ratio (AUC_{0-24 brain}/AUC_{0-24 freeplasma}) of 0.33±0.1. Plasma and brain tissue concentrations at individual time points correlated well (R=0.59, p=0.001).

At steady-state time over minimal inhibitory concentration (t<MIC) -values of more than 40% of dosing interval were achieved up to an MIC of 16mg/L for plasma and 4mg/L for brain tissue.

Conclusion While MIC₉₀ values could not be achieved in brain tissue for relevant bacteria, current dosing strategies of cefuroxime might be sufficient to treat pathogens with MIC values up to 4mg/L. Activity of cefuroxime in brain tissue might be overestimated when relying exclusively on plasma levels. Although currently insufficient data after single dose administration exist, lower brain-plasma ratios observed after the first dose might warrant a loading dose for treatment and perioperative prophylaxis.

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Novel treatment of Staphylococcus aureus device-related infections using fibrinolytic agents [PublishAheadOfPrint]

Objective: Staphylococcal infections involving biofilms represent a significant challenge in the treatment of patients with device-related infections. Staphylococcus aureus biofilms have been shown to be SaeRS-regulated and dependent on coagulase-catalysed conversion of fibrinogen into fibrin on surfaces coated with human plasma. Here we investigated the treatment of staphylococcal biofilm device-related infections by digesting the fibrin biofilm matrix with and without existing antimicrobials.

Methods: The fibrinolytic agents plasmin, streptokinase, nattokinase and the recombinant trypsin-like protease TrypLE™ were used to digest and treat S. aureus biofilms grown in vitro using in vivo like static biofilm assays with and without antimicrobials. Cytotoxicity, potential to induce a cytokine response in whole human blood and risk of induction of tolerance to fibrinolytic agents were investigated. A rat model of intravascular catheter infection was established to investigate the efficacy of selected fibrinolytic agents in vivo.

Results: Under biomimetic conditions the fibrinolytic agents effectively dispersed established S. aureus biofilms and in combination with common anti-staphylococcal antimicrobials effectively killed bacterial cells being released from the biofilm. These fibrinolytic agents were not cytotoxic and did not affect host immune response. The rat model of infection successfully demonstrated the activity of the selected fibrinolytic agents alone and in combination with antimicrobials on established biofilm in vivo.

Conclusion: TrypLE™ and nattokinase most successfully removed adherent cells from plasma-coated surfaces and significantly improved the efficacy of existing antimicrobials against S. aureus biofilms in vitro and in vivo. These biofilm dispersal agents represent a viable future treatment option for S. aureus device-related infections.

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Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease [PublishAheadOfPrint]

Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of non-cavitary nodular bronchiectatic (NB) Mycobacterium avium complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent non-cavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (n = 26) or intermittent therapy (n = 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared with the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent non-cavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent non-cavitary NB MAC lung disease.

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Host - pathogen - treatment triad: host factors matter most in MRSA bacteremia outcomes [PublishAheadOfPrint]

Background: Previous studies have separately emphasized the importance of host, pathogen and treatment characteristics in determining short term or in-hospital mortality for patients with methicillin resistant Staphylococcus aureus (MRSA) bloodstream infections. Less is known about the relative importance of these factors and their interaction in determining short, medium and long-term mortality.

Methods: This is an observational cohort study where all patients admitted to University of New Mexico Health Sciences Center (UNM HSC) between July 2002 and August 2013 with MRSA positive blood cultures were recorded. We collected patients' demographic and treatment data along with genetic markers of the MRSA isolates. Outcomes of interest were determinants of short (30 days), medium (30-90 days) and long-term (>90 days) mortality.

Results: This study included 273 patients with MRSA bacteremia. Short, medium and long-term mortality were 18.7%, 26.4% and 48% respectively. Thirty-day mortality was influenced by host variables along with host-pathogen interaction characteristics. Pitt bacteremia score, malignancy and healthcare exposure contributed to 30 - 90-day mortality while duration of therapy longer than 4 weeks had a protective effect. Age remained a significant risk factor for greater than 90-day mortality while admission leukocytosis was protective. Infection represented the most frequent cause of death for all 3 time frames and it varied from 72.6% in the first 30 days, 60% for 30-90 days to 35.7% at more than 90 days (p= 0.003).

Conclusion: Host characteristics impact short, medium and long term mortality in MRSA bloodstream infections more than genetic pathogen markers and treatment factors.

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Usefulness of our proposed olfactory scoring system during endoscopic sinus surgery in patients with chronic rhinosinusitis

Abstract

Introduction

The primary aim of the current study was to examine the usefulness of our proposed olfactory scoring system in chronic rhinosinusitis (CRS) patients with olfactory disorders (n = 213) receiving endoscopic sinus surgery (ESS).

Materials and methods

Analyzed patients were divided into two groups: an eosinophilic CRS (ECRS) group (n = 153); and a non-ECRS group (n = 60). The T&T recognition threshold test was used to evaluate olfaction at baseline and at 3 and 12 months after ESS. Patients with mean recognition threshold < 2.0 at 3 or 12 months or with a decrease of ≥ 1.0 as compared with baseline were defined as showing clinical improvement. We scored mucosal conditions as normal (0 points), edema (1 point), and polyp (2 points) at the canopy of olfactory cleft (OC), middle and superior turbinates, superior nasal meatus, and sphenoethmoidal recess during ESS. The total score of OCs (SOCs) was calculated (range 0–20 points). We compared SOCs between ECRS and non-ECRS groups. Factors related to olfactory improvement were also investigated using uni- and multivariate analyses.

Results

SOCs in the ECRS and non-ECRS groups showed significant correlations with mean recognition thresholds at baseline and at 3 and 12 months. In the multivariate analysis for predicting improvement of mean recognition threshold, lower SOCs were significantly associated with olfactory improvement factors at 3 and 12 months postoperatively in the ECRS group.

Conclusion

SOCs appears promising for estimating olfactory prognosis after ESS in CRS patients.

http://ift.tt/2A1k3cd

Sialendoscopy in treating pediatric salivary gland disorders: a systematic review

Abstract

Objective

The primary aim of this study is to conduct a systematic review in order to evaluate the use of sialendoscopy in treating pediatric salivary gland disorders.

