Proceedings of the NASHNP Companion Meeting, March 18th, 2018, Vancouver, BC, Canada: Salivary Neuroendocrine Carcinoma—An Overview of a Rare Disease with an Emphasis on Determining Tumor Origin

Abstract

Salivary neuroendocrine carcinomas are rare and the overwhelming majority is high-grade. The parotid gland is the most commonly involved site followed by the submandibular gland. Most arise de novo but rare examples occurring as a high-grade transformation of another type of salivary gland neoplasm exist. There is significant morphologic and immunophenotypic overlap with neuroendocrine carcinomas of other sites, especially the skin. Like cutaneous neuroendocrine (or Merkel cell) carcinomas, approximately three-fourths are cytokeratin 20 positive. Cytokeratin 20 positive salivary neuroendocrine carcinomas are often referred to as being of the 'Merkel cell type' since most other non-cutaneous neuroendocrine carcinomas are cytokeratin 20 negative. Salivary neuroendocrine carcinomas may be challenging to separate from Merkel cell carcinomas of the head and neck on pathologic grounds because the latter often metastasize to the parotid gland. Clinical history is often relied upon to separate primary salivary tumors from cutaneous metastases but may not be helpful in all cases. Here we review the clinical, pathologic and molecular features of salivary neuroendocrine carcinomas focusing on high-grade major salivary gland tumors. The difficulty in separating salivary tumors from metastatic Merkel cell carcinoma will be highlighted.

http://ift.tt/2FN6Yq3

Update on Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Incidence of MCC continues to rise, and risk factors include advanced age, pale skin, chronic sun exposure, and immune suppression. Diagnosing MCC utilizes a combination of morphology and immunohistochemistry. Merkel cell polyomavirus (MCPyV) is present in approximately 70–80% of MCCs and represents a key pathogenic driver in those MCCs. In contrast, MCPyV-negative MCCs arise through progressive accumulation of ultraviolet-light induced somatic mutations. Staging of MCC proceeds according to the American Joint Commission on Cancer (AJCC) 8th Edition, which utilizes features of the primary tumor together with regional lymph node(s) (clinically and/or pathologically detected) and/or distant metastases. Many potentially useful biomarkers have been studied to refine risk stratification in MCC. In recent years, the host immune infiltrate has been leveraged as immune checkpoint blockade has emerged as an efficacious mode of treatment for patients with advanced MCC.

http://ift.tt/2tYqfis

Human Papillomavirus-Related Neuroendocrine Carcinomas of the Head and Neck

Abstract

Human papillomavirus (HPV)-related head and neck carcinoma (HNC) represents an important subgroup of head and neck cancer that is characterized by a consistent microscopic appearance and a favorable prognosis. A growing experience with HPV testing, however, has uncovered variants that deviate from the prototypic HPV-HNC with respect to morphology. While these HPV-HNCs may deviate morphologically from the prototype, they do not appear to stray far from the favorable clinical outcome assigned to HPV-positive status. In effect, HPV positivity trumps traditional prognostic features predicated on morphology such as tumor grade and histologic subtype when it comes to predicting clinical behavior. For the diagnostic pathologist, the pedestrian task of tumor grading and subtyping would seem to be of little prognostic or therapeutic relevance when it comes to HPV-HNC. Recognition and documentation of neuroendocrine differentiation is a most notable exception. Forms of HPV-HNC have now been reported that morphologically resemble small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of other sites, and that immunohistochemically exhibit neuroendocrine differentiation. Despite the presence of HPV, these SCCs and LCNECs share the same aggressive clinical behavior of their counterparts in the lung and other sites where the high grade neuroendocrine phenotype is associated with early distant spread and poor overall survival. Consequently, the high grade neuroendocrine phenotype should be regarded as an aggressive form of HPV-HNC where tumor morphology displaces HPV positivity as the most important prognostic feature.

http://ift.tt/2ppqQoL

Proceedings of the NASHNP Companion Meeting, March 18th, 2018, Vancouver, BC, Canada: Salivary Neuroendocrine Carcinoma—An Overview of a Rare Disease with an Emphasis on Determining Tumor Origin

Abstract

Salivary neuroendocrine carcinomas are rare and the overwhelming majority is high-grade. The parotid gland is the most commonly involved site followed by the submandibular gland. Most arise de novo but rare examples occurring as a high-grade transformation of another type of salivary gland neoplasm exist. There is significant morphologic and immunophenotypic overlap with neuroendocrine carcinomas of other sites, especially the skin. Like cutaneous neuroendocrine (or Merkel cell) carcinomas, approximately three-fourths are cytokeratin 20 positive. Cytokeratin 20 positive salivary neuroendocrine carcinomas are often referred to as being of the 'Merkel cell type' since most other non-cutaneous neuroendocrine carcinomas are cytokeratin 20 negative. Salivary neuroendocrine carcinomas may be challenging to separate from Merkel cell carcinomas of the head and neck on pathologic grounds because the latter often metastasize to the parotid gland. Clinical history is often relied upon to separate primary salivary tumors from cutaneous metastases but may not be helpful in all cases. Here we review the clinical, pathologic and molecular features of salivary neuroendocrine carcinomas focusing on high-grade major salivary gland tumors. The difficulty in separating salivary tumors from metastatic Merkel cell carcinoma will be highlighted.

http://ift.tt/2FN6Yq3

Human Papillomavirus-Related Neuroendocrine Carcinomas of the Head and Neck

Abstract

Human papillomavirus (HPV)-related head and neck carcinoma (HNC) represents an important subgroup of head and neck cancer that is characterized by a consistent microscopic appearance and a favorable prognosis. A growing experience with HPV testing, however, has uncovered variants that deviate from the prototypic HPV-HNC with respect to morphology. While these HPV-HNCs may deviate morphologically from the prototype, they do not appear to stray far from the favorable clinical outcome assigned to HPV-positive status. In effect, HPV positivity trumps traditional prognostic features predicated on morphology such as tumor grade and histologic subtype when it comes to predicting clinical behavior. For the diagnostic pathologist, the pedestrian task of tumor grading and subtyping would seem to be of little prognostic or therapeutic relevance when it comes to HPV-HNC. Recognition and documentation of neuroendocrine differentiation is a most notable exception. Forms of HPV-HNC have now been reported that morphologically resemble small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of other sites, and that immunohistochemically exhibit neuroendocrine differentiation. Despite the presence of HPV, these SCCs and LCNECs share the same aggressive clinical behavior of their counterparts in the lung and other sites where the high grade neuroendocrine phenotype is associated with early distant spread and poor overall survival. Consequently, the high grade neuroendocrine phenotype should be regarded as an aggressive form of HPV-HNC where tumor morphology displaces HPV positivity as the most important prognostic feature.

http://ift.tt/2ppqQoL

Proceedings of the NASHNP Companion Meeting, March 18th, 2018, Vancouver, BC, Canada: Salivary Neuroendocrine Carcinoma—An Overview of a Rare Disease with an Emphasis on Determining Tumor Origin

Abstract

Salivary neuroendocrine carcinomas are rare and the overwhelming majority is high-grade. The parotid gland is the most commonly involved site followed by the submandibular gland. Most arise de novo but rare examples occurring as a high-grade transformation of another type of salivary gland neoplasm exist. There is significant morphologic and immunophenotypic overlap with neuroendocrine carcinomas of other sites, especially the skin. Like cutaneous neuroendocrine (or Merkel cell) carcinomas, approximately three-fourths are cytokeratin 20 positive. Cytokeratin 20 positive salivary neuroendocrine carcinomas are often referred to as being of the 'Merkel cell type' since most other non-cutaneous neuroendocrine carcinomas are cytokeratin 20 negative. Salivary neuroendocrine carcinomas may be challenging to separate from Merkel cell carcinomas of the head and neck on pathologic grounds because the latter often metastasize to the parotid gland. Clinical history is often relied upon to separate primary salivary tumors from cutaneous metastases but may not be helpful in all cases. Here we review the clinical, pathologic and molecular features of salivary neuroendocrine carcinomas focusing on high-grade major salivary gland tumors. The difficulty in separating salivary tumors from metastatic Merkel cell carcinoma will be highlighted.

http://ift.tt/2FN6Yq3

Update on Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Incidence of MCC continues to rise, and risk factors include advanced age, pale skin, chronic sun exposure, and immune suppression. Diagnosing MCC utilizes a combination of morphology and immunohistochemistry. Merkel cell polyomavirus (MCPyV) is present in approximately 70–80% of MCCs and represents a key pathogenic driver in those MCCs. In contrast, MCPyV-negative MCCs arise through progressive accumulation of ultraviolet-light induced somatic mutations. Staging of MCC proceeds according to the American Joint Commission on Cancer (AJCC) 8th Edition, which utilizes features of the primary tumor together with regional lymph node(s) (clinically and/or pathologically detected) and/or distant metastases. Many potentially useful biomarkers have been studied to refine risk stratification in MCC. In recent years, the host immune infiltrate has been leveraged as immune checkpoint blockade has emerged as an efficacious mode of treatment for patients with advanced MCC.

http://ift.tt/2tYqfis

Transverse Cervical Artery Pseudoaneurysm: An Unusual Delayed Complication of Radical Neck Dissection

Abstract

Pseudoaneurysm formation in the transverse cervical artery, post radical neck dissection, leading to massive hemorrhage, is a rare but life threatening occurrence. We report a patient with pseudoaneurysm of transverse cervical artery, post salvage radical neck dissection, presenting with recurrent and significant hemorrhage after 3 weeks of surgery. A pseudoaneurysm involving transverse cervical artery was revealed by digital subtraction angiography and treated by endovascular coil embolization.

