Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility

Publication date: Available online 31 August 2017
Source:Developmental Cell
Author(s): Jeremy D. Rotty, Hailey E. Brighton, Stephanie L. Craig, Sreeja B. Asokan, Ning Cheng, Jenny P. Ting, James E. Bear
The Arp2/3 complex nucleates branched actin, forming networks involved in lamellipodial protrusion, phagocytosis, and cell adhesion. We derived primary bone marrow macrophages lacking Arp2/3 complex (Arpc2^−/−) and directly tested its role in macrophage functions. Despite protrusion and actin assembly defects, Arpc2^−/− macrophages competently phagocytose via FcR and chemotax toward CSF and CX3CL1. However, CR3 phagocytosis and fibronectin haptotaxis, both integrin-dependent processes, are disrupted. Integrin-responsive actin assembly and αM/β2 integrin localization are compromised in Arpc2^−/− cells. Using an in vivo system to observe endogenous monocytes migrating toward full-thickness ear wounds we found that Arpc2^−/− monocytes maintain cell speeds and directionality similar to control. Our work reveals that the Arp2/3 complex is not a general requirement for phagocytosis or chemotaxis but is a critical driver of integrin-dependent processes. We demonstrate further that cells lacking Arp2/3 complex function in vivo remain capable of executing important physiological responses that require rapid directional motility.

Graphical abstract

Teaser

Using a combination of cell culture-based and in vivo mouse experiments, Rotty et al. demonstrate that the actin-nucleating Arp2/3 complex is not absolutely required for macrophage FcR phagocytosis, chemotaxis, or in vivo monocyte directional motility. Rather, the complex has a critical role in regulating integrin-dependent macrophage processes.


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YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis

Publication date: Available online 31 August 2017
Source:Developmental Cell
Author(s): Xiaohong Wang, Aida Freire Valls, Géza Schermann, Ying Shen, Ivan M. Moya, Laura Castro, Severino Urban, Gergely M. Solecki, Frank Winkler, Lars Riedemann, Rakesh K. Jain, Massimilano Mazzone, Thomas Schmidt, Tamás Fischer, Georg Halder, Carmen Ruiz de Almodóvar
Vascular endothelial growth factor (VEGF) is a major driver of blood vessel formation. However, the signal transduction pathways culminating in the biological consequences of VEGF signaling are only partially understood. Here, we show that the Hippo pathway effectors YAP and TAZ work as crucial signal transducers to mediate VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium-specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton and that activated YAP/TAZ induce a transcriptional program to further control cytoskeleton dynamics and thus establish a feedforward loop that ensures a proper angiogenic response. Lack of YAP/TAZ also results in altered cellular distribution of VEGFR2 due to trafficking defects from the Golgi apparatus to the plasma membrane. Altogether, our study identifies YAP/TAZ as central mediators of VEGF signaling and therefore as important regulators of angiogenesis.

Graphical abstract

Teaser

Wang et al. identify YAP/TAZ as essential co-transcription factors in endothelial cells during developmental angiogenesis. They describe that YAP/TAZ are activated by VEGF and that their activity is needed for transducing the VEGF signal into a specific transcriptional program, required for a full angiogenic response.


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Measuring Cutaneous Lesions: Trends in Clinical Practice.

BACKGROUND: Knowing the size of a cutaneous lesion can be important for tracking its progression over time, selecting the proper treatment modality, surgical planning, determining prognosis, and accurate billing. However, providers vary in their consistency, accuracy, and methods of measuring cutaneous lesions. OBJECTIVE: To investigate the clinical practices of US dermatologists and dermatologic surgeons regarding how they determine the size of cutaneous lesions. MATERIALS AND METHODS: A survey was electronically distributed to members of the American Society for Dermatologic Surgery. RESULTS: Four hundred twenty-six dermatologists completed the online survey. When a lesion is suspected to be malignant, 85% of respondents obtained exact measurements most, if not all, of the time; however, only 8% did for benign lesions. Most providers determined lesion sizes themselves rather than delegating to staff. When performing visual estimation, approximately three-quarters believed that they were accurate to within 1 to 2 mm. The top reasons for obtaining exact measurements were for tracking atypical pigmented lesions, determining treatment pathways, and accurate billing. CONCLUSION: The majority of respondents believed that lesion size affected management decisions; however, the need for exact measurement remains controversial, particularly for benign lesions. Future studies may investigate whether taking exact versus estimated measurements has an effect on outcomes. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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A Novel Mohs Precision Tool.

BACKGROUND: Effective treatment by Mohs micrographic surgery requires preparation of high-quality slides. OBJECTIVE: To examine a novel tissue alignment device designed to address variability in tissue processing because of excessive sample trimming. MATERIALS AND METHODS: A device was designed to account for angular errors and unparalleled tissue embedding. A retrospective chart review was performed both with and without the use of the device over the course of a 4-year period (2012-2015). RESULTS: Between January 1, 2012, and June 10, 2014, before device implementation, mean number of stages per case was 1.65 (n = 3,680) and mean number of surgeries per day was 6.34 (n = 640). Between June 11, 2014, and October 02, 2015, with device implemented, the average number of stages per case between decreased to 1.58 (n = 2,562) and the number of daily surgeries increased to 7.05 (n = 358). This represents a significant decrease in number of stages per case by 0.07 stages (95% CI: -0.01 to -0.13, p = .02), as well as an increase in the number of cases per day by 0.71 cases (95% CI: 0.12-1.3, p

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Repair of 2 Nearby Cheek Defects.

No abstract available

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Validation and Application of the Webb and Rivera Score in the Academic Setting.

No abstract available

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A Prospective, Open-Label Study of Hyaluronic Acid-Based Filler With Lidocaine (VYC-15L) Treatment for the Correction of Infraorbital Skin Depressions.

BACKGROUND: Infraorbital skin depressions are one of the most troublesome facial areas for aesthetically aware patients. OBJECTIVE: Evaluate effectiveness and safety of Juvederm Volbella with Lidocaine (VYC-15L; Allergan plc, Dublin, Ireland) for correction of bilateral infraorbital depressions. METHODS: In this 12-month, prospective, uncontrolled, open-label study, subjects aged >=18 years with infraorbital depressions rated >=1 on the Allergan Infra-oRbital Scale (AIRS) received injections of VYC-15L with optional touch-up treatment on Day 14. The primary efficacy measure was >=1 AIRS grade improvement from baseline at month 1. RESULTS: Of 80 subjects initially treated with VYC-15L, 75 (94%) completed the study. All injections were intentionally deep, most using multiple microbolus technique. At 1 month, 99.3% of eyes achieved >=1 AIRS grade improvement. The responder rate (subjects with >=1 AIRS grade improvement in both eyes) was 99% at month 1, 92% at month 6, and 54% at month 12. Most injection site reactions (e.g., bruising, redness, irregularities/bumps) were mild and resolved by day 14. Late-onset mild to moderate edema was observed in 11% of eyes at month 6% and 4% of eyes at month 12. CONCLUSION: VYC-15L is effective and safe for the treatment of infraorbital depressions, with effectiveness lasting up to 12 months. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Pearly Facial Nodule as a Presentation of Late Metastasis of Retroperitoneal Leiomyosarcoma.