Methods

Eligible articles were identified through a comprehensive search of electronic databases. Using predefined inclusion criteria, published articles on sialendoscopy in children were selected and reviewed.

Results

17 articles including 323 pediatric patients and 424 salivary glands managed by sialendoscopy were identified. The most common salivary gland disorder affected was the parotid (83% of cases), followed by the submandibular gland (16.5% of cases). Juvenile recurrent parotitis (68.9%) was the most frequent diagnosis followed by sialolithiasis (14.7%). The most common complication was ductal perforation. During a pooled mean follow-up time of 18.3 months, recurrences were reported in 14.5% of patients mostly in patients diagnosed with juvenile recurrent parotitis.

Conclusion

Sialendoscopy is a minimally invasive diagnostic and therapeutic tool for inflammatory salivary gland disorders in pediatric patients. Based on the current review, sialendoscopy can be successfully implemented in cases of pediatric salivary gland disorders.

http://ift.tt/2AWvFgQ

Reply to the letter “Laryngopharyngeal reflux disease in the elderly”

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The outcome of cochlear implantation among children with genetic syndromes

Abstract

Objective

To assess the outcome and efficacy of cochlear implantation in children with genetic syndromes.

Method

Study design: case–control study.

Setting

A cochlear implantation tertiary referral center.

Patients

All pediatric cochlear implantation recipients with Waardenburg syndrome, Usher syndrome, Dandy–Walker syndrome, or albinism. A control group was appropriately matched to the syndromic group with regard to age at implantation and duration of device use.

Intervention

Cochlear implantation.

Main outcome measures

Subjects' auditory abilities, speech intelligibility, and pure tone thresholds were compared between the syndromic and non-syndromic group.

Results

A total of 25 subjects (13 syndromic and 12 non-syndromic) participated in the study. Neither auditory ability nor speech intelligibility scores differed significantly by group. The final PTA of both the groups showed normal-to-mild hearing loss: 26 dB HL in the syndromic group and 23 dB HL for the control group.

Conclusions

Cochlear implant recipients with genetic syndromes achieved similar levels auditory perception and speech intelligibility as their peers with a genetic syndrome. The presence of any of the genetic syndromes described herein should not be a contraindication to cochlear implant provision, as it would have a positive impact on the patients' sensory perception and lifestyle.

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Prognostic value of the lymph node ratio in oropharyngeal carcinoma stratified for HPV-status

Abstract

Objective

Lymph node ratio (LNR) was shown to be a prognostic factor in laryngeal and oral cavity primaries. The purpose of this study was to investigate the impact of the lymph node ratio in oropharyngeal squamous cell carcinoma (OPSCC) with a high incidence of HPV-related disease. Therefore, the role of LNR was evaluated as an additional predictive parameter to the 8th edition of AJCC TNM staging system.

Methods

From December 2009 to August 2015, patients diagnosed with primary oropharyngeal squamous cell carcinoma were prospectively enrolled. After tumor resection with uni- or bilateral neck dissection, patients with ≥ 1 nodal metastasis (pN+) were eligible for a retrospective LNR analysis.

Results

137 patients underwent tumor resection with uni- or bilateral neck dissection. The proportion of HPV-associated disease was 42%. Most patients (n = 96; 70%) presented with involved neck nodes. In p16-positive OPSCC, the rate of pN + cases was significantly increased compared to p16-negative OPSCC (86% vs. 58%, p = 0.007). Patients with LNR ≤ 10% had a significant better overall survival (OS) and disease-specific survival (DSS). However, when stratified for p16-status, LNR ≤ 10% had a significant impact on OS only for HPV-associated tumors (p = 0.027), whereas LNR of ≤ 10% was not a significant predictor for better OS in p16-negative OPSCC (p = 0.143).

Conclusion

The LNR with a cut-off value of 10% serves as an additional prognostic parameter in HPV-related OPSCC and may help to improve risk stratification in combination with the revised AJCC 8th edition TNM classification.

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Reply to the Letter to the Editor concerning “Combined microscopic/endoscopic management of petrous apex lesions”

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Metastasierung kutaner Plattenepithelkarzinome im HNO-Bereich

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-122745

Hintergrund Kutane Plattenepithelkarzinome können lymphogen sowohl nach intraparotideal, als auch nach zervikal metastasieren. Prognostisch scheinen sich gemäß mehreren Studien die beiden Metastasierungswege zu unterscheiden. Wir möchten mit klinikeigenen Daten das Metastasierungsverhalten hinsichtlich der Prognose untersuchen. Material und Methoden In die retrospektive Studie aufgenommen wurden 29 Kaukasier mit einem Plattenepithelkarzinom der Haut im Kopf-Halsbereich, welche sich zwischen 2004 und 2016 an unserer Hals-Nasen-Ohren-Klinik vorgestellt haben. Bei allen Patienten wurde eine Tumorresektion mit Neck dissection durchgeführt. Sowohl das präoperative Staging, wie auch die Nachsorge erfolgten mittels Ultraschall oder Computertomographie (konventionell oder PET Scan). Die Patienten wurden nach Metastasierungsverhalten eingeteilt und die entsprechenden Überlebensraten wurden ermittelt. Ergebnisse 11 Patienten hatten zervikale Metastasen, 4 Patienten parotideale Metastasen, 5 Patienten hatten beides. Bei 9 Patienten wurde eine prophylaktische Neck dissection bei cN0 durchgeführt. Ein lokoregionäres Tumorrezidiv trat in insgesamt 24 % der Fälle auf, davon waren alle mit einer zervikalen Metastasierung assoziiert. Die 5-Jahres Überlebensrate betrug in diesen Fällen 71 %. Im Gegensatz dazu betrug diese bei alleiniger parotidealer Metastasierung 100 %. Im Rahmen der prophylaktischen Neck dissection wurden in einem Fall okkulte Metastasen diagnostiziert. Schlussfolgerungen Eine zervikale Metastasierung geht im Gegensatz zu einer alleinigen parotidealen Metastasierung mit einer schlechteren Prognose einher. Die Überlebensrate nach chirurgischer Therapie, sowie gegebenenfalls zusätzlichen adjuvanten Radiotherapie ist insgesamt gut (79 %). Die Rolle einer prophylaktischen Neck dissection bei cN0 und entsprechenden Risikofaktoren ist nicht abschließend geklärt.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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IgG4-related disease presenting as hoarseness and postcricoid ulcer