http://ift.tt/2HPhCsJ

The Role of Preoperative Computed Tomography of Temporal Bone in Atticotomy as a New Tool for Determining the Approach

Abstract

The temporal bone is a complex anatomical structure and so preoperatively computed tomography (CT) of the temporal bone is important for choice of the surgical procedure. In this study, evaluation of the surgical difficulty to conduct transmastoid atticotomy with the coronary cut of CT temporal bone. Additional, attic pathology intraoperative is evaluated. The current research is a retrospective study of 79 patients with chronic suppurative otitis media (safe type) with the preoperative opacity of the attic in CT temporal bone. The researcher correlates difficulty to do transmastoid attictomy with the distance in mm between the roof of external audiatory canal (EAC) and tegmen with ruler directly in the coronary cut of CT temporal bone at the the level of internal auditory canal (IAC). The researcher also compares attic pathology intraoperative with preoperative CT attic opacity. In group of surgically difficulty average distance between the superior wall of EAC and tegmen on preoperative CT at the level of IAC is 2–5 mm while distance in easily surgical approach is from 6 to 10 mm. 68.4%(54/79) of cases had pathology in attic in the form of granulation tissue in 50 cases and glue in 4 cases. Preoperative CT temporal bone is very important to detect atticotomy approach either transmastoid or transcanal, through measuring the distance in mm between the roof of EAC and tegmen with ruler directly in the coronal cut of CT temporal bone at the level of internal auditory canal. The opacity of the attic in Preoperative CT does not mean that there is a pathology in the attic.

http://ift.tt/2G7D12Y

Transverse Cervical Artery Pseudoaneurysm: An Unusual Delayed Complication of Radical Neck Dissection

Abstract

Pseudoaneurysm formation in the transverse cervical artery, post radical neck dissection, leading to massive hemorrhage, is a rare but life threatening occurrence. We report a patient with pseudoaneurysm of transverse cervical artery, post salvage radical neck dissection, presenting with recurrent and significant hemorrhage after 3 weeks of surgery. A pseudoaneurysm involving transverse cervical artery was revealed by digital subtraction angiography and treated by endovascular coil embolization.

http://ift.tt/2HPhCsJ

The Role of Preoperative Computed Tomography of Temporal Bone in Atticotomy as a New Tool for Determining the Approach

Abstract

The temporal bone is a complex anatomical structure and so preoperatively computed tomography (CT) of the temporal bone is important for choice of the surgical procedure. In this study, evaluation of the surgical difficulty to conduct transmastoid atticotomy with the coronary cut of CT temporal bone. Additional, attic pathology intraoperative is evaluated. The current research is a retrospective study of 79 patients with chronic suppurative otitis media (safe type) with the preoperative opacity of the attic in CT temporal bone. The researcher correlates difficulty to do transmastoid attictomy with the distance in mm between the roof of external audiatory canal (EAC) and tegmen with ruler directly in the coronary cut of CT temporal bone at the the level of internal auditory canal (IAC). The researcher also compares attic pathology intraoperative with preoperative CT attic opacity. In group of surgically difficulty average distance between the superior wall of EAC and tegmen on preoperative CT at the level of IAC is 2–5 mm while distance in easily surgical approach is from 6 to 10 mm. 68.4%(54/79) of cases had pathology in attic in the form of granulation tissue in 50 cases and glue in 4 cases. Preoperative CT temporal bone is very important to detect atticotomy approach either transmastoid or transcanal, through measuring the distance in mm between the roof of EAC and tegmen with ruler directly in the coronal cut of CT temporal bone at the level of internal auditory canal. The opacity of the attic in Preoperative CT does not mean that there is a pathology in the attic.

http://ift.tt/2G7D12Y

Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969–2013

Thyroid, Ahead of Print.


http://ift.tt/2DFdVDx

Surgical Management of the Drooling Child

Abstract

Purpose of Review

Our goal is to present the most up-to-date options in the surgical management of drooling in the paediatric population. While the clinical assessment of the drooling child and conservative management options are discussed, this review focuses on the most recent evidence for surgical interventions to treat drooling in children.

Recent Findings

In terms of advances in the management of drooling, further experience and outcomes with the use of botulinum toxin injections is discussed. Moreover, the latest evidence-base for salivary duct ligation and relocation procedures are presented. Finally, the trans-oral approach to submandibular gland excision for the management of drooling may gain popularity through the aim of reducing surgical morbidity.

Summary

The drooling child should be managed with an evidence-based stepwise approach delivered by a multidisciplinary team (MDT). Children with normal neurological development should be treated conservatively through parental reassurance. There are numerous interventions available for the drooling child with impaired neuromuscular development. When conservative measures fail, treatment options include botulinum toxin injections and surgical procedures such as salivary duct ligation, salivary duct relocation and salivary gland excision. Management must be targeted to the individual needs and comorbidities of the child to maximise treatment outcomes.

http://ift.tt/2GIIfAa

Pre-S2 Start Codon Mutation of Hepatitis B Virus Subgenotype B3 Effects on NF-κB Expression and Activation in Huh7 Cell Lines

Viral Immunology, Ahead of Print.


http://ift.tt/2ppGnVx

The Presence of Rape Myths in the Virtual World: A Qualitative Textual Analysis of the Steubenville Sexual Assault Case

Violence and Gender, Ahead of Print.


http://ift.tt/2GIqRvr

Psychological Abuse in the Context of Social Media

Violence and Gender, Ahead of Print.


http://ift.tt/2u2io3x

An Exploratory Evaluation of Bystander Intervention Training for Resident Assistants

Violence and Gender, Ahead of Print.


http://ift.tt/2FNl76B

Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata [PublishAheadOfPrint]

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three IV rezafungin dosing regimens: (i) single 400-mg dose, (ii) 400 mg for Week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the non-clinical PK-PD targets associated with net fungal stasis and 1-log₁₀ CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin dosing regimen. At the MIC₉₀ for C. albicans and C. glabrata, single dose rezafungin 400 mg achieved probabilities of PK-PD target attainment ≥90% through Week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through Week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through Week 6 following administration of the weekly dosing regimens at or above the MIC₁₀₀ values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin dosing regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.

http://ift.tt/2FVHK4G

Toxoplasma calcium-dependent protein kinase 1 inhibitors: probing activity and resistance using cellular thermal shift assays [PublishAheadOfPrint]

In Toxoplasma gondii, calcium-dependent protein kinase 1 (CDPK1) is an essential protein kinase required for invasion of host cells. We have developed several hundred CDPK1 inhibitors, many of which block invasion. Inhibitors with similar IC₅₀s were tested in thermal shift assays for their ability to stabilize CDPK1 in cell lysates, in intact cells, or in purified form. Compounds that inhibited parasite growth stabilized CDPK1 in all assays. In contrast, two compounds that showed poor growth inhibition stabilized CDPK1 in lysates but not in cells. Thus, cellular exclusion could explain exceptions in the correlation between the action on the target and cellular activity. We used thermal shift assays to examine CDPK1 in two clones that were independently selected by growth in the CDPK1 inhibitor RM-1-132 and that have increased EC₅₀s for the compound. The A and C clones have distinct point mutations in the CDPK1 kinase domain, H201Q and L96P respectively, residues that lie near one another in the inactive isoform. Purified mutant proteins showed similar RM-1-132 IC₅₀s and thermal shifts to wild type CDPK1. Reduced inhibitor stabilization (and presumed reduced interaction) was only observed in cellular thermal shift assays. This highlights the utility of cellular thermal shift assays in demonstrating that resistance involves reduced on-target engagement (even if biochemical assays suggest otherwise). Indeed, similar EC₅₀s were observed upon over-expression of the mutant proteins as in the corresponding drug-selected parasites, although high levels of CDPK1(H201Q) only modestly increased resistance as compared to high levels of wild type enzyme.

http://ift.tt/2GKASs3

Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data [PublishAheadOfPrint]

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent in vitro activity against Candida albicans and Candida glabrata, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration. Data from two Phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via IV infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles across a population and can provide dose selection decision support for future clinical studies.

http://ift.tt/2FVHFOq

Cell swelling induced by the antimalarial KAE609 (cipargamin) and other PfATP4-associated antimalarials [PublishAheadOfPrint]

For an increasing number of antimalarial agents identified in high throughput phenotypic screens there is evidence that they target PfATP4, a putative Na⁺ efflux transporter on the plasma membrane of the human malaria parasite, Plasmodium falciparum. For several such 'PfATP4-associated' compounds it has been noted that their addition to parasitised erythrocytes results in cell swelling. Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling both of isolated blood-stage parasites and of intact parasitised erythrocytes. The swelling of isolated parasites is dependent on the presence of Na⁺ in the external environment and may be attributed to the osmotic consequences of Na⁺ uptake. The swelling of the parasitised erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds.

http://ift.tt/2GLiwac

Design of a broad-range bacteriophage cocktail that reduces Pseudomonas aeruginosa biofilms and treats acute infections in two animal models. [PublishAheadOfPrint]

The alarming diffusion of multidrug resistant (MDR) bacterial strains requires investigations on non-antibiotic therapies. Amongst them, the use of bacteriophages (phages) as antimicrobial agents, namely phage therapy, is a promising treatment strategy with support by recent successful compassionate treatments in Europe and the U.S.A. In this work, we combined host range and genomic information to design a 6-phage cocktail killing several clinical strains of P. aeruginosa, including those collected from Italian cystic fibrosis (CF) patients, and analyzed the cocktail performance. We demonstrated that the cocktail composed of four novel (PYO2, DEV, E215 and E217) and two previously characterized (PAK_P1 and PAK_P4) phages was able to lyse P. aeruginosa both in planktonic liquid cultures and in biofilm. In addition, we showed that the phage cocktail could cure acute respiratory infection in mouse and treat bacteremia in the wax moth Galleria mellonella larvae. Furthermore, administration of the cocktail to larvae prior to bacterial infection provided prophylaxis. In this regard, efficiency of the phage cocktail was found to be unaffected by the MDR or mucoid phenotype of the pseudomonal strain. The cocktail was found to be superior to individual phages in destroying biofilms and providing a faster treatment in mice. We also found the Galleria larvae model to be cost-effective for testing clinical strains susceptibility to phages, suggesting that it could be implemented in the frame of developing personalized phage therapies.

