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Predictive factors for complications associated with penetrated fish bones outside the upper gastrointestinal tract

Abstract

Purpose

To investigate predictive risk factors for complications associated with migrating fish bones in the surrounding tissue of upper gastrointestinal tract.

Methods

A retrospective analysis over 12 years was conducted of 45 cases of buried fish bones in the surrounding tissue of upper gastrointestinal tract with complications. Meanwhile, a control group, including 39 cases of prolonged buried fish bones in the surrounding tissue of upper gastrointestinal tract without complications, was set. Patient clinical data were collected and analyzed to predict the risk factors for complications.

Results

The results of Chi-square test and univariate analysis both showed a significant difference in length of fish bone (> 2 cm), a history of concurrent medical illness (diabetes mellitus and renal hypofunction), symptoms (medium or heavy pain and dysphagia), and duration of significant symptoms (> 7 days) between the complication group and non-complication group. Multivariate analysis further identified length (> 2 cm), diabetes mellitus, medium or heavy pain, dysphagia, and duration of significant symptoms (> 7 days) as independent risk factors for complications.

Conclusions

The consequences of fish bones migrating outside the upper gastrointestinal tract are various in different people. Awareness should be raised when encountering a patient ingesting a long fish bone, having a history of diabetes mellitus, presenting with significant discomforts, or these discomforts lasting for a long time. This study will help practitioners counsel their patients on the risks and `benefits of surgery versus observation of this condition.

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Role of the Hydrophobic Bridge in the Carbapenemase Activity of Class D {beta}-Lactamases [Mechanisms of Resistance]

Class D carbapenemases are enzymes of utmost clinical importance due to their ability to confer resistance to the last resort carbapenem antibiotics. We investigated the role of the conserved hydrophobic bridge in the carbapenemase activity of OXA-23, the major carbapenemase of the important pathogen, Acinetobacter baumannii. We show that substitution of the bridge residue Phe110 affects resistance to meropenem and doripenem and has little effect on MICs of imipenem. The opposite effect was observed upon substitution of the other bridge residue, Met221. Complete disruption of the bridge by the F110A/M221A substitution resulted in a significant loss of affinity for doripenem and meropenem, and to a lesser extent, for imipenem, which is reflected in the reduced MICs of these antibiotics. In the wild-type OXA-23, the pyrrolidine ring of the meropenem tail forms a hydrophobic interaction with Phe110 of the bridge. Similar interactions would ensue with ring-containing doripenem but not with imipenem, which lacks this ring. Our structural studies showed that this interaction with the meropenem tail is missing in the F110A/M221A mutant. These data explain why disruption of the interaction between the enzyme and the carbapenem substrate impacts the affinity and MICs of meropenem and doripenem to a larger degree than those of imipenem. Our structures also show that the bridge directs the acylated carbapenem into a specific tautomeric conformation. However, it is not this conformation, but rather the stabilizing interaction between the tail of the antibiotic and the hydrophobic bridge that contributes to the carbapenemase activity of class D β-lactamases.

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Endonuclease Activity Inhibition of the NS1 Protein of Parvovirus B19 as a Novel Target for Antiviral Drug Development [Antiviral Agents]

Human parvovirus B19 (B19V), a member of the genus Erythroparvovirus of the family Parvoviridae, is a small non-enveloped virus that has a single-stranded DNA (ssDNA) genome of 5.6 kilobases with two inverted terminal repeats (ITRs). B19V infection often results in severe hematological disorders and fetal death in humans. B19V replication follows a model of rolling hairpin-dependent DNA replication, in which the large non-structural protein NS1 introduces a site-specific single strand nick in the viral DNA replication origins, which locate at the ITRs. NS1 executes endonuclease activity through the N-terminal origin binding domain. Nicking of the viral replication origin is a pivotal step in rolling hairpin-dependent viral DNA replication. Here, we developed a fluorophore-based in vitro nicking assay of the replication origin using the origin binding domain of the NS1 and compared it with the radioactive in vitro nicking assay. We used both assays to screen a set of small molecule compounds (96) that have potential anti-nuclease activity. We found that the fluorophore-based in vitro nicking assay demonstrate sensitivity and specificity values as high as the radioactive assay. Among the 96 compounds, we identified 8 which have an inhibition of >80% at 10 µM in both the fluorophore-based and radioactive in vitro nicking assays. We further tested 3 compounds that have flavonoid-like structure for IC₅₀in vitro that falls in the range of 1-3 µM. Importantly, they also exhibited inhibition of B19V DNA replication in UT7/Epo-S1 cells and ex vivo expanded human erythroid progenitor cells.

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Real-life experience with ceftolozane/tazobactam in patients with hematologic malignancy and Pseudomonas aeruginosa infection: a case-control study [Clinical Therapeutics]

Background:

We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam.

Materials/methods:

We performed a single-center case-control study including all patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) and compared them with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy.

Results:

Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 y vs 57.6 y, p=0.012) and less frequently had bacteremia (52.6% vs 86.8%, p=0.008). They also had a worse MASCC score (10.2 vs 16.1, p=0.0001), more hospital-acquired infections (78.9% vs 47.4%, p=0.013), and more XDR P. aeruginosa (47.4% vs 21.1%, p=0.015).

Cases received a median of 14 days (7-18) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16; 84.2%) because of resistance (9; 47.4%), failure (4; 21.1%), and toxicity (3; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue infection (5.3%). No toxicity was attributed to ceftolozane/tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis.

There were no significant differences in clinical cure at day 14 (89.5% vs 71.1%, p=0.183) or recurrence (15.8% vs 10.5%, p=0.675). Thirty-day mortality was lower among cases (5.3% vs 28.9%, p=0.045).

Conclusions:

Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains.

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Spreading patterns of NDM-producing Enterobacteriaceae in clinical and environmental settings in Yangon, Myanmar [Epidemiology and Surveillance]

The spread of carbapenemase-producing Enterobacteriaceae (CPE) has become a global concern, contributing to widespread carbapenem resistance. However, the specific dissemination patterns of carbapenemase genes have not been intensively investigated in developing countries, including Myanmar, where NDM-type carbapenemases are spreading in clinical settings. In the present study, we phenotypically and genetically characterized 91 CPE isolates obtained from clinical (n = 77) and environmental (n = 14) samples in Yangon, Myanmar. We determined the dissemination of plasmids harboring genes encoding NDM-1 and its variants using whole-genome sequencing and plasmid analysis. IncFII plasmids harboring bla_NDM-5 and IncX3 plasmids harboring bla_NDM-4 or bla_NDM-7 were the most prevalent plasmid types identified among the isolates. The IncFII plasmids were predominantly carried by clinical isolates of Escherichia coli, and their clonal expansion was observed within the same ward of a hospital. By contrast, the IncX3 plasmids were found in phylogenetically divergent isolates from clinical and environmental samples classified into nine species, suggesting the widespread dissemination of plasmids via horizontal transfer. Half of the environmental isolates were found to possess IncX3 plasmids, and this type of plasmid was confirmed to transfer more effectively to recipient organisms at a relatively low temperature (25°C) compared to the IncFII plasmid. Moreover, various other plasmid types were identified harboring bla_NDM-1, including IncFIB, IncFII, IncL/M, and IncA/C₂, among clinical isolates of Klebsiella pneumoniae or Enterobacter cloacae complex. Overall, our results highlight three distinct patterns of the dissemination of bla_NDM-harboring plasmids among CPE isolates in Myanmar, contributing to gaining a better understanding of their molecular epidemiology and dissemination in an endemic setting.

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The Fungal Cyp51 Specific Inhibitor VT-1598 Demonstrates In vitro and In vivo Activity against Candida auris [Experimental Therapeutics]

Candida auris is an emerging pathogen associated with significant mortality and often multi-drug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris. Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 hours post-inoculation with vehicle control, oral VT-1598 (5, 15, and 50 mg/kg once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm, and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 μg/mL and MICs ranging from 0.03 to 8 μg/mL. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival 15 and >21 days for VT-1598 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (1.88 to 3.61 log₁₀ CFU/g reduction) compared to control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.

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Modeling prevention of malaria and selection of drug resistance with different dosing schedules of dihydroartemisinin-piperaquine preventive therapy during pregnancy in Uganda [Clinical Therapeutics]

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and probability of genotypes of interest using nonlinear mixed effects modeling. Increasing piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant compared to wild type infections (pfmdr1 N86: 9.6 ng/mL, 86Y: 19.6 ng/mL; pfcrt K76: 6.5 ng/mL, 76T: 19.6 ng/mL). Comparing monthly, weekly, and daily dosing, daily low dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly: 607, DHA-PQ monthly: 198, DHA-PQ daily: 1; for pfcrt 76T: SP monthly: 1564, DHA-PQ monthly: 283, DHA-PQ daily: 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with pfmdr1/pfcrt mutant compared to wild type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP.

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Successful treatment of a bacteremia due to NDM-1-producing Morganella morganii with Aztreonam and Ceftazidime-avibactam combination in a pediatric patient with hematologic malignancy [Letters]

Worldwide spread of multiresistant bacteria, especially carbapenemase-producing Enterobacteriaceae, can lead to situations for which no antibiotic therapy option is available....

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The direct and indirect inhibition effects of resveratrol against Toxoplasma gondii tachyzoites in vitro [Experimental Therapeutics]

Toxoplasma gondii is one of the most widespread obligatory parasitic protozoa which infect nearly all the warm-blooded animals, leading to toxoplasmosis. Current administration of the therapeutic drugs like the combination of pyrimethamine and sulfadiazine shows high rates of toxic side effects and encounters drug resistance in some cases. Resveratrol is a natural plant extracts with multiple functions, such as anti-bacterial, anti-cancer and anti-parasite activities. In this study, we evaluated the inhibitory effects of resveratrol upon the tachyzoites of Toxoplasma gondii RH strain extracellularly and intracellularly. We demonstrated that resveratrol possessed a direct anti-toxoplasma activity by reducing the population of extracellularly grown tachyzoites, probably through disturbing the redox homeostasis of the parasites. Moreover, resveratrol was also able to release the burden of cellular stress, promote the apoptosis and maintain the autophagic status of macrophages that were turned out to be regulated by intracellular parasites, thereby functioning indirectly in eliminating T. gondii. In conclusion, resveratrol has both direct and indirect anti-toxoplasma effects against the RH tachyzoites and may possess a potential to be further evaluated and employed in toxoplasmosis treatment.