Immunoglobulin G4–related disease (IgG4-RD) is an uncommon immune-mediated disorder with heterogeneous clinicopathologic features and variable disease manifestations.1 IgG4-RD is characterized by single-organ or multiorgan involvement, and tissue infiltration with IgG4 plasma cells and associated fibrosclerosis.2–5 Autoimmune pancreatitis represents the prototype of IgG4-RD, yet involvement of almost all organs has been reported.1–7 Elevated IgG4 serum concentration is noted in the majority of patients with IgG4-RD and is generally related to the more severe disease phenotype.

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Diagnostic and treatment effects of sialendoscopy for patients with swelling of the parotid gland when sialoliths are undetected with computed tomography

Between August 2009 and May 2016, 74 patients underwent sialoendoscopic surgery. 32 patients had parotid gland disease and 9 patients had intermittent swelling of the parotid gland and sialoliths were not detected with CT imaging. 4 patients were diagnosed with idiopathic Stensen's duct stenosis. Sialendoscopy directly confirmed Stensen's duct stenosis in 2 patients. However, the sialendoscope was unable to be inserted in the other 2 patients, who had stenosis of the orifice of the Stensen's duct.

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In This Issue [IN THIS ISSUE]

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Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria [NOVEL IMMUNOLOGICAL METHODS]

We describe an MHC class II (I-A^b)–restricted TCR transgenic mouse line that produces CD4⁺ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4⁺ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8⁺ T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4⁺ T cells and the previously described PbT-I CD8⁺ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8⁺ DC (a subset of XCR1⁺ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4⁺ T cell responses. Depletion of CD8⁺ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4⁺ T cell immunity during malaria and provides evidence that CD4⁺ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8⁺ DC.

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Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation [IMMUNE REGULATION]

The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K–protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K–PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity. In this study, we further examined the molecular pathway linking PKB and Cbl-b in murine models. Our data show that the protein kinase GSK-3, one of the first targets identified for PKB, catalyzes two previously unreported phosphorylation events at Ser⁴⁷⁶ and Ser⁴⁸⁰ of Cbl-b. GSK-3 inactivation by PKB abrogates phosphorylation of Cbl-b at these two sites and results in reduced Cbl-b protein levels. We further show that constitutive activation of PKB in vivo results in a loss of tolerance that is mediated through the downregulation of Cbl-b. Altogether, these data indicate that the PI3K–PKB–GSK-3 pathway is a novel regulatory axis that is important for controlling the decision between T cell activation and tolerance via Cbl-b.

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Ubc9 Binds to ADAP and Is Required for Rap1 Membrane Recruitment, Rac1 Activation, and Integrin-Mediated T Cell Adhesion [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Although the immune adaptor adhesion and degranulation-promoting adaptor protein (ADAP) acts as a key mediator of integrin inside-out signaling leading to T cell adhesion, the regulation of this adaptor during integrin activation and clustering remains unclear. We now identify Ubc9, the sole small ubiquitin-related modifier E2 conjugase, as an essential regulator of ADAP where it is required for TCR-induced membrane recruitment of the small GTPase Rap1 and its effector protein RapL and for activation of the small GTPase Rac1 in T cell adhesion. We show that Ubc9 interacted directly with ADAP in vitro and in vivo, and the association was increased in response to anti-CD3 stimulation. The Ubc9-binding domain on ADAP was mapped to a nuclear localization sequence (aa 674–700) within ADAP. Knockdown of Ubc9 by short hairpin RNA or expression of the Ubc9-binding–deficient ADAP mutant significantly decreased TCR-induced integrin adhesion to ICAM-1 and fibronectin, as well as LFA-1 clustering, although it had little effect on the TCR proximal signaling responses and TCR-induced IL-2 transcription. Furthermore, downregulation of Ubc9 impaired TCR-mediated Rac1 activation and attenuated the membrane targeting of Rap1 and RapL, but not Rap1-interacting adaptor molecule. Taken together, our data demonstrate for the first time, to our knowledge, that Ubc9 acts as a functional binding partner of ADAP and plays a selective role in integrin-mediated T cell adhesion via modulation of Rap1-RapL membrane recruitment and Rac1 activation.

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Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt ROR{gamma}t+ and Follicular Phenotypes [CUTTING EDGE]

Regulatory T cells (Tregs) adopt specialized phenotypes defined by coexpression of lineage-defining transcription factors, such as RORt, Bcl-6, or PPAR, alongside Foxp3. These Treg subsets have unique tissue distributions and diverse roles in maintaining organismal homeostasis. However, despite extensive functional characterization, the factors driving Treg specialization are largely unknown. In this article, we show that c-Maf is a critical transcription factor regulating this process in mice, essential for generation of both RORt⁺ Tregs and T follicular regulatory cells, but not for adipose-resident Tregs. c-Maf appears to function primarily in Treg specialization, because IL-10 production, expression of other effector molecules, and general immune homeostasis are not c-Maf dependent. As in other T cells, c-Maf is induced in Tregs by IL-6 and TGF-β, suggesting that a combination of inflammatory and tolerogenic signals promote c-Maf expression. Therefore, c-Maf is a novel regulator of Treg specialization, which may integrate disparate signals to facilitate environmental adaptation.