http://ift.tt/2HPkO7L

Genetic determinants of high-level oxacillin resistance in MRSA [PublishAheadOfPrint]

Methicillin-resistant Staphylococcus aureus (MRSA) strains carry either a mecA- or a mecC-mediated mechanism of resistance to beta-lactam antibiotics and the phenotypic expression of resistance shows extensive strain-to-strain variation. In recent communications we identified genetic determinants associated with the stringent stress response that play a major role in the antibiotic resistant phenotype of the historically earliest "archaic" clone of MRSA and in the mecC carrying MRSA strain LGA251. Here, we sought to test whether or not the same genetic determinants also contribute to the resistant phenotype of highly and homogeneously resistant (H*R) derivatives of a major contemporary MRSA clone USA300. We found that the resistance phenotype was linked to six genes (fruB, gmk, hpt, purB, prsA, and relA), which were most frequently targeted among the analyzed 20 H*Rs (one mutation per clone in 19 out of the 20 H*Rs). Besides the strong parallels with our previous findings (five out of the six genes matched), all but one of the repeatedly targeted genes were found to be linked to guanine metabolism pointing to the key role that this pathway plays in defining the level of antibiotic resistance independent of the clonal type of MRSA.

http://ift.tt/2Gb0PDv

Comparison of septic shock due to MDR Acinetobacter baumannii or Klebsiella pneumoniae carbapenemase--producing K. pneumoniae in ICU patients [PublishAheadOfPrint]

Objectives: a significant cause of mortality in intensive care unit (ICU) is represented by multidrug-resistant (MDR) gram-negative bacteria, such as MDR Acinetobacter baumannii (MDR-AB) and Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp). Aim of the present study was the comparison of clinical features, therapy and outcome of patients who developed septic shock due to either MDR-AB or KPC-Kp.

Methods: were retrospectively analyzed patients admitted to the intensive care unit (ICU) of a teaching hospital, from November 2010 to December 2015, who developed septic shock due to MDR-AB or KPC-Kp infection.

Results: data from 220 patients were analyzed: 128 (58.2%) were diagnosed with septic shock due to KPC-Kp and 92 (41.8%) were diagnosed with septic shock due to MDR-AB, respectively. The 30-day mortality rate was significantly higher for the MDR-AB group (84.8% Vs 44.5%, p<0.001). Steroid exposure and pneumonia were associated with MDR-AB infection, whereas hospitalization in the previous 90 days, primary bacteremia, and KPC-Kp colonization were associated with KPC-Kp infection. For patients with KPC-Kp infections, the use of ≥ 2 antibiotics active in vitro as empiric or definitive therapy was associated with higher 30-day survival, while isolation of colistin-resistant strains was linked to mortality. For patients with MDR-AB infections, age >60 years and SAPS II >45 points were associated with increased mortality rates.

Conclusions: septic shock due to MDR-AB infection is associated with very high mortality rates, compared to septic shock due to KPC-Kp. Analysis of clinical features of these critically-ill patients might help physicians in choosing appropriate empirical antimicrobial therapy.

http://ift.tt/2FVHv9M

The TonB-receptor repertoire of Pseudomonas aeruginosa for the uptake of siderophore-drug conjugates [PublishAheadOfPrint]

The conjugation of siderophores to antimicrobial molecules is an attractive strategy to overcome the low outer membrane permeability of Gram-negative bacteria. In this Trojan horse approach the transport of drug conjugates is redirected via TonB-dependent receptors (TBDR), involved in the uptake of essential nutrients including iron. Previous reports have demonstrated the involvement of the TBDRs PiuA and PirA from Pseudomonas aeruginosa and their orthologues in Acinetobacter baumannii in the uptake of siderophore-beta-lactam drug conjugates. By in silico screening, we further identified a PiuA orthologue, termed PiuD, present in clinical isolates including strain LESB58. The piuD gene in LESB58 is located at the same genetic locus as piuA in PAO1. PiuD shares a similar crystal structure as PiuA and is involved in the transport of the siderophore-drug conjugates BAL30072, MC-1 and cefiderocol in strain LESB58. To screen for additional siderophore-drug uptake systems, we overexpressed 28 of the 34 TBDRs of strain PAO1 and identified PfuA, OptE, OptJ and the pyochelin receptor FptA as novel TBDRs conferring increased susceptibility to siderophore-drug conjugates. The existence of a TBDR repertoire in P. aeruginosa, able to transport siderophore-drug molecules, potentially decreases the likelihood of resistance emergence during therapy.

http://ift.tt/2GO2Rax

Outcome of E1224/benznidazole combination treatment upon infection with multi-drug resistant Trypanosoma cruzi strain in mice. [PublishAheadOfPrint]

Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. A first set of experiments assessed the range of E1224 doses required to induce parasitological cure using T. cruzi strains with different susceptibilities to benznidazole (Y and Colombian). All E1224 doses were effective in suppressing the parasitemia and preventing the death, however, parasitological cure was observed only in mice infected with Y strain. Considering these results, we evaluated the effect of combined treatment against Colombian, a multi-drug-resistant T. cruzi strain. After exclusion of antagonistic effects using in vitro assays, infected mice were treated with E1224 and benznidazole in monotherapy or combination, at day 4 or 10 post-inoculation. All treatments were well tolerated and effective in suppressing parasitemia, however, parasitological and PCR assays indicated no cure among mice treated with monotherapies. Intriguingly, the outcome of combination therapy was dependent on treatment onset. Early treatment using optimal doses of E1224/benznidazole induced a 100% cure rate, but this association could not eliminate a well-established infection. The beneficial effect of combination therapy was evidenced by further reductions of the patent parasitemia period in the group receiving combined therapy compared with monotherapies. Our results demonstrated a positive interaction between E1224/benznidazole against murine T. cruzi infection using a multi-drug resistant strain and highlighted the importance of a stringent experimental model in the evaluation of new therapies.

http://ift.tt/2FVHqmu

Preclinical profile of AB-423, an inhibitor of Hepatitis B virus pgRNA encapsidation [PublishAheadOfPrint]

AB-423 is a sulfamoylbenzamide (SBA) class of HBV capsid inhibitor in Phase 1 clinical trials. In cell culture models AB-423 showed potent inhibition of HBV replication (EC₅₀/EC₉₀ = 0.08-0.27 μM/0.33-1.32 μM) with no significant cytotoxicity (CC₅₀ >10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC₅₀ values. AB-423 inhibited HBV genotypes A through D and nucleos/tide-resistant variants in vitro. Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pgRNA and rcDNA indicating it is a class II capsid inhibitor. In a de novo infection model AB-423 prevented the conversion of encapsidated rcDNA to cccDNA presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer:dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents such as nucleos/tide analogs, RNAi agents, or interferon-α resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher liver accumulation. A 7-day BID administration of AB-423 in a hydrodynamic injection mouse model of HBV model resulted in a dose-dependent reduction in serum HBV DNA levels and combination with ETV or ARB-1467 resulted in a trend towards greater antiviral activity than either agent alone consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports further evaluation for safety, pharmacokinetics and antiviral activity in CHB patients.

http://ift.tt/2GKLs2q

Beta-Lactams combinations with Vancomycin provide synergy against VSSA, hVISA, and VISA [PublishAheadOfPrint]

Background: Increasing utilization of vancomycin due to the high prevalence of methicillin-resistant S. aureus (MRSA) infections has lead to the emergence of vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA). In vitro data suggest the potential for potent synergy between several beta-lactams and vancomycin. The objective of this study is to evaluate the synergy between beta-lactams and vancomycin against MRSA that is vancomycin susceptible, vancomycin susceptible Staphylococcus aureus (VSSA), hVISA, and VISA.

Methods: Fifty randomly selected clinical MRSA strains with varying susceptibility to vancomycin were evaluated for vancomycin alone and vancomycin in combination with varying concentrations of cefazolin (CFZ), cefepime (FEP), ceftaroline (CPT), and nafcillin (NAF) minimum inhibitory concentration (MIC). The potential for synergy was assessed by 24h time-kills.

Results: Beta-lactams reduced vancomycin MIC values against all strains (4-16 fold reduction). In time-kill studies against MRSA, CFZ, FEP, CPT, and NAF all demonstrated a similar extent of killing at 24h, and all showed synergistic activity with vancomycin against VSSA, hVISA, and VISA. Each of these combinations was also superior to any single agent against isolates of all three phenotypes, and each was bactericidal (P < 0.001 for all comparisons). All single agent exposures demonstrated no activity at 24h.