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Diverse vectors and mechanisms spread NDM beta-lactamases among carbapenem resistant Enterobacteriaceae in the Greater Boston area [Epidemiology and Surveillance]

New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM carrying strains of E. coli and E. cloacae complex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3114-bp region containing the bla_NDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed broad capacity for bla_NDM transmission by conjugation, transposition, and complex inter-plasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naïve strains to acquire multi- and extensively-drug resistance profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization, to inform clinical decisions to prevent further spread.

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Optimal Piperacillin/Tazobactam Dosing Strategies against ESBL-producing Enterobacteriaceae [Experimental Therapeutics]

Piperacillin/tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae. However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin/tazobactam to efficacy using a modified pharmacokinetic/pharmacodynamic index. Using a clinical Klebsiella pneumoniae isolate expressing CTX-M-15, piperacillin MICs were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory E_max model. A hollow fiber infection model (HFIM) was used to evaluate the efficacy of escalating tazobactam dosing with a fixed piperacillin exposure. Simulated drug concentrations from the HFIM were incorporated in the E_max model to determine the percentage of free-time above instantaneous MIC (%fT>MICi) associated with each experimental exposure. The target %fT>MICi associated with growth suppression was prospectively validated using a SHV-12-producing isolate of Escherichia coli and 2 other CTX-M-15-producing K. pneumoniae isolates. Based on our reference isolate, piperacillin/tazobactam exposures of %fT>MICi ≥55.1% were associated with growth suppression. Despite underlying differences, these findings were consistent with prospective observations in 3 other clinical isolates. Our modeling approach can be applied relatively easily in the clinical setting and appeared to be robust in predicting the effectiveness of various piperacillin/tazobactam exposures. This modified pharmacokinetic/pharmacodynamic index could be used to characterize response to other β-lactam/β-lactamase inhibitor combinations.

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An IncR Plasmid harbored by a hypervirulent, carbapenem resistant Klebsiella pneumoniae strain possesses five tandem repeats of the blaKPC-2::NTEKPC-Id fragment [Mechanisms of Resistance]

Completed sequences of three plasmids from a carbapenem-resistant, hypervirulent Klebsiella pneumoniae isolate, SH9, were obtained. In addition to the a pLVPK-like virulence-conferring plasmid (pVir-CR-HvKP_SH9), the two MDR plasmids (pKPC-CR-HvKP4_SH9 and pCTX-M-CR-HvKP4_SH9) were predicted to originate from a single pKPC-CR-HvKP4-like multi-replicon plasmid through homologous recombination. Interestingly, bla_KPC-2 gene was detectable in five tandem repeats exhibiting the format of a NTE_KPC-Id-like transposon (IS26-Tn3-ISKpn8-bla_KPC-2-ISKpn6-korC-orf-IS26). The data suggested the important role of DNA recombination on mediating active plasmid evolution.

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Two Cases of Cartilaginous Choristoma—Not Chondroma of the Bony External Auditory Canal

The presence of a cartilaginous mass on the bony external auditory canal is an unusual finding. Currently, two different diagnoses have been used to describe this type of mass: chondroma and cartilaginous choristoma. There is currently no consensus on which diagnosis is appropriate for this type of lesion. Choristoma is defined as a tumor-like growth of normal tissue occurring in an abnormal location. Histological examination alone cannot be used to distinguish between cartilaginous choristoma and chondroma, as both lesions comprise normal mature hyaline cartilage. To diagnose a mass as cartilaginous choristoma on the bony external auditory canal, it is necessary to confirm that it does not originate from the underlying periosteum. Here, we present the cases of two patients with typical cartilaginous masses on the bony external auditory canal, in which the surgical findings showed that the masses were not in contact with the underlying periosteum, indicating that cartilaginous choristoma—not chondroma—is an appropriate diagnosis for these mass lesions. The clinical findings (characteristic appearance and location) reported here may aid clinicians in the diagnostic and surgical management of these cartilaginous masses.

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Classic pseudoxanthoma elasticum in a girl with sickle cell disease

Abstract

A pseudoxanthoma elasticum (PXE)–like phenotype develops in a subset of patients with inherited hemoglobinopathies. Although PXE tissue changes are thought to develop in the absence of ABCC6 mutations in patients with beta‐thalassemia, ABCC6 mutations have not been well evaluated among sickle cell disease patients with PXE‐like disease. To our knowledge, we describe the first patient with sickle cell disease, PXE skin findings, and two confirmed pathogenic ABCC6 mutations. This case suggests that ABCC6 testing is warranted for sickle cell disease patients with the PXE‐like phenotype and that the pathogenesis of PXE manifestations in beta‐thalassemia and sickle cell disease may differ.

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When It Isn’t Tonsillitis

Repeated bouts of strep throat and suspected tonsillitis led Shelby Boatwright's primary care physician to refer her to William Yao,...

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ENT Doctors at UT Physicians Provide Comprehensive ENT Care in Southeast Houston

The Department of Otorhinolaryngology-Head & Neck Surgery at McGovern Medical School at UTHealth now offers comprehensive care in southeast Houston....

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UT Physicians Sinus Surgeons Use Augmented Reality Technology During Minimally Invasive Sinus Procedures.

"Augmented reality, which uses 3-D mapping and imagery, enhances our understanding of complex anatomy so surgical procedures are more precise,"...

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Disseminated Histoplasmosis with Miliary Histoplasmosis, Neurohistoplasmosis, and Histoplasma capsulatum Bacteremia in Probable Neurosarcoidosis

Introduction. Neurosarcoidosis, either isolated or as part of systemic sarcoidosis, is an uncommon entity and has diagnostic uncertainty. Treatment for neurosarcoidosis can increase the risk of infections, including fungal infections such as disseminated histoplasmosis. Neurosarcoidosis may further predispose patients to infections of the central nervous system. Case Presentation. A 54-year-old male with a history of probable neurosarcoidosis on methotrexate and infliximab presented with encephalopathy, hypoxia, and reported fevers. The patient was found to have disseminated histoplasmosis involving the lungs (miliary histoplasmosis), central nervous system (neurohistoplasmosis), and bloodstream. The Histoplasma capsulatum infection was treated with amphotericin and then voriconazole. Discussion. Patients with neurosarcoidosis are suspected to have blood-brain barrier dysfunction. Lumbar puncture should be considered as part of initial investigative studies for infection. Empiric antimicrobial therapy for a patient with neurosarcoidosis on immunosuppressive agents may need to include antifungal agents.

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Radical espontânea por cole de MAE

Radical espontânea por cole de MAE

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Colesteatoma de MAE-Inicial

Colesteatoma de MAE -Inicial

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Thrombosis of the internal jugular vein in the ENT-department — Prevalence, causes and therapy: A retrospective analysis

Less than 5% of deep vein thrombosis is due to thrombosis of the internal jugular vein. Genetic, malignant or inflammatory underlying diseases as well as insertion of venous catheters can be responsible for this pathology. Due to its rare occurrence, it is difficult to find systematic research about thrombosis of the internal jugular vein.

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Sinonasal inverted papilloma associated with small cell neuroendocrine carcinoma: A case report and literature review of rare malignancies associated with inverted papilloma

We report a rare case of sinonasal inverted papilloma (IP) associated with small cell neuroendocrine carcinoma (SNEC). To our knowledge, this is the first report to describe SNEC found during the treatment of sinonasal IP. Surgery and five cycles of cisplatin plus etoposide with concurrent intensity modulated radiation therapy were performed. Neither local recurrence nor distant metastasis was noted during 6 years of post-diagnostic follow-up. The prognosis of SNEC is very poor. Treatment planning for sinonasal IP should consider a possible association with this rare but aggressive malignancy, whose treatment is completely different from that of squamous cell carcinoma, a malignancy which is commonly associated with IP.

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Diagnosis and Management of Delusional Parasitosis

Delusional parasitosis can be effectively managed with second generation antipsychotic agents. Extrapyramidal and metabolic side effects are major limiting factors in the choice of therapy.Based on the published data on efficacy, incidence of side effects and attributable risk, risperidone (.5-4mg/day) is a reasonable first-line choice for pharmacotherapy.

https://ift.tt/2C42CHp

Factors associated with suspected nonmelanoma skin cancers, dysplastic nevus, and cutaneous melanoma among first-time SPOTme screening program participants (2009-2010)

No study of the SPOTme program to date has comprehensively analyzed the risk factors associated with suspected non-melanoma skin cancers, dysplastic nevi, and cutaneous melanoma. This research underscores key shared risk factors that can be meaningful for earlier detection of cutaneous malignancies.

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In This Issue [IN THIS ISSUE]

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Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling [TRANSPLANTATION]

Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB-, C3-, C4-, C5-, C5aR1-, C5aR2-, and C6-deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1β, IL-9, and IL-12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI.

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CD8{alpha}+ Dendritic Cells Dictate Leukemia-Specific CD8+ T Cell Fates [TUMOR IMMUNOLOGY]

APCs are essential for the orchestration of antitumor T cell responses. Batf3-lineage CD8α⁺ and CD103⁺ dendritic cells (DCs), in particular, are required for the spontaneous initiation of CD8⁺ T cell priming against solid tumors. In contrast, little is known about the APCs that regulate CD8⁺ T cell responses against hematological malignancies. Using an unbiased approach, we aimed to characterize the APCs responsible for regulating CD8⁺ T cell responses in a syngeneic murine leukemia model. We show with single-cell resolution that CD8α⁺ DCs alone acquire and cross-present leukemia Ags in vivo, culminating in the induction of leukemia-specific CD8⁺ T cell tolerance. Furthermore, we demonstrate that the mere acquisition of leukemia cell cargo is associated with a unique transcriptional program that may be important in regulating tolerogenic CD8α⁺ DC functions in mice with leukemia. Finally, we show that systemic CD8α⁺ DC activation with a TLR3 agonist completely prevents their ability to generate leukemia-specific CD8⁺ T cell tolerance in vivo, resulting instead in the induction of potent antileukemia T cell immunity and prolonged survival of leukemia-bearing mice. Together, our data reveal that Batf3-lineage DCs imprint disparate CD8⁺ T cell fates in hosts with solid tumors versus systemic leukemia.