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IgG1 Is Required for Optimal Protection after Immunization with the Purified Porin OmpD from Salmonella Typhimurium [IMMUNOTHERAPY AND VACCINES]

In mice, the IgG subclass induced after Ag encounter can reflect the nature of the Ag. Th2 Ags such as alum-precipitated proteins and helminths induce IgG1, whereas Th1 Ags, such as Salmonella Typhimurium, predominantly induce IgG2a. The contribution of different IgG isotypes to protection against bacteria such as S. Typhimurium is unclear, although as IgG2a is induced by natural infection, it is assumed this isotype is important. Previously, we have shown that purified S. Typhimurium porins including outer membrane protein OmpD, which induce both IgG1 and IgG2a in mice, provide protection to S. Typhimurium infection via Ab. In this study we report the unexpected finding that mice lacking IgG1, but not IgG2a, are substantially less protected after porin immunization than wild-type controls. IgG1-deficient mice produce more porin-specific IgG2a, resulting in total IgG levels that are similar to wild-type mice. The decreased protection in IgG1-deficient mice correlates with less efficient bacterial opsonization and uptake by macrophages, and this reflects the low binding of outer membrane protein OmpD–specific IgG2a to the bacterial surface. Thus, the Th2-associated isotype IgG1 can play a role in protection against Th1-associated organisms such as S. Typhimurium. Therefore, individual IgG subclasses to a single Ag can provide different levels of protection and the IgG isotype induced may need to be a consideration when designing vaccines and immunization strategies.

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Cutting Edge: Processing of Oxidized Peptides in Macrophages Regulates T Cell Activation and Development of Autoimmune Arthritis [CUTTING EDGE]

APCs are known to produce NADPH oxidase (NOX) 2–derived reactive oxygen species; however, whether and how NOX2-mediated oxidation affects redox-sensitive immunogenic peptides remains elusive. In this study, we investigated a major immunogenic peptide in glucose-6-phosphate isomerase (G6PI), a potential autoantigen in rheumatoid arthritis, which can form internal disulfide bonds. Ag presentation assays showed that presentation of this G6PI peptide was more efficient in NOX2-deficient (Ncf1^m1J/m1J mutant) mice, compared with wild-type controls. IFN-–inducible lysosomal thiol reductase (GILT), which facilitates disulfide bond–containing Ag processing, was found to be upregulated in macrophages from Ncf1 mutant mice. Ncf1 mutant mice exhibited more severe G6PI peptide-induced arthritis, which was accompanied by the increased GILT expression in macrophages and enhanced Ag-specific T cell responses. Our results show that NOX2-dependent processing of the redox-sensitive autoantigens by APCs modify T cell activity and development of autoimmune arthritis.

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Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B [CLINICAL AND HUMAN IMMUNOLOGY]

Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott–Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Here, we describe two brothers with hematopoietic and immunologic symptoms reminiscent of Wiskott–Aldrich syndrome (WAS). However, these patients lacked mutations in any of the genes previously associated with WAS. Whole-exome sequencing revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208VfsX20), in Arp2/3 complex component ARPC1B that causes a frame shift resulting in premature termination. Modeling of the disease in zebrafish revealed that ARPC1B plays a critical role in supporting T cell and thrombocyte development. Moreover, the defects in development caused by ARPC1B loss could be rescued by the intact human ARPC1B ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of ARPC1B is restricted to hematopoietic cells, potentially explaining why a mutation in ARPC1B has now been observed as a cause of WAS, whereas mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed.

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Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation [ALLERGY AND OTHER HYPERSENSITIVITIES]

Understanding functions of Foxp3⁺ regulatory T cells (Tregs) during allergic airway inflammation remains incomplete. In this study, we report that, during cockroach Ag–induced allergic airway inflammation, Foxp3⁺ Tregs are rapidly mobilized into the inflamed lung tissues. However, the level of Treg accumulation in the lung was different depending on the type of inflammation. During eosinophilic airway inflammation, ~30% of lung-infiltrating CD4 T cells express Foxp3, indicative of Tregs. On the contrary, only ~10% of infiltrating CD4 T cells express Foxp3 during neutrophilic airway inflammation. Despite the different accumulation, the lung inflammation and inflammatory T cell responses were aggravated following Treg depletion, regardless of the type of inflammation, suggesting regulatory roles for Tregs. Interestingly, however, the extent to which inflammatory responses are aggravated by Treg depletion was significantly greater during eosinophilic airway inflammation. Indeed, lung-infiltrating Tregs exhibit phenotypic and functional features associated with potent suppression. Our results demonstrate that Tregs are essential regulators of inflammation, regardless of the type of inflammation, although the mechanisms used by Tregs to control inflammation may be shaped by environmental cues available to them.

http://ift.tt/2AUY1b0

A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury [IMMUNE REGULATION]

Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 x Il22bp double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b⁺Ly6C⁺ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22–induced Cxcl10 expression.

http://ift.tt/2A2lhnB

Endogenous Calcitriol Synthesis Controls the Humoral IgE Response in Mice [ALLERGY AND OTHER HYPERSENSITIVITIES]

The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)₂D₃ (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D₃-1α-hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus. Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA-specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1. Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell–specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization.

http://ift.tt/2A3I2I1

Serum IgA Immune Complexes Promote Proinflammatory Cytokine Production by Human Macrophages, Monocytes, and Kupffer Cells through Fc{alpha}RI-TLR Cross-Talk [INNATE IMMUNITY AND INFLAMMATION]

IgA is predominantly recognized to play an important role in host defense at mucosal sites, where it prevents invasion of pathogens by neutralization. Although it has recently become clear that IgA also mediates other immunological processes, little remains known about the potential of IgA to actively contribute to induction of inflammation, particularly in nonmucosal organs and tissues. In this article, we provide evidence that immune complex formation of serum IgA plays an important role in orchestration of inflammation in response to pathogens at various nonmucosal sites by eliciting proinflammatory cytokines by human macrophages, monocytes, and Kupffer cells. We show that opsonization of bacteria with serum IgA induced cross-talk between FcαRI and different TLRs, leading to cell type–specific amplification of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-23. Furthermore, we demonstrate that the increased protein production of cytokines was regulated at the level of gene transcription, which was dependent on activation of kinases Syk and PI3K. Taken together, these data demonstrate that the immunological function of IgA is substantially more extensive than previously considered and suggest that serum IgA–induced inflammation plays an important role in orchestrating host defense by different cell types in nonmucosal tissues, including the liver, skin, and peripheral blood.

http://ift.tt/2A29tSe

Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self-Antigen and Those That Present Antigen [ANTIGEN RECOGNITION AND RESPONSES]

Aire controls the fate of autoreactive thymocytes (i.e., clonal deletion or development into regulatory T cells [Tregs]) through transcriptional control of the expression of tissue-restricted self-antigens (TRAs) from medullary thymic epithelial cells (mTECs) and bone marrow (BM)-derived cells. Although TRAs expressed by mTECs and BM-derived cells are suggested to complement each other to generate a full spectrum of TRAs, little is known about the relative contribution of TRAs from each component for establishment of self-tolerance. Furthermore, the precise role of Aire in specific types of Aire-expressing APCs remains elusive. We have approached these issues by generating two different types of transgenic mouse (Tg) model, which express a prefixed model self-antigen driven by the insulin promoter or the Aire promoter. In the insulin-promoter Tg model, mTECs alone were insufficient for clonal deletion, and BM-derived APCs were required for this action by utilizing Ag transferred from mTECs. In contrast, mTECs alone were able to induce Tregs, although at a much lower efficiency in the absence of BM-derived APCs. Importantly, lack of Aire in mTECs, but not in BM-derived APCs, impaired both clonal deletion and production of Tregs. In the Aire-promoter Tg model, both mTECs and BM-derived APCs could independently induce clonal deletion without Aire, and production of Tregs was impaired by the lack of Aire in mTECs, but not in BM-derived APCs. These results suggest that the fate of autoreactive thymocytes together with the requirement for Aire depend on the cell types that express self-antigens and the types of APCs involved in tolerance induction.

http://ift.tt/2AW1PJt

Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis [CLINICAL AND HUMAN IMMUNOLOGY]

Irreversible tissue recession in chronic inflammatory diseases is associated with dysregulated immune activation and production of tissue degradative enzymes. In this study, we identified elevated levels of matrix metalloproteinase (MMP)-12 in gingival tissue of patients with the chronic inflammatory disease periodontitis (PD). The source of MMP12 was cells of monocyte origin as determined by the expression of CD14, CD68, and CD64. These MMP12-producing cells showed reduced surface levels of the coinhibitory molecule CD200R. Similarly, establishing a multicellular three-dimensional model of human oral mucosa with induced inflammation promoted MMP12 production and reduced CD200R surface expression by monocyte-derived cells. MMP12 production by monocyte-derived cells was induced by CSF2 rather than the cyclooxygenase-2 pathway, and treatment of monocyte-derived cells with a CD200R ligand reduced CSF2-induced MMP12 production. Further, MMP12-mediated degradation of the extracellular matrix proteins tropoelastin and fibronectin in the tissue model coincided with a loss of Ki-67, a protein strictly associated with cell proliferation. Reduced amounts of tropoelastin were confirmed in gingival tissue from PD patients. Thus, this novel association of the CD200/CD200R pathway with MMP12 production by monocyte-derived cells may play a key role in PD progression and will be important to take into consideration in the development of future strategies to diagnose, treat, and prevent PD.

http://ift.tt/2AUkgxQ

B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells [AUTOIMMUNITY]

Follicular regulatory T (T_FR) cells are a newly defined regulatory T cell (Treg) subset that suppresses follicular helper T cell–mediated B cell responses in the germinal center reaction. The precise costimulatory signal requirements for proper T_FR cell differentiation and function are still not known. Using conditional knockout strategies of CD28, we previously demonstrated that loss of CD28 signaling in Tregs caused autoimmunity in mice (termed CD28-Treg mice), characterized by lymphadenopathy, accumulation of activated T cells, and cell-mediated inflammation of the skin and lung. In this study, we show that CD28 signaling is required for T_FR cell differentiation. Treg-specific deletion of CD28 caused a reduction in T_FR cell numbers and function, which resulted in increased germinal center B cells and Ab production. Moreover, residual CD28-deficient T_FR cells showed a diminished suppressive capacity as assessed by their ability to inhibit Ab responses in vitro. Surprisingly, genetic deletion of B cells in CD28-Treg mice prevented the development of lymphadenopathy and CD4⁺ T cell activation, and autoimmunity that mainly targeted skin and lung tissues. Thus, autoimmunity occurring in mice with CD28-deficient Tregs appears to be driven primarily by loss of T_FR cell differentiation and function with resulting B cell–driven inflammation.

http://ift.tt/2A2l5ET

Proinflammatory T Cell Status Associated with Early Life Adversity [CLINICAL AND HUMAN IMMUNOLOGY]

Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69⁺CD8⁺ T cells (p = 0.022), increased numbers of HLA-DR⁺ CD4 and HLA-DR⁺ CD8 T cells (p < 0.001), as well as increased numbers of CD25⁺CD8⁺ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4⁺CXCR3^–CCR6⁺ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells.

http://ift.tt/2AUs7M2

Broad Susceptibility of Nucleolar Proteins and Autoantigens to Complement C1 Protease Degradation [AUTOIMMUNITY]

Anti-nuclear autoantibodies, which frequently target the nucleoli, are pathogenic hallmarks of systemic lupus erythematosus (SLE). Although the causes of these Abs remain broad and ill-defined, a genetic deficiency in C1 complex (C1qC1r₂C1s₂) or C4 is able to induce these Abs. Considering a recent finding that, in dead cells, nucleoli were targeted by C1q and two nucleolar autoantigens were degraded by C1r/C1s proteases, we considered that C1 could help protect against antinuclear autoimmunity by broadly degrading nucleolar proteins or autoantigens. Nucleoli were isolated to homogeneity and structurally defined. After C1 treatment, cleaved nucleolar proteins were identified by proteomic two-dimensional fluorescence difference gel electrophoresis and mass spectrometry, and further verified by Western blotting using specific Abs. The extent of nucleolar autoantigen degradation upon C1 treatment was estimated using SLE patient autoantibodies. The isolated nucleoli were broadly reactive with SLE patient autoantibodies. These nucleoli lacked significant autoproteolysis, but many nucleolar proteins and autoantigens were degraded by C1 proteases; >20 nucleolar proteins were identified as C1 cleavable. These were further validated by Western blotting using specific Abs. The broad autoantigenicity of the nucleoli may attribute to their poor autoproteolysis, causing autologous immune stimulation upon necrotic exposure. However, C1q targets at these nucleoli to cause C1 protease activation and the cleavage of many nucleolar proteins or autoantigens. This may represent one important surveillance mechanism against antinuclear autoimmunity because C1 genetic deficiency causes anti-nuclear autoantibodies and SLE disease.