Conclusions: The combination of vancomycin and beta-lactams significantly improved antibacterial activity against VSSA, hVISA, and VISA compared to any agent alone, supporting the potential use of vancomycin/beta-lactams combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergy of vancomycin against these Staphylococcus strains.

http://ift.tt/2HLKORm

Pain: A Neglected Problem in the Low-Resource Setting

Approximately 80% of the world's population lives in countries with little or no access to pain management. These countries also have 74% of the world's deaths from cancer and human immunodeficiency virus. Appropriate use of oral opioids can control 80%–90% of cancer pain. However, only 6.7% of the world's medical opioids are available in these low-resource countries. With the Lancet Commission on Global Surgery calling for a significant expansion of surgical services, postoperative pain management will need to be an increasing focus of our attention. There are multiple barriers to providing effective pain management. These include the type and funding of the health care system, the size and educational level of the workforce, the ease of access to effective medications, and the expectations and knowledge base of the community. Some barriers can be addressed by education at the undergraduate level, postgraduate level, and community level. Others will require continued advocacy at government level. Only when we tackle these problems will the considerable neglect of access to effective pain treatment in low- and middle-income countries be lessened.

http://ift.tt/2HNnSBm

Strengthening the Anesthesia Workforce in Low- and Middle-Income Countries

The majority of the world's population lacks access to safe, timely, and affordable surgical care. Although there is a health workforce crisis across the board in the poorest countries in the world, anesthesia is disproportionally affected. This article explores some of the key issues that must be tackled to strengthen the anesthesia workforce in low- and lower-middle-income countries. First, we need to increase the overall number of safe anesthesia providers to match a huge burden of disease, particularly in the poorest countries in the world and in remote and rural areas. Through using a task-sharing model, an increase is required in both nonphysician anesthesia providers and anesthesia specialists. Second, there is a need to improve and support the competency of anesthesia providers overall. It is important to include a broad base of knowledge, skills, and attitudes required to manage complex and high-risk patients and to lead improvements in the quality of care. Third, there needs to be a concerted effort to encourage interprofessional skills and the aspects of working and learning together with colleagues in a complex surgical ecosystem. Finally, there has to be a focus on developing a workforce that is resilient to burnout and the challenges of an overwhelming clinical burden and very restricted resources. This is essential for anesthesia providers to stay healthy and effective and necessary to reduce the inevitable loss of human resources through migration and cessation of professional practice. It is vital to realize that all of these issues need to be tackled simultaneously, and none neglected, if a sustainable and scalable solution is to be achieved.

http://ift.tt/2FNOuFA

Safe Surgery Globally by 2030: The Essential Role of Anesthesia, The View From Obstetrics

No abstract available

http://ift.tt/2GHMVX9

Safe Surgery Globally by 2030: The View From Anesthesia

No abstract available

http://ift.tt/2FNVVwM

Global Access to Safe Anesthesia: Addressing the Gap

No abstract available

http://ift.tt/2HLIXMl

Atemwegsmanagement – der schwierige Atemweg beim thoraxchirurgischen Patienten

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 187-197
DOI: 10.1055/s-0043-114679

Das Management des schwierigen Atemwegs bei thoraxchirurgischen Patienten ist in den gültigen Leitlinien kaum abgebildet und stellt insbesondere in der Thoraxanästhesie mit der notwendigen Seitentrennung der Atemwege durch einen Doppellumentubus oder Bronchusblocker eine Herausforderung dar. Die Definition des schwierigen Atemwegs mit erschwerter Maskenbeatmung, Laryngoskopie oder endotrachealer Intubation wird überwiegend durch Veränderungen der Anatomie der oberen Atemwege (schwieriger oberer Atemweg) charakterisiert. Pathologische Veränderungen in der tracheobronchialen Anatomie, die die Platzierung des Doppellumentubus oder anderer Atemwegshilfen erschweren (schwieriger unterer Atemweg; schwierige Seitentrennung), sind in die Definition miteinzubeziehen. Der vorliegende Artikel beschreibt die Identifikation von Risikopatienten, Techniken, Empfehlungen und Algorithmen für das Management bei erwartet und unerwartet schwierigem Atemweg. Darüber hinaus gibt er einen Überblick über die Auswahl verschiedener Verfahren und Hilfsmittel zur Seitentrennung der Lungen zur Etablierung einer Ein-Lungen-Ventilation.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Intraoperatives Ketamin verhindert weder Delir, noch reduziert es postoperativen Schmerz

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 165-165
DOI: 10.1055/a-0577-0303

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Atemwegsmanagement in der Thoraxanästhesie

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 171-172
DOI: 10.1055/a-0577-4101

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Überwachung des Analgesieniveaus unter Allgemeinanästhesie

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 166-167
DOI: 10.1055/a-0577-0557

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Gastrointestinale Anastomoseninsuffizienz: operatives vs. konservatives Vorgehen

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 212-219
DOI: 10.1055/s-0042-120994

Eine Anastomoseninsuffizienz ist nach Resektionen und Rekonstruktionen im Gastrointestinaltrakt eine häufige Komplikation – ihre Folgen sind eine Verlängerung des stationären Aufenthaltes, eine schlechtere Prognose und eine erhöhte Letalität der betroffenen Patienten 1, 2. Der folgende Beitrag beleuchtet konservative und operative Therapieoptionen der Anastomoseninsuffizienz und zeigt Strategien zu ihrer Vermeidung und Früherkennung auf.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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REBOA bei der Körperstammblutung – die Bedeutung für den Anästhesisten

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 168-169
DOI: 10.1055/a-0577-0573

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Atemwegsmanagement in der Thoraxanästhesie mit dem Doppellumentubus

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 174-185
DOI: 10.1055/s-0043-114678

Die Seitentrennung der Lungen mit konsekutiver Ein-Lungen-Ventilation ist der zentrale Bestandteil des Atemwegsmanagements in der Thoraxanästhesie. Das Indikationsspektrum umfasst dabei die thoraxchirurgischen und prozedurbezogenen Notwendigkeiten wie auch die patientenspezifischen Faktoren. Von der Vielzahl der technischen Möglichkeiten der Separation der Lungenflügel bleiben routinemäßig nur die Anwendung des Doppellumentubus oder des Bronchusblockers übrig. Die ausgewiesene Kenntnis der tracheobronchialen Anatomie bis zur Segmentebene durch den Anästhesisten ist ebenso notwendig wie der standardmäßige Einsatz einer flexiblen Fiberoptik. Diese Arbeit gibt grundlegende Empfehlungen für die klinische Routine, stellt eine Übersicht zum derzeitigen Stellenwert im Atemwegsmanagement in der Thoraxanästhesie mit dem Doppellumentubus dar und berücksichtigt kontroverse Diskussionen zu Größe und Design.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Infektionen durch Mycobacterium chimaera nach kardiochirurgischen Eingriffen

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 168-168
DOI: 10.1055/a-0577-0619

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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http://ift.tt/2GbLbHE

Atemwegsmanagement in der Thoraxanästhesie mit dem Bronchusblocker

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 198-210
DOI: 10.1055/s-0043-114677

Bronchusblocker stellen für die Ein-Lungen-Ventilation eine Alternative zum Doppellumentubus dar – bei spezifischen Patientengruppen können sie sogar die einzige Option für die Lungenisolation sein. In diesem Beitrag werden Indikationen für Bronchusblocker gezeigt und die verfügbaren Modelle mit praktischen Hinweisen vorgestellt. Im Anschluss wird die klinische Anwendbarkeit der Bronchusblocker mit der des Doppellumentubus verglichen.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Ungewöhnlicher Fall eines schweren Polytraumas beim Kleinkind – Happy End trotz Fallstricken

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 220-223
DOI: 10.1055/s-0043-109008

Ein 16 Monate alter Junge erleidet bei einem Verkehrsunfall ein schwerstes Polytrauma (dislozierte offene Beckenfraktur, pelvines Décollement und hämorrhagischer Schock). Die dabei auftretenden Besonderheiten und Fallstricke in der präklinischen und frühen klinischen Versorgung dieses schweren und seltenen Traumas bei pädiatrischen Patienten werden herausgearbeitet, wobei besonders auf die damit einhergehenden medizinisch-einsatztaktischen Schwierigkeiten eingegangen wird.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Weniger postoperative Komplikationen nach individuellem Blutdruckmanagement

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 165-166
DOI: 10.1055/a-0576-9925

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Short-term LXR activation improves epidermal barrier features in mild-to-moderate atopic dermatitis: a randomized controlled trial

The prevalence of atopic dermatitis/AD has increased over the last decade to affect 17-24% of the children and 4-10% of the adults.1, 2 AD disease pathogenesis involves Th2/Th22 immune activation and barrier dysregulation.3-5 The epidermal barrier abnormalities in AD include defects in terminal differentiation (e.g., loricrin/LOR, filaggrin/FLG), tight junctions/TJ, lipids, S100As, antimicrobial peptides/AMPs and epidermal hyperplasia.6, 7 Compromised epidermal barrier also plays a major role in allergic sensitization, possibly leading to other atopic associations, including asthma, allergic rhinitis and food allergies.

http://ift.tt/2FUhVSv

Concordance with anaphylaxis care guidelines and the impact on healthcare resource utilization in the USA

For patients who have experienced anaphylaxis, United States (US) guidelines recommend first-line therapy with epinephrine to prevent fatalities, as well as prescription of an epinephrine auto-injector (EAI), referral to an allergist/immunologist, and training to identify and avoid the responsible allergen.1–3 However, adherence to these guidelines is low4–6 and generally, patients face increased healthcare resource utilization (HCRU) and associated costs.4

http://ift.tt/2G89cQ8

Hepatitis B vaccine non-responders: possible mechanisms and solutions

Hepatitis B (HBV) is a viral illness that chronically infects 240 million people worldwide, leads to cirrhotic liver disease, and increases risk of hepatocellular carcinoma. The HBV vaccine has decreased HBV infection and along with human papilloma virus (HPV) vaccine are the only vaccines that prevent cancer. Despite the effectiveness of HBV vaccine, some populations do not develop protective responses. The risk groups for poor response include those with immunosuppression or dialysis-dependent, end-stage renal disease.