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Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida [INNATE IMMUNITY AND INFLAMMATION]

The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to Francisella tularensis subspecies novicida infection, leading to maturation of IL-1β and IL-18 and pyroptosis. AIM2 is critical for host protection against F. novicida infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase-1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to F. novicida infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in F. novicida–infected bone marrow–derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow–derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome.

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The Goldilocks Zone of Type I IFNs: Lessons from Human Genetics [BRIEF REVIEWS]

Type I IFNs (IFN-Is) are powerful cytokines. They provide remarkable protection against viral infections, but their indiscriminate production causes severe self-inflicted damage that can be lethal, particularly in early development. In humans, inappropriately high IFN-I levels caused by defects in the regulatory mechanisms that control IFN-I production and response result in clinical conditions known as type I interferonopathies. In essence, type I interferonopathies define the upper limit of safe, IFN-related inflammation in vivo. Conversely, the loss of IFN-I responsiveness increases susceptibility to viral infections, but, surprisingly, most affected individuals survive despite these inborn errors of immunity. These findings suggest that too much IFN-I early in life is toxic, but that insensitivity to IFN-I is perhaps not the death sentence it was initially thought to be. Human genetic analyses have suggested that seemingly insignificant levels of IFN-regulated gene activity may be sufficient for most of the antiviral defenses used by humans in natura.

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Filtering Next-Generation Sequencing of the Ig Gene Repertoire Data Using Antibody Structural Information [SYSTEMS IMMUNOLOGY]

Next-generation sequencing of the Ig gene repertoire (Ig-seq) produces large volumes of information at the nucleotide sequence level. Such data have improved our understanding of immune systems across numerous species and have already been successfully applied in vaccine development and drug discovery. However, the high-throughput nature of Ig-seq means that it is afflicted by high error rates. This has led to the development of error-correction approaches. Computational error-correction methods use sequence information alone, primarily designating sequences as likely to be correct if they are observed frequently. In this work, we describe an orthogonal method for filtering Ig-seq data, which considers the structural viability of each sequence. A typical natural Ab structure requires the presence of a disulfide bridge within each of its variable chains to maintain the fold. Our Ab Sequence Selector (ABOSS) uses the presence/absence of this bridge as a way of both identifying structurally viable sequences and estimating the sequencing error rate. On simulated Ig-seq datasets, ABOSS is able to identify more than 99% of structurally viable sequences. Applying our method to six independent Ig-seq datasets (one mouse and five human), we show that our error calculations are in line with previous experimental and computational error estimates. We also show how ABOSS is able to identify structurally impossible sequences missed by other error-correction methods.

https://ift.tt/2RNSdVO

Blocking Matrix Metalloproteinase-9 Abrogates Collagen-Induced Arthritis via Inhibiting Dendritic Cell Migration [AUTOIMMUNITY]

Trafficking of dendritic cells (DCs) to lymph nodes (LNs) to present Ags is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Matrix metalloproteinase-9 (MMP-9) is the key molecule for DC migration. Thus, blocking MMP-9 to inhibit DC migration may be a novel strategy to treat RA. In this study, we used anti–MMP-9 Ab to treat collagen-induced arthritis (CIA) in DBA/1J mice and demonstrated that anti–MMP-9 Ab treatment significantly suppressed the development of CIA via the modulation of DC trafficking. In anti–MMP-9 Ab–treated CIA mice, the number of DCs in draining LNs was obviously decreased. In vitro, anti–MMP-9 Ab and MMP-9 inhibitor restrained the migration of mature bone marrow–derived DCs in Matrigel in response to CCR7 ligand CCL21. In addition, blocking MMP-9 decreased T and B cell numbers in LNs of CIA mice but had no direct influence on the T cell response to collagen II by CD4⁺ T cells purified from LNs or spleen. Besides, anti–MMP-9 Ab did not impact on the expression of MHC class II, CD40, CD80, CD86, and chemokine receptors (CCR5 and CCR7) of DCs both in vivo and in vitro. Furthermore, we discovered the number of MMP-9^–/– DCs trafficking from footpads to popliteal LNs was dramatically reduced as compared with wild type DCs in both MMP-9^–/– mice and wild type mice. Taken together, these results indicated that DC-derived MMP-9 is the crucial factor for DC migration, and blocking MMP-9 to inhibit DC migration may constitute a novel strategy of future therapy for RA and other similar autoimmune diseases.

https://ift.tt/2QnuG17

High Fc{gamma}R Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy [TUMOR IMMUNOLOGY]

Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL-2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8⁺ T cells all mitigated the therapeutic response, showing a coordinated immune rejection by innate and adaptive immune cells. FcRs were essential for the therapeutic effect, with a dominant role for FcRI and a minor role for FcRIII and FcRIV. FcR expression on NK cells and granulocytes was dispensable, indicating that other tumoricidal functions of NK cells were involved and implicating that FcRI, -III, and -IV exerted their activity on macrophages. Indeed, F4/80⁺Ly-6C⁺ inflammatory macrophages in the tumor microenvironment displayed high levels of these receptors. Whereas administration of the anti-TRP1 Ab alone reduced the frequency of these macrophages, the combination with a TLR agonist retained these cells in the tumor microenvironment. Thus, the addition of innate stimulatory compounds, such as TLR ligands, to tumor-specific Ab therapy could greatly enhance its efficacy in solid cancers via optimal exploitation of FcRs.

https://ift.tt/2RRjYNa

Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential [NOVEL IMMUNOLOGICAL METHODS]

In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor–recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.

https://ift.tt/2RWiAbW

Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus-Specific CD8+ T Cells [CUTTING EDGE]

Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8⁺ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8⁺ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8⁺ T cells are characterized by a polyfunctional IFN- signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8⁺ T cells responding to ZIKV infection.

https://ift.tt/2Qmre7d

Programming of CD8 T Cell Quantity and Polyfunctionality by Direct IL-1 Signals [INFECTIOUS DISEASE AND HOST RESPONSE]

IL-1, generally considered an amplifier of adaptive immune responses, has been proposed for use as adjuvant during immunization with weak immunogens. However, its effects on memory T cell function remain largely undefined. Using the murine model of acute viral infection, in this paper, we show that in addition to augmenting the size of the Ag-specific pool, IL-1 signals act directly on CD8 T cells to promote the quality of effector and memory responses. Ablation of IL-1R1 or MyD88 signaling in T cells led to functional impairment; both the ability to produce multiple cytokines on a per cell basis (polyfunctionality) and the potential for recall proliferation in response to antigenic restimulation were compromised. IL-1 supplementation during priming augmented the expansion of Ag-specific CD8 T cells through the MyD88–IRAK1/4 axis, resulting in a larger memory pool capable of robust secondary expansion in response to rechallange. Together, these findings demonstrate a critical role of the IL-1–MyD88 axis in programming the quantity and quality of memory CD8 T cell responses and support the notion that IL-1 supplementation may be exploited to enhance adoptive T cell therapies against cancers and chronic infections.

https://ift.tt/2RJZENv

Cutting Edge: B Cells Expressing Cyclic Citrullinated Peptide-Specific Antigen Receptor Are Tolerized in Normal Conditions [CUTTING EDGE]

Generation of neoantigens by citrullination is implicated in the production of anti–citrullinated protein Abs in rheumatoid arthritis, but citrullination is also a physiological process. To verify whether citrullin-specific B cells are immunologically ignorant or tolerant in normal conditions, transgenic (Tg) mice expressing IgM with the V region of an anti–cyclic citrullinated peptide (CCP) mAb cloned from a rheumatoid arthritis patient were generated. CCP-specific B cells developed in the anti-CCP IgM Tg mice with an alteration of bone marrow B cell fractions, and the number of mature B cells decreased compared with wild-type or the control anti–influenza nucleoprotein–specific IgM Tg mice. In addition, B cells in anti-CCP IgM Tg mice are functionally anergic. Thus, tolerance is induced in CCP-specific B cells in vivo, suggesting that the immune systems are naturally exposed to citrullinated Ags, and anti-CCP Ab production requires additional steps beyond the generation of neoantigens by citrullination.

https://ift.tt/2Qs2hqL

Cutting Edge: FHR-1 Binding Impairs Factor H-Mediated Complement Evasion by the Malaria Parasite Plasmodium falciparum [CUTTING EDGE]

Human complement is the first line of defense against invading pathogens, including the malaria parasite Plasmodium falciparum. We previously demonstrated that human complement represents a particular threat for the clinically relevant blood stages of the parasite. To evade complement-mediated destruction, the parasites acquire factor H (FH) via specific receptors. We now report that the FH-related protein FHR-1 competes with FH for binding to the parasites. FHR-1, which is composed of five complement control protein domains with variable homology to FH but lacks C3b regulatory activity, accumulates on the surfaces of intraerythrocytic schizonts and free merozoites. Although binding of FH to schizont-infected RBCs and merozoites is increased in FHR-1–deficient human serum, the addition of recombinant FHR-1 decreases FH binding. The presence of FHR-1 consequently impairs C3b inactivation and parasite viability. We conclude that FHR-1 acts as a protective factor in human immunity by counteracting FH-mediated microbial complement evasion.

https://ift.tt/2Qnv7sh

TLR-7 Stress Signaling in Differentiating and Mature Eosinophils Is Mediated by the Prolyl Isomerase Pin1 [ALLERGY AND OTHER HYPERSENSITIVITIES]