http://ift.tt/2AW1M0f

Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis [IMMUNE REGULATION]

Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of lethality upon mutation of both Regnase-1 and Roquin. By using a Regnase-1 conditional allele, we show that mutations of both Regnase-1 and Roquin in T cells leads to massive lymphocyte activation. In contrast, mutation of either Regnase-1 or Roquin affected T cell activation to a lesser extent than the double mutation, indicating that Regnase-1 and Roquin function nonredundantly in T cells. Interestingly, Regnase-1 and Roquin double-mutant mice suffered from severe inflammation and early formation of fibrosis, especially in the heart, along with the increased expression of Ifng, but not Il4 or Il17a. Consistently, mutation of both Regnase-1 and Roquin leads to a huge increase in the Th1, but not the Th2 or Th17, population in spleens compared with T cells with a single Regnase-1 or Roquin deficiency. Regnase-1 and Roquin are capable of repressing the expression of a group of mRNAs encoding factors involved in Th1 differentiation, such as Furin and Il12rb1, via their 3' untranslated regions. Moreover, Regnase-1 is capable of repressing Roquin mRNA. This cross-regulation may contribute to the synergistic control of T cell activation/polarization. Collectively, our results demonstrate that Regnase-1 and Roquin maintain T cell immune homeostasis and regulate Th1 polarization synergistically.

http://ift.tt/2AUs5DU

The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice [AUTOIMMUNITY]

Type 1 diabetes (T1D) has a strong genetic component. The insulin dependent diabetes (Idd)22 locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NODcALR-(D8Mit293-D8Mit137)/Mx (NOD-Idd22) recombinant congenic mouse strain was generated in which NOD mice carry the full Idd22 confidence interval. NOD-Idd22 mice exhibit almost complete protection from spontaneous T1D and a significant reduction in insulitis. Our goal was to unravel the mode of Idd22-based protection using in vivo and in vitro models. We determined that Idd22 did not impact immune cell diabetogenicity or β cell resistance to cytotoxicity in vitro. However, NOD-Idd22 mice were highly protected against adoptive transfer of T1D. Transferred CTLs trafficked to the pancreatic lymph node and proliferated to the same extent in NOD and NOD-Idd22 mice, yet the accumulation of pathogenic CTLs in the islets was significantly reduced in NOD-Idd22 mice, correlating with disease resistance. Pancreatic endothelial cells from NOD-Idd22 animals expressed lower levels of adhesion molecules, even in response to inflammatory stimuli. Lower adhesion molecule expression resulted in weaker adherence of T cells to NOD-Idd22 endothelium compared with NOD-derived endothelium. Taken together, these results provide evidence that Idd22 regulates the ability of β cell–autoreactive T cells to traffic into the pancreatic islets and may represent a new target for pharmaceutical intervention to potentially prevent T1D.

http://ift.tt/2A31uEC

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1 [IMMUNE REGULATION]

T cell expression of TIM-3 following Ag encounter has been associated with a continuum of functional states ranging from effector memory T cells to exhaustion. We have designed an in vitro culture system to specifically address the impact of anti–TIM-3/TIM-3 engagement on human Ag-specific CD8 T cells during a normal response to Ag and found that anti–TIM-3 treatment enhances T cell function. In our in vitro T cell culture system, MART1-specific CD8 T cells were expanded from healthy donors using artificial APCs. To ensure that the T cells were the only source of TIM-3, cells were rechallenged with peptide-loaded artificial APCs in the presence of anti–TIM-3 Ab. In these conditions, anti–TIM-3 treatment promotes generation of effector T cells as shown by acquisition of an activated phenotype, increased cytokine production, enhanced proliferation, and a transcription program associated with T cell differentiation. Activation of mTORC1 has been previously demonstrated to enhance CD8 T cell effector function and differentiation. Anti–TIM-3 drives CD8 T cell differentiation through activation of the mTORC1 as evidenced by increased levels of phosphorylated S6 protein and rhebl1 transcript. Altogether these findings suggest that anti–TIM-3, together with Ag, drives differentiation in favor of effector T cells via the activation of mTOR pathway. To our knowledge, this is the first report demonstrating that TIM-3 engagement during Ag stimulation directly influences T cell differentiation through mTORC1.

http://ift.tt/2AUs3vM

Mer Receptor Tyrosine Kinase Signaling Prevents Self-Ligand Sensing and Aberrant Selection in Germinal Centers [AUTOIMMUNITY]

Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer^–/–) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection. In this study, we generated Mer^–/– mice with a global MyD88, TLR7, or TLR9 deficiency and cell type–specific MyD88 deficiency to study the functional correlation between Mer and TLRs in the development of GC responses and autoimmunity. We found that GC B cell–intrinsic sensing of self-RNA, but not self-DNA, released from dead cells accumulated in GCs drives enhanced GC responses in Mer^–/– mice. Although self-ligands directly affect GC B cell responses, the loss of Mer in dendritic cells promotes enhanced T cell activation and proinflammatory cytokine production. To study the impact of Mer deficiency on the development of autoimmunity, we generated autoimmune-prone B6.Sle1b mice deficient in Mer (Sle1b.Mer^–/–). We observed accelerated autoimmunity development even under conditions where Sle1b.Mer^–/– mice did not exhibit increased AC accumulation in GCs compared with B6.Sle1b mice, indicating that Mer immunoregulatory signaling in APCs regulates B cell selection and autoimmunity. We further found significant expansion, retention, and class-switching of autoreactive B cells in GCs under conditions where ACs accumulated in GCs of Sle1b.Mer^–/– mice. Altogether, both the phagocytic and immunomodulatory functions of Mer regulate GC responses to prevent the development of autoimmunity.

http://ift.tt/2AWegow

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy [IMMUNOTHERAPY AND VACCINES]

CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.

http://ift.tt/2AUs0jA

Das Cochleaimplantat in der sozialgerichtlichen Rechtsprechung

Zusammenfassung

Hintergrund

Da sich die Indikation für eine CI-Versorgung erweitert hat („Single-Sided Deafness" [SSD], elektrisch akustische Stimulation [EAS], bilaterale Versorgung, Versorgung bei sehr langer Taubheit) und daher zunehmend mehr Patienten für eine solche Versorgung infrage kommen, kommt es auch immer öfter zu Auseinandersetzungen mit den Kostenträgern hinsichtlich der Frage, ob die Kosten für die Operation und die Nachsorgekosten durch die Krankenversicherungen getragen werden müssen.

Zielsetzung/Fragestellung

Dieser Artikel gibt einen Überblick über Urteile der deutschen Sozialgerichte. Es wurde untersucht, ob und in welchen Fällen es für den einzelnen Patienten empfehlenswert ist, den Klageweg zu beschreiten, und mit welcher Verfahrensdauer gerechnet werden muss.

Material und Methoden

Ausgewertet wurden die beiden größten kommerziellen juristischen Datenbanken sowie die durch die Sozialgerichtsbarkeit veröffentlichten Urteile. Als Suchparameter dienten verschiedene Kombinationen aus den Begriffen „Cochlear", „Cochlea", „Implant" und „Implantat". Drei Entscheidungen wurden durch direkte Anforderung beim entscheidenden Gericht erlangt, eine weitere in einem Artikel aufgeführt. Die besprochenen Entscheidungen ergingen im Zeitraum 2003 bis 2017.

Ergebnisse

Insgesamt wurden 12 Entscheidungen gefunden. Die Hauptsacheentscheidungen gingen bis auf einen Fall alle zugunsten der Patienten aus. Bei dem Verfahren, in dem die Klägerin nicht Recht bekam, handelte es sich um einen Ausnahmesachverhalt. Ein Kläger unterlag zwar im Verfahren auf einstweiligen Rechtsschutz, in der Hauptsache erkannte die Krankenversicherung seinen Anspruch auf eine CI-Versorgung jedoch an. Die Verfahren dauerten zwischen 1;8 Jahren und 9;5 Jahren.

Schlussfolgerung

Trotz des zeitlichen Aufwands lohnt sich die Beschreitung des Rechtswegs. Das grundsätzlich kostenfreie sozialgerichtliche Verfahren führt in den meisten Fällen dazu, dass die gesetzlichen Krankenversicherungen zur Tragung der Kosten für ein CI verpflichtet werden.

http://ift.tt/2AMnYZV

Study Suggests That Where Guidelines Disagree, Physicians’ Experiences With Their Patients, Family and Friends Shape Breast Cancer Screening Recommendations

Results of a national survey of more than 800 physicians suggest that their experiences with patients, family members and friends with breast cancer are linked with their recommendations for routine mammograms. Specifically, physicians who reported knowing at least one patient, family member or friend with a poor breast cancer prognosis and who had not been screened were more likely to recommend routine screening for their younger and older patients, age groups where routine screening is controversial.

http://ift.tt/2AVe48L

Zentrale und periphere Aspekte der Lärmschwerhörigkeit

Zusammenfassung

Lärm stellt in den entwickelten Industrieländern ein großes sozioökonomisches Problem dar. Für die Behandlung der durch die Lärmschwerhörigkeit auftretenden audiologischen Phänomene ist ein vertieftes Verständnis der zugrunde liegenden Schädigungsmechanismen peripherer und zentraler Anteile der Hörbahn notwendig. Die mechanische Schädigung, die Ischämie, die Exzitotoxizität sowie die auditorische Synaptopathie stellen die wesentlichen lärminduzierten Schädigungsprozesse in der Cochlea dar. Neben cochleären pathologischen Veränderungen treten jedoch auch zentralnervöse Schädigungen infolge der Lärmexposition auf. Aufgrund der Überstimulation kommt es sehr frühzeitig zum Zellverlust im Versorgungsgebiet des N. cochlearis. Der spätere Zellverlust in höheren auditorischen Kerngebieten ist im Gegensatz dazu auf die sensorische Deprivation zurückzuführen. Insgesamt wird dem strukturellen Verlust durch eine Modulation der Spontanaktivität im Sinne der Netzwerkhomöostase entgegenreguliert. Dennoch nimmt sehr wahrscheinlich die Verarbeitungsgüte durch die lärminduzierten neuroplastischen Veränderungen ab. Die Lärmschwerhörigkeit ist somit durch eine Reihe von peripheren und zentralen Veränderungen gekennzeichnet, die bisher nur teilweise einer Therapie zugänglich sind. Besonders im Hinblick auf die auditorische Synaptopathie und die zentralen Verarbeitungsdefizite werden neue therapeutische Ansätze benötigt, um audiologische Phänomene wie Tinnitus, Hyperakusis oder schlechtes Diskriminationsvermögen effektiv behandeln zu können.

http://ift.tt/2BHyGPb

Clinical predictors of chronic rhinosinusitis: do the Canadian clinical practice guidelines for acute and chronic rhinosinusitis predict CT-confirmation of disease?

Abstract

Background

The diagnosis of chronic rhinosinusitis (CRS) based on clinical presentation alone remains challenging. To improve the accuracy of clinical diagnosis, the Canadian Rhinosinusitis Guidelines recommend the use of specific symptom and endoscopic criteria. Our study objective was to determine whether symptom and endoscopic criteria, as defined by the Canadian Rhinosinusitis Guidelines, accurately predict CT-confirmed CRS diagnosis.

Methods

A retrospective cohort study of 126 patients who underwent CT sinuses based on clinical suspicion of possible CRS. The presence of symptom and endoscopic criteria, as defined by the Canadian Rhinosinusitis Guidelines, were compared between patients with and without a CT-confirmed CRS diagnosis using two-tailed Fisher's exact tests. Positive predictive values and likelihood ratios were determined for each symptom and endoscopic finding.

Results

Overall, 56.3% of patients had a CT-confirmed diagnosis of CRS. With the exception of nasal polyps, none of the symptom or endoscopic criteria had a statistically significant correlation with positive CT sinuses. For symptom criteria, positive predictive values ranged from 52.4% to 63.4%; likelihood ratios ranged from 0.85 to 1.34. For endoscopic criteria, positive predictive values and likelihood ratios were 71.4% and 1.94 (edema); 63.0% and 1.32 (discharge); and 92.9% and 10.1 (nasal polyps). 35.2% of patients with CT-confirmed CRS had normal endoscopic exams.

Conclusion

The Canadian Rhinosinusitis Guidelines' symptom and endoscopic criteria for CRS, with the exception of nasal polyps on endoscopy, do not accurately predict CT-confirmed disease. In addition, a normal endoscopic exam does not rule out CRS.

http://ift.tt/2zNvzDQ

Synergy of Pembrolizumab Anti-PD-1 Immunotherapy With Chemotherapy for Poorly Chemo-responsive Thyroid and Salivary Gland Tumors

Conditions:   Thyroid Cancer;   Salivary Gland Cancer
Interventions:   Drug: Pembrolizumab;   Drug: Docetaxel
Sponsor:   University of Chicago
Not yet recruiting

http://ift.tt/2iL8qP8

BRIDGE: Proactive Psychiatry Consultation and Case Management for Patients With Cancer

Conditions:   Cancer;   Severe Major Depression;   Schizophrenia;   Bipolar Disorder;   Lung Cancer;   Breast Cancer;   Head and Neck Cancer;   Gastrointestinal Cancer
Intervention:   Other: Proactive Psychiatry Consultation
Sponsors:   Massachusetts General Hospital;   Harvard Risk Management Foundation
Not yet recruiting

http://ift.tt/2ALAkl7

Primary Prevention of Concussion in Youth Ice Hockey Players

Condition:   Concussion
Interventions:   Other: Specific intervention;   Other: Control intervention
Sponsor:   Sport Injury Prevention Research Centre
Recruiting

http://ift.tt/2AL94mL

A Study to Evaluate the Safety, Tolerability, and Antitumor Activity of INCB001158 Plus Epacadostat, With or Without Pembrolizumab, in Advanced Solid Tumors

Condition:   Advanced or Metastatic Solid Tumors
Interventions:   Drug: INCB001158;   Drug: Epacadostat;   Drug: Pembrolizumab
Sponsor:   Incyte Corporation
Not yet recruiting

http://ift.tt/2iM3qdj

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors

Abstract

A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3⁺CD4⁻CD8⁻(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.

http://ift.tt/2jLzuuk

Post-treatment neutrophil-to-lymphocyte ratio at week 6 is prognostic in patients with advanced non-small cell lung cancers treated with anti-PD-1 antibody

Abstract

We investigated inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) that may predict the response to anti-PD-1 (programmed cell death protein 1) antibody therapy. Data from 54 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibodies were retrospectively analyzed. The NLR was assessed at baseline and 6 weeks after the start of treatment (post-treatment). Eighteen of 54 patients (33.3%) had objective responses to treatment. Older age, absence of brain metastasis, low post-treatment NLR (< 5), and immune-related adverse events were significantly associated with response. Patients with a high post-treatment NLR (≥ 5) had significantly shorter progression-free survival (PFS) than those with a low post-treatment NLR (median, 1.3 vs. 6.1 months, p < 0.001). Multivariate analysis demonstrated that high post-treatment NLR [hazard ratio (HR) 15.1, 95% confidence interval (CI) 1.5–50.1, p < 0.001], liver metastasis (HR 4.9, 95% CI 1.9–12.4, p = 0.001), and brain metastasis (HR 3.2, 95% CI 1.3–8.2, p = 0.013) were independent prognostic factors of shorter PFS. Overall survival (OS) was significantly different in patients with high and low post-treatment NLRs (median, 2.1 vs. 14.0 months, p < 0.001). A high post-treatment NLR remained an independent prognostic factor for OS in multivariate analysis (HR 3.9, 95% CI 1.6–9.2, p = 0.003). The NLR at 6 weeks after treatment initiation was a prognostic marker in patients with advanced NSCLC treated with anti-PD-1 antibody. Further studies are warranted to evaluate the role of the 6-week NLR as a predictor in anti-PD-1 antibody treatment.

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Relapsing Ipsilateral Vestibular Neuritis

In 2013, a 70-year-old male was admitted with an acute episode of vertigo, nausea, and vomiting with duration of one day. The patient's background included prehypertension, vitiligo, left ventricular hypertrophy, and Sjögren's syndrome. He denied any previous episode of vertigo or migraine manifestations. Neither hearing loss nor tinnitus or otorrhea was detected at the time of evaluation. No neurological symptoms were found. There was a left-beating spontaneous nystagmus Grade 3. The patient could stand still and walk on his own with some help without falling. Day 1 vHIT showed a significant reduction in VOR gain and refixation saccades after head impulses were delivered in the planes of the right anterior and horizontal semicircular canals. MRI showed no significant findings. He was treated with steroids. A vHIT performed 14 days later showed recovery of gains and no refixation saccades. In 2015, the patient had a new episode of acute vertigo. The clinical examination was similar, and the vHIT revealed a new drop of right superior and lateral canal gains. Cervical and ocular VEMPs were performed, and no significant asymmetry was detected. Serum PCR for herpes viruses resulted negative. Contrast MRI was performed without relevant brain findings.

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A Rare Presentation of Rhinosporidiosis

Abstract

Rhinosporidiosis is a common condition seen in India specially in endemic areas and in low socio economic areas. Here we present with a rare presentation of cheek swelling caused by obstruction of stenson's duct with a short history of 5 months. Sialolith of parotid duct is uncommon presentation but not unheard of, the subsequent treatment and further histopathology of the ductoceol reveled the causative factor for the obstruction of parotid duct was Rhinosporidiosis which a very rare presentation with very few cases reported in literature. On further investigations it was found to be primary Rhinosporidiosis. Hence it is eminent that Rhinosporidiosis should also be kept in mind while looking for a cause for salivary duct obstruction specially in endemic areas.

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