Clinician, dental student and orthognathic patient perception of black and white silhouette lateral profile dimensions of ideal chin position in a chinese population

Publication date: Available online 12 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Zhiwei Jiang, Long Tan, Lingling Hu, Chaowei Wang, Huiming Wang, Zhijian Xie
Objectives.This study aimed to investigate differences in influence of chin prominence and length on perception of facial esthetics in Chinese dental clinicians, orthoganthic patients, and dental students.Study Design.The male and female silhouette lateral profiles were modified to obtain 28 facial profiles by altering chin prominence and length by 3 mm in the sagittal and vertical planes. Images were rated by 70 clinicians, 30 orthognathic patients, and 100 dental students on a 7-point Likert scale.Results.Perceived attractiveness is highest when the male chin prominence (MCP) was -3 mm to 3 mm, and the female chin prominence (FCP) was 3 mm. In contrast, male chin length (MCL) (0 mm to 3 mm) and female chin length (FCL) (0 mm) were considered the most attractive. In the sagittal and vertical profiles, MCP (-9 mm), FCP (-9 mm), FCL (-9 mm), and MCL (-9 mm) were ranked least attractive.Conclusions.The overall direction of esthetic opinion is similar in the orthoganthic patients, clinicians and dental students. The greater the retrusion or protrusion of the chin and the shorter or longer of the chin length, the less the rates of facial esthetics and the greater the desire for surgery.



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MRI-based determination of occlusal splint thickness for temporomandibular joint disk derangement: a randomized controlled clinical trial

Publication date: Available online 12 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Ayman F. Hegab, Ahmed Hossni Youssef, Hossam I. Abd Al hameed, Khaled Said Karam
Objective: This prospective study examined a method using magnetic resonance imaging (MRI) to assess the appropriate effective occlusal splint vertical thickness in management of disk derangement. Study Design: Patients were diagnosed as having internal disk displacement of the TMJ and were divided into two groups. Group I (Disk Displacement with Reduction-DDR): This group was subdivided randomly into 2 subgroups. Subgroup IA (control group): patients treated using 3-mm-thick splints. Subgroup IB (study group): patients treated using MRI-based splint thickness. Group II (Disk Displacement without Reduction-DDNR): This group was subdivided randomly into 2 subgroups. Subgroup IIA (control group): patients treated using 3-mm-thick splints. Subgroup IIB (study group): patients treated using MRI-based splint thickness. The primary outcome variables were maximum voluntary mouth opening (MVMO) and visual analogue scale (VAS) for pain. The secondary outcome variable was joint sounds. The final sample was composed of 162 subjects (Group I = 90 and Group II = 72). Results: Statistical analysis showed significant improvement of the clinical outcomes in subgroups IB and IIB as compared to that in subgroups IA and IIA. Conclusion: On the basis of MRI measurements and clinical outcome, the current study recommended 4 mm and 6mm vertical splint thickness for DDR and DDNR respectively for 1 year.



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A novel ROGDI gene mutation is associated with kohlschutter-tonz syndrome

Publication date: Available online 12 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Nalini Aswath, Sankar Narayanan Ramakrishnan, Nithya Teresa, Arvind Ramanathan
BackgroundKohlschutter-tonz syndrome (KTS) is a rare neurodegenerative disorder that presents with seizures, developmental regression and characteristic hypoplastic dental enamel indicative of amelogenesis imperfecta besides dysmorphologies. Genetic analysis has identified loss of function mutations within the coding region of ROGDI gene, which indeed has been reported in KTS patients of European or Jewish decent. In the present study, we have investigated the genetic status of ROGDI in a fourteen year old South Indian patient of Dravidian race born to consanguineous parents, who was clinically diagnosed with KTS.MethodsIn order to confirm the clinical diagnosis of KTS in the patient, primers were designed flanking each of the eleven exons of ROGDI gene. 50ng of chromosomal DNA extracted from peripheral blood of the patient and his parents were then used to amplify with the above primers and were subjected to direct sequencing with the same primers.ResultGenetic analysis identified a novel homozygous nonsense mutation in the exon 6 of ROGDI gene that caused premature termination of ROGDI translation resulting in truncation and loss of function of the ROGDI protein. Taken together, the clinical presentation and loss of function mutation in ROGDI gene confirms the clinical diagnosis of KTS.



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Clinical Analysis of Recurrence Patterns in Patients With Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy

Annals of Otology, Rhinology &Laryngology, Ahead of Print.


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Paula Moynihan: 'We really need to look at a holistic, systemic approach'

Jonathan Lewney, Associate Editor for the BDJ Portfolio, interviews Professor Paula Moynihan. Paula is Professor of Nutrition & Oral Health at Newcastle University School of Dental Sciences, Director of Newcastle University Centre for Oral Health Research, and Director of the World Health Organisation Collaborating Centre for Nutrition and Oral Health. In December 2016, Paula was elected Vice-President of the International Association of Dental Research (IADR), which means she will become IADR President in 2019.

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Oral health: Treating refugees

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Honours, awards, appointments

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Essential courses this November

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Health policy: Hospital cutbacks

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Oral surgery: The drug holiday

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NHS FP17 form printing error

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Perspectives: 'Patients with 40-60/day habits are now few and far between'

What impact has the smoking ban had on dental patients, ten years down the line? asks Kate Quinlan.

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Erratum: Quick release mechanism

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Book Review: Evidence-Based Caries Prevention

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Oral surgery II: Part 2. The maxillary sinus (antrum) and oral surgery

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Focal infection revisited – the swinging of the pendulum

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Articaine: friend or foe?

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Cost Effectiveness of Imatinib, Dasatinib, and Nilotinib as First-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia in China

Abstract

Background and Objective

Tyrosine kinase inhibitors (TKIs) have obvious effects on chronic myeloid leukemia (CML), but they are expensive in China. Moreover, the overall cost of treatment of CML is high and the medical economic burden of patients with CML on the government is heavy. This study tested the cost effectiveness of imatinib, nilotinib, and dasatinib as first-line treatment in Chinese patients who were first diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP).

Methods

A state-transition Markov model combining clinical effectiveness, utility, and cost data was used. Sensitivity analyses were conducted to determine the robustness of the model outcomes.

Results

The imatinib-first, dasatinib-first, and nilotinib-first strategy offered patients 9.76, 9.87, and 9.72 quality-adjusted life years (QALYs) at a cost of US$303,502.42, US$381,681.03, and US$305,509.92 over 20 years, respectively. The nilotinib-first strategy exhibited the lowest utility and highest price and was thus eliminated. An incremental cost-effectiveness analysis of the imatinib-first strategy and the dasatinib-first strategy showed that the dasatinib-first strategy yielded an incremental cost–utility ratio (ICER) of 710,714.64 $/QALY compared with the imatinib-first strategy, which exceeded the threshold; hence, the dasatinib-first strategy was not cost effective and was eliminated. The results were robust for multiple sensitivity analyses.

Conclusion

From the perspective of the Chinese medical system, imatinib is likely to be more cost effective than dasatinib and nilotinib for patients who were first diagnosed with CML-CP.

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Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood–brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo.

Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non–tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models.

Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.

Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215–26. ©2017 AACR.

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Clinical Development of PD-1/PD-L1 Immunotherapy for Gastrointestinal Cancers: Facts and Hopes

Gastrointestinal (GI) cancers are among the most deadly malignancies. Although serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumors of each primary anatomical site but also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success. Molecular characteristics of tumors and their interaction with the tumor microenvironment would further affect development of combination therapy, including immunotherapy. Currently, immune checkpoint blockade attracts the most intense research, and the successful integration of these novel agents in GI cancers in the treatment paradigm requires an in-depth understanding of the diverse immune environment of these cancers. Clin Cancer Res; 23(20); 6002–11. ©2017 AACR.

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Highlights of This Issue

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T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk

Adoptive therapy with T-cell receptor (TCR)–engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross-reactivity toward noncognate peptides. Clin Cancer Res; 23(20); 6012–20. ©2017 AACR.

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Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.

Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.

Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.

Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267–78. ©2017 AACR.

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Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics

Purpose: Pancreatic adenocarcinomas (PAAD) often are not diagnosed until their late stages, leaving no effective treatments. Currently, immunotherapy provides a promising treatment option against this malignancy. However, a set of immunotherapy agents benefit patients with many types of cancer, but not PAAD. Sharing the origin in the same organ, diabetes and PAAD tend to occur concurrently. We aimed to identify the impact of diabetes on immunotherapy of PAAD by conducting a comparative genomics analysis.

Experimental Design: We analyzed level 3 PAAD genomics data (RNAseq, miRNAseq, DNA methylation, somatic copy number, and somatic mutation) from The Cancer Genome Atlas (TCGA) and Firehose. The differential molecular profiles in PAAD with/out diabetes were performed by the differential gene expression, pathway analysis, epigenetic regulation, somatic copy-number alteration, and somatic gene mutation.

Results: Differential gene expression analysis revealed a strong enrichment of immunogenic signature genes in diabetic individuals, including PD-1 and CTLA4, that were currently targetable for immunotherapy. Pathway analysis further implied that diabetic individuals were defective in immune modulation genes. Somatic copy-number aberration (SCNA) analysis showed a higher frequency of amplification and deletion occurred in the cohort without diabetes. Integrative analysis revealed strong association between differential gene expression, and epigenetic regulations, however, seemed not affected by SCNAs. Importantly, our somatic mutation analysis showed that the occurrence of diabetes in PAAD was associated with a large set of gene mutations encoding genes participating in immune modulation.

Conclusions: Our analysis reveals the impact of diabetes on immunodeficiency in PAAD patients and provides novel insights into new therapeutic opportunities. Clin Cancer Res; 23(20); 6363–73. ©2017 AACR.

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Increased IFN{gamma}+ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy

Purpose: Low-dose DNA-demethylating agent decitabine therapy is effective in a subgroup of cancer patients. It remains largely elusive for the biomarker to predict therapeutic response and the underlying antitumor mechanisms, especially the impact on host antitumor immunity.

Experimental Design: The influence of low-dose decitabine on T cells was detected both in vitro and in vivo. Moreover, a test cohort and a validation cohort of advanced solid tumor patients with low-dose decitabine-based treatment were involved. The activation, proliferation, polarization, and cytolysis capacity of CD3⁺ T cells were analyzed by FACS and CCK8 assay. Kaplan–Meier and Cox proportional hazard regression analysis were performed to investigate the prognostic value of enhanced T-cell activity following decitabine epigenetic therapy.

Results: Low-dose decitabine therapy enhanced the activation and proliferation of human IFN⁺ T cells, promoted Th1 polarization and activity of cytotoxic T cells both in vivo and in vitro, which in turn inhibited cancer progression and augmented the clinical effects of patients. In clinical trials, increased IFN⁺ T cells and increased T-cell cytotoxicity predicted improved therapeutic responses and survival in the test cohort and validation cohort.

Conclusions: We find that low-dose decitabine therapy promotes antitumor T-cell responses by promoting T-cell proliferation and the increased IFN⁺ T cells may act as a potential prognostic biomarker for the response to decitabine-based antitumor therapy. Clin Cancer Res; 23(20); 6031–43. ©2017 AACR.

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Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.

Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEX^mGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8⁺ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.

Results: Treatment with OncoVEX^mGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3⁺/CD8⁺) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8⁺ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEX^mGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEX^mGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8⁺ anti-AH1 T cells and systemic efficacy.

Conclusions: The data support a dual MOA for OncoVEX^mGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8⁺-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190–202. ©2017 AACR.

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Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.

Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.

Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.

Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044–53. ©2017 AACR.

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Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

Purpose: Drugs targeting DNA repair and cell-cycle checkpoints have emerged as promising therapies for small-cell lung cancer (SCLC). Among these, the WEE1 inhibitor AZD1775 has shown clinical activity in a subset of SCLC patients, but resistance is common. Understanding primary and acquired resistance mechanisms will be critical for developing effective WEE1 inhibitor combinations.

Experimental Design: AZD1775 sensitivity in SCLC cell lines was correlated with baseline expression level of 200 total or phosphorylated proteins measured by reverse-phase protein array (RPPA) to identify predictive markers of primary resistance. We further established AZD1775 acquired resistance models to identify mechanism of acquired resistance. Combination regimens were tested to overcome primary and acquired resistance to AZD1775 in in vitro and in vivo SCLC models.

Results: High-throughput proteomic profiling demonstrate that SCLC models with primary resistance to AZD1775 express high levels of AXL and phosphorylated S6 and that WEE1/AXL or WEE1/mTOR inhibitor combinations overcome resistance in vitro and in vivo. Furthermore, AXL, independently and via mTOR, activates the ERK pathway, leading to recruitment and activation of another G2-checkpoint protein, CHK1. AZD1775 acquired resistance models demonstrated upregulation of AXL, pS6, and MET, and resistance was overcome with the addition of AXL (TP0903), dual-AXL/MET (cabozantinib), or mTOR (RAD001) inhibitors.

Conclusions: AXL promotes resistance to WEE1 inhibition via downstream mTOR signaling and resulting activation of a parallel DNA damage repair pathway, CHK1. These findings suggest rational combinations to enhance the clinical efficacy of AZD1775, which is currently in clinical trials for SCLC and other malignancies. Clin Cancer Res; 23(20); 6239–53. ©2017 AACR.

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PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors

Purpose: To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.

Experimental Design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n = 12) or combination BRAF/MEK inhibitors (n = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, n = 17), early during treatment (EDT, n = 8), and progression (PROG, n = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC.

Results: Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.

Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor–treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. Clin Cancer Res; 23(20); 6054–61. ©2017 AACR.

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Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM.

Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry.

Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN^High and GLN^Low, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN^High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN^High cultures are CD133^neg and display a mesenchymal signature in contrast to CD133^pos GLN^Low GBM cells.

Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292–304. ©2017 AACR.

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Pediatric Phase I Trial and Pharmacokinetic Study of Trebananib in Relapsed Solid Tumors, Including Primary Tumors of the Central Nervous System ADVL1115: A Children's Oncology Group Phase I Consortium Report

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK).

Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI.

Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI.

Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

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miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/{beta}-catenin Complex in Lung Adenocarcinoma

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.

Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA–protein complex and HDGF/DDX5/β-catenin complex.

Results: We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK–Ras-c–Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF–β-catenin–c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA–FAK–Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin–c-Myc, which suppresses miR-296-3p and further activates PRKCA–FAK–Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA.

Conclusions: Our study provides a novel mechanism that the miR-296-3p–PRKCA–FAK–Ras–c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. Clin Cancer Res; 23(20); 6336–50. ©2017 AACR.

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Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

Purpose: Precise detection of copy number aberrations (CNA) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next-generation sequencing (NGS) is inexpensive, high throughput, and easily feasible, allowing single-nucleotide variant calls, but CNA estimation from this remains challenging.

Experimental Design: We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration-resistant prostate cancer biopsies and used capture-based whole-exome sequencing (WES), array comparative genomic hybridization (aCGH), and FISH to explore the viability of this approach.

Results: We showed that this method produced highly reproducible CNA results (r = 0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted NGS were comparable with WES (r = 0.86) and aCGH (r = 0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN, and RB1), CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results. The frequency of CNAs in our population was comparable with that previously described (i.e., deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intratumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.

Conclusions: Targeted NGS and CNVkit-based analyses provide a robust, precise, high-throughput, and cost-effective method for CNA estimation for the delivery of more precise patient care. Clin Cancer Res; 23(20); 6070–7. ©2017 AACR.

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Genomics of Immunotherapy-Associated Hyperprogressors--Response

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T2-FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower-grade Gliomas: A TCGA/TCIA Project

Purpose: Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes.

Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2–FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate–substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular–radiographic associations. A separate institutional cohort (n = 82) was analyzed to validate the T2–FLAIR mismatch sign.

Results: Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [ = 0.234 (0.111–0.358)], T2–FLAIR mismatch sign [ = 0.728 (0.538–0.918)], lesion margins [ = 0.292 (0.135–0.449)], and peritumoral edema [ = 0.173 (0.096–0.250)]. All 15 cases that were positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2–FLAIR mismatch sign [ = 0.747 (0.536–0.958)]; all 10 cases positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.00001; PPV = 100%, NPV = 76%).

Conclusions: Among lower-grade gliomas, T2–FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q non-codeleted molecular subtype. Clin Cancer Res; 23(20); 6078–85. ©2017 AACR.

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Gallbladder

Gallbladder: A pear-shaped organ located below the liver that stores the bile secreted by the liver. During and after a fatty meal, the gallbladder contracts, delivering the bile through the bile ducts into the intestines to help with digestion.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Spray drying egg using either maltodextrin or nopal mucilage as stabilizer agents

Abstract

In this work, a comparative study between spray drying (SD) of fresh egg by either maltodextrin (MD) or nopal-mucilage (MN) as stabilizing vectors was made. The powders obtained were characterized for drying performance, moisture content, chemical proximate analysis, thermal analysis (TGA), chemical composition (FTIR), microscopy (SEM) and rheology (viscoelasticity and steady state simple shear viscosity). Infrared analysis showed that MN has the effect of a thickening agent rather than an encapsulating one. Results indicated that SD egg with MN produced a high thermal and mechanical stable product and rendered the highest drying performance, producing a more uniform and defined sphere-shaped morphology in comparison to egg SD either alone and with MD.

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A rare vulval manifestation of acrochordons in a young woman

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Schnitzler syndrome: A rare cause of chronic recalcitrant urticaria successfully treated with Anakinra

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Fate of triclocarban in agricultural soils after biosolid applications

Abstract

Triclocarban [N-(4-chlorophenyl)-N-(3,4-dichlorophenyl) urea] (TCC) is an antimicrobial agent utilized in a variety of consumer products. It is commonly released into domestic wastewaters and upon treatment, it is known to accumulate in biosolids. This study examines the occurrence of TCC in biosolids and its long-term fate in biosolid-treated soils. TCC levels in the biosolids from a large waste water treatment plant (WWTP) over 2 years showed little variability at 18,800 ± 700 ng g⁻¹ dry wt. (mean ± SEM). Surface soil samples (top 10 cm) were collected from 26 commercial farms located in northern VA, US that had received biosolid applications from the WWTP. Samples were grouped as farms receiving no biosolids, farms with a single biosolid application, and those receiving multiple biosolid applications from 1992 to 2006. Our results illustrate that TCC soil residues remained years after biosolid application. The two most important parameters controlling TCC topsoil concentrations were the biosolid application rate and the period since the last application. No TCC removal was observed in farms where the time since biosolid application was between 7 and 9 months. TCC concentration analyzed 7 and 8 years after biosolid applications were 45.8 ± 6.1 and 72.4 ± 15.3 ng g⁻¹ dry wt., respectively, showing its persistence in soils and build-up upon multiple biosolid applications. A soil TCC half-life of 287.5 ± 45.5 days was estimated.

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Estimating the L5S1 flexion/extension moment in symmetrical lifting using a simplified ambulatory measurement system

Publication date: Available online 12 October 2017
Source:Journal of Biomechanics
Author(s): Axel S. Koopman, Idsart Kingma, Gert S. Faber, Jonas Bornmann, Jaap H. van Dieën
Mechanical loading of the spine has been shown to be an important risk factor for the development of low-back pain. Inertial motion capture (IMC) systems might allow measuring lumbar moments in realistic working conditions, and thus support evaluation of measures to reduce mechanical loading. As the number of sensors limits applicability, the objective of this study was to investigate the effect of the number of sensors on estimates of L5S1 moments.Hand forces, ground reaction forces (GRF) and full-body kinematics were measured using a gold standard (GS) laboratory setup. In the ambulatory setup, hand forces were estimated based on the force plates measured GRF and body kinematics that were measured using (subsets of) an IMC system. Using top-down inverse dynamics, L5S1 flexion/extension moments were calculated.RMSerrors (Nm) were lowest (16.6) with the full set of 17 sensors and increased to 20.5, 22 and 30.6, for 8, 6 and 4 sensors. Absolute errors in peak moments (Nm) ranged from 17.7 to 16.4, 16.9 and 49.3 Nm, for IMC setup's with 17, 8, 6 and 4 sensors, respectively. When horizontal GRF were neglected for 6 sensors, RMSerrors and peak moment errors decreased from 22 to 17.3 and from 16.9 to 13 Nm, respectively.In conclusion, while reasonable moment estimates can be obtained with 6 sensors, omitting the forearm sensors led to unacceptable errors. Furthermore, vertical GRF information is sufficient to estimate L5S1 moments in lifting.



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Intersegmental Kinetics Significantly Impact Mapping from Finger Musculotendon Forces to Fingertip Forces

Publication date: Available online 12 October 2017
Source:Journal of Biomechanics
Author(s): Dan Qiu, Sang Wook Lee, Mukarram Amine, Derek G. Kamper
Predicting the fingertip force vector resulting from excitation of a given muscle remains a challenging but essential task in finger biomechanical modeling. While the conversion of musculotendon force to fingertip force can significantly be affected by finger posture, current techniques utilizing geometric moment arms may not capture such complex postural effects. Here, we attempted to elucidate the postural effects on the mapping between musculotendon force and fingertip force through in vitro experiments. Computer-controlled tendon loading was implemented on the 7 index finger musculotendons of 5 fresh-frozen cadaveric hands across different postures. The resulting fingertip forces/moments were used to compute the effective static moment arm (ESMA), relating tendon force to joint torque, at each joint. The ESMAs were subsequently modeled in three different manners: independent of joint angle; dependent only upon the corresponding joint angle; or dependent upon all joint angles. We found that, for the reconstruction of the fingertip force vector, the multi-joint ESMA model yielded the best outcome, both in terms of direction and magnitude of the vector (mean reconstruction error < 4° in direction and < 2% in the magnitude), which indicates that intersegmental force transmission through a joint is affected by the posture of neighboring joints. Interestingly, the ESMA model that considers geometric changes of individual joints, the standard model used in biomechanical stimulations, often yielded worse reconstruction results than the simple constant-value ESMA model. Our results emphasize the importance of accurate description of the multi-joint dependency of the conversion of tendon force to joint moment for proper prediction of fingertip force direction.



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Estimation and validation of spatio-temporal parameters for sprint running using a radio-based tracking system

Publication date: Available online 12 October 2017
Source:Journal of Biomechanics
Author(s): Thomas Seidl, Daniel Linke, Martin Lames
Spatio-temporal parameters like step length, step frequency and ground contact time are directly related to sprinting performance. There is still a lack of knowledge, however, on how these parameters interact.Recently, various algorithms for the automatic detection of step parameters during sprint running have been presented which have been based on data from motion capture systems, video cameras, opto-electronic systems or Inertial measurement units. However, all of these methods suffer from at least one of the following shortcomings: they are (a) not applicable for more than one sprinter simultaneously, (b) only capable of capturing a small volume or (c) do not provide accurate spatial parameters. To circumvent these issues, the radio-based local position measurement system RedFIR could be used to obtain spatio-temporal information during sprinting based on lightweight transmitters attached to the athletes. To assess and optimize the accuracy of these parameters 19 100 m sprints of twelve young elite athletes (age: 16.5 ± 2.3 years) were recorded by a radio-based tracking system and a opto-electronic reference instrument. Optimal filter parameters for the step detection algorithm were obtained based on RMSE differences between estimates and reference values on an unseen test set. Attaching a transmitter above the ankle showed the best results.Bland-Altman analysis yielded 95% limits of agreement of [-14.65 cm,15.05 cm] for step length [-0.016 s,0.016 s] for step time and [-0.020 s,0.028 s] for ground contact time, respectively. RMS errors smaller than 2% for step length and step time show the applicability of radio-based tracking systems to provide spatio-temporal parameters. This creates new opportunities for performance analysis that can be applied for any running discipline taking place within a stadium. Since analysis for multiple athletes is available in real-time this allows immediate feedback to coaches, athletes and media.



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THE RIB CAGE REDUCES INTERVERTEBRAL DISC PRESSURES IN CADAVERIC THORACIC SPINES BY SHARING LOADING UNDER APPLIED DYNAMIC MOMENTS

Publication date: Available online 12 October 2017
Source:Journal of Biomechanics
Author(s): Dennis E. Anderson, Erin M. Mannen, Rebecca Tromp, Benjamin M. Wong, Hadley L. Sis, Eileen S. Cadel, Elizabeth A. Friis, Mary L. Bouxsein
The effects of the rib cage on thoracic spine loading are not well studied, but the rib cage may provide stability or share loads with the spine. Intervertebral disc pressure provides insight into spinal loading, but such measurements are lacking in the thoracic spine. Thus, our objective was to examine thoracic intradiscal pressures under applied pure moments, and to determine the effect of the rib cage on these pressures. Human cadaveric thoracic spine specimens were positioned upright in a testing machine, and Dynamic pure moments (0 to ±5 N·m) with a compressive follower load of 400 N were applied in axial rotation, flexion - extension, and lateral bending. Disc pressures were measured at T4-T5 and T8-T9 using needle-mounted pressure transducers, first with the rib cage intact, and again after the rib cage was removed. Changes in pressure vs. moment slopes with rib cage removal were examined. Pressure generally increased with applied moments, and pressure-moment slope increased with rib cage removal at T4-T5 for axial rotation, extension, and lateral bending, and at T8-T9 for axial rotation. The results suggest the intact rib cage carried about 62% and 56% of axial rotation moments about T4-T5 and T8-T9, respectively, as well as 42% of extension moment and 36-43% of lateral bending moment about T4-T5 only. The rib cage likely plays a larger role in supporting moments than compressive loads, and may also play a larger role in the upper thorax than the lower thorax.



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Improving the ability to review preoperative radiographs intraoperatively in trauma and orthopaedic theatres at Lancashire teaching hospitals

Background

The ability to review preoperative radiographs during trauma and orthopaedic surgery is essential for the surgeon to provide optimum treatment to the patient. However, due to current information technology (IT) systems, screen-savers frequently interrupt the ability to review images and theatre staff are not routinely available to deactivate the screen-saver. This prolongs theatre time for the patient and affects the quality of care provided. The aim of this quality improvement project was to improve the availability of radiographs for the surgeon to review intraoperatively.

Method/results

Data were collected from all trauma and orthopaedic theatres at two hospital sites covering all subspecialties and including emergency and elective cases. Baseline measurements showed that the frequency of preoperative radiographs not interrupted during an operation was 0% (0/50). Following this the Trust's IT systems were improved to prevent activation of the screen-saver on the theatre computers using the generic theatre login details. After the first-cycle intervention, data were collected showing 52% (14/27) of preoperative radiographs were not interrupted by a screen-saver. The cause for this result being less than expected was investigated and found to be due to an alternative computer login being used on the theatre computers at one of the hospital sites. Education of theatre staff was then undertaken to ensure the correct theatre login was used and notices to remind staff placed on the theatre computers. After the second-cycle intervention, data were collected showing that 100% (26/26) of preoperative radiographs were not interrupted during operative time allowing the surgeon to review images when required.

Conclusion/implications

This quality improvement project has made changes to theatre IT systems and practices of theatre staff which has resulted in a significant improvement in the ability for the operating surgeon to review preoperative radiographs intraoperatively.

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Reducing hospital admissions of healthy children with functional constipation: a quality initiative

Functional constipation (FC) is a common medical problem in children, with minimal risk of long-term complications. We determined that a large number of children were being admitted to our children's hospital for FC in which there was no neurological or anatomical cause. Our hospital experienced a patient complication in which a patient died after inpatient treatment of FC. Subsequently, we developed a standardised approach to determine when paediatric patients needed hospitalisation for FC, as well as to develop a regimented outpatient therapeutic approach for such children to prevent hospitalisation. Our quality improvement initiative resulted in a large decrease in the number of children with FC admitted into the hospital as well as a decrease in the number of children needing faecal disimpaction in the operating room. Our quality improvement process can be used to decrease hospitalisations, decrease healthcare costs and improve patient care for paediatric FC.

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Preventing cerebral palsy in preterm labour: a multiorganisational quality improvement approach to the adoption and spread of magnesium sulphate for neuroprotection

Magnesium sulphate has been demonstrated to be an effective neuroprotectant for babies delivered prematurely (under 37 weeks' gestational age). Antenatal administration reduces infant mortality and cerebral palsy (CP); however, uptake in the UK has been significantly lower than other countries. A quality improvement (QI) project (PReventing Cerebral palsy in Pre Term labour (PReCePT)) was carried out in the West of England, UK, to raise awareness of evidence and to improve the uptake of magnesium sulphate as neuroprotectant in preterm deliveries. Five National Health Service (NHS) Trusts and the West of England Academic Health Science Network participated in the QI project. The project was underpinned by a multifaceted QI approach that included: patient and clinical coproduction of resources; recruitment of clinical champions to support the local microsystems and create a stimulating/supporting environment for change; Plan, Do, Study, Act cycles; training for over 600 NHS staff and awareness raising and strategic influencing of key leaders. A baseline audit and regular measurement of the number of eligible women receiving magnesium sulphate was undertaken at each hospital site, and the overall programme was evaluated using data from an international benchmarking organisation for neonatal care outcomes—the Vermont Oxford Network. During the project 664 staff received magnesium sulphate training. The use of magnesium sulphate increased across the West of England from an average baseline of 21% over the 2 years preceding the project to 88% by the conclusion of the project. The project was also able to influence the development of a national data collection process for benchmarking the use of magnesium sulphate for neuroprotection in preterm deliveries in the U.K. PReCePT appears to have had a favourable effect on the uptake of magnesium sulphate across the West of England. The project has also provided learning about how to stimulate adoption and spread of evidence using a QI approach across a network.

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Improving waiting times in the orthopaedic outpatient clinic

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Private dental practice gets green light after unanimous vote

A new private dental practice has been given the green light for St Margarets after a unanimous vote at last night's planning meeting . Dr Samantha Laycock and Dr Hetal Patel applied to build the surgery at 161 St Margarets Road, Twickenham, just two doors down from another practice Amber Dental, in an area where there are 15 dental practices within a 1.5 mile radius.

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PreOp Breast Center Special • Patient Education & Engagement

PreOp Breast Center Special • Patient Education & Engagement
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This video represents the 1) Breast Self Examination 2) Breast incision Biopsy 3) Modified Radical Mastectomy 4) Handwashing and 5) Basic Wound Care

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Onychomycosis and Immunodepression

Abstract

Purpose of Review

This review summarizes the most relevant information on onychomycosis in patients with immunosuppressive disorders and also compares the distinctive characteristics and approach with the general population.

Recent Findings

Onychomycosis in immunocompromised patients has a similar clinical presentation to the one in the general population, yet there are still differences. For instance, the white variety also known as mycotic leukonychia is characteristic among the group, being more common among patients with HIV/AIDS. Proximal subungual onychomycosis (PSO) and white superficial onychomycosis (WSO) have been proposed as markers of disease progression among HIV patients. Among the diabetic, onychomycosis in general has been found closely linked with complications.

Summary

The prevalence of onychomycosis in immunocompromised patients is up to three times higher when compared the one described in the general population, representing an important public health problem, closely related to the patient's quality of life. Therefore, it is important to identify the characteristic clinical presentation among this group of patients, diagnose accordingly, and initiate appropriate therapy to avoid complications and improve outcome.

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Oestrogen retains human periodontal ligament stem cells stemness in long-term culture

Abstract

Objectives

During long-term culture, loss of stemness is observed which greatly restricts the application of human periodontal ligament stem cells (hPDLSCs) in tissue regeneration. Oestrogen (E2) was found to significantly enhance the proliferation and osteogenic differentiation capacity in mesenchymal stem cells. Therefore, in this study, we investigated effects of E2 on hPDLSCs stemness in long-term culture.

Materials and methods

Effects of E2 on hPDLSCs stemness were systematically evaluated. To characterize underlying the mechanisms, its effects on PI3K/AKT signalling pathway were determined.

Results

Our results showed that E2 was able to enhance the proliferation, modify cell cycle, up-regulate stemness-related genes expression, promote osteogenic differentiation and elevate the positive rate of CD146 and STRO-1 over 10 passages in hPDLSCs. Importantly, PI3K/AKT signing pathway might play a role in these effects.

Conclusions

These findings suggest that E2 retains hPDLSCs stemness in long-term culture, which might enhance its application in tissue engineering.

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Remote Monitoring of Automated Peritoneal Dialysis Patients: Assessing Clinical and Economic Value

Telemedicine and e-Health , Vol. 0, No. 0.


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Asynchronous Telepsychiatry: A Component of Stepped Integrated Care

Telemedicine and e-Health , Vol. 0, No. 0.


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Back to School: 2017

Telemedicine and e-Health Oct 2017, Vol. 23, No. 10: 777-778.


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NEMO peptide inhibits the growth of pancreatic ductal adenocarcinoma by blocking NF-κB activation

Publication date: 28 December 2017
Source:Cancer Letters, Volume 411
Author(s): Zhuonan Zhuang, Hao Li, Harold Lee, Mitzi Aguilar, Takashi Gocho, Huaiqiang Ju, Tomonori Iida, Jianhua Ling, Jie Fu, Min Wu, Yichen Sun, Yu Lu, Paul J. Chiao
NF-κB essential modulator (NEMO) binds and regulates IκB kinase (IKK) and is required for NF-κB activation. The NEMO-binding domain peptide (NBDP) of IKK was found to inhibit NF-κB activation and promote apoptosis in cancer cells. Studies have shown that constitutive NF-κB activation, one of the signature molecular alterations in pancreatic ductal adenocarcinoma (PDAC), is a potential therapeutic target. However, preclinical and therapeutic evidence that supports direct targeting of IKK activation in therapy is lacking. The aim of this study was to determine whether the combination of NBDP and gemcitabine would sensitize pancreatic cancer to the gemcitabine. We confirmed that NBDP inhibited NF-κB activation and found that NBDP indeed promoted chemo-sensitivity to gemcitabine in PDAC. NBDP increased PARP and caspase 3 cleavage in the apoptosis pathway, increased apoptosis of PDAC cells, and suppressed PDAC cell growth in vitro. In addition, NBDP combined with gemcitabine significantly decreased levels of NF-κB activity and inhibited the growth of PDAC in vivo in an orthotopic xenograft mouse model. Mechanistic investigations showed that NBDP effectively competed with NEMO/IKKγ for binding to IKKs and thus inhibited IKK and NF-κB activation, down-regulated expression levels of Erk, and decreased PDAC cell growth. Taken together, our current data demonstrate that NBDP sensitizes human pancreatic cancer to gemcitabine by inhibiting the NF-κB pathway. NBDP is a potential adjuvant chemotherapeutic agent for treating pancreatic cancer.



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Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells

Publication date: 28 December 2017
Source:Cancer Letters, Volume 411
Author(s): Kirtikar Shukla, Himangshu Sonowal, Ashish Saxena, Kota V. Ramana, Satish K. Srivastava
Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2′-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage.

Graphical abstract

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Validation of a clinical trial composite endpoint for patients with necrotizing soft tissue infections

OBJECTIVE: Our objective was to develop and validate a composite endpoint for patients with necrotizing soft tissue infections that incorporates: local tissue injury, systemic organ dysfunction, and mortality. METHODS: The Necrotizing Infection Clinical Composite Endpoint (NICCE) was defined as follows:(i) alive at day 28, (ii) three or less debridements before day 14, (iii) no amputation beyond first debridement, (iv) modified sequential organ failure assessment score score (mSOFA) at day 14 ≤ 1. To be considered a success, all individual criteria must be met. Several data sets were used to assess validity: (i) a retrospective data set of 198 patients treated during 2013 at 12 US trauma centers; (ii) a subset with high disease acuity, admission mSOFA score of 3 or higher (n = 69); and (iii) 40 patients from a multicenter, phase 2 randomized trial of a CD28 immunomodulator (AB103). Clinical success based on each parameter and the composite score was assessed. RESULTS: Using the retrospective data set for all patients and those with high disease severity (respectively), survival rates were 92% and 84%; day 14 mSOFA 1 or lower score was 69% and 51%; three or less debridements was 84% and 77%; and no subsequent amputations were 96% and 94%. Overall, the percent meeting all success criteria for NICCE was 58% (all patients) and 33% (mSOFA > 3). NICCE success was also associated with reduced utilization of health care resources, intensive care unit–free days were median (interquartile range) of 25.3 (21.9–28) and 19.6 (4.3–25.1) days (one-sided Wilcoxon p

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Atmospheric deposition of inorganic nitrogen in a semi-arid grassland of Inner Mongolia, China

Abstract

Due to increasing global demand for crop production and energy use, more and more reactive nitrogen (Nr) has been generated and emitted to the environment. As a result, global atmospheric nitrogen (N) deposition has tripled since the industrial revolution and the ecological environment and human health have been harmed. In this study, we measured dry and wet/bulk N deposition from July 2013 to December 2015 in a semi-arid grassland of Duolun County, Inner Mongolia, China. The samples of dry and wet/bulk N deposition were collected monthly with a DELTA (DEnuder for Long Term Atmospheric sampling) system and with Gradko passive samplers and a precipitation gauge. The measured results show that the annual mean concentrations of NH₃, NO₂, HNO₃, particulate NH₄⁺ (pNH₄⁺) and particulate NO₃⁻ (pNO₃⁻) in atmosphere were 2.33, 1.90, 0.18, 1.42 and 0.42 μg N/m³, respectively, and that the annual mean volume-weighted concentrations of NH₄⁺-N and NO₃⁻-N in precipitation were 2.71 and 1.99 mg N/L, respectively. The concentrations of Nr components (including NH₃, NO₂, HNO₃, pNH₄⁺, pNO₃⁻, NH₄⁺-N and NO₃⁻-N) exhibited different seasonal variations. Specifically, NO₂ and HNO₃ exhibited higher concentrations in autumn than in summer, while the other Nr components (NH₃, pNH₄⁺, pNO₃⁻, NH₄⁺-N and NO₃⁻-N) showed the highest values in summer. Based on measured concentrations of Nr components and their deposition velocities estimated using the GEOS-Chem global atmospheric chemical transport model, the calculated annual mean dry deposition fluxes were 3.17, 1.13, 0.63, 0.91 and 0.36 kg N/(hm²•a) for NH₃, NO₂, HNO₃, pNH₄⁺ and pNO₃⁻, respectively, and the calculated annual mean wet/bulk deposition fluxes were 5.37 and 3.15 kg N/(hm²•a) for NH₄⁺-N and NO₃⁻-N, respectively. The estimated annual N deposition (including dry N deposition and wet/bulk N deposition) reached 14.7 kg N/(hm²•a) in grassland of Duolun County, approaching to the upper limit of the N critical load (10–15 kg N/(hm²•a)). Dry and wet/bulk deposition fluxes of all Nr components (with an exception of HNO₃) showed similar seasonal variations with the maximum deposition flux in summer and the minimum in winter. Reduced Nr components (e.g., gaseous NH₃ and pNH₄⁺ in atmosphere and NH₄⁺-N in precipitation) dominated the total N deposition at the sampling site (accounted for 64% of the total N deposition), suggesting that the deposited atmospheric Nr mainly originated from agricultural activities. Considering the projected future increases in crop and livestock production in Inner Mongolia, the ecological and human risks to the negative effects of increased N deposition could be increased if no mitigation measures are taken.

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Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimers disease [Research]

Interactions of the presynaptic proteins, neuronal pentraxin 2 (NPTX2) and neurexin 2α (NRXN2α), with their respective postsynaptic functional partners, GluA4-containing glutamate (AMPA4) receptor and neuroligin 1 (NLGN1), enhance excitatory synaptic activity in some areas of the hippocampus and cerebral cortex. As early damage of such excitatory circuits in the brain tissues of participants with Alzheimer's disease (AD) correlates with cognitive losses, plasma neuron-derived exosome (NDE) levels of these 2 pairs of specialized synaptic proteins were quantified to assess their biomarker characteristics. The NDE contents of all 4 proteins were decreased significantly in AD dementia (n = 46), and diminished levels of AMPA4 and NLGN1 correlated with the extent of cognitive loss. In a preclinical period, 6–11 yr before the onset of dementia, the NDE levels of all but NPTX2 were significantly lower than those of matched controls, and levels of all proteins declined significantly with the development of dementia. Reductions in NDE levels of these specialized excitatory synaptic proteins may therefore be indicative of the extent of cognitive loss and may reflect progression of the severity of AD.—Goetzl, E. J., Abner, E. L., Jicha, G. A., Kapogiannis, D., Schwartz, J. B. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease.

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A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis [Molecular Bases of Disease]

Fibrosis can disrupt tissue structure and integrity and impair organ function. Fibrosis is characterized by abnormal collagen accumulation in the extracellular matrix. Pharmacological inhibition of collagen secretion therefore represents a promising strategy for the management of fibrotic disorders, such as liver and lung fibrosis. Hsp47 is an endoplasmic reticulum (ER)-resident collagen-specific molecular chaperone essential for correct folding of procollagen in the ER. Genetic deletion of Hsp47 or inhibition of its interaction with procollagen interferes with procollagen triple helix production, which vastly reduces procollagen secretion from fibroblasts. Thus, Hsp47 could be a potential and promising target for the management of fibrosis. In this study, we screened small molecule compounds that inhibit the interaction of Hsp47 with collagen from chemical libraries using surface plasmon resonance (BIAcore), and found a molecule AK778 and its cleavage product Col003 competitively inhibited the interaction and caused the inhibition of collagen secretion by destabilizing the collagen triple helix. Structural information obtained with NMR analysis revealed that Col003 competitively binds to the collagen binding site on Hsp47. We propose that these structural insights could provide a basis for designing more effective therapeutic drugs for managing fibrosis.

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Mevalonate 5-diphosphate mediates ATP binding to the mevalonate diphosphate decarboxylase from the bacterial pathogen Enterococcus faecalis [Enzymology]

The mevalonate pathway produces isopentenyl diphosphate (IPP), a building block for polyisoprenoid synthesis, and is a crucial pathway for growth of the human bacterial pathogen Enterococcus faecalis. The final enzyme in this pathway, mevalonate diphosphate decarboxylase (MDD), acts on mevalonate diphosphate (MVAPP) to produce IPP while consuming ATP. This essential enzyme has been suggested as a therapeutic target for the treatment of drug-resistant bacterial infections. Here we report functional and structural studies on the mevalonate diphosphate decarboxylase from E. faecalis (MDDEF). The MDDEF crystal structure in complex with ATP (MDDEF-ATP) revealed that the phosphate binding loop (amino acid 97-105) is not involved in ATP binding and that the phosphate tail of ATP in this structure is in an outward-facing position pointing away from the active site. This suggested that binding of MDDEF to MVAPP is necessary to guide ATP into a catalytically favorable position. Enzymology experiments show that the MDDEF performs a sequential ordered bi-substrate reaction with MVAPP as the first substrate, consistent with the ITC experiments. On the basis of isothermal titration calorimetry (ITC) results, we propose that this initial, prerequisite binding of MVAPP enhances ATP binding. In summary, our findings reveal a substrate-induced substrate-binding event that occurs during the MDDEF-catalyzed reaction. The disengagement of the phosphate binding loop concomitant with the alternative ATP-binding configuration may provide the structural basis for antimicrobial design against these pathogenic enterococci.

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Neutrophil elastase increases airway ceramide levels via upregulation of serine palmitoyltransferase

Altered sphingolipid metabolism is associated with increased inflammation; however, the impact of inflammatory mediators, including neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. Using a well-characterized mouse model of NE oropharyngeal aspiration, we investigated a potential link between NE-induced airway inflammation and increased synthesis of various classes of sphingolipids, including ceramide species. Sphingolipids in bronchoalveolar lavage fluids (BAL) were identified and quantified using reverse phase high-performance liquid chromatography/electrospray ionization tandem mass spectrometry analysis. BAL total and differential cell counts, CXCL1/keratinocyte chemoattractant (KC) protein levels, and high mobility group box 1 (HMGB1) protein levels were determined. NE exposure increased BAL long chain ceramides, total cell and neutrophil counts, and upregulated KC and HMGB1. The mRNA and protein levels of serine palmitoyltransferase (SPT) long chain subunits 1 and 2, the multimeric enzyme responsible for the first, rate-limiting step of de novo ceramide generation, were determined by Q/RT-PCR and western analyses, respectively. NE increased lung SPT long chain subunit 2 (SPTLC2) protein levels but not SPTLC1, and had no effect on mRNA for either subunit. To assess whether de novo ceramide synthesis was required for NE-induced inflammation, myriocin, a SPT inhibitor, or a vehicle control was administered intraperitoneally 2h prior to NE administration. Myriocin decreased BAL d18:1/22:0 and d18:1/24:1 ceramide, KC and HMGB1 induced by NE exposure. These results support a feed-forward cycle of NE-generated ceramide and ceramide-driven cytokine signaling that may be a potential target for intervention in lung disease typified by chronic neutrophilic inflammation.

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Ion channels of the lung and their role in disease pathogenesis

Maintenance of normal epithelial ion and water transport in the lungs includes providing a thin layer of surface liquid that coats the conducting airways. This airway surface liquid is critical for normal lung function in a number of ways, but perhaps most importantly, is required for normal mucociliary clearance and bacterial removal. Preservation of the appropriate level of hydration, pH and viscosity for the airway surface liquid requires the proper regulation and function of a battery of different types of ion channels and transporters. Here we discuss how alterations in ion channel/transporter function often lead to lung pathologies.

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Toll-like receptor 2 and 4 have Opposing Roles in the Pathogenesis of Cigarette Smoke-induced Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of morbidity and death and imposes major socioeconomic burdens globally. It is a progressive and disabling condition that severely impairs breathing and lung function. There is a lack of effective treatments for COPD, which is a direct consequence of the poor understanding of the underlying mechanisms involved in driving the pathogenesis of the disease. Toll-like receptor (TLR)2 and TLR4 are implicated in chronic respiratory diseases, including COPD, asthma and pulmonary fibrosis. However, their roles in the pathogenesis of COPD are controversial and conflicting evidence exists. In the current study, we investigated the role of TLR2 and TLR4 using a model of cigarette smoke (CS)-induced experimental COPD that recapitulates the hallmark features of human disease. TLR2, TLR4 and associated co-receptor mRNA expression were increased in the airways in both experimental and human COPD. Compared to WT mice, CS-induced pulmonary inflammation was unaltered in TLR2-deficient (Tlr2-/-), TLR4-deficient (Tlr4-/-) mice. CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2-/- mice but was attenuated in Tlr4-/- mice compared to CS-exposed WT controls. However, Tlr2-/- mice had increased CS-induced emphysema-like alveolar enlargement, apoptosis and impaired lung function, whilst these features were reduced in Tlr4-/- mice compared to CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD.

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iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Publication date: Available online 12 October 2017
Source:Cancer Cell
Author(s): Wenjie Ge, Kunming Zhao, Xingwen Wang, Huayi Li, Miao Yu, Mengmeng He, Xuting Xue, Yifu Zhu, Cheng Zhang, Yiwei Cheng, Shijian Jiang, Ying Hu
Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Here, we demonstrate that iASPP, a known p53 inhibitor, lowers ROS independently of p53. Mechanistically, iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance both in vitro and in vivo. Thus, iASPP is an antioxidative factor and represents a promising target to improve cancer treatment, regardless of p53 status.

Graphical abstract

Teaser

Ge et al. show that iASPP, a known p53 inhibitor, functions independently of p53 to compete with Keap1 for Nrf2 binding, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation and antioxidative transactivation. The iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance.


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The Impact of Religiosity on Substance Abuse and Obesity in African Americans

Abstract

Among the African American community, there exist many health disparities which warrant greater examination through the practice of social work. The aim of the present research was to explore the impact of religiosity on substance abuse and obesity among African American populations by employing a systematic review of the current body of literature on this subject. While many of the studies reviewed found at least a weak relationship between religiosity and obesity, such results were not consistent across all materials examined. Among those studies that found a correlation between these factors, many demonstrated that religiosity had a positive impact on substance abuse and obesity. A discussion of the implications of these findings is submitted as a means of illuminating the significance of all research findings that were examined. Limitations such as more standardized criteria for inclusion of research material are identified and discussed. Implications for future research are presented to promote the advancement of future efforts in this area research.

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Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

AbstractThe absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation,Ush1c c.216G>A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells. Here, we show thatUsh1c c.216AA mice lack OHC function as evidenced by the absence of distortion product otoacoustic emissions (DPOAEs) in response to low-, mid-, and hi...

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Therapeutic hypothermia in acute traumatic spinal cord injury

Therapeutic hypothermia is already widely acknowledged as an effective neuroprotective intervention, especially within the acute care setting in relation to conditions such as cardiac arrest and neonatal encephalopathy. Its multifactorial mechanisms of action, including lowering metabolic rate and reducing acute inflammatory cellular processes, ultimately provide protection for central nervous tissue from continuing injury following ischaemic or traumatic insult. Its clinical application within acute traumatic spinal cord injury would therefore seem very plausible, it having the potential to combat the pathophysiological secondary injury processes that can develop in the proceeding hours to days following the initial injury. As such it could offer invaluable assistance to lessen subsequent sensory, motor and autonomic dysfunction for an individual affected by this devastating condition. Yet research surrounding this intervention's applicability in this field is somewhat lacking, the majority being experimental. Despite a recent resurgence of interest, which in turn has produced encouraging results, there is a real possibility that this potentially transformational intervention for treating traumatic spinal cord injury could remain an experimental therapy and never reach clinical implementation.

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Phosphate replacement in the critically ill: potential implications for military patients

Background

Severe hypophosphataemia in the intensive care unit (ICU) setting has been widely associated with adverse clinical outcomes across multiple organ systems, as well as increased mortality. However, the clinical significance of mild or moderate hypophosphataemia remains uncertain. This can lead to heterogeneous phosphate replacement protocols across different institutions. The aim of this study was to assess the significance of mild and moderate hypophosphataemia on clinical outcomes across several organ systems.

Method

All patients over a 3-week period in our ICU were retrospectively analysed with admission serum phosphate compared with subsequent clinical outcomes after admission. Low serum phosphate (0.3–1.0 mmol/L), according to local protocol, was compared with normal serum phosphate (>1.0 mmol/L).

Results

Of the 72 patients admitted to intensive therapy unit during this period, 14/72 (19%) had phosphate levels deemed low (<1.0 mmol/L) and received phosphate supplementation. No significant difference was found between groups in terms of cardiac arrhythmias (p=0.55), capillary blood glucose (p=0.08) and serum lactate (p=0.32). Low phosphate (0.3–1.0 mmol/L) was not associated with increased likelihood of requiring ventilation. Platelet count was significantly lower in the low phosphate group (p=0.008).

Conclusion

In our study, mild and moderate hypophosphataemia was not associated with adverse clinical outcome across most organ systems analysed. Given the current evidence and results of this study, we would suggest that there is a trend towards over-replacement of phosphate, representing a potential clinical safety issue as well as clear financial implications.

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Erratum

For "Loss of PTEN Expression Is Associated With High MicroRNA 24 Level and Poor Prognosis in Patients With Tongue Squamous Cell Carcinoma" (Zhao J., et al, J Oral Maxillofac Surg 75: 1449.e1-1449.e8, 2017), the authors have notified the Journal that their original data report contained an error. In the Results section of the Abstract on page 1449.e1 and in the first paragraph of the Results section on page 1449.e5, the data pertaining to the loss of PTEN expression that was detected was incorrect.

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A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Vincent A. de Weger, Frederik E. Stuurman, Jeroen J.M.A. Hendrikx, Johannes J. Moes, Emilia Sawicki, Alwin D.R. Huitema, Bastiaan Nuijen, Bas Thijssen, Hilde Rosing, Marianne Keessen, Marja Mergui-Roelvink, Jos H. Beijnen, Jan H.M. Schellens, Serena Marchetti
IntroductionTwo solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.MethodsAdult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.ResultsModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.ConclusionOral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.



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Tip-Enhanced Raman Spectromicroscopy of Co(II)-Tetraphenylporphyrin on Au(111): Toward the Chemists’ Microscope

ACS Nano

DOI: 10.1021/acsnano.7b06183

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Serum cortisol level in indian patients with severe sepsis/septic shock

Ragavendra Suresh, Naveet Wig, Prasan Kumar Panda, VP Jyotsna, PK Chaturvedi, RM Pandey

Journal of Emergencies, Trauma, and Shock 2017 10(4):194-198

Background: The relationship between cortisol level and sepsis is not known in Indian patients of severe sepsis/septic shock. Aims: The study was done to determine the optimal range of cortisol levels, defining the adrenocortical response, and predicting the mortality, if possible, in the above type of patients. Settings and Designs: The study was a single-centered prospective cohort study, conducted in a tertiary referral center, North India. Materials and Methods: Sixty patients with severe sepsis (n = 30) and septic shock (n = 30) were recruited. Basal and postcosyntropin (1 μg)-stimulated cortisol levels were measured, and all patients were closely monitored with daily assessments of clinical and laboratory variables. Western diagnostic criteria were followed for defining adrenal insufficiency (AI). The end point was the survival assessed at day 28 or death, whichever came earlier. Results: The mean basal (T0) and poststimulation (T30) cortisol levels were 31.77 ± 15.9 μg/dL and 37.58 ± 17.31 μg/dL, respectively. In all sepsis patients, 48.33% qualified as AI at T0 ≤ 24 μg/dL, 61.67% at delta cortisol (Δ = T30-T0) ≤7 μg/dL, and 78.33% at Δ ≤9 μg/dL. Using receiver operating characteristic curve, the area under the curve (AUC) was 0.4954, signifying poor prediction to death. Conclusions: Indians have completely different characteristics of cortisol levels in sepsis patients, in comparison to the Western data. They have higher range of basal cortisol levels, higher percentage of AI, and an inability to predict mortality with the cortisol levels. Hence, there is requirement of an international study to confirm the dichotomy of the results.

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Isolated traumatic basal ganglia hematoma in children

Sushanta K Sahoo, Sidharth Vankipuram, Chhitij Srivastava

Journal of Emergencies, Trauma, and Shock 2017 10(4):215-216



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Emergency departments need psychiatric emergency protocols!

Bhavesh Jarwani

Journal of Emergencies, Trauma, and Shock 2017 10(4):169-170



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Necrotizing fasciitis: How reliable are the cutaneous signs?

Ho Jun Kiat, Yap Hui En Natalie, Lateef Fatimah

Journal of Emergencies, Trauma, and Shock 2017 10(4):205-210

Necrotizing fasciitis (NF) is a surgical emergency. It is often aggressive and characterized by the rapidly progressive inflammatory infection of the fascia that causes extensive necrosis of the subcutaneous tissue and fascia, relatively sparing the muscle and skin tissue. As the disease progresses, thrombosis of the affected cutaneous perforators subsequently devascularizes the overlying skin. The course indeed can be a fulminant one. The diagnosis of NF, especially in the early stages, is extremely challenging, and it can be very close in presentation to other skin and subcutaneous tissue infections. The primary site of the pathology is the deep fascia. Necrosis of the tissues and fascia may manifest as erythema without sharp margins, swelling, warmth, shiny, and exquisitely tender areas. Pain out of proportion to physical examination findings may be observed. The subcutaneous tissue may be firm and indurated such that the underlying muscle groups cannot be distinctly palpated. Eventually, as the overlying skin is stripped of its blood supply, skin necrosis ensues and hemorrhagic bullae form. Bacteremia and sepsis invariably develop when the infection is well established. This paper discusses some of issues related to the cutaneous signs found in NF and also provides a review the current, available literature on the subject matter.

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Management of psychiatric emergencies in free-standing emergency departments: a paradigm for excellence?

Veronica Tucci, Syed Moiz Ahmed, David Hoyer, Nidal Moukaddam

Journal of Emergencies, Trauma, and Shock 2017 10(4):171-173



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What's new in emergencies trauma and shock - Adequate pain management in the emergency department - A dream come true!

Sandeep Sahu

Journal of Emergencies, Trauma, and Shock 2017 10(4):167-168



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Emergency physician screening and management of trauma patients with alcohol involvement

Kai H Lee, James B Olsen, Jiandong Sun

Journal of Emergencies, Trauma, and Shock 2017 10(4):174-179

Background: Alcohol screening and brief intervention (SBI) in trauma patients has been reported in literature to be effective in changing harmful drinking patterns and injury recurrence. Despite good evidence that SBI can benefit patients and provide a more holistic care, it is not routinely implemented in acute medical settings in Australia, in particular emergency departments (EDs). Objective: This paper aims to assess the knowledge, confidence, and practice of alcohol SBI in trauma patients by emergency physicians throughout Australia and New Zealand through an online survey. Methods: Major EDs in Australia and Zealand were approached to participate in an online survey. Results from the survey were analyzed using simple descriptive summary statistics. Results: Fifty-eight physicians participated in the online survey. Almost all physicians reported at least 10% of all patients managed in ED had traumatic injuries and 35% had alcohol involvement. About 66% were consultant physicians and 84% had 5 or more years of practice. Sixty-four percent agreed to have adequate training in SBI, 22% had adequate time and resources, 47% would like more training in patient screening, and 72% were more likely to deliver SBI in 5 min. Limited time and resources were seen as major barriers. It was found that better understating of SBI may lead to higher confidence and more practice, or vice versa. Conclusion: High proportion of participants in this survey felt under-equipped to deliver SBI due to time limitation, perceived lack of resources, unsuitable environment, and supportive staff. There exists an opportunity to develop a shortened and efficient SBI program that can improve utilization of SBI in an emergency setting.

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Quantifying Burnout among Emergency Medicine Professionals

William Wilson, Jeffrey Pradeep Raj, Girish Narayan, Murtuza Ghiya, Shakuntala Murty, Bobby Joseph

Journal of Emergencies, Trauma, and Shock 2017 10(4):199-204

Background: Burnout is a syndrome explained as serious emotional depletion with poor adaptation at work due to prolonged occupational stress. It has three principal components namely emotional exhaustion(EE), depersonalization(DP) and diminished feelings of personal accomplishment(PA). Thus, we aimed at measuring the degree of burnout in doctors and nurses working in emergency medicine department (EMD) of 4 select tertiary care teaching hospitals in South India. Methods: A cross sectional survey was conducted among EMD professionals using a 30-item standardized pilot tested questionnaire as well as the Maslach burnout inventory. Univariate and Multivariate analyses were conducted using binary logistic regression models to identify predictors of burnout. Results: Total number of professionals interviewed were 105 of which 71.5% were women and 51.4% were doctors. Majority (78.1%) belonged to the age group 20-30 years. Prevalence of moderate to severe burnout in the 3 principal components EE, DP and PA were 64.8%, 71.4% and 73.3% respectively. After multivariate analysis, the risk factors [adjusted odds ratio (95% confidence intervals) for DP included facing more criticism [3.57(1.25,10.19)], disturbed sleep [6.44(1.45,28.49)] and being short tempered [3.14(1.09,9.09)]. While there were no statistically significant risk factors for EE, being affected by mortality [2.35(1.12,3.94)] and fear of medication errors [3.61(1.26, 10.37)] appeared to be significant predictors of PA. Conclusion: Degree of burn out among doctors and nurses is moderately high in all of the three principal components and some of the predictors identified were criticism, disturbed sleep, short tempered nature, fear of committing errors and witnessing death in EMD.

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