http://ift.tt/2FSN6O5

Validity and responsiveness of the urticaria activity and impact measure (U-AIM), a new patient-reported tool

Chronic spontaneous urticaria (CSU), also known as chronic idiopathic urticaria (CIU), may produce hives, itch, and angioedema. The Urticaria Activity and Impact Measure (U-AIM) is a newly developed 9-item patient-reported measure designed for use in routine clinical practice to assess CSU activity and impact over the previous 7 days.

http://ift.tt/2FMloX9

Self-reported adverse reactions associated with mycoprotein (Quorn-brand) containing foods Michael F. Jacobson, PhD, Center for Science in the Public Interest

Mycoprotein, which is produced by a mold and is the basis of Quorn-brand meat substitutes, is a novel cause of allergic and gastrointestinal reactions, but little information has been available on its associated symptomatology.

http://ift.tt/2HP0SBT

YouTube as a source of information for obstructive sleep apnea

Assess the quality of information on obstructive sleep apnea (OSA) presented on YouTube for patients.

http://ift.tt/2G4F6wH

Multicenter phase I/II study of chemoradiotherapy with high-dose CDDP for head and neck squamous cell carcinoma in Japan

Recent data indicated that concurrent chemoradiotherapy (CCRT) using high dose cisplatin (CDDP) is the most useful treatment for advanced head and neck squamous cell carcinoma (SCC). Regarding the dose of CDDP, 100mg/m2 is most recommended in Western countries. However, in terms of a balance of efficacy and adverse events, appropriate dose of cytotoxic drugs such as CDDP may be different among the different ethnic groups. In this multicenter phase I/II study, we aimed to identify the optimal dose of CDDP in CCRT for patients with advanced head and neck SCC in the Japanese.

http://ift.tt/2IDWZAP

Severe immunodeficiency associated with acute lymphoblastic leukemia and its treatment

Immunodeficiency can be associated with acute lymphoblastic leukemia (ALL) in various ways. ALL can be a feature of various primary immunodeficiencies including, but not limited, to X-linked agammaglobulinemia, chromosomal breakage disorders such as ataxia telangiectasia, and GATA2 haploinsufficiency.1–4 ALL also can be secondary to an infection such as human immunodeficiency virus. A congenital leukemia such as ALL can lead to abnormal newborn screening results for severe combined immunodeficiency.

http://ift.tt/2GaGfDf

HLA Class II-Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection [IMMUNOGENETICS]

Transplant recipients developing donor-specific HLA class II (HLA-II) Abs are at higher risk for Ab-mediated rejection (AMR) and transplant vasculopathy. To understand how HLA-II Abs cause AMR and transplant vasculopathy, we determined the signaling events triggered in vascular endothelial cells (EC) following Ab ligation of HLA-II molecules. HLA-II expression in EC was induced by adenoviral vector expression of CIITA or by pretreatment with TNF-α/IFN-. Ab ligation of class II stimulated EC proliferation and migration. Class II Ab also induced activation of key signaling nodes Src, focal adhesion kinase, PI3K, and ERK that regulated downstream targets of the mammalian target of rapamycin (mTOR) pathway Akt, p70 ribosomal S6 kinase, and S6 ribosomal protein. Pharmacological inhibitors and small interfering RNA showed the protein kinases Src, focal adhesion kinase, PI3K/Akt, and MEK/ERK regulate class II Ab-stimulated cell proliferation and migration. Treatment with rapalogs for 2 h did not affect HLA-II Ab-induced phosphorylation of ERK; instead, mTOR complex (mTORC)1 targets were dependent on activation of ERK. Importantly, suppression of mTORC2 for 24 h with rapamycin or everolimus or treatment with mTOR active-site inhibitors enhanced HLA-II Ab-stimulated phosphorylation of ERK. Furthermore, knockdown of Rictor with small interfering RNA caused overactivation of ERK while abolishing phosphorylation of Akt Ser⁴⁷³ induced by class II Ab. These data are different from HLA class I Ab-induced activation of ERK, which is mTORC2-dependent. Our results identify a complex signaling network triggered by HLA-II Ab in EC and indicate that combined ERK and mTORC2 inhibitors may be required to achieve optimal efficacy in controlling HLA-II Ab-mediated AMR.

http://ift.tt/2FNlIVR

NKG2D-MICA Interaction: A Paradigm Shift in Innate Recognition [PILLARS OF IMMUNOLOGY]

http://ift.tt/2G7MFTy

Blockade of Host {beta}2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs [TRANSPLANTATION]

Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that β2-adrenergic receptor (β2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a β2AR blocker significantly increases the GVT effect of donor CD8⁺ T cells by decreasing tumor burden without increasing graft-versus-host disease. β2AR-deficient host mice have significantly increased effector memory and central memory CD8⁺ T cells and improved reconstitution of T cells, including CD4⁺Foxp3⁺ regulatory T cells. Notably, β2AR deficiency induces increased CD11c⁺ DC development. Also, β2AR-deficient bone marrow–derived DCs induce higher CD8⁺ T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that β2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host β2AR signaling in suppressing T cell reconstitution and GVT activity.

http://ift.tt/2FLEaxX

Pillars Article: Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA. Science. 1999. 285: 727-729 [PILLARS OF IMMUNOLOGY]

http://ift.tt/2HMYYSt

{alpha}M{beta}2 Is Antiatherogenic in Female but Not Male Mice [INNATE IMMUNITY AND INFLAMMATION]

Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin α_Mβ₂ (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. α_M^–/–/ApoE^–/– and ApoE^–/– mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, α_M deficiency accelerated development of atherosclerosis in female but not in male mice. The size of aortic root lesions was 3–4.5-fold larger in female α_M^–/–/ApoE^–/– than in ApoE^–/– mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female α_M^–/–/ApoE^–/– mice due to enhanced proliferation. α_Mβ₂ elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by α_M^–/–/ApoE^–/– macrophages. This difference was attributed to enhanced expression of lipid uptake receptors, CD36 and scavenger receptor A1 (SR-A1), in female mice. Macrophages from female α_M^–/–/ApoE^–/– mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) α and β. As their antagonists inhibited the effect of 17β-estradiol (E₂), E₂ decreased CD36, SR-A1, and foam cell formation in ApoE^–/– macrophages in an ERα- and ERβ-dependent manner. However, female α_M^–/–/ApoE^–/– macrophages failed to respond to E₂ and maintained elevated CD36, SR-A1, and lipid accumulation. FoxM1 inhibition in ApoE^–/– macrophages reduced ERs and enhanced CD36 and SR-A1 expression, whereas FoxM1 overexpression in α_M^–/–/ApoE^–/– macrophages reversed their proatherogenic phenotype. We demonstrate a new, surprising atheroprotective role of α_Mβ₂ in female ApoE^–/– mice. α_Mβ₂ maintains ER expression in macrophages and E₂-dependent inhibition of foam cell formation.

http://ift.tt/2FNuzXk

Development, Homeostasis, and Functions of Intestinal Intraepithelial Lymphocytes [BRIEF REVIEWS]

The intestine is continuously exposed to commensal microorganisms, food, and environmental agents and also serves as a major portal of entry for many pathogens. A critical defense mechanism against microbial invasion in the intestine is the single layer of epithelial cells that separates the gut lumen from the underlying tissues. The barrier function of the intestinal epithelium is supported by cells and soluble factors of the intestinal immune system. Chief among them are intestinal intraepithelial lymphocytes (iIELs), which are embedded in the intestinal epithelium and represent one of the single largest populations of lymphocytes in the body. Compared with lymphocytes in other parts of the body, iIELs exhibit unique phenotypic, developmental, and functional properties that reflect their key roles in maintaining the intestinal epithelial barrier. In this article, we review the biology of iIELs in supporting normal health and how their dysregulation can contribute to disease.

http://ift.tt/2GbokvQ

Brutons Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages [IMMUNE SYSTEM DEVELOPMENT]

Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a Btk^flox/Cre-ER^T2 mouse model was developed and used to excise Btk after B cell populations were established. Mice lacking Btk from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult Btk^flox/Cre-ER^T2 mice, Btk excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional Btk excision, contrasting their near absence in global Btk-deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global Btk deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects.

http://ift.tt/2G4kKUj

Cutting Edge: A New Player in the Alternative Complement Pathway, MASP-1 Is Essential for LPS-Induced, but Not for Zymosan-Induced, Alternative Pathway Activation [CUTTING EDGE]

The complement system is a sophisticated network of proteases. In this article, we describe an unexpected link between two linear activation routes of the complement system: the lectin pathway (LP) and the alternative pathway (AP). Mannose-lectin binding–associated serine protease (MASP)-1 is known to be the initiator protease of the LP. Using a specific and potent inhibitor of MASP-1, SGMI-1, as well as other MASP-1 inhibitors with different mechanisms of action, we demonstrated that, in addition to its functions in the LP, MASP-1 is essential for bacterial LPS-induced AP activation, whereas it has little effect on zymosan-induced AP activation. We have shown that MASP-1 inhibition prevents AP activation, as well as attenuates the already initiated AP activity on the LPS surface. This newly recognized function of MASP-1 can be important for the defense against certain bacterial infections. Our results also emphasize that the mechanism of AP activation depends on the activator surface.

http://ift.tt/2FXxSHt

IL-12+IL-18 Cosignaling in Human Macrophages and Lung Epithelial Cells Activates Cathelicidin and Autophagy, Inhibiting Intracellular Mycobacterial Growth [INFECTIOUS DISEASE AND HOST RESPONSE]

The ability of Mycobacterium tuberculosis to block host antimicrobial responses in infected cells provides a key mechanism for disease pathogenesis. The immune system has evolved to overcome this blockade to restrict the infection, but it is not clear whether two key innate cytokines (IL-12/IL-18) involved in host defense can enhance antimycobacterial mechanisms. In this study, we demonstrated that the combination of IL-12 and IL-18 triggered an antimicrobial response against mycobacteria in infected macrophages (THP-1 and human primary monocyte-derived macrophages) and pulmonary epithelial A549 cells. The inhibition of intracellular bacterial growth required p38–MAPK and STAT4 pathways, the vitamin D receptor, the vitamin D receptor–derived antimicrobial peptide cathelicidin, and autophagy, but not caspase-mediated apoptosis. Finally, the ability of IL-12+IL-18 to activate an innate antimicrobial response in human primary macrophages was dependent on the autonomous production of IFN- and the CAMP/autophagy pathway. Together, these data suggest that IL-12+IL-18 cosignaling can trigger the antimicrobial protein cathelicidin and autophagy, resulting in inhibition of intracellular mycobacteria in macrophages and lung epithelial cells.

http://ift.tt/2G9OMpU

Elevated Expression of IL-33 and TSLP in the Airways of Human Asthmatics In Vivo: A Potential Biomarker of Severe Refractory Disease [ALLERGY AND OTHER HYPERSENSITIVITIES]

The epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 have been implicated in asthma pathogenesis because they promote Th2-type cytokine synthesis, but their expression is relatively poorly documented in "real-life" human asthma. Using bronchoalveolar lavage fluid (BALF), we measured airway concentrations of these mediators and compared them with those of Th1- and Th2-type cytokines, airway infiltration of neutrophils and eosinophils, and lung function in a large group of asthmatic patients with a range of disease severity (n = 70) and control subjects (n = 30). The median BALF concentrations of IL-33, TSLP, IL-4, IL-5, IL-13, and IL-12p70, but not IL-25, IL-2, or IFN-, were significantly elevated in asthmatics compared with controls (p < 0.05). The concentrations of IL-33 and TSLP, but not IL-25, correlated inversely with the lung function (forced expiratory volume in the first second) of asthmatics (IL-33: r = –0.488, p < 0.0001; TSLP: r = –0.565, p < 0.0001) independently of corticosteroid therapy. When divided according to disease severity and corticosteroid therapy, all subgroups of asthmatics had elevated median numbers of eosinophils in BALF, whereas the patients with more severe disease who were treated with corticosteroids had higher numbers of neutrophils compared with milder asthmatics not so treated and control subjects (p < 0.05). The data implicate TSLP and IL-33 in the pathogenesis of asthma that is characterized by persistent airway inflammation and impaired lung function despite intensive corticosteroid therapy, highlighting them as potential molecular targets.

http://ift.tt/2G3apIt

c-Src-Dependent and -Independent Functions of Matk in Osteoclasts and Osteoblasts [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown. The inhibitory effect of Matk on osteoclasts was closely related with the inhibition of c-Src activity. Intriguingly, Matk overexpression in osteoblasts reduced bone nodule formation. Conversely, Matk knockdown increased osteoblast function. Most importantly, binding of Matk to Runx2 resulted in the inhibition of Runx2 translocation into the nucleus and downregulation of Runx2 target genes. Taken together, our findings demonstrated that Matk plays a critical role in bone metabolism by impairing the functions of osteoclasts and osteoblasts via distinct mechanisms involving inhibition of c-Src–dependent and –independent signaling pathways.

http://ift.tt/2FNuyme

Peptide-MHC Class I Tetramers Can Fail To Detect Relevant Functional T Cell Clonotypes and Underestimate Antigen-Reactive T Cell Populations [ANTIGEN RECOGNITION AND RESPONSES]

Peptide-MHC (pMHC) multimers, usually used as streptavidin-based tetramers, have transformed the study of Ag-specific T cells by allowing direct detection, phenotyping, and enumeration within polyclonal T cell populations. These reagents are now a standard part of the immunology toolkit and have been used in many thousands of published studies. Unfortunately, the TCR-affinity threshold required for staining with standard pMHC multimer protocols is higher than that required for efficient T cell activation. This discrepancy makes it possible for pMHC multimer staining to miss fully functional T cells, especially where low-affinity TCRs predominate, such as in MHC class II–restricted responses or those directed against self-antigens. Several recent, somewhat alarming, reports indicate that pMHC staining might fail to detect the majority of functional T cells and have prompted suggestions that T cell immunology has become biased toward the type of cells amenable to detection with multimeric pMHC. We use several viral- and tumor-specific pMHC reagents to compare populations of human T cells stained by standard pMHC protocols and optimized protocols that we have developed. Our results confirm that optimized protocols recover greater populations of T cells that include fully functional T cell clonotypes that cannot be stained by regular pMHC-staining protocols. These results highlight the importance of using optimized procedures that include the use of protein kinase inhibitor and Ab cross-linking during staining to maximize the recovery of Ag-specific T cells and serve to further highlight that many previous quantifications of T cell responses with pMHC reagents are likely to have considerably underestimated the size of the relevant populations.

http://ift.tt/2FWlgAz

Correction: Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression [CORRECTIONS]

http://ift.tt/2G94hys

FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces [AUTOIMMUNITY]

Factor H related-protein 5 (CFHR5) is a surface-acting complement activator and variations in the CFHR5 gene are linked to CFHR glomerulonephritis. In this study, we show that FHR5 binds to laminin-521, the major constituent of the glomerular basement membrane, and to mesangial laminin-211. Furthermore, we identify malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells (Homo sapiens), as new FHR5 ligands. Using a set of novel deletion fragments, we show that FHR5 binds to laminin-521, MAA epitopes, heparin, and human necrotic cells (HUVECs) via the middle region [short consensus repeats (SCRs) 5-7]. In contrast, surface-bound FHR5 contacts C3b via the C-terminal region (SCRs8-9). Thus, FHR5 uses separate domains for C3b binding and cell surface interaction. MAA epitopes serve as a complement-activating surface by recruiting FHR5. The complement activator FHR5 and the complement inhibitor factor H both bind to oxidation-specific MAA epitopes and FHR5 competes with factor H for binding. The C3 glomerulopathy–associated FHR2_1–2-FHR5 hybrid protein is more potent in MAA epitope binding and activation compared with wild-type FHR5. The implications of these results for pathology of CFHR glomerulonephritis are discussed. In conclusion, we identify laminins and oxidation-specific MAA epitopes as novel FHR5 ligands and show that the surface-binding site of FHR5 (SCRs5-7) is separated from the C3b binding site (SCRs8-9). Furthermore, FHR5 competes with factor H for binding to MAA epitopes and activates complement on these modified structures.

http://ift.tt/2FLlDBL

The Alternative NF-{kappa}B Pathway in Regulatory T Cell Homeostasis and Suppressive Function [IMMUNE SYSTEM DEVELOPMENT]

CD4⁺Foxp3⁺ regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-B family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-B pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2, in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2-deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-B signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity.

http://ift.tt/2HMMTwi

Human Binge Alcohol Intake Inhibits TLR4-MyD88 and TLR4-TRIF Responses but Not the TLR3-TRIF Pathway: HspA1A and PP1 Play Selective Regulatory Roles [CLINICAL AND HUMAN IMMUNOLOGY]

Binge/moderate alcohol suppresses TLR4–MyD88 proinflammatory cytokines; however, alcohol's effects on TLR–TRIF signaling, especially after in vivo exposure in humans, are unclear. We performed a comparative analysis of the TLR4–MyD88, TLR4–TRIF, and TLR3–TRIF pathways in human monocytes following binge alcohol exposure. Mechanistic regulation of TLR–TRIF signaling by binge alcohol was evaluated by analyzing IRF3 and TBK1, upstream regulator protein phosphatase 1 (PP1), and immunoregulatory stress proteins HspA1A and XBP-1 in alcohol-treated human and mouse monocytes/macrophages. Two approaches for alcohol exposure were used: in vivo exposure of primary monocytes in binge alcohol–consuming human volunteers or in vitro exposure of human monocytes/murine macrophages to physiological alcohol concentrations (25–50 mM ethanol), followed by LPS (TLR4) or polyinosinic-polycytidylic acid (TLR3) stimulation ex vivo. In vivo and in vitro binge alcohol exposure significantly inhibited the TLR4–MyD88 cytokines TNF-α and IL-6, as well as the TLR4–TRIF cytokines/chemokines IFN-β, IP-10, and RANTES, in human monocytes, but not TLR3–TRIF–induced cytokines/chemokines, as detected by quantitative PCR and ELISA. Mechanistic analyses revealed TBK-1–independent inhibition of the TLR4–TRIF effector IRF3 in alcohol-treated macrophages. Although stress protein XBP-1, which is known to regulate IRF3-mediated IFN-β induction, was not affected by alcohol, HspA1A was induced by in vivo alcohol in human monocytes. Alcohol-induced HspA1A was required for inhibition of TLR4–MyD88 signaling but not TLR4–TRIF cytokines in macrophages. In contrast, inhibition of PP1 prevented alcohol-mediated TLR4–TRIF tolerance in macrophages. Collectively, our results demonstrate that in vivo and in vitro binge alcohol exposure in humans suppresses TLR4–MyD88 and TLR4–TRIF, but not TLR3–TRIF, responses. Whereas alcohol-mediated effects on the PP1–IRF3 axis inhibit the TLR4–TRIF pathway, HspA1A selectively suppresses the TLR4–MyD88 pathway in monocytes/macrophages.

http://ift.tt/2FXxOrd

Inflammatory Monocytes Drive Influenza A Virus-Mediated Lung Injury in Juvenile Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

Healthy children are more likely to die of influenza A virus (IAV) infection than healthy adults. However, little is known about the mechanisms underlying the impact of young age on the development of life-threatening IAV infection. We report increased mortality in juvenile mice compared with adult mice at each infectious dose of IAV. Juvenile mice had sustained elevation of type I IFNs and persistent NLRP3 inflammasome activation in the lungs, both of which were independent of viral titer. Juvenile mice, but not adult mice, had increased MCP-1 levels that remained high even after viral clearance. Importantly, continued production of MCP-1 was associated with persistent recruitment of monocytes to the lungs and prolonged elevation of inflammatory cytokines. Transcriptional signatures of recruited monocytes to the juvenile and adult IAV-infected lungs were assessed by RNA-seq. Genes associated with a proinflammatory signature were upregulated in the juvenile monocytes compared with adult monocytes. Depletion of monocytes with anti-CCR2 Ab decreased type I IFN secretion, NLRP3 inflammasome activation, and lung injury in juvenile mice. This suggests an exaggerated inflammatory response mediated by increased recruitment of monocytes to the lung, and not an inability to control viral replication, is responsible for severe IAV infection in juvenile mice. This study provides insight into severe IAV infection in juveniles and identifies key inflammatory monocytes that may be central to pediatric acute lung injury secondary to IAV.

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The PI3K{delta}-Selective Inhibitor Idelalisib Minimally Interferes with Immune Effector Function Mediated by Rituximab or Obinutuzumab and Significantly Augments B Cell Depletion In Vivo [CLINICAL AND HUMAN IMMUNOLOGY]

Idelalisib is a highly selective oral inhibitor of PI3K indicated for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential effects, we investigated the impact of PI3K inhibition by idelalisib on the effector mechanisms of rituximab and obinutuzumab. At clinically relevant concentrations, idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity and phagocytosis on human lymphoma cell lines, while maintaining the superiority of obinutuzumab-mediated Ab-dependent cellular cytotoxicity. Consistent with this, idelalisib did not influence obinutuzumab-mediated B cell depletion in whole-blood B cell–depletion assays. Further, idelalisib significantly enhanced obinutuzumab-mediated direct cell death of chronic lymphocytic leukemia cells. In murine systems, in vivo inhibition of PI3K minimally interfered with maximal rituximab- or obinutuzumab-mediated depletion of leukemic targets. In addition, the duration of rituximab- and obinutuzumab-mediated depletion of leukemia cells was extended by combination with PI3K inhibition. Collectively, these data demonstrate that PI3K inhibition does not significantly affect the effector mechanisms induced by rituximab or obinutuzumab and provides an effective in vivo therapeutic combination. Therefore, combinations of obinutuzumab and idelalisib are currently being assessed in clinical studies.

http://ift.tt/2FMDVml

Septic Shock Shapes B Cell Response toward an Exhausted-like/Immunoregulatory Profile in Patients [INFECTIOUS DISEASE AND HOST RESPONSE]

Septic shock is accompanied by the development of immune dysfunctions whose intensity and duration are associated with increased risk of secondary infections and mortality. Although B lymphocytes play a pivotal role in the immune response to infections, no comprehensive exploration of circulating B cell status has been performed during the immunosuppressive phase of septic shock. Thus, our aim was to extensively characterize the phenotype and function of B cells in septic shock, including IL-10 production. Circulating B lymphocyte phenotype and function were evaluated by flow cytometry on fresh whole blood and after ex vivo stimulation in adult septic shock patients sampled at day 1, 3, and 6 after the onset of shock. The circulating B cell number was reduced in septic shock patients, whereas the B cell proportion among total lymphocytes was increased. The remaining circulating B lymphocytes presented with decreased MHC class II expression and increased CD21^low CD95^high exhausted-like phenotype but showed no change in maturation status. Circulating B cell functions were markedly altered after sepsis with reduced ex vivo activation and proliferation capacities. Finally, B cell response after septic shock was characterized by a clear plasmacytosis and an increased IL-10 production in remaining B cells from patients after ex vivo stimulation. During the sepsis-induced immunosuppression phase, B cell response is altered and is oriented toward an exhausted-like/immunoregulatory profile. Further studies are now needed to confirm the immunoregulatory properties of B lymphocytes and evaluate their role in sepsis-induced immunosuppression.

http://ift.tt/2FXxFEb

Reciprocal Regulation of Glycolysis-Driven Th17 Pathogenicity and Regulatory T Cell Stability by Cdc42 [IMMUNE REGULATION]

A balance between Th17 cells and regulatory T cells (Tregs) is important for host immunity and immune tolerance. The underlying molecular mechanisms remain poorly understood. Here we have identified Cdc42 as a central regulator of Th17/Treg balance. Deletion of Cdc42 in T cells enhanced Th17 differentiation but diminished induced Treg differentiation and suppressive function. Treg-specific deletion of Cdc42 decreased natural Tregs but increased effector T cells including Th17 cells. Notably, Cdc42-deficient Th17 cells became pathogenic associated with enhanced glycolysis and Cdc42-deficient Tregs became unstable associated with weakened glycolytic signaling. Inhibition of glycolysis in Cdc42-deficient Th17 cells diminished their pathogenicity and restoration of glycolysis in Cdc42-deficient Tregs rescued their instability. Intriguingly, Cdc42 deficiency in T cells led to exacerbated wasting disease in mouse models of colitis and Treg-specific deletion of Cdc42 caused early, fatal lymphoproliferative diseases. In summary, we show that Cdc42 is a bona fide regulator of peripheral tolerance through suppression of Th17 aberrant differentiation/pathogenicity and promotion of Treg differentiation/stability/function involving metabolic signaling and thus Cdc42 pathway might be harnessed in autoimmune disease therapy.

http://ift.tt/2FVl3Oa

YouTube as a source of information for obstructive sleep apnea

Publication date: Available online 19 March 2018
Source:American Journal of Otolaryngology
Author(s): Sameer Singh, Stanley Liu, Robson Capasso, Robert C. Kern, Christopher J. Gouveia
PurposeAssess the quality of information on obstructive sleep apnea (OSA) presented on YouTube for patients.Materials and methods"Obstructive sleep apnea" was entered into the YouTube search. Two independent reviewers categorized and analyzed videos utilizing a customized scoring-system along with search position, likes, and views.ResultsForty-eight videos were analyzed. Most were educational (52.1%). Educational and news videos had significantly higher scores, but had no significant differences in search position, likes/day, or views/day. Most videos mentioned positive airway pressure (65%), and nearly half (44%) mentioned mandibular devices in the management of OSA. Few videos discussed surgery (13%) or otolaryngology (15%).ConclusionYouTube is a promising source of information for OSA patients. Educational and news videos are of highest quality. General quality measures like search position, views, and likes are not correlated with formally scored value. Sleep surgery and otolaryngologists are minimally mentioned, representing an opportunity for improvement.



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Editorial Board

Publication date: March–April 2018
Source:American Journal of Otolaryngology, Volume 39, Issue 2





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In Response

No abstract available

http://ift.tt/2GKs3P9

The Role of the WFSA in Reaching the Goals of the Lancet Commission on Global Surgery

No abstract available

http://ift.tt/2tYjA82

Safe Surgery Globally by 2030: The View From Anesthesia

No abstract available

http://ift.tt/2FNVVwM

Higher Operating Table for Optimal Needle-Entry Angle and Less Discomfort During Spinal Anesthesia

The aim of this study was to find the optimal table height to facilitate insertion of the spinal needle at a 90° angle and to reduce the anesthesiologist's discomfort. Sixty patients were randomly allocated according to landmarks on the anesthesiologist's body: umbilicus (group U), lowest rib margin (R), xiphoid process (X), and nipple (N). The coronal insertion angle between the patient's skin and the spinal needle was obtuse in groups U and R, and 90° in group X. We demonstrated that high operating tables at the xiphoid and nipple level facilitate more optimal needle entry angles while reducing the discomfort and joint flexion of anesthesiologists during spinal anesthesia.

http://ift.tt/2u1bpb9

Safe Surgery Globally by 2030: The View From Surgery

No abstract available

http://ift.tt/2GJeqjb

Oxytocin Study Raises Concerns About Carbetocin Use

No abstract available

http://ift.tt/2tXf8Gw

Safe Surgery Globally by 2030: The Essential Role of Anesthesia, The View From Obstetrics

No abstract available

http://ift.tt/2GHMVX9

Improving Anesthesia Safety in Low-Resource Settings

The safety of anesthesia characteristic of high-income countries today is not matched in low-resource settings with poor infrastructure, shortages of anesthesia providers, essential drugs, equipment, and supplies. Health care is delivered through complex systems. Achieving sustainable widespread improvement globally will require an understanding of how to influence such systems. Health outcomes depend not only on a country's income, but also on how resources are allocated, and both vary substantially, between and within countries. Safety is particularly important in anesthesia because anesthesia is intrinsically hazardous and not intrinsically therapeutic. Nevertheless, other elements of the quality of health care, notably access, must also be considered. More generally, there are certain prerequisites within society for health, captured in the Jakarta declaration. It is necessary to have adequate infrastructure (notably for transport and primary health care) and hospitals capable of safely carrying out the "Bellwether Procedures" (cesarean delivery, laparotomy, and the treatment of compound fractures). Surgery, supported by safe anesthesia, is critical to the health of populations, but avoidable harm from health care (including very high mortality rates from anesthesia in many parts of the world) is a major global problem. Thus, surgical and anesthesia services must not only be provided, they must be safe. The global anesthesia workforce crisis is a major barrier to achieving this. Many anesthetics today are administered by nonphysicians with limited training and little access to supervision or support, often working in very challenging circumstances. Many organizations, notably the World Health Organization and the World Federation of Societies of Anaesthesiologists, are working to improve access to and safety of anesthesia and surgery around the world. Challenges include collaboration with local stakeholders, coordination of effort between agencies, and the need to influence national health policy makers to achieve sustainable improvement. It is conceivable that safe anesthesia and perioperative care could be provided for essential surgical services today by clinicians with moderate levels of training using relatively simple (but appropriately designed and maintained) equipment and a limited number of inexpensive generic medications. However, there is a minimum standard for these resources, below which reasonable safety cannot be assured. This minimum (at least) should be available to all. Not only more resources, but also more equitable distribution of existing resources is required. Thus, the starting point for global access to safe anesthesia is acceptance that access to health care in general should be a basic human right everywhere.

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Error: Blood Pressure and Irmageddon

No abstract available

http://ift.tt/2GJOMdZ

Impact of Anesthetic Regimen on Remote Ischemic Preconditioning in the Rat Heart In Vivo

Remote ischemic preconditioning (RIPC) seems to be a promising cardioprotective strategy with contradictive clinical data suggesting the anesthetic regimen influencing the favorable impact of RIPC. This study aimed to investigate whether cardio protection by RIPC is abolished by anesthetic regimens. Male Wistar rats were randomized to 6 groups. Anesthesia was either maintained by pentobarbital (Pento) alone or a combination of sevoflurane (Sevo) and remifentanil or propofol (Prop) and remifentanil in combination with and without RIPC. RIPC reduced infarct size in Pento- and Sevo-anesthetized rats (Pento-RIPC: 30% ± 9% versus Pento-control [Con]: 65% ± 6%, P

http://ift.tt/2u2ijN9

A Value-Based Revolution Afoot

No abstract available

http://ift.tt/2FPrRAQ

ABC of Clinical Leadership, 2nd ed

No abstract available

http://ift.tt/2u1Y3eB

Propofol Anesthesia and Remote Ischemic Preconditioning: An Unfortunate Relationship

No abstract available

http://ift.tt/2GMDlSY

In Response

No abstract available

http://ift.tt/2u01p1Z

GIK: The Cure We Have Been Waiting For?

No abstract available

http://ift.tt/2GNnvYl

Education: The Heart of the Matter

There are inadequate numbers of anesthesia providers in many parts of the world. Good quality educational programs are needed to increase provider numbers, train leaders and teachers, and increase knowledge and skills. In some countries, considerable external support may be required to develop self-sustaining programs. There are some key themes related to educational programs in low- and middle-income countries: (1) Programs must be appropriate for the local environment—there is no "one-size-fits-all" program. In some countries, nonuniversity programs may be appropriate for training providers. (2) It is essential to train local teachers—a number of short courses provide teacher training. Overseas attachments may also play an important role in developing leadership and teaching capacity. (3) Interactive teaching techniques, such as small-group discussions and simulation, have been incorporated into many educational programs. Computer learning and videoconferencing offer additional educational possibilities. (4) Subspecialty education in areas such as obstetric anesthesia, pediatric anesthesia, and pain management are needed to develop leadership and increase capacity in subspecialty areas of practice. Examples include short subspecialty courses and clinical fellowships. (5) Collaboration and coordination are vital. Anesthesiologists need to work with ministries of health and other organizations to develop plans that are matched to need. External organizations can play an important role. (6) Excellent education is required at all levels. Training guidelines could help to standardize and improve training. Resources should be available for research, as well as monitoring and evaluation of educational programs.

http://ift.tt/2u01faT

SmartTots: Quo Vadis?

No abstract available

http://ift.tt/2GJhThC

Global Surgery System Strengthening: It Is All About the Right Metrics

Progress in achieving "universal access to safe, affordable surgery, and anesthesia care when needed" is dependent on consensus not only about the key messages but also on what metrics should be used to set goals and measure progress. The Lancet Commission on Global Surgery not only achieved consensus on key messages but also recommended 6 key metrics to inform national surgical plans and monitor scale-up toward 2030. These metrics measure access to surgery, as well as its timeliness, safety, and affordability: (1) Two-hour access to the 3 Bellwether procedures (cesarean delivery, emergency laparotomy, and management of an open fracture); (2) Surgeon, Anesthetist, and Obstetrician workforce >20/100,000; (3) Surgical volume of 5000 procedures/100,000; (4) Reporting of perioperative mortality rate; and (5 and 6) Risk rates of catastrophic expenditure and impoverishment when requiring surgery. This article discusses the definition, validity, feasibility, relevance, and progress with each of these metrics. The authors share their experience of introducing the metrics in the Pacific and sub-Saharan Africa. We identify appropriate messages for each potential stakeholder—the patients, practitioners, providers (health services and hospitals), public (community), politicians, policymakers, and payers. We discuss progress toward the metrics being included in core indicator lists by the World Health Organization and the World Bank and how they have been, or may be, used to inform National Surgical Plans in low- and middle-income countries to scale-up the delivery of safe, affordable, and timely surgical and anesthesia care to all who need it.

http://ift.tt/2u1yJFN

Surveying the Literature: Synopsis of Recent Key Publications

No abstract available

http://ift.tt/2GHNGzk

Ultrasound-Assisted Versus Fluoroscopic-Guided Lumbar Sympathetic Ganglion Block: A Prospective and Randomized Study

BACKGROUND: Fluoroscopy (FL)-guided lumbar sympathetic ganglion block (LSGB) is widely performed to diagnose and manage various diseases associated with sympathetically maintained pain. Recently, numerous ultrasound (US)-assisted procedures in pain medicine have been attempted, showing an advantage of low radiation exposure. This randomized, prospective trial compared the procedural outcomes and complications between FL-guided and US-assisted LSGBs. METHODS: Fifty LSGBs were randomly divided into 2 groups: FL-guided (FL group) or US-assisted (US group) LSGB group. Both groups received FL-guided or US-assisted LSGB with 10 mL of 0.25% levobupivacaine. The primary end point was the total procedure time. Secondary outcomes were success rate, imaging time, onset time (based on temperature rise), dosage of radiation exposure, other procedure-related outcomes, and complications. RESULTS: Total procedure time and success rate were not statistically different between the 2 groups, whereas imaging time of the US group was longer than that of the FL group (P = .012). The onset time was faster in the US group (P = .019), and bone touching during the procedure was less frequent in the US group (P = .001). Moreover, radiation exposure was significantly lower in the US group than in the FL group (P

http://ift.tt/2u0OYTk

Neurogenic inflammation in fibromyalgia

Abstract

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization. As such, fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems. This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.

http://ift.tt/2FNU8I4

Dentigerous cyst

Lester D. Thompson, MD

Patients are usually asymptomatic, so these cysts are incidentally discovered during routine dental imaging.

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Inhibitory activity towards human α-amylase in cereal foods

Publication date: Available online 19 March 2018
Source:LWT
Author(s): Pierre Gélinas, Carole McKinnon, Fleur Gagnon
Wheat flour and vital wheat gluten contain high levels of α-amylase inhibitors (AI), a potential trigger of non-celiac gluten or wheat sensitivity (NCGS). The aim of this study was to determine inhibitory activity towards α-amylase from human saliva in cereal foods. No AI activity was detected in commercial foods such as cake, cookie, cracker, muffin, pretzel or ready-to-eat (RTE) cereals, except one RTE cereal with minimally-cooked vital wheat gluten (IC50 = 418 μg mL⁻¹). Commercial pan bread and earth-oven artisan bread had variable AI activity, from high (IC50 = 1100 μg mL⁻¹) to non-detectable (˃ 10 000 μg mL⁻¹). Little AI activity, from 3693 to 9732 μg mL⁻¹, was detected in bread under-baked in the laboratory for 30 min at 190 °C and made without sugar, or with 6 g/100 g vital wheat gluten or 0.3 g/100 g emulsifiers (monoglycerides; SSL); there was no AI activity in bread baked at 225 °C. Very high AI activity was found in wheat flour dusting on bread crust, from 239 to 359 μg mL⁻¹. If thoroughly-heated, cereal foods would be safe for individuals willing to limit exposure to wheat AI, except bread with much flour dusting and foods formulated with minimally-cooked vital wheat gluten.



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"Split to save": Accessing mandibular lesions using sagittal split osteotomy with virtual surgical planning

Stanley Yung-Chuan Liu, MD, DDS; Douglas Sidell, MD; Leh-Kiong Huon, MD; Carlos Torre, MD

Abstract

Large, benign intramandibular lesions are frequently removed by resection followed by extensive free tissue transfer or delayed bone grafting. We outline a protocol to remove benign mandibular lesions using sagittal split osteotomy (SSO) with virtual surgical planning (VSP) to mitigate risks involved with this effective, tissue-saving approach. Patients with benign mandibular lesions accessed by SSO with VSP during 2014 were included in this study. Computed tomographic data were imported into VSP software. Using VSP, the exact locations of mandibular lesions and the inferior alveolar nerve canal were delineated. SSO was designed virtually and provided surgeons exact measurements to gain access to lesions and to avoid vital structures intraoperatively. SSO with VSP preserved the cortical mandibular bone and the inferior alveolar neurovascular bundle in 3 patients with benign mandibular lesions. Twelve months after surgery, no patient had pathologic fracture, prolonged paresthesia (except for the patient who required inferior alveolar nerve resection), or malocclusion. No patient required bone grafting. There were no functional or aesthetic jaw deficits. SSO is an effective approach to access intramandibular lesions. The technique does not result in loss of mandibular bone, and patients return to full masticatory function compared with those who require resection and reconstruction. VSP may mitigate technical challenges associated with SSO.

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