The response of eosinophils (Eos) to respiratory virus has emerged as an important link between pulmonary infection and allergic asthmatic exacerbations. Eos activate innate immune responses through TLR signaling. In this study, using mouse and human Eos and mice lacking the prolyl isomerase Pin1 selectively in Eos, we show that Pin1 is indispensable for eosinophilopoiesis in the bone marrow (BM) and mature cell function in the presence of TLR7 activation. Unbiased in vivo analysis of mouse models of allergic airway inflammation revealed that TLR7 activation in knockout mice resulted in systemic loss of Eos, reduced IFN production, and an inability to clear respiratory viruses. Consistent with this finding, BM mouse Eos progenitors lacking Pin1 showed markedly reduced cell proliferation and survival after TLR7 activation. Mechanistically, unlike wild-type cells, Pin1 null mouse Eos were defective in the activation of the endoplasmic reticulum stress-induced unfolded protein response. We observed significant reductions in the expression of unfolded protein response components and target genes, aberrant TLR7 cleavage and trafficking, and reduced granule protein production in knockout Eos. Our data strongly suggest that Pin1 is required for BM Eos generation and function during concurrent allergen challenge and viral infection.

https://ift.tt/2QqfSic

The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell-Specific Expression of RALDH2 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

RALDH2 expressed in dendritic cells (DCs) plays a critical role in the development of regulatory T cells in mesenteric lymph nodes. Despite the importance of RALDH2 in intestinal immunity, little is known about the mechanism of DC-specific expression of RALDH2. In the current study, we focused on the hematopoietic cell–specific transcription factors PU.1 and IRF4 as the determinants of Aldh1a2 gene expression. The mRNA level of Aldh1a2, and subsequently the enzyme activity, were decreased by knockdown of PU.1 and IRF4 in bone marrow–derived DCs (BMDCs) of BALB/c mice. Chromatin immunoprecipitation assays showed that PU.1 and IRF4 bound to the Aldh1a2 gene ~2 kb upstream from the transcription start site in BMDCs. A reporter assay and an EMSA revealed that the Aldh1a2 promoter was synergistically transactivated by a heterodimer composed with PU.1 and IRF4 via the EICE motif at –1961/–1952 of the gene. The effect of small interfering RNAs for Spi1 and Irf4 and specific binding of PU.1 and IRF4 on the Aldh1a2 gene were also observed in DCs freshly isolated from spleen and mesenteric lymph nodes, respectively. GM-CSF stimulation upregulated the Aldh1a2 transcription in Flt3 ligand–generated BMDCs, in which the IRF4 expression and the PU.1 recruitment to the Aldh1a2 promoter were enhanced. We conclude that PU.1 and IRF4 are transactivators of the Aldh1a2 gene in vitro and ex vivo.

https://ift.tt/2RQ1QmI

DRB4*01:01 Has a Distinct Motif and Presents a Proinsulin Epitope That Is Recognized in Subjects with Type 1 Diabetes [AUTOIMMUNITY]

DRB4*01:01 (DRB4) is a secondary HLA-DR product that is part of the high-risk DR4/DQ8 haplotype that is associated with type 1 diabetes (T1D). DRB4 shares considerable homology with HLA-DR4 alleles that predispose to autoimmunity, including DRB1*04:01 and DRB1*04:04. However, the DRB4 protein sequence includes distinct residues that would be expected to alter the characteristics of its binding pockets. To identify high-affinity peptides that are recognized in the context of DRB4, we used an HLA class II tetramer-based approach to identify epitopes within multiple viral Ags. We applied a similar approach to identify antigenic sequences within glutamic acid decarboxylase 65 and pre-proinsulin that are recognized in the context of DRB4. Seven sequences were immunogenic, eliciting high-affinity T cell responses in DRB4⁺ subjects. DRB1*04:01-restricted responses toward many of these peptides have been previously described, but responses to a novel pre-proinsulin 9–28 peptide were commonly observed in subjects with T1D. Furthermore, T cells that recognized this peptide in the context of DRB4 were present at significantly higher frequencies in patients with T1D than in healthy controls, implicating this as a disease-relevant specificity that may contribute to the breakdown of β cell tolerance in genetically susceptible individuals. We then deduced a DRB4 motif and confirmed its key features through structural modeling. This modeling suggested that the core epitope within the pre-proinsulin 9–28 peptide has a somewhat unusual binding motif, with tryptophan in the fourth binding pocket of DRB4, perhaps influencing the availability of this complex for T cell selection.

https://ift.tt/2QqCoYw

Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3+ Regulatory T Cells [IMMUNE REGULATION]

Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3⁺ regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell–mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation.

https://ift.tt/2QrCtLB

Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease [CLINICAL AND HUMAN IMMUNOLOGY]

Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1β and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1β and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1β and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1β and IL-18 and seemed to suppress the production of IL-1β and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD.

https://ift.tt/2QrCxuP

Multiplexed FluoroSpot for the Analysis of Dengue Virus- and Zika Virus-Specific and Cross-Reactive Memory B Cells [NOVEL IMMUNOLOGICAL METHODS]

Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne pathogens that have a significant impact on human health. Immune sera, mAbs, and memory B cells (MBCs) isolated from patients infected with one DENV type can be cross-reactive with the other three DENV serotypes and even more distantly related flaviviruses such as ZIKV. Conventional ELISPOTs effectively measure Ab-secreting B cells but because they are limited to the assessment of a single Ag at a time, it is challenging to distinguish serotype-specific and cross-reactive MBCs in the same well. We developed a novel multifunction FluoroSpot assay using fluorescently labeled DENV and ZIKV (FLVs) that measures the cross-reactivity of Abs secreted by single B cells. Conjugation efficiency and recognition of FLVs by virus-specific Abs were confirmed by flow cytometry. Using a panel of DENV immune, ZIKV immune, and naive PBMC, FLVs were able to simultaneously detect DENV serotype-specific, ZIKV-specific, DENV serotype cross-reactive, and DENV/ZIKV cross-reactive Abs secreted by individual MBCs. Our findings indicate that the FLVs are sensitive and specific tools to detect specific and cross-reactive MBCs. These reagents will allow the assessment of the breadth as well as the durability of DENV/ZIKV B cell responses following vaccination or natural infection. This novel approach using FLVs in a FluoroSpot assay can be applied to other diseases such as influenza in which prior immunity with homosubtype- or heterosubtype-specific MBCs may influence subsequent infections.

https://ift.tt/2RNSb08

Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool [CLINICAL AND HUMAN IMMUNOLOGY]

Autonomous migration is a central characteristic of immune cells, and changes in this function have been correlated to the progression and severity of diseases. Hence, the identification of pathologically altered leukocyte migration patterns might be a promising approach for disease surveillance and prognostic scoring. However, because of the lack of standardized and robust assays, migration patterns have not been clinically exploited so far. In this study, we introduce an easy-to-use and cross-laboratory, standardized two-dimensional migration assay for neutrophil granulocytes from peripheral blood. By combining time-lapse video microscopy and automated cell tracking, we calculated the average migration of neutrophils from 111 individual participants of the German Heinz Nixdorf Recall MultiGeneration study under steady-state, formyl-methionyl-leucyl-phenylalanine–, CXCL1-, and CXCL8-stimulated conditions. Comparable values were obtained in an independent laboratory from a cohort in Belgium, demonstrating the robustness and transferability of the assay. In a double-blinded retrospective clinical analysis, we found that neutrophil migration strongly correlated with the Revised International Prognostic Scoring System scoring and risk category of myelodysplastic syndrome (MDS) patients. In fact, patients suffering from high-risk subtypes MDS with excess blasts I or II displayed highly significantly reduced neutrophil migration. Hence, the determination of neutrophil migration patterns might represent a useful tool in the surveillance of MDS. Taken together, we suggest that standardized migration assays of neutrophils and other leukocyte subtypes might be broadly applicable as prognostic and surveillance tools for MDS and potentially for other diseases.

https://ift.tt/2QmqOgW

Talin1 Methylation Is Required for Neutrophil Infiltration and Lipopolysaccharide-Induced Lethality [INNATE IMMUNITY AND INFLAMMATION]

Talin1, a well-established integrin coactivator, is critical for the transmigration of neutrophils across the vascular endothelium into various organs and the peritoneal cavity during inflammation. Several posttranslational modifications of talin1 have been proposed to play a role in this process. In this study, we show that trimethylation of talin1 at Lys2454 by cytosolic Ezh2 is substantially increased in murine peritoneal neutrophils upon induction of peritonitis. By reconstituting talin1-deficient mouse myeloid cells with wild-type, methyl-mimicking, or unmethylatable talin1 variants, we demonstrate that methylation of talin1 at Lys2454 is important for integrin-dependent neutrophil infiltration into the peritoneal cavity. Furthermore, we show that treatment with an Ezh2 inhibitor or reconstitution of talin1-deficient myeloid cells with unmethylatable talin1 significantly reduces the number of organ-infiltrating neutrophils and protects mice from LPS-induced mortality.

https://ift.tt/2RNnok3

Destructive lesion of the temporomandibular joint: A case of tophaceous pseudogout

Jessica B. Howell, MD; Yula A. Indeyeva, MD; Stephanie E. Ambrose, MD; Evan R. Reiter, MD

Abstract

Tophaceous pseudogout of the temporomandibular joint is a rare entity that clinically and radiographically mimics neoplastic or infectious conditions. Diagnosis requires histopathologic examination. Given the rarity of this condition, there is a paucity of information pertaining to the surgical approach, reconstructive options, and postoperative outcomes.

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Association of Meniere disease with human leukocyte antigen in Taiwanese population

Kai-Chieh Chan, MD; Che-Ming Wu, MD; Wan-Ling Ho, MD, PhD; Ping-Chin Lai, MD, PhD

Abstract

The etiology of Ménière disease (MD) is multifactorial; genetic factors seem to play an important role. The associations between MD and human leukocyte antigen (HLA) status have been studied previously in several populations and have shown that the HLA alleles imparting susceptibility varied. In the present study, we explored HLA status in Taiwanese patients with definitive MD. HLA was typed via polymerase chain reaction, sequence-specific oligonucleotide genotyping in 35 patients with MD diagnosed using the criteria of the American Academy of Otolaryngology-Head and Neck Surgery and 70 unrelated healthy controls. HLA allele association tests were used to evaluate differences in allelic frequencies between the patients and controls. The allelic frequency of HLA-A*11 was significantly greater in MD patients than in controls (52.9 vs. 31.4%, odds ratio: 2.45, 95% confidence interval: 1.4 to 4.4, p = 0.004, p corrected = 0.03). Thus, A*11 may be a useful HLA biomarker in Taiwanese patients with MD. Further larger-scale studies are required.

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Evaluation of bendable surgical suction devices made of shape-memory alloy for the endonasal transsphenoid removal of pituitary tumors

Ronny Grunert, PhD; Sandra Klietz, BEng; Paul A. Gardner, MD; Juan C. Fernandez-Miranda, MD; Carl H. Snyderman, MD, MBA

Abstract

In minimally invasive surgeries, it can be difficult to reach desired anatomic areas with rigid instruments, especially when obstacles are present in the surgical corridor (e.g., during transnasal pituitary surgery). We developed a new kind of suction device constructed of the shape-memory alloy Nitinol (nickel titanium), which is adaptable to a patient's specific anatomy. Use of this device minimizes surgical risks by allowing physicians to use an endonasal transsphenoid approach. The suction device, which is equipped with a cannula made of the shape-memory alloy, was planned and manufactured with three different handpiece designs. Experienced pituitary surgeons tested the prototypes in human cadaver skulls and rated the devices on specific questionnaires. The results of their evaluation indicate that this device is a suitable tool for improving the surgical procedure. Its potential benefits include a more effective surgery and reductions in the risk of injury, the duration of surgery, and costs.

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A fistulating oropharyngeal lesion

Richard Heyes, MBChB (Hons), MRCS DO-HNS; Courtney M. Tomblinson, MD; David G. Lott, MD

Abstract

Post-transplant lymphoproliferative disorder (PTLD) is a unifying term for a spectrum of lymphoid expansion entities brought about by immunosuppression. It can present throughout the head and neck, and tonsillar involvement is not limited to children. We report the case of a 67-year-old woman who developed odynophagia associated with putrid halitosis 4 months after she had undergone renal transplantation. Direct visualization of the oropharynx revealed multiple sites of severe ulceration and erythema, with erosion of both the anterior and posterior right tonsillar pillars and a necrotic ulceration fistulating deeply. Biopsy analysis led to a diagnosis of PTLD. The patient underwent rituximab monotherapy and responded well. However, after the cessation of therapy, she experienced a recurrence that necessitated chemotherapy, which resulted in a lasting remission. At follow-up 5 years later, she remained PTLD-free with stable stage 4 chronic kidney disease.

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The root cause of physician burnout cannot be solved with resilience efforts

Michael M. Johns, MD, III

The burnout problem can be traced largely to loss of physician autonomy and marginalization of physicians in decision making.

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Laryngeal hereditary hemorrhagic telangiectasia

Jerome R. Lechien, PHD, MS; Camille Finck, MD, PhD

Laryngeal telengiectasia involving the vocal folds is known to cause hemorrhages, which are often difficult to control given the vascular wall fragility.

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Stapes footplate defect as a source of CSF leak and otogenic meningitis in a patient with a cochlear implant

Maria Vartanyan, MD; Fiona Hill, MBBS; Kumiko Orimoto, MD, PhD; Stephen O'Leary, PhD, FRACS, FAHMS

Clinicians should be proactive in ensuring that cochlear implant patients have received comprehensive immunization.

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Aggressive fibromatosis of the parotid gland

Vishaal Patel, MD; Virginia Falvello, MD; Marion Hughes, MD; Barry Schaitkin, MD

Abstract

Extra-abdominal fibromatosis (EAF) is a rare, locally aggressive tumor that originates in fascial structures. It accounts for less than 0.3% of all tumors diagnosed. Head and neck tumors account for only 7% of those, and only a few cases occurring in the parotid gland have been previously reported. We describe the case of a 34-year-old woman who presented with a painful parotid mass. She was found to have an EAF of her right parotid gland. Medical management with antibiotics and immunosuppression therapy was unsuccessful. Surgical resection was required for both a definitive diagnosis and management. Preoperative findings on computed tomography, magnetic resonance imaging, and both fine-needle aspiration biopsy and surgical biopsy were nonspecific, as is typical in EAF cases.

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An unusual presentation of papillary thyroid carcinoma in a pediatric patient: A case report

Matthew G. Cravens, BS, BA; Tyson J. Nielsen, MD; Erynne A. Faucett, MD; Audrey B. Erman, MD

Abstract

Cystic neck masses in the pediatric population are common but rarely concerning for malignancy. Given this typically benign nature, they are frequently managed conservatively. Here we present an unusual case of a waxing and waning cystic neck mass in a pediatric patient. After surgical removal, the mass was found to be metastatic papillary thyroid cancer. This is a unique presentation in the pediatric age group that has not yet been described. Based on this case, we suggest an expanded differential in any workup for a cystic neck mass to include papillary thyroid carcinoma, regardless of the patient's age.

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Huge neck lymphangioma removed in toto with minimal access

Vikas Malhotra, MBBS, MS(ENT), DNB; Nikhil Arora, MBBS, MS(ENT), DNB; Pankhuri Mittal, MBBS, MS(ENT), DNB

Treatment selection should be based on the size, depth, and location of the lesion, as well as potential morbidity and surgical complications.

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Design and psychometric testing of the Attitude towards the Prevention of IAD instrument

https://ift.tt/2rv1MNJ

Epidemiologie primärer Hirntumoren bei Kindern und Erwachsenen in Deutschland

Zusammenfassung

Der Artikel gibt einen Überblick über die Epidemiologie primärer Hirntumoren in Deutschland, basierend auf den Daten der bevölkerungsbezogenen Krebsregister der Bundesländer, Krebsregistern und dem deutschen Kinderkrebsregister. Etwa 6700 Personen erkrankten im Jahr 2014 in Deutschland an einem bösartigen Hirntumor, davon 229 Kinder. 5770 Menschen starben im Jahr 2015 an dieser Erkrankung. Die alterststandardisierten Erkrankungs- und Sterberaten zeigen seit 1999 keine wesentlichen Veränderungen. Bei Erwachsenen machen die hochmalignen Glioblastome (Astrozytome WHO-Grad IV) mehr als zwei Drittel aller Erkrankungen aus, während bei Kindern die embryonalen Tumoren mit etwa einem Drittel der Fälle die häufigste Form darstellen. Die Prognose ist abhängig von der Histologie; relative Fünfjahresüberlebensraten liegen zwischen Werten deutlich unter 10 % (Astrozytom IV) und um 80 % (Ependymome und Keimzelltumoren). Nichtmaligne Tumoren des hirneigenen Gewebes (ohne Tumoren der Hirnnerven und -häute) sind mit geschätzten rund 850 Neuerkrankungen pro Jahr vergleichsweise selten.

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Gliome

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Microneedling by dermapen and glycolic acid peel for the treatment of acne scars: Comparative study

Summary

Background

Many methods have been performed to achieve a satisfying outcome in acne scars but some of them were high cost and also were associated with low results and some complications.

Objectives

To evaluate and compare the efficacy and safety therapy of glycolic acid (GA) peel, microneedling with dermapen and a combination of both procedures in treatment of atrophic acne scars.

Patents and methods

This study was conducted on 30 patients suffering from acne scars. They were randomly assigned into three groups, each group included 10 patients; group I was treated with GA peel, group II treated was with microneedling. Group III received a combination of both procedures. All patients received six sessions with 2‐week intervals. The clinical assessment was based on the qualitative global scar grading system before and after treatment, quartile grading scale, and degree of patient satisfaction.

Results

There was a statistically significant decrease in acne scars grade after treatment among the studied groups (P = 0.04) but it was higher in group III. There was improvement in boxcar, ice pick, and rolling scars in all groups, respectively (P = 0.03, P = 0.04, P = 0.04). Patients' satisfaction was higher in group III (P = 0.04).

Conclusion

The combination of dermapen and GA peel is more effective than monotherapy.

https://ift.tt/2zRIDdn

Six years of experience using an advanced algorithm for botulinum toxin application

Summary

Background

Botulinum toxin (BTX) products continue to be widely used for facial rejuvenation. Variables to consider prior to BTX treatment include the anatomical area to be treated, gender, muscle mass, ethnicity, skin thickness, and the effects of aging.

Objective

To describe a treatment algorithm which has been developed for facial rejuvenation to help physicians to easily and systematically customize BTX treatment, and to describe its use in a large number of patients.

Methods and Materials

Prior to treatment, digital images of patients were obtained while relaxed and while forming different facial expressions. This information was used to plan the depth, dose, and location of BTX injections (onabotulinumtoxinA; Botox^®; Allergan, Inc). Dilution was 100 U of BTX to 1 mL 0.9% preserved saline. Injections were performed with 30 U insulin syringes and 30 gauge needles.

Results

The treatment algorithm described here has been used by the author for facial rejuvenation for more than 5 years. It was originally based on published guidelines; however, by carefully noting treatment outcomes, the number and location of injection points and the dose of BTX used have been modified to create the current treatment system.

Conclusion

Published guidelines for the use of BTX are an excellent starting point for clinicians with little experience; however, each practitioner is likely to develop their own algorithm for achieving good facial rejuvenation outcomes.

https://ift.tt/2PvN2YH

Evaluation of oral tranexamic acid in the treatment of melasma

Summary

Background

Melasma is an acquired, chronic, recurrent hypermelanosis that occurs exclusively in areas exposed to the sun. Its treatment can be very challenging. Tranexamic acid (TA) is an inhibitor of plasmin, and it is a synthetic derivative of the amino acid lysine that reversibly blocks binding sites on the plasminogen molecule, inhibiting the plasminogen activator from converting plasminogen to plasmin.

Aims

This study evaluated the efficacy of oral TA in the treatment of melasma in patients from a philanthropic dermatological clinic.

Patients/Methods

This was a monocentric, randomized, double‐blind, controlled clinical trial. Patients with facial melasma were randomly divided into the following two groups: A (TA 250 mg orally twice daily) or B (oral placebo twice daily). Evaluations were performed before and after 12 weeks of treatment with photographs, colorimetry, MELASQoL, and MASI. All patients were instructed to use tinted sunscreen (SPF 50).

Results

Of the 47 patients selected, 37 completed the study, with 20 in group A and 17 in group B; the patients consisted of one male and 36 females, and the mean age was 43.97 years old. Based on the four methods of evaluation, the melasma in 50% of patients in group A improved versus only 5.9% of patients in group B (P < 0.005). There was an improvement according to all evaluation methods in the treatment group. No patient had severe side effects.

Conclusions

We conclude that tranexamic acid was effective in 50% of patients according to four methods of evaluation when compared to the placebo.

https://ift.tt/2PvkVZt

Difficult-to-diagnose diabetes in a patient treated with cyclophosphamide – the contradictory roles of immunosuppressant agents: a case report

Cyclophosphamide may induce autoimmune diabetes through a decrease in suppressor T cells and increase of proinflammatory T helper type 1 response in animal models. In humans, this association is not as clear d...

https://ift.tt/2zTlYgX

A comprehensive ontologies-based framework to support the retrofitting design of energy-efficient districts

Costa, G; Sicilia, A; Lilis, GN; Rovas, DV; Izkara, J; (2016) A comprehensive ontologies-based framework to support the retrofitting design of energy-efficient districts. In: Christodoulou, SE and Scherer, R, (eds.) Proceedings of the 11th European Conference on Product and Process Modelling (ECPPM2016),. (pp. pp. 673-681). CRC Press, Taylor & Francis Group: Limassol, Cyprus. Green open access

https://ift.tt/2rtHLHm

Lessons from the Rademacher complexity for deep learning

Sokolic, J; Gyries, R; Sapiro, G; Rodrigues, MRD; (2016) Lessons from the Rademacher complexity for deep learning. In: Bengio, Samy and Kingsbury, Brian, (eds.) Proceedings of the workshop track - International Conference on Learning Representations 2016: ICLR 2016. ICLR: San Juan, Puerto Rico.

https://ift.tt/2G9EYgQ

3D printed micro-scale fiber optic probe for intravascular pressure sensing

Poduval, R; Coote, J; Mosse, C; Finlay, M; Papakonstantinou, I; Desjardins, A; (2018) 3D printed micro-scale fiber optic probe for intravascular pressure sensing. Proceedings of Biosensing and Nanomedicine XI , 10728 , Article 107280B (2018). 10.1117/12.2321980 . Green open access

https://ift.tt/2rwI0l7

Exploring the Role of Data-supported Social Interaction manifested through Public Displays

Ji, Y; Fatah gen. Schieck, A; (2018) Exploring the Role of Data-supported Social Interaction manifested through Public Displays. In: Proceedings of Media Architecture Biennale - 2018. ACM: Beijing, China. (In press). Green open access

https://ift.tt/2rwnGAo

The role of teacher regulatory talk in students' self-regulation development across cultures

Torres Nunez, PE; Whitebread, D; McLellan, R; (2018) The role of teacher regulatory talk in students' self-regulation development across cultures. New Directions for Child and Adolescent Development , 2018 (162) pp. 89-114. 10.1002/cad.20259 .

https://ift.tt/2G9xDh4

Current status of food waste generation and management in China

Li, Y; Jin, Y; Borrion, A; Li, H; (2018) Current status of food waste generation and management in China. [Review]. Bioresource Technology 10.1016/j.biortech.2018.10.083 . (In press).

https://ift.tt/2G9v4vE

Simulation model generation combining IFC and CityGML data

Lilis, GN; Giannakis, GI; Katsigarakis, K; Costa, G; Sicilia, A; Garcia-Fuentes, M; Rovas, DV; (2016) Simulation model generation combining IFC and CityGML data. In: Christodoulou, SE and Scherer, R, (eds.) Proceedings of the 11th European Conference on Product and Process Modelling (ECPPM2016),. (pp. pp. 215-222). CRC Press, Taylor & Francis Group: Limassol, Cyprus. Green open access

https://ift.tt/2rterRk

Corrigendum to “Kinetic studies on organic degradation and its impacts on improving methane production during anaerobic digestion of food waste” [Appl. Energy 213 (2018) 135–147] (Applied Energy (2018) 213 (136–147)

Li, Y; Jin, Y; Li, H; Borrion, A; Yu, Z; Li, J; (2018) Corrigendum to "Kinetic studies on organic degradation and its impacts on improving methane production during anaerobic digestion of food waste" [Appl. Energy 213 (2018) 135–147] (Applied Energy (2018) 213 (136–147). [Corrigendum]. Applied Energy , 229 p. 1284. 10.1016/j.apenergy.2018.05.118 .

https://ift.tt/2G8BATb

Reflections and speculations on the progress in Geographic Information Systems (GIS): a geographic perspective

Lu, G; Batty, M; Strobl, J; Lin, H; Zhu, A-X; Chen, M; (2019) Reflections and speculations on the progress in Geographic Information Systems (GIS): a geographic perspective. [Review]. International Journal of Geographical Information Systems , 33 (2) pp. 346-367. 10.1080/13658816.2018.1533136 . (In press). Green open access

https://ift.tt/2Gbtqtn

An ontology-based tool for automated configuration and deployment of technical building management services

Schneider, GF; Kalantari, Y; Kontes, G; Steiger, S; Rovas, DV; (2016) An ontology-based tool for automated configuration and deployment of technical building management services. In: Grunewald, John, (ed.) Proceedings of 2016 Central European Symposium on Building Physics. Fraunhofer IRB Verlag: Dresden, Germany,.

https://ift.tt/2Gax2vB

Author Correction: Osmotic modulation of chromatin impacts on efficiency and kinetics of cell fate modulation

Lima, AF; May, G; Díaz-Colunga, J; Pedreiro, S; Paiva, A; Ferreira, L; Enver, T; ... Pires das Neves, R; + view all Lima, AF; May, G; Díaz-Colunga, J; Pedreiro, S; Paiva, A; Ferreira, L; Enver, T; Iborra, FJ; Pires das Neves, R; - view fewer (2018) Author Correction: Osmotic modulation of chromatin impacts on efficiency and kinetics of cell fate modulation. [Corrigendum]. Scientific Reportsvolume , 8 , Article 11303. 10.1038/s41598-018-29328-3 . Green open access

https://ift.tt/2rumqOf

Special Issue: Social media and the visual

Adami, E; Jewitt, C; (2016) Special Issue: Social media and the visual. [Editorial comment]. Visual Communication , 15 (3) pp. 263-270. 10.1177/1470357216644153 . Green open access

https://ift.tt/2rt2riT

Bystanders to Nazi Violence? The transformation of German society in the 1930s

Fulbrook, M; (2018) Bystanders to Nazi Violence? The transformation of German society in the 1930s. In: Bystanders to Nazi Violence? The Transformation of German Society in the 1930s. (pp. 8-39). Yad Vashem: Jerusalem. (In press).

https://ift.tt/2rtJk8d

State-selective electric-field ionization of Rydberg positronium

Alonso, AM; Gurung, L; Sukra, BAD; Hogan, SD; Cassidy, DB; (2018) State-selective electric-field ionization of Rydberg positronium. Physical Review A , 98 (5) , Article 053417. 10.1103/PhysRevA.98.053417 . Green open access

https://ift.tt/2rt2rzp

Sample Preparation for Endopeptidomic Analysis in Human Cerebrospinal Fluid

Hansson, KT; Skillback, T; Pernevik, E; Holmen-Larsson, J; Brinkmalm, G; Blennow, K; Zetterberg, H; Hansson, KT; Skillback, T; Pernevik, E; Holmen-Larsson, J; Brinkmalm, G; Blennow, K; Zetterberg, H; Gobom, J; - view fewer (2017) Sample Preparation for Endopeptidomic Analysis in Human Cerebrospinal Fluid. JOVE-Journal of Visualized Experiments (130) , Article e56244. 10.3791/56244 .

https://ift.tt/2GixCI2

Early childhood investment impacts social decision-making four decades later

Luo, Y; Hétu, S; Lohrenz, T; Hula, A; Dayan, P; Ramey, SL; Sonnier-Netto, L; ... Ramey, C; + view all Luo, Y; Hétu, S; Lohrenz, T; Hula, A; Dayan, P; Ramey, SL; Sonnier-Netto, L; Lisinski, J; LaConte, S; Nolte, T; Fonagy, P; Rahmani, E; Montague, PR; Ramey, C; - view fewer (2018) Early childhood investment impacts social decision-making four decades later. Nature Communicationsvolume , 9 , Article 4705. 10.1030/s41467-018-07138-5 . Green open access

https://ift.tt/2G9v2E2

Second-level space boundary topology generation from CityGML inputs

Lilis, GN; Rovas, DV; Prieto, I; (2016) Second-level space boundary topology generation from CityGML inputs. In: Proceedings of the 3rd International Building Performance Simulation Asssociation (IBPSA) Conference 2016. (pp. pp. 297-304). IBPSA-England: Newcastle, UK.

https://ift.tt/2G52MlQ

Seasonal variation in the performance of QuantiFERON-TB Gold In-Tube assays used for the diagnosis of tuberculosis infection

Tebruegge, M; Curtis, N; Clifford, V; Fernandez-Turienzo, C; Klein, N; Fidler, K; Mansour, S; ... Morris-Jones, S; + view all Tebruegge, M; Curtis, N; Clifford, V; Fernandez-Turienzo, C; Klein, N; Fidler, K; Mansour, S; Elkington, P; Morris-Jones, S; - view fewer (2018) Seasonal variation in the performance of QuantiFERON-TB Gold In-Tube assays used for the diagnosis of tuberculosis infection. Tuberculosis , 110 pp. 26-29. 10.1016/j.tube.2018.03.002 . Green open access

https://ift.tt/2GixeJA

Development and preliminary testing of the Brief Developmental Assessment: an early recognition tool for children with heart disease

Wray, J; Brown, KL; Ridout, D; Lakhanpaul, M; Smith, L; Scarisbrick, A; O'Curry, S; Wray, J; Brown, KL; Ridout, D; Lakhanpaul, M; Smith, L; Scarisbrick, A; O'Curry, S; Hoskote, A; - view fewer (2018) Development and preliminary testing of the Brief Developmental Assessment: an early recognition tool for children with heart disease. Cardiology in the Young , 28 (4) pp. 582-591. 10.1017/S1047951117002918 . Green open access

https://ift.tt/2rtHHaA

The Lancet Countdown on health and climate change: from 25 years of inaction to a global transformation for public health (vol 391, pg 540, 2017)

Watts, N; Amann, M; Ayeb-Karlsson, S; Chambers, J; Hamilton, I; Lowe, R; Pye, S; ... Latifi, AM; + view all Watts, N; Amann, M; Ayeb-Karlsson, S; Chambers, J; Hamilton, I; Lowe, R; Pye, S; Owfi, F; Rabbaniha, M; Tabatabaei, M; Latifi, AM; - view fewer (2018) The Lancet Countdown on health and climate change: from 25 years of inaction to a global transformation for public health (vol 391, pg 540, 2017). [Corrigendum]. The Lancet , 391 (10120) p. 540. 10.1016/S0140-6736(17)33046-5 . Green open access

https://ift.tt/2rD3Wv3

A modified method of local infiltration for endoscopic stapes surgery: how I do it

Abstract

Purpose

To present a modified method of local infiltration (MMLI) for endoscopic stapes surgery to reduce surgical time, bleeding and complications.

Materials and methods

This study involved 70 patients who underwent stapes surgery for otosclerosis by endoscopic and microscopic approaches. The MMLI was applied as follows: local infiltration was performed with one hand while the other hand inserted the endoscope into the ear canal to observe vasoconstriction signs on the monitor; the single site of infiltration was located at the center of the anterior conchal cartilage. Operative time, intraoperative blood loss, preservation of anatomical structures, postoperative hearing and complications were evaluated.

Results

The MMLI allowed for quick bleeding control and a clear and dry operative field. Operative time, intraoperative blood loss and preservation of anatomical structures were significantly reduced in the endoscopic group (P < 0.00) versus the microscopic group. The scutum was removed less frequent in the endoscopic group 7.1% versus 53.6% of the microscopic group (P < 0.00). The chorda tympani was preserved in all cases but it was more manipulated in the microscopic group 39.3% versus 9.5% of the endoscopic group (P < 0.00). No complications were observed and the hearing outcomes were significantly better than the preoperative thresholds.

Conclusions

This is the first report on the use of a MMLI for endoscopic stapes surgery. Using this method, the surgeon performs the infiltration at one site and concurrently observes the vasoconstriction signs without the use of a microscope, frontal lamp or speculum. This method provides benefits in terms of operative time and complications.

https://ift.tt/2EchRiW

A Trial to Evaluate the Efficacy of Poziotinib, Pan HER Inhibitor in Recurrent/Metastatic Esophageal Cancer (R/M ESCC)

Condition:   Inoperable or Recurrent or Metastatic Esophageal Squamous Carcinoma
Intervention:   Drug: Treatment with Poziotinib
Sponsor:   Yonsei University
Not yet recruiting

https://ift.tt/2EdtTJ6

Laparoscopic Appendectomy Performed by Junior SUrgeonS: Impact of 3D Visualization on Surgical Outcome

Conditions:   Appendicolith;   Appendicitis;   Appendicitis With Perforation;   Appendicitis Peritonitis;   Appendiceal Abscess;   Appendicitis Acute
Interventions:   Procedure: 3D Laparoscopic Appendectomy;   Procedure: 2D Laparoscopic Appendectomy
Sponsor:   Azienda Ospedaliera Spedali Civili di Brescia
Recruiting

https://ift.tt/2Enj4F2

Dual exposure to smoking and household air pollution is associated with an increased risk of severe asthma in adults in Brazil

The relationship between smoking, household pollution, dual exposure and severity of asthma in adults has not been sufficiently studied. We examined and compared the effects of cigarette smoking, domestic wood...

https://ift.tt/2G9sENo

Secondhand Smoke and Cancer

A fact sheet that summarizes the studies on the health effects of exposure to environmental (secondhand) tobacco smoke.

https://ift.tt/2C0Sorb

Incidental findings on 18-FDG PET–CT in head and neck cancer. A retrospective case-control study of incidental findings on 18-FDG PET–CT in patients with head and neck cancer

Abstract

Purpose

Use of 18-FDG PET–CT is increasing in patients with head and neck cancer, enabling the identification of metastases or synchronous malignancies, but also 'incidental' disease. We aimed to establish the rate of 'incidental' findings resulting from 18-FDG PET-specific imaging, that would not have been otherwise identified on other imaging, in patients with head and neck cancer undergoing staging or surveillance of disease.

Methods

18-FDG PET–CT was performed for investigation or surveillance. Case notes were reviewed retrospectively. Unexpected findings identifiable on CT imaging alone, or by FDG-PET were recorded. For those only identifiable with FDG-PET, findings were divided into either 'incidental' or 'intentional', and benign or malignant.

Results

93 patients underwent 18- FDG PET–CT. 86.0% had new pathology identified. 3.2% had a new malignancy identified. 37.6% had new findings on FDG-PET that would not have been identified on CT alone: 5.4% had 'intentional findings' (metastasis), and 32.3% had 'incidental findings' (synchronous malignancy or benign). 1.1% had a new malignancy on FDG-PET alone.

Conclusions

Intentional and incidental findings are likely on 18-FDG PET–CT. Whilst important for patient management, there is an associated emotional and financial cost, which needs acknowledgement and further investigation.

https://ift.tt/2UAHMa3

Parent-reported BIS/BAS scales for children : factor structure and measurement invariance across age and gender

https://ift.tt/2L9huHf

Anatomy and evolution of database search engines : a central component of mass spectrometry based proteomic workflows

https://ift.tt/2C02I2O

Nachsorge und Lebensqualität nach Therapie eines Ovarialkarzinoms

Zusammenfassung

Hintergrund

Die leitliniengerechte Therapie des Ovarialkarzinoms beinhaltet meist eine Kombination aus operativem und systemtherapeutischem Ansatz; für viele Patientinnen schließt sich eine Erhaltungstherapie an. Nach Abschluss von OP und Chemotherapie beginnt für die Betroffenen die Nachsorgephase. Nach der initialen Konfrontation mit der Diagnosestellung und den beeinträchtigenden Therapien, kommt bei den meisten Betroffenen der Wunsch auf, in ein „normales" Leben zurückzukehren. Erkrankungs- und therapieassoziierte Folgen können diesem Wunsch jedoch konträr gegenüberstehen.

Ergebnisse

Die standardisierte Nachsorge erfolgt über 5 Jahre. Sie umfasst in den ersten 3 Jahren ein 3‑monatiges Intervall, anschließend ist eine halbjährliche Untersuchung für die folgenden 2 Jahre vorgesehen. Der Nachsorge schließen sich regelmäßige Kontrollen im Rahmen der Krebsfrüherkennungsprogramme an. In den letzten Jahren hat sich die symptomgesteuerte Nachsorge etabliert, sodass bildgebende Verfahren nur bei klinischem Verdacht auf ein Rezidiv oder möglichen therapeutischen Konsequenzen eingesetzt werden sollen. Ein routinemäßiger Einsatz von Tumormarkerkontrollen (CA125) bei fehlender klinischer Symptomatik ist laut S3-Leitlinie nicht indiziert.

Schlussfolgerung

Das Erreichen individueller Lebensqualität, einschließlich sexueller Bedürfnisse, ist ein essenzielles Thema der Nachsorge. Der Bedarf der Betroffenen an professioneller Unterstützung ist sehr unterschiedlich. Dies verlangt von den betreuenden Ärzten Erfahrung, eine hohe kommunikative Kompetenz und besonderes Einfühlungsvermögen.

https://ift.tt/2rv4ouZ

Parkinson's disease treatments: focus on transcranial direct current stimulation (tDCS)

Tahtis, V; Kaski, D; (2017) Parkinson's disease treatments: focus on transcranial direct current stimulation (tDCS). Journal of Parkinsonism and Restless Legs Syndrome , 2017 (7) pp. 55-70. 10.2147/JPRLS.S128146 . Green open access

https://ift.tt/2L6kEvy

Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease

Olsson, M; Arlig, J; Hedner, J; Blennow, K; Zetterberg, H; (2018) Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease. Sleep , 41 (5) , Article zsy025. 10.1093/sleep/zsy025 .

https://ift.tt/2C0iiLE

Frailty as a Predictor of Emergency Department Utilization among Community-Dwelling Older People: A Systematic Review and Meta-Analysis

Kojima, G; (2018) Frailty as a Predictor of Emergency Department Utilization among Community-Dwelling Older People: A Systematic Review and Meta-Analysis. [Letter]. Journal of the American Medical Directors Association 10.1016/j.jamda.2018.10.004 . (In press).

https://ift.tt/2L840fc

Compassionate collaboration, choice and creativity: Learning Communities against the grain in hierarchical institutions

Hargreaves, E; (2019) Compassionate collaboration, choice and creativity: Learning Communities against the grain in hierarchical institutions. Impact (In press).

https://ift.tt/2L9Nknp

How Inclusive, User-Centered Design Research Can Improve Psychological Therapies for Psychosis: Development of SlowMo

Hardy, A; Wojdecka, A; West, J; Matthews, E; Golby, C; Ward, T; Lopez, ND; ... Garety, P; + view all Hardy, A; Wojdecka, A; West, J; Matthews, E; Golby, C; Ward, T; Lopez, ND; Freeman, D; Waller, H; Kuipers, E; Bebbington, P; Fowler, D; Emsley, R; Dunn, G; Garety, P; - view fewer (2018) How Inclusive, User-Centered Design Research Can Improve Psychological Therapies for Psychosis: Development of SlowMo. Journal of Medical Internet Research Mental Health , 5 (4) , Article e11222. 10.2196/11222 . Green open access

https://ift.tt/2L9NkUr

Review of Robert A. Karl's Forgotten Peace: Reform, Violence, and the Making of Contemporary Colombia