No abstract available

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Orifice Preserving Double Opposing Z-Plasty for Partial Split Ear Lobe Repair: A Review of 25 Cases.

BACKGROUND: Surgeons often come across split earlobe (SEL) deformities in their clinical practice which usually result from wearing heavy earrings for a long duration. It is of utmost importance to achieve a satisfactory repair with increased strength in one go. OBJECTIVE: To describe a strong repair for partial SEL with preservation of the orifice. MATERIALS AND METHODS: This study is a retrospective review of 25 patients (36 earlobes), who underwent repair of partial SEL deformity with an orifice preserving double opposing Z-plasty in the hospital, from January 2014 to June 2015. The duration of follow-up was 12 months. RESULTS: Adequate cosmetic results were obtained in all patients with no need for revision surgery due to recurrence or scar dehiscence. Patients did not report any difficulty in wearing earrings and were satisfied with the aesthetic outcome. CONCLUSION: The orifice preserving double opposing Z-plasty technique seems to offer an efficacious method of repair of partial SEL deformity with an acceptable scar. The technique is simple and reproducible with good aesthetic outcomes and minimal complications. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Venous Treatment of Lipodermatosclerosis to Improve Ambulatory Function.

No abstract available

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Male Body Contouring.

BACKGROUND: Men are increasingly seeking out cosmetic procedures, especially minimally and noninvasive body-contouring procedures. OBJECTIVE: With the relative lack of scientific evidence related specifically to the use of body-contouring procedures in men, there is a need for more education and scientific discussion in this growing group. MATERIALS AND METHODS: Understanding the male anatomy and esthetics, and how body-contouring techniques and new modalities can be used in men, can lead to better outcomes. CONCLUSIONS: This review of body contouring in men emphasizes currently available literature and author experiences. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Cutaneous Metastases of Melanoma Affecting Exclusively Skin Graft Donor and Receiving Sites: A Novel Clinical Presentation.

No abstract available

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Pathologists' Use of Second Opinions in Interpretation of Melanocytic Cutaneous Lesions: Policies, Practices, and Perceptions.

BACKGROUND: Research examining the role of second opinions in pathology for diagnosis of melanocytic lesions is limited. OBJECTIVE: To assess current laboratory policies, clinical use of second opinions, and pathologists' perceptions of second opinions for melanocytic lesions. MATERIALS AND METHODS: Cross-sectional data collected from 207 pathologists in 10 US states who diagnose melanocytic lesions. The web-based survey ascertained pathologists' professional information, laboratory second opinion policy, use of second opinions, and perceptions of second opinion value for melanocytic lesions. RESULTS: Laboratory policies required second opinions for 31% of pathologists and most commonly required for melanoma in situ (26%) and invasive melanoma (30%). In practice, most pathologists reported requesting second opinions for melanocytic tumors of uncertain malignant potential (85%) and atypical Spitzoid lesions (88%). Most pathologists perceived that second opinions increased interpretive accuracy (78%) and protected them from malpractice lawsuits (62%). CONCLUSION: Use of second opinions in clinical practice is greater than that required by laboratory policies, especially for melanocytic tumors of uncertain malignant potential and atypical Spitzoid lesions. Quality of care in surgical interventions for atypical melanocytic proliferations critically depends on the accuracy of diagnosis in pathology reporting. Future research should examine the extent to which second opinions improve accuracy of melanocytic lesion diagnosis. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Paramedian Forehead Flap Salvage Through Pedicle Full-Thickness Skin Graft.

No abstract available

http://ift.tt/2eo18eC

Pilot Study Examining the Safety and Efficacy of Calcium Hydroxylapatite Filler With Integral Lidocaine Over a 12-Month Period to Correct Temporal Fossa Volume Loss.

BACKGROUND: Age-related volume loss in the temporal fossae is due to thinning of the epidermis, loss of subcutaneous structural volume, and change in the bony architecture. Temporal concavities are important areas of 3-dimensional volume restoration. The temporal fossae is becoming an increasingly popular area for patients seeking soft tissue augmentation with injectable fillers such as calcium hydroxylapatite with integral lidocaine [CaHA (+)]. OBJECTIVE: This pilot study aims to define the safety, efficacy, technique, and patient-reported outcomes for injectable CaHA (+) to correct volume loss in the temporal fossae over a 12-month period. MATERIALS AND METHODS: This was a single-investigator, nonblinded study involving 20 participants. Participants received filler injection into their temporal fossae, with follow-up evaluations at Day 14, 6 weeks, and 3, 6, 9, and 12 months. RESULTS: CaHA (+) results in statistically significant improvement in temporal fossae appearance lasting up to 12 months. Subjects reported "moderate" global aesthetic improvement over the 12-month period. CONCLUSION: As the cosmetic field continues to advance, it is important for practitioners to have access to research regarding the efficacy and safety of injectables. These results show that CaHA (+) is an effective and safe option to correct temporal fossae volume loss associated with high patient satisfaction. (C) 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Delayed Paleness After Hyaluronic Acid Filler Injection: A Warning Sign of Vascular Compromise.

No abstract available

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Mesenchymal Stromal Cell Therapy: After the Gold Rush.

No abstract available

http://ift.tt/2iMwXTp

Long-term Functioning of Allogeneic Islets in Subcutaneous Tissue Pretreated with a Novel Cyclic Peptide without Immunosuppressive Medication.

Background: There exists a need for a minimally invasive method of islet transplantation without immunosuppressive drugs for the treatment of type 1 diabetes. Methods: In diabetic ACI rats, an agarose rod containing the cyclic oligopeptide SEK-1005 (agarose-SEK rod) was implanted at 2 dorsal subcutaneous sites. Then these rods were removed, and 1500 islets isolated from F344 rats were transplanted into each of the pockets. Results: Ten days after implantation of agarose-SEK rods, vascularized pockets were present. Nonfasting blood glucose levels confirmed long-term survival of the allogeneic islet grafts, without immunosuppressive therapy, in 8 of 10 recipients. Flow cytometry and gene expression analyses were performed to investigate the mechanisms underlying graft acceptance. Agarose-SEK rod implantation led to the formation of granulomatous tissue containing regulatory T cells that suppressed immune reactions against the allogeneic islet grafts. Conclusions: These results indicate that the use of an agarose-SEK rod to prevascularize a subcutaneous site may be a useful method for achieving successful allogeneic islet transplantation without immunosuppression. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Operant models of relapse in zebrafish (Danio rerio): Resurgence, renewal, and reinstatement

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Toshikazu Kuroda, Yuto Mizutani, Carlos R.X. Cançado, Christopher A. Podlesnik
Zebrafish are a widely used animal model in biomedical research, as an alternative to mammals, for having features such as a fully sequenced genome, high fecundity, and low-cost maintenance, but behavioral research with these fish remains scarce. The present study investigated whether zebrafish could be a new animal model for studies on the relapse of behavior (e.g., addiction and overeating) after the behavior has been extinguished. Specifically, we examined whether zebrafish would show three different types of relapse commonly studied with other species: resurgence, renewal, and reinstatement. For resurgence, a target response (i.e., approaching a sensor) was established by presenting a reinforcer (i.e., shrimp eggs) contingent upon the response in Phase 1; the target response was extinguished while introducing reinforcement for an alternative response in Phase 2; neither response produced the reinforcer in Phase 3. For renewal, a target response was established under Context A in Phase 1 and was extinguished under Context B in Phase 2; the fish were placed back in Context A in Phase 3, where extinction remained in effect. For reinstatement, a target response was established in Phase 1 and was extinguished in Phase 2; the reinforcer was presented independently of responding in Phase 3. Each type of relapse occurred in Phase 3. These results replicate and extend previous findings on relapse to a new species and suggest that zebrafish can be a useful animal model for studying the interactions of biological and environmental factors that lead to relapse.