Castañeda, N; (2017) Review of Robert A. Karl's Forgotten Peace: Reform, Violence, and the Making of Contemporary Colombia. [Review]. NACLA Report on the Americas , 49 (2) pp. 222-223. 10.1080/10714839.2017.1331830 . Green open access

https://ift.tt/2C2e8mE

Next Generation Sequencing Analysis in Early Onset Dementia Patients

Bonvicini, C; Scassellati, C; Benussi, L; Di Maria, E; Maj, C; Ciani, M; Fostinelli, S; ... Gennarelli, M; + view all Bonvicini, C; Scassellati, C; Benussi, L; Di Maria, E; Maj, C; Ciani, M; Fostinelli, S; Mega, A; Bocchetta, M; Lanzi, G; Giacopuzzi, E; Ferraboli, S; Pievani, M; Fedi, V; Defanti, CA; Giliani, S; Ghidoni, R; Frisoni, GB; Gennarelli, M; - view fewer (2018) Next Generation Sequencing Analysis in Early Onset Dementia Patients. Journal of Alzheimer's Disease 10.3233/JAD-180482 . (In press). Green open access

https://ift.tt/2L83PR4

Children's scale errors are a natural consequence of learning to associate objects with actions: a computational model

Grzyb, BJ; Nagai, Y; Asada, M; Cattani, A; Floccia, C; Cangelosi, A; (2018) Children's scale errors are a natural consequence of learning to associate objects with actions: a computational model. Developmental Science 10.1111/desc.12777 . (In press).

https://ift.tt/2C0S8Zr

The role of blood and CSF biomarkers in the evaluation of new treatments against multiple sclerosis

Lycke, J; Zetterberg, H; (2017) The role of blood and CSF biomarkers in the evaluation of new treatments against multiple sclerosis. [Review]. Expert Review of Clinical Immunology , 13 (12) pp. 1143-1153. 10.1080/1744666X.2017.1400380 . Green open access

https://ift.tt/2L9Nmf1

Feeling less than other people: attainment scores as symbols of children’s worth

Hargreaves, E; (2019) Feeling less than other people: attainment scores as symbols of children's worth. Forum (In press).

https://ift.tt/2C0idYm

Embodied GHG emissions of building materials in Shanghai

Huang, B; Chen, Y; McDowall, W; Türkeli, S; Bleischwitz, R; Geng, Y; (2019) Embodied GHG emissions of building materials in Shanghai. Journal of Cleaner Production , 210 pp. 777-785. 10.1016/j.jclepro.2018.11.030 .

https://ift.tt/2L90S2m

Welfare micropublics and inequality: urban super-diversity in a time of austerity

Berg, ML; Gidley, B; Krausova, A; (2019) Welfare micropublics and inequality: urban super-diversity in a time of austerity. Ethnic and Racial Studies (In press).

https://ift.tt/2C0i5YS

Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure

Gifford, KA; Liu, D; Neal, JE; Acosta, LMY; Bell, SP; Wiggins, ME; Wisniewski, KM; ... Jefferson, AL; + view all Gifford, KA; Liu, D; Neal, JE; Acosta, LMY; Bell, SP; Wiggins, ME; Wisniewski, KM; Godfrey, M; Logan, LA; Hohman, TJ; Pechman, KR; Libon, DJ; Blennow, K; Zetterberg, H; Jefferson, AL; - view fewer (2018) Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure. Assessment 10.1177/1073191118773870 . Green open access

https://ift.tt/2C0X7ZT

The psychotherapist as the crucial factor in fostering the relationships in the triangle supporting the child: second audit and evaluation of the child psychotherapy service at the Randolph Beresford early years centre

Pretorius, I-M; Batiste-Harel, D; Martin, P; (2018) The psychotherapist as the crucial factor in fostering the relationships in the triangle supporting the child: second audit and evaluation of the child psychotherapy service at the Randolph Beresford early years centre. Infant Observation: International Journal of Infant Observation and Its Applications 10.1080/13698036.2018.1553684 . (In press).

https://ift.tt/2BZXiou

Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease

Tanna, P; Georgiou, M; Aboshiha, J; Strauss, RW; Kumaran, N; Kalitzeos, A; Weleber, RG; Tanna, P; Georgiou, M; Aboshiha, J; Strauss, RW; Kumaran, N; Kalitzeos, A; Weleber, RG; Michaelides, M; - view fewer (2018) Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease. Translational Vision Science & Technology , 7 (6) , Article 10. 10.1167/tvst.7.6.10 . Green open access

https://ift.tt/2L9Nifh

Subjective visual vertical assessment with mobile virtual reality system

Uloziene, I; Totiliene, M; Paulauskas, A; Blazauskas, T; Marozas, V; Kaski, D; Ulozas, V; (2018) Subjective visual vertical assessment with mobile virtual reality system. Medicina , 53 (6) pp. 394-402. 10.1016/j.medici.2018.02.002 . Green open access

https://ift.tt/2C2ULtP

Competition for University Places and Parental Time Investments: Evidence From the UK

Sevilla, AS; Borra, C; (2020) Competition for University Places and Parental Time Investments: Evidence From the UK. Economic Inquiry (In press).

https://ift.tt/2L9sqou

Discovery of Middle Jurassic trench deposits in the Bangong-Nujiang suture zone: Implications for the timing of Lhasa-Qiangtang initial collision

Sun, G; Hu, X; Xu, Y; BouDagher-Fadel, MK; (2018) Discovery of Middle Jurassic trench deposits in the Bangong-Nujiang suture zone: Implications for the timing of Lhasa-Qiangtang initial collision. Tectonophysics 10.1016/j.tecto.2018.12.001 . (In press).

https://ift.tt/2Leo9Al

Shedding Light on the Molecular Pathology of Amyloid Plaques in Transgenic Alzheimer's Disease Mice Using Multimodal MALDI Imaging Mass Spectrometry

Kaya, I; Zetterberg, H; Blennow, K; Hanrieder, J; (2018) Shedding Light on the Molecular Pathology of Amyloid Plaques in Transgenic Alzheimer's Disease Mice Using Multimodal MALDI Imaging Mass Spectrometry. ACS Chemical Neuroscience , 9 (7) pp. 1802-1817. 10.1021/acschemneuro.8b00121 . Green open access

https://ift.tt/2C0PPWn

Healthcare leadership with political astuteness (HeLPA): a qualitative study of how service leaders understand and mediate the informal‘power and politics’of major health system change

Waring, J; Bishop, S; Clarke, J; Exworthy, M; Fulop, NJ; Hartley, J; Ramsay, AIG; (2018) Healthcare leadership with political astuteness (HeLPA): a qualitative study of how service leaders understand and mediate the informal'power and politics'of major health system change. BMC Health Services Research , 18 (198) 10.1186/s12913-018-3728-z . Green open access

https://ift.tt/2C0hHto

Etiology of subjective taste loss

Background

Taste complaints are commonly encountered in clinical practice. Although changes in taste function may arise from varied etiologies, numerous other factors may impact patients' taste perceptions, the most common of which is olfactory dysfunction. Thus, patients with taste complaints may or may not have measurable deficits in taste function. This poses a challenge to providers faced with evaluation of patients with taste disorders, and may delay diagnosis and management.

Methods

We retrospectively examined records of 1108 patients evaluated at the Virginia Commonwealth University Health System Smell and Taste Clinic and compared patients' subjective taste complaints with results of objective testing of the senses of taste and smell.

Results

A total of 358 patients had a subjective taste complaint and results from both gustatory and olfactory function tests. Patients were grouped by subjective complaint as "taste only" (n = 63) or "taste and smell" (n = 295). Of patients reporting a "taste‐only" complaint, 25.4% had abnormal gustatory function, whereas 44.4% had abnormal olfactory function. For those reporting taste‐and‐smell complaints, only 9.5% had abnormal gustatory function, whereas 86.8% had abnormal olfactory function.

Conclusion

This study supports the hypothesis that patients who present with a taste complaint are more likely to have an underlying olfactory than gustatory impairment. However, those with a taste‐only complaint are more likely to have objective gustatory deficits than those with a taste‐and‐smell complaint. These findings may prove useful to healthcare providers who evaluate patients presenting with complaints of taste loss.

https://ift.tt/2Qpg9Sw

A large screen for paraneoplastic neurological autoantibodies; diagnosis and predictive values

Publication date: Available online 10 December 2018

Source: Clinical Immunology

Author(s): Lior Seluk, Alisa Taliansky, Hagith Yonath, Boris Gilburd, Howard Amital, Yehuda Shoenfeld, Shaye Kivity

Abstract

Background

Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins ("well characterized" PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital.

Methods

Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002–2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay.

Results

During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist.

Conclusions

The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

https://ift.tt/2Pvcz40

Central compartment revision surgery for persistent or recurrent thyroid carcinoma: analysis of survival and complication rate

Abstract

Purpose

Locoregional recurrence of thyroid carcinoma is relatively common and reported rate are between 5 and 20%. Cervical nodes are usually involved, especially at the central compartment. The management of recurrent thyroid carcinoma at central compartment still remains challenging because of higher incidence of complication rate. The aim of the study is to evaluate the survival and complications rate after revision surgery.

Methods

Retrospective cohort study on a group of patients that underwent revision surgery for persistent or recurrent thyroid carcinoma from January 1, 2003 to December 31, 2017. Survival outcomes were calculated using Kaplan–Meier method. Significant variables on univariate analysis were subjected to a Cox proportional hazards regression multivariate model.

Results

Fifty-two patients involved, 22 male (40%) and 30 female (60%). Mean age was 54 years old (range 24–85). Mean follow-up was 79 months, median follow-up was 85 months, with a range between 8 and 153 months. The 5-year overall survival was 90.8% while at 10 years it was 69.8%. The 5-year disease-specific survival was 93.5%, while at 10 years it dropped to 77.9%. The rate of recurrent laryngeal nerve paralysis and persistent hypocalcemia in our series were 1.3% and 5.9%, respectively. No evidence of thoracic duct, esophageal or laryngeal and tracheal injury was found in this case series. Regarding prognostic factors, univariate and multivariate analysis highlighted as statistically significant: the aggressive histological variants, the presence extranodal extension or soft-tissue metastasis.

Conclusion

The surgical option remains the gold standard in locoregional recurrences of thyroid carcinoma and should be performed by experienced surgeons to reduce postoperative complications.

https://ift.tt/2C1VeMS