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Games people play: How video games improve probabilistic learning

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Sabrina Schenk, Robert K. Lech, Boris Suchan
Recent research suggests that video game playing is associated with many cognitive benefits. However, little is known about the neural mechanisms mediating such effects, especially with regard to probabilistic categorization learning, which is a widely unexplored area in gaming research. Therefore, the present study aimed to investigate the neural correlates of probabilistic classification learning in video gamers in comparison to non-gamers. Subjects were scanned in a 3T magnetic resonance imaging (MRI) scanner while performing a modified version of the weather prediction task. Behavioral data yielded evidence for better categorization performance of video gamers, particularly under conditions characterized by stronger uncertainty. Furthermore, a post-experimental questionnaire showed that video gamers had acquired higher declarative knowledge about the card combinations and the related weather outcomes. Functional imaging data revealed for video gamers stronger activation clusters in the hippocampus, the precuneus, the cingulate gyrus and the middle temporal gyrus as well as in occipital visual areas and in areas related to attentional processes. All these areas are connected with each other and represent critical nodes for semantic memory, visual imagery and cognitive control. Apart from this, and in line with previous studies, both groups showed activation in brain areas that are related to attention and executive functions as well as in the basal ganglia and in memory-associated regions of the medial temporal lobe. These results suggest that playing video games might enhance the usage of declarative knowledge as well as hippocampal involvement and enhances overall learning performance during probabilistic learning. In contrast to non-gamers, video gamers showed better categorization performance, independently of the uncertainty of the condition.



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Activation of TLR4/STAT3 signaling in VTA contributes to the acquisition and maintenance of morphine-induced conditioned place preference

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Jia-Xin Chen, Kang-Mei Huang, Meng Liu, Jin-Xiang Jiang, Jian-Peng Liu, Yu-Xiang Zhang, Chen Yang, Wen-Jun Xin, Xue-Qin Zhang
Morphine, commonly used to relieve the acute or chronic pain, has a high potential for addiction and exerts rewarding effects via a critical role for mesolimbic dopamine system. Studies suggest that addiction-related behavior is highly associated with inflammatory immune response, but the mechanisms are poorly understood. The present study showed that intra-VTA microinjection of TLR4 antagonist LPS-RS prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rats. In addition, chronic morphine treatment significantly activated STAT3 on day 6 and 11 in VTA, and bilateral microinjection of STAT3 inhibitor S3I-201 into the VTA suppressed the acquisition and maintenance of morphine-induced CPP in rats. Furthermore, local knockout of STAT3 by injection of the AAV-Cre-GFP into the VTA area of STAT3^flox/flox mice also significantly impaired the acquisition of morphine CPP. Importantly, the TLR4 expression is colocalized with p-STAT3-positive cell in VTA, and repeated injection of LPS-RS significantly attenuated the STAT3 activation in VTA induced by chronic morphine treatment. Collectively, these data suggest that TLR4/STAT3 signaling pathway in VTA might play a critical role in the acquisition and maintenance of morphine CPP, and provides new evidence that TLR4/STAT3 signaling pathway might be a potential target for treatment of morphine addiction.



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Development of an opioid self-administration assay to study drug seeking in zebrafish

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Gabriel D. Bossé, Randall T. Peterson
The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction.



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Structural hemispheric asymmetries underlie verbal Stroop performance

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Antonino Vallesi, Ilaria Mazzonetto, Ettore Ambrosini, Laura Babcock, Mariagrazia Capizzi, Sandra Arbula, Vincenza Tarantino, Carlo Semenza, Alessandra Bertoldo
Performance on tasks involving cognitive control such as the Stroop task is often associated with left lateralized brain activations. Based on this neuro-functional evidence, we tested whether leftward structural grey matter asymmetries would also predict inter-individual differences in combatting Stroop interference. To check for the specificity of the results, both a verbal Stroop task and a spatial one were administered to a total of 111 healthy young individuals, for whom T1-weighted magnetic resonance imaging (MRI) images were also acquired. Surface thickness and area estimations were calculated using FreeSurfer. Participants' hemispheres were registered to a symmetric template and Laterality Indices (LI) for the surface thickness and for the area at each vertex in each participant were computed. The correlation of these surface LI measures with the verbal and spatial Stroop effects (incongruent–congruent difference in trial performance) was assessed at each vertex by means of general linear models at the whole-brain level. We found a significant correlation between performance and surface area LI in an inferior posterior temporal cluster (overlapping with the so-called visual word form area, VWFA), with a more left-lateralized area in this region associated with a smaller Stroop effect only in the verbal task. These results point to an involvement of the VWFA for higher-level processes based on word reading, including the suppression of this process when required by the task, and could be interpreted in the context of cross-hemispheric rivalry.



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Differential behavioral effects of ethanol pre-exposure in male and female zebrafish (Danio rerio)

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Carly L. Clayman, Elizabeth J. Malloy, David N. Kearns, Victoria P. Connaughton
Alcohol exposure in adolescence is a contributing factor toward reward-seeking behavior in adulthood. This reward-seeking behavior is assessed in animal models using the conditioned place preference (CPP) paradigm. In this study, ethanol-induced change in time spent by zebrafish on the initially non-preferred tank side was studied by conditioning adult zebrafish to ethanol dissolved in water (0.00% 1.00%; 1.25%; 1.50%; 1.60%; 1.75% vol/vol) paired with an initially non-preferred environment. Following a single conditioning cycle, fish swam unrestricted in the CPP chamber to assess changes in preference. Daily 20-min pre-exposure to ethanol for 1 week during the juvenile stage starting at either 20days post fertilization (dpf) or 40 dpf altered percent time spent on the ethanol-paired side in adulthood in a dose-dependent and sex-dependent manner. The results suggest that male and female zebrafish are an effective model in which to investigate behavioral correlates of ethanol-induced changes in neural circuits implicated in reward and anxiety.

Graphical abstract

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Real-time changes in corticospinal excitability related to motor imagery of a force control task

Publication date: 29 September 2017
Source:Behavioural Brain Research, Volume 335
Author(s): Tsuyoshi Tatemoto, Junko Tsuchiya, Atsuki Numata, Ryuji Osawa, Tomofumi Yamaguchi, Shigeo Tanabe, Kunitsugu Kondo, Yohei Otaka, Kenichi Sugawara
ObjectiveTo investigate real-time excitability changes in corticospinal pathways related to motor imagery in a changing force control task, using transcranial magnetic stimulation (TMS).MethodsTen healthy volunteers learnt to control the contractile force of isometric right wrist dorsiflexion in order to track an on-screen sine wave form. Participants performed the trained task 40 times with actual muscle contraction in order to construct the motor image. They were then instructed to execute the task without actual muscle contraction, but by imagining contraction of the right wrist in dorsiflexion. Motor evoked potentials (MEPs), induced by TMS in the right extensor carpi radialis muscle (ECR) and flexor carpi radialis muscle (FCR), were measured during motor imagery. MEPs were induced at five time points: prior to imagery, during the gradual generation of the imaged wrist dorsiflexion (Increasing phase), the peak value of the sine wave, during the gradual reduction (Decreasing phase), and after completion of the task. The MEP ratio, as the ratio of imaged MEPs to resting-state, was compared between pre- and post-training at each time point.ResultsIn the ECR muscle, the MEP ratio significantly increased during the Increasing phase and at the peak force of dorsiflexion imagery after training. Moreover, the MEP ratio was significantly greater in the Increasing phase than in the Decreasing phase. In the FCR, there were no significant consistent changes.ConclusionCorticospinal excitability during motor imagery in an isometric contraction task was modulated in relation to the phase of force control after image construction.



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Identification and segmentation of myelinated nerve fibers in a cross-sectional optical microscopic image using a deep learning model

Publication date: 1 November 2017
Source:Journal of Neuroscience Methods, Volume 291
Author(s): Tatsuhiko Naito, Yu Nagashima, Kenichiro Taira, Naohiro Uchio, Shoji Tsuji, Jun Shimizu
BackgroundThe morphometric analysis of myelinated nerve fibers of peripheral nerves in cross-sectional optical microscopic images is valuable. Several automated methods for nerve fiber identification and segmentation have been reported. This paper presents a new method that uses a deep learning model of a convolutional neural network (CNN). We tested it for human sural nerve biopsy images.MethodsThe method comprises four steps: normalization, clustering segmentation, myelinated nerve fiber identification, and clump splitting. A normalized sample image was separated into individual objects with clustering segmentation. Each object was applied to a CNN deep learning model that labeled myelinated nerve fibers as positive and other structures as negative. Only positives proceeded to the next step. For pretraining the model, 70,000 positive and negative data each from 39 samples were used. The accuracy of the proposed algorithm was evaluated using 10 samples that were not part of the training set. A P-value of <0.05 was considered statistically significant.ResultsThe total true-positive rate (TPR) for the detection of myelinated fibers was 0.982, and the total false-positive rate was 0.016. The defined total area similarity (AS) and area overlap error of segmented myelin sheaths were 0.967 and 0.068, respectively. In all but one sample, there were no significant differences in estimated morphometric parameters obtained from our method and manual segmentation.Comparison with existing methodsThe TPR and AS were higher than those obtained using previous methods.ConclusionsHigh-performance automated identification and segmentation of myelinated nerve fibers were achieved using a deep learning model.



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An operant-based detection method for inferring tinnitus in mice

Publication date: Available online 31 August 2017
Source:Journal of Neuroscience Methods
Author(s): Hongyan Zuo, Debin Lei, Shobhana Sivaramakrishnan, Benjamin Howie, Jessica Mulvany, Jianxin Bao
BackgroundSubjective tinnitus is a hearing disorder in which a person perceives sound when no external sound is present. It can be acute or chronic. Because our current understanding of its pathology is incomplete, no effective cures have yet been established. Mouse models are useful for studying the pathophysiology of tinnitus as well as for developing therapeutic treatments.New MethodWe have developed a new method for determining acute and chronic tinnitus in mice, called sound-based avoidance detection (SBAD). The SBAD method utilizes one paradigm to detect tinnitus and another paradigm to monitor possible confounding factors, such as motor impairment, loss of motivation, and deficits in learning and memory.ResultsThe SBAD method has succeeded in monitoring both acute and chronic tinnitus in mice. Its detection ability is further validated by functional studies demonstrating an abnormal increase in neuronal activity in the inferior colliculus of mice that had previously been identified as having tinnitus by the SBAD method.Comparisonwith Existing Methods The SBAD method provides a new means by which investigators can detect tinnitus in a single mouse accurately and with more control over potential confounding factors than existing methods.ConclusionThis work establishes a new behavioral method for detecting tinnitus in mice. The detection outcome is consistent with functional validation. One key advantage of mouse models is they provide researchers the opportunity to utilize an extensive array of genetic tools. This new method could lead to a deeper understanding of the molecular pathways underlying tinnitus pathology.



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Improving Oral Bioavailability of Cyclic Peptides by N-Methylation

Publication date: Available online 31 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Andreas F.B. Räder, Florian Reichart, Michael Weinmüller, Horst Kessler
The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization –biological activity and oral availability– is required to overcome this problem. Moreover, most simple "rules" for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N–methylation of cyclic peptides in strategies to optimize bioavailabilities.

Graphical abstract

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Towards semisynthetic natural compounds with a biaryl axis: oxidative phenol coupling in Aspergillus niger

Publication date: Available online 31 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Katharina Gloria Hugentobler, Michael Müller
Regio- and stereoselective phenol coupling is difficult to achieve using synthetic strategies. However, in nature, cytochrome P450 enzyme-mediated routes are employed to achieve complete axial stereo- and regiocontrol in the biosynthesis of compounds with potent bioactivity. Here, we report a synthetic biology approach whereby the bicoumarin metabolic pathway in Aspergillus niger was specifically tailored towards the formation of new coupling products. This strategy represents a manipulation of the bicoumarin pathway in A. niger via interchange of the phenol-coupling biocatalyst and could be applied to other components of the pathway to access a variety of atropisomeric natural product derivatives.

Graphical abstract

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Identification of novel PDEδ interacting proteins

Publication date: Available online 31 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Philipp Küchler, Gunther Zimmermann, Michael Winzker, Herbert Waldmann, Slava Ziegler
Prenylation is a post-translational modification that increases the affinity of proteins for membranes and mediates protein-protein interactions. The retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDEδ) is a prenyl binding protein that is essential for the shuttling of small GTPases between different membrane compartments and, thus, for their proper functioning. Although the prenylome comprises up to 2% of the mammalian proteome, only few prenylated proteins are known to interact with PDEδ. A proteome-wide approach was employed to map the PDEδ interactome among the prenylome and revealed RAB23, CDC42 and CNP as novel PDEδ interacting proteins. Moreover, PDEδ associates with the lamin A mutant progerin in a prenyl-dependent manner. These findings shed new light on the role of PDEδ in binding (and regulating) prenylated proteins in cells.

Graphical abstract

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Synthesis and β-sheet propensity of constrained N-amino peptides

Publication date: Available online 31 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Matthew P. Sarnowski, Kyle P. Pedretty, Nicole Giddings, H. Lee Woodcock, Juan R. Del Valle
The stabilization of β-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable β-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between -hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on β-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong β-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on β-sheet folding.

Graphical abstract

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Using Engineered Bacteria to Characterize Infection Dynamics and Antibiotic Effects In Vivo

Publication date: Available online 31 August 2017
Source:Cell Host & Microbe
Author(s): Laura K. Certain, Jeffrey C. Way, Matthew J. Pezone, James J. Collins
Synthetic biology has focused on engineering microbes to synthesize useful products or to serve as living diagnostics and therapeutics. Here we utilize a host-derived Escherichia coli strain engineered with a genetic toggle switch as a research tool to examine in vivo replicative states in a mouse model of chronic infection, and to compare in vivo and in vitro bacterial behavior. In contrast to the effect of antibiotics in vitro, we find that the fraction of actively dividing bacteria remains relatively high throughout the course of a chronic infection in vivo and increases in response to antibiotics. Moreover, the presence of non-dividing bacteria in vivo does not necessarily lead to an antibiotic-tolerant infection, in contrast to expectations from in vitro experiments. These results demonstrate the utility of engineered bacteria for querying pathogen behavior in vivo, and the importance of validating in vitro studies of antibiotic effects with in vivo models.

Graphical abstract

Teaser

Using Escherichia coli engineered with a genetic toggle switch, Certain et al. demonstrate ongoing bacterial replication in a mouse model of chronic infection, even with antibiotic treatment. This finding runs contrary to the expectation that antibiotics preferentially eliminate actively dividing bacteria and highlights the in vivo utility of synthetic biology.


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Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses

Publication date: Available online 31 August 2017
Source:Cell Host & Microbe
Author(s): Chris Lauber, Stefan Seitz, Simone Mattei, Alexander Suh, Jürgen Beck, Jennifer Herstein, Jacob Börold, Walter Salzburger, Lars Kaderali, John A.G. Briggs, Ralf Bartenschlager
Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.

Graphical abstract

Teaser

Hepatitis B viruses are enveloped viruses of global medical importance. Lauber et al. report the discovery of nackednaviruses, a non-enveloped sister family to hepatitis B viruses in fish. Both lineages separated >400 million years ago. The envelope gene of hepatitis B viruses emerged de novo, followed by virus-host co-evolution over geologic eras.


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Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages

Publication date: Available online 31 August 2017
Source:Cell Host & Microbe
Author(s): Pedro Escoll, Ok-Ryul Song, Flávia Viana, Bernhard Steiner, Thibault Lagache, Jean-Christophe Olivo-Marin, Francis Impens, Priscille Brodin, Hubert Hilbi, Carmen Buchrieser
The intracellular bacteria Legionella pneumophila encodes a type IV secretion system (T4SS) that injects effector proteins into macrophages in order to establish and replicate within the Legionella-containing vacuole (LCV). Once generated, the LCV interacts with mitochondria through unclear mechanisms. We show that Legionella uses both T4SS-independent and T4SS-dependent mechanisms to respectively interact with mitochondria and induce mitochondrial fragmentation that ultimately alters mitochondrial metabolism. The T4SS effector MitF, a Ran GTPase activator, is required for fission of the mitochondrial network. These effects of MitF occur through accumulation of mitochondrial DNM1L, a GTPase critical for fission. Furthermore mitochondrial respiration is abruptly halted in a T4SS-dependent manner, while T4SS-independent upregulation of cellular glycolysis remains elevated. Collectively, these alterations in mitochondrial dynamics promote a Warburg-like phenotype in macrophages that favors bacterial replication. Hence the rewiring of cellular bioenergetics to create a replication permissive niche in host cells is a virulence strategy of L. pneumophila.

Graphical abstract

Teaser

Escoll et al. show that L. pneumophila establishes transient and highly dynamic contacts with mitochondria in a T4SS-independent manner, while secretion of the T4SS effector MitF induces mitochondrial fragmentation. L. pneumophila-induced modulation of mitochondrial dynamics promotes a switch in the metabolism of the infected cell that favors bacterial replication.


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TOC

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Proton Pump Inhibitor-related Mortality: Let Us Not Be Dead Wrong

We need to be very wary when research might be misinterpreted easily in ways that might scare patients and physicians away from appropriate medication use.

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Calendar Listings

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Instructions for Contributors

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Editorial Board

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Calendar

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Co-occurrence of tobacco product use, substance use, and mental health problems among youth: Findings from wave 1 (2013–2014) of the population assessment of tobacco and health (PATH) study

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Kevin P. Conway, Victoria R. Green, Karin A. Kasza, Marushka L. Silveira, Nicolette Borek, Heather L. Kimmel, James D. Sargent, Cassandra A. Stanton, Elizabeth Lambert, Nahla Hilmi, Chad J. Reissig, Kia J. Jackson, Susanne E. Tanski, David Maklan, Andrew J. Hyland, Wilson M. Compton
IntroductionCigarette use is associated with substance use and mental health problems among youth, but associations are unknown for non-cigarette tobacco product use, as well as the increasingly common poly-tobacco use.MethodsThe current study examined co-occurrence of substance use and mental health problems across tobacco products among 13,617 youth aged 12–17years from Wave 1 (2013–2014) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. Participants self-reported ever cigarette, e-cigarette, smokeless tobacco, traditional cigar, cigarillo, filtered cigar, hookah, and other tobacco product use; alcohol, marijuana, and other drugs; and lifetime substance use, internalizing and externalizing problems.ResultsIn multivariable regression analyses, use of each tobacco product was associated with substance use, particularly cigarillos and marijuana (AOR=18.9, 95% CI: 15.3–23.4). Cigarette (AOR=14.7, 95% CI: 11.8–18.2) and cigarillo (AOR=8.1, 95% CI: 6.3–10.3) use were strongly associated with substance use problems and tobacco users were more likely to report internalizing (AOR=1.6, 95% CI: 1.4–1.8) and externalizing (AOR=1.4, 95% CI: 1.3–1.6) problems. Female tobacco users were more likely to have internalizing problems than male tobacco users. Poly-tobacco users were more likely than exclusive users to use substances (AOR=3.4, 95% CI: 2.7–4.3) and have mental health (AOR=1.2, 95% CI: 1.0–1.5) and substance use (AOR=4.7, 95% CI: 3.4–6.6) problems.ConclusionsRegardless of the tobacco product used, findings reveal high co-occurrence of substance use and mental health problems among youth tobacco users, especially poly-tobacco users. These findings suggest the need to address comorbidities among high risk youth in prevention and treatment settings.



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Drinking to cope with depression mediates the relationship between social avoidance and alcohol problems: A 3-wave, 18-month longitudinal study

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Jamie-Lee Collins, Kara Thompson, Simon B. Sherry, Maria Glowacka, Sherry H. Stewart
Undergraduates with high social anxiety have increased alcohol problems, despite lower or equivalent alcohol use levels. Drinking motives mediate the cross-sectional relationship between social anxiety and alcohol problems, with coping and conformity motives being the most commonly observed mediators. Our study extended prior research by using a longitudinal design, examining coping with anxiety motives (CAM) and coping with depression motives (CDM) separately using path analysis, simultaneously considering a variety of drinking motives in the model, and focusing on a particularly severe form of social anxiety – namely, social avoidance. We collected data from 219 undergraduates (72.6% women, mean age of 20.59years) over three waves spaced six months apart. Results indicated CDM mediated the prospective relationship between social avoidance and alcohol problems. Findings suggest socially avoidant students' escalations in CDM explain their increased alcohol problems over time. Future research should examine involvement of depression and social isolation in contributing to this pathway to alcohol problems.



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Postcessation weight gain concern as a barrier to smoking cessation: Assessment considerations and future directions

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Lisa J. Germeroth, Michele D. Levine
PurposeConcern about postcessation weight gain may be one potential barrier to quitting smoking. In this 'mini-review' of recent literature, we summarize findings on the relationship between postcessation weight gain concern and smoking cessation, and evaluate varied use of postcessation weight gain concern assessments and potential moderators of the postcessation weight gain concern-cessation association.MethodsWe conducted a search using the terms "smoking" OR "smoking cessation" AND "weight concern" for articles published between January 1, 2011 and December 31, 2016. We identified 17 studies assessing postcessation weight gain concern, seven of which evaluated the postcessation weight gain concern-cessation association.ResultsThe relationship between postcessation weight gain concern and smoking cessation was mixed. Recent studies varied in their assessments of postcessation weight gain concern, many of which were not validated and assessed correlates of this construct. Studies varied in their adjustment of demographic (e.g., sex), smoking-specific (e.g., smoking level), and weight-specific (e.g., body mass index) variables.ConclusionsThe use of non-validated assessments and variability in testing covariates/moderators may contribute to conflicting results regarding the postcessation weight gain concern-cessation relationship. We recommend validating an assessment of postcessation weight gain concern, maintaining vigilance in testing and reporting covariates/moderators, and investigating trajectories of this construct over time and by smoking status to inform future assessment and intervention efforts.



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The association between multidimensional feminine norms, binge drinking and alcohol-related problems among young adult college women

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Derek Kenji Iwamoto, William Corbin, Stephanie Takamatsu, Jeanett Castellanos
Alcohol consumption among women has steadily increased over the past 30years, and women's drinking behavior is now similar to that of men's. The escalation of alcohol use among women highlights the critical need to examine gender issues and motivational factors that contribute to binge drinking and related problems within this population. Feminine norms or the socially constructed beliefs, messages and attitudes about what it means to be a woman may contribute to within-group differences in drinking patterns among women. The current study examined the relationship between multidimensional feminine norms and binge drinking and alcohol-related problems among 1910 college women. Participants completed a self-report measure of binge drinking, alcohol-related problems, conformity to feminine norms, alcohol expectancies and descriptive norms. Controlling for the covariates descriptive norms, positive alcohol expectancies, and sorority membership, adherence to feminine norms related to sexual fidelity and belief that one needs to be sweet and nice were negatively associated to binge drinking, while adhering to investment in appearance was positively associated to binge drinking and alcohol-related problems. Distinct feminine norms also had a significant indirect effect on alcohol-related problems through binge drinking. This study significant contributes to the literature by elucidating the theoretically gender-relevant risk and protective aspects of feminine norms in relation to binge drinking and related problems, and provides important information that might be used in clinical and prevention efforts to reduce alcohol-related harm among a vulnerable group: college women.



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Perception of intoxication in a field study of the night-time economy: Blood alcohol concentration, patron characteristics, and event-level predictors

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Christine E. Kaestle, Nicolas Droste, Amy Peacock, Raimondo Bruno, Peter Miller
ObjectiveDetermine the relationship of subjective intoxication to blood alcohol concentration (BAC) and examine whether patron and event-level characteristics modify the relationship of BAC to subjective intoxication.MethodsAn in-situ systematic random sample of alcohol consumers attending night-time entertainment districts between 10pm and 3am on Friday and Saturday nights in five Australian cities completed a brief interview (n=4628). Participants reported age, sex, and pre-drinking, energy drink, tobacco, illicit stimulant and other illicit drug use that night, and their subjective intoxication and BAC were assessed.ResultsMale and female drinkers displayed equally low sensitivity to the impact of alcohol consumption when self-assessing their intoxication (BAC only explained 19% of variance). The marginal effect of BAC was not constant. At low BAC, participants were somewhat sensitive to increases in alcohol consumption, but at higher BAC levels that modest sensitivity dissipated (actual BAC had less impact on self-assessed intoxication). The slope ultimately leveled out to be non-responsive to additional alcohol intake. Staying out late, pre-drinking, and being young introduced biases resulting in higher self-assessed intoxication regardless of actual BAC. Further, both energy drinks and stimulant use modified the association between BAC and perceived intoxication, resulting in more compressed changes in self-assessment as BAC varies up or down, indicating less ability to perceive differences in BAC level.ConclusionsThe ability of intoxicated patrons to detect further intoxication is impaired. Co-consumption of energy drinks and/or stimulant drugs is associated with impaired intoxication judgment, creating an additional challenge for the responsible service and consumption of alcohol.



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A biosocial cognitive model of cannabis use in emerging adulthood

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Zoe E. Papinczak, Jason P. Connor, Paul Harnett, Matthew J. Gullo
ObjectivesThe aim of this study was to test a new theoretical model of cannabis use incorporating biologically-based personality traits and social cognition. This biosocial cognitive theory (bSCT) has robust support in alcohol studies, but has not been applied to cannabis. The model proposes two pathways linking dimensions of impulsivity to cannabis use. The first predicts that the association between Reward Sensitivity (SR) and cannabis use is mediated by positive outcome expectancies. The second predicts that the relationship between Rash Impulsiveness (RI) and cannabis use is mediated by cannabis refusal self-efficacy. An extended version of this model was also tested and included a third pathway linking Punishment Sensitivity (SP) to cannabis use via higher negative outcome expectancies.MethodParticipants were 252 18-to-21-year-olds who completed questionnaires assessing cannabis use, personality and social cognition. Theoretical models were tested using structural equation modeling.ResultsThe bSCT model provided a good fit to the data (CFI=0.95; RMSEA=0.07; SRMR=0.06). Positive cannabis expectancies and refusal self-efficacy partially mediated the association between SR and cannabis use (p<0.05). Cannabis refusal self-efficacy fully mediated the relationship between RI and cannabis use (p<0.05). The addition of a third SP pathway did not improve model fit.ConclusionsConsistent with alcohol studies, the association between impulsivity and cannabis use is largely mediated by social cognition. The bSCT may provide novel insights to inform prevention and treatment of problematic cannabis use.



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Trends in average days' supply of opioid medications in Medicaid and commercial insurance

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Ali Bonakdar Tehrani, Rachel Mosher Henke, Mir M. Ali, Ryan Mutter, Tami L. Mark
ObjectivesTo calculate trends in adult average days' supply for six commonly prescribed opioids: hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol to assess whether physicians changed prescribing practices at the time of the intensifying epidemic.MethodsWe used 2005–2015 Truven Health MarketScan Commercial Claims and Encounters data to measure trends in opioid average days' supply among commercially insured individuals and 2005–2014 MarketScan Multi-State Medicaid data to measure trends in opioid average days' supply among Medicaid beneficiaries.ResultsFor Medicaid, we found an increase in days' supply for all drugs except morphine. The largest percentage increase was for oxycodone, which increased 4.5days (37%). Opioid days' supply for individuals with commercial insurance exhibited similar but steeper trends. The largest increase was also for oxycodone, which increased 6days (56%). Between 2013 and 2015, when the opioid epidemic had begun to be widely publicized, there was no decline in the median days supplied for any of the opioids.ConclusionsOur results find that days' supply of opioids are increasing despite public health campaigns and media attention on the risks of opioid prescribing. More effective interventions to curb opioid prescribing are needed to reverse these trends.



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Ethanol-induced autonomic responses and risk taking increase in young adults with a positive family history of alcohol problems

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Florencia Caneto, Ricardo Marcos Pautassi, Angelina Pilatti
The mechanisms that underlie the greater prevalence of alcohol use disorders in individuals with a positive family history (FH+) of alcohol abuse are still under investigation. These subjects may exhibit differential sensitivity to alcohol's effects on psychomotor stimulation and impulsivity. Alcohol-induced psychomotor stimulation, measured as the heart rate (HR) response, is a proxy for the positive rewarding effects of the drug. We analyzed alcohol-induced effects on time perception (Time Production Task), risk taking (Balloon Analogue Risk Task [BART]), and HR in FH+ and FH− participants. In the FH+ and FH− groups, women and men received 0.6 and 0.7g/kg alcohol, respectively. The alcohol dose yielded a breath alcohol concentration of 0.08% throughout the experiment. The control groups received placebo, and the subjective perception of alcohol intoxication was assessed. Alcohol intoxication significantly increased HR and the adjusted average number of pumps on the BART (a measure of risk taking) in FH+ men and women but not in FH− participants. Behavioral impulsivity was unaffected by alcohol or a FH of alcohol abuse. FH− but not FH+ participants who received alcohol reported significantly greater subjective perception of alcohol's effects than their placebo counterparts. These results indicate that FH+ individuals presented heightened sensitivity to alcohol-induced HR stimulation and alcohol-induced risk taking compared with their FH− counterparts. FH+ subjects, however, were insensitive to the subjective effects of alcohol. This idiosyncratic response pattern may be a likely pathway by which a FH of alcohol problems promotes alcohol drinking.



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PTSD symptom presentation among people with alcohol and drug use disorders: Comparisons by substance of abuse

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Emily R. Dworkin, Sonya Wanklyn, Paul R. Stasiewicz, Scott F. Coffey
Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) commonly co-occur, and there is some evidence to suggest that PTSD symptom clusters are differentially related to various substances of abuse. However, few studies to date have compared PTSD symptom patterns across people with different types of SUDs, and fewer still have accounted for the presence of comorbidity across types of SUDs in understanding symptom patterns. Thus, in the current study, we use a treatment-seeking sample of people with elevated symptoms of PTSD and problem alcohol use to explore differential associations between past-year SUDs with active use and PTSD symptoms, while accounting for the presence of multiple SUDs. When comparing alcohol and drug use disorders, avoidance symptoms were elevated in those with alcohol use disorder, and hyperarousal symptoms were elevated in those who had a drug use disorder. In the subsample with alcohol use disorder, hyperarousal symptoms were elevated in people with co-occurring cocaine use disorders and numbing symptoms were elevated in people with co-occurring sedative/hypnotic/anxiolytic use disorder. These findings provide evidence for different symptom cluster patterns between PTSD and various types of SUDs and highlight the importance of examining the functional relationship between specific substances of abuse when understanding the interplay between PTSD and SUDs.



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Incremental predictive validity of the Addiction Severity Index psychiatric composite score in a consecutive cohort of patients in residential treatment for drug use disorders

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Birgitte Thylstrup, Kim Bloomfield, Morten Hesse
BackgroundThe Addiction Severity Index (ASI) is a widely used assessment instrument for substance abuse treatment that includes scales reflecting current status in seven potential problem areas, including psychiatric severity. The aim of this study was to assess the ability of the psychiatric composite score to predict suicide and psychiatric care after residential treatment for drug use disorders after adjusting for history of psychiatric care.MethodsAll patients treated for drug use disorders in residential treatment centers in Denmark during the years 2000–2010 with complete ASI data were followed through national registers of psychiatric care and causes of death (N=5825). Competing risks regression analyses were used to assess the incremental predictive validity of the psychiatric composite score, controlling for previous psychiatric care, length of intake, and other ASI composite scores, up to 12years after discharge.ResultsA total of 1769 patients received psychiatric care after being discharged from residential treatment (30.3%), and 27 (0.5%) committed suicide. After adjusting for all covariates, psychiatric composite score was associated with a higher risk of receiving psychiatric care after residential treatment (subhazard ratio [SHR]=3.44, p<0.001), and of committing suicide (SHR=11.45, p<0.001).ConclusionsThe ASI psychiatric composite score has significant predictive validity and promises to be useful in identifying patients with drug use disorders who could benefit from additional mental health treatment.



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Recent cannabis use among Veterans in the United States: Results from a national sample

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Alan K. Davis, Lewei A. Lin, Mark A. Ilgen, Kipling M. Bohnert
BackgroundCompared to civilians, little is known about cannabis use among Veterans in the general United States (US) population. This study aimed to examine the prevalence and correlates of recent medical and non-medical cannabis use among this important US sub-population.MethodData came from the 2014 National Survey on Drug Use and Health. Bivariate and multivariable analyses were conducted that were weighted to account for the complex survey design.ResultsApproximately 9% of Veterans in the US reported past year cannabis use. Older, and female, Veterans had lower odds of past year cannabis use. Veterans who were unmarried, out of the work force, had greater functioning disability, nicotine dependence, heavy episodic alcohol use, alcohol use disorder, and drug use had greater odds of past year cannabis use. In states where medical cannabis was legal in 2014, approximately 41% of Veterans who used cannabis in the past year used medically. Those who used medically were older and less likely to engage in recent heavy episodic drinking or to meet criteria for alcohol abuse/dependence, compared to Veterans using non-medically.ConclusionCompared to non-Veterans in the US general population, recent cannabis use was similar or slightly lower among Veterans. However, among those with past year use, the proportion of those using medically was more than double that of the general population. Because only non-medical cannabis use was associated with higher rates of heavy episodic alcohol use and alcohol use disorder, it may be important to address problematic alcohol consumption among this high-risk group.



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Use of hormonal contraceptives and smoking cessation: A preliminary report

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Alicia M. Allen, Samantha Carlson, Lynn E. Eberly, Dorothy Hatsukami, Megan E. Piper
Although endogenous sex hormones influence smoking-related outcomes, little is known about the effect of exogenous sex hormones. Therefore, the goal of this preliminary study was to examine differences in withdrawal symptoms and cessation between women using hormonal contraceptives (HC), women not using hormonal contraceptives (no-HC) and men.Utilizing data from two recently completed smoking cessation randomized clinical trials, we selected participants who were between the ages of 18–35years old. Participants were classified based on use of hormonal contraceptives and gender, then matched based on pharmacotherapy randomization assignment and baseline cigarettes per day. Participants provided self-reported assessments on withdrawal, craving and negative affect, and smoking status was assessed for 52weeks after quit date.Participants (N=130) were 28.7±0.4years old and smoked 16.8±0.6 cigarettes/day. Compared to both no-HC and men, the HC group had significantly greater withdrawal one week prior to the quit date, on the quit date and one week after the quit date. During the first week of attempted abstinence, craving declined in HC and in men, but increased in no-HC. At end of treatment, the HC group was at 3.73 times higher odds of being abstinent compared to men (95% confidence interval: 1.12–12.40). There were no group differences in abstinence rates at Week 26 or 52.These data suggest that HC users may experience more adverse levels of withdrawal, though may be more likely to achieve short-term abstinence. Future research is needed to replicate our observations and explore mechanisms of action.



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Substance use disorders among immigrants in the United States: A research update

Publication date: January 2018
Source:Addictive Behaviors, Volume 76
Author(s): Christopher P. Salas-Wright, Michael G. Vaughn, Trenette T. Clark Goings, David Córdova, Seth J. Schwartz
IntroductionThere is a critical need for the most current information available on the prevalence of substance use disorders (SUD) among immigrants vis-à-vis that of individuals born in the United States (US). We report the prevalence of SUDs among immigrants from major world regions and top immigrant-sending countries, and assess key moderators (i.e., age, gender, family income, age of migration, time in US) of the relationship between immigrant status and SUD risk.MethodThe data source used for the present study is the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III, 2012–2013), a nationally representative survey of 36,309 civilian, non-institutionalized adults ages 18 and older in the US. Logistic regression was employed to examine the relationship between immigrant status and SUD risk.ResultsImmigrants were found to be substantially less likely than US-born individuals to be diagnosed with a past-year or lifetime SUD, including alcohol, cannabis, cocaine, and opioid use disorders. These findings held across major world region and among immigrants from the top-ten immigrant sending nations, and across differences in age, gender, family income, age of migration, and time spent in the US.ConclusionsResults from the present study provide up-to-date and cogent evidence that immigrants use alcohol and drugs, and meet criteria for SUDs, at far lower rates than do US-born individuals. Moreover, we provide new evidence that the protective effect of nativity holds for immigrants from an array of global regions and sending countries, and across key demographic and migration-related differences.



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Preface to the proceedings of the Workshop on Eosinophils in Allergy and Related Diseases 2016

Publication date: September 2017
Source:Allergology International, Volume 66, Supplement
Author(s): Kohei Yamauchi




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Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

http://ift.tt/2etJb1C

Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

http://ift.tt/2etJb1C

Prognostic value of tumor PD-L1 expression combined with CD8+ tumor infiltrating lymphocytes in high grade serous ovarian cancer

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Qiaohong Wang, Weihua Lou, Wen Di, Xia Wu
Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but the relationship between tumor PD-L1 expression and tumor-infiltrating lymphocytes (TILs), and their association with clinical outcomes in patients with high grade serous ovarian cancer (HGSOC) remain ambiguous. We detected the expression of PD-L1 and CD3⁺, CD4⁺, CD8⁺ TILs in 107 patients with HGSOC by immunohistochemical analysis. Using a 5% threshold, 24.30% and 15.89% cases were found with positive expression of PD-L1 in the membrane of tumor cells and TILs respectively. Carcinoma PD-L1 expression mainly localized to the tumor invasive front and was associated with advanced FIGO stage (p=0.023) and abundant stromal CD8⁺ TILs infiltration (p=0.020). Tumors containing PD-L1⁺ TILs were more likely to have PD-L1 expression by the carcinoma cells (p<0.001). Univariate and multivariate analyses demonstrated that a higher number of intraepithelial CD3⁺ or CD8⁺ TILs was an independent prognostic factor for longer overall survival (OS), whereas tumor PD-L1 expression was a predictive factor for poorer OS only in univariate analysis. PD-L1 expression in TILs was not a prognostic factor in univariate analysis. The Kaplan-Meier curves of the four sub-groups and log-rank test showed that patients with negative tumor PD-L1 expression/higher numbers of intraepithelial CD8⁺ TILs had the longest median OS, while those with positive tumor PD-L1 expression/lower numbers of intraepithelial CD8⁺ TILs had the shortest median OS (p<0.001). Our results indicate that tumor PD-L1 expression in combination with intraepithelial CD8⁺ TILs infiltration has prognostic impact in patients with HGSOC. These biomarkers may be useful for the stratification of patients. Further evaluation of PD-1/PD-L1 as therapeutic targets for HGSOC is warranted.



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Attenuation of cyclosporine A induced nephrotoxicity by schisandrin B through suppression of oxidative stress, apoptosis and autophagy

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Qiao Lai, Zhengzhong Luo, Chunying Wu, Sisi Lai, Hanmei Wei, Tongming Li, Qing Wang, Yang Yu
Cyclosporine A (CsA) is a potent immunosuppressive agent whose clinical usage is limited by nephrotoxicity. Schisandrin B (SchB), isolated from the fruit of Schisandra chinensis, is a natural compound with multiple pharmacological activities that has been shown to attenuate organ injury caused by CsA. Hence, the primary objective of the current study was to evaluate whether SchB has a cytoprotective effect on CsA-induced nephrotoxicity in human proximal tubular epithelial cell line (HK-2). This study demonstrated that pre-incubation of HK-2 cells with 2.5–10.0μM SchB ameliorated CsA induced cytotoxicity caused by oxidative stress as evidenced by reduced levels of intracellular reactive oxygen species (ROS) and LDH release along with increased levels of mitochondrial membrane potential (ΔΨm) and glutathione (GSH). Also, it was demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) activation was involved in modulating cellular oxidative stress, where SchB promoted Nrf2 translocation into the nucleus and downstream target gene expression of heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and Glutamate-cysteine ligase modifier subunit (GCLM). Additionally, SchB was found to enhance cell survival via reducing apoptosis rate as well as recover the CsA induced blockade of autophagic flux. Collectively, these findings demonstrated that SchB mediated alleviation of CsA induced nephrotoxicity by preventing the accumulation of ROS by way of suppressing oxidative stress, apoptosis and autophagy.



http://ift.tt/2wrED0B

Epigallocatechin-3-gallate inhibits TLR4 signaling through the 67-kDa laminin receptor and effectively alleviates acute lung injury induced by H9N2 swine influenza virus

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Ming-ju Xu, Bao-jian Liu, Cun-lian Wang, Guo-hua Wang, Yong Tian, Shao-hua Wang, Jun Li, Pei-yao Li, Rui-hua Zhang, Dong Wei, Shu-fei Tian, Tong Xu
Epigallocatechin-3-gallate (EGCG) was found to inhibit the Toll-like receptor 4 (TLR4) pathway involved in influenza virus pathogenesis. Here, the effect of EGCG on TLR4 in an H9N2 virus-induced acute lung injury mouse model was investigated. BALB/c mice were inoculated intranasally with A/Swine/Hebei/108/2002 (H9N2) virus or noninfectious allantoic fluid, and treated with EGCG and E5564 or normal saline orally for 5 consecutive days. PMVECs were treated with EGCG or anti-67kDa laminin receptor (LR). Lung physiopathology, inflammation, oxidative stress, viral replication, and TLR4/NF-κB/Toll-interacting protein (Tollip) pathway in lung tissue and/or PMVECs were investigated. EGCG attenuated lung histological lesions, decreased lung W/D ratio, cytokines levels, and inhibited MPO activity and prolonged mouse survival. EGCG treatment also markedly downregulated TLR4 and NF-κB protein levels but Tollip expression was upregulated compared with that in untreated H9N2-infected mice (P<0.05). In PMVECs, anti-67LR antibody treatment significantly downregulated Tollip levels; however, the TLR4 and NF-κB protein levels dramatically increased compared with that in the EGCG-treated group (P<0.05). EGCG remarkably downregulated TLR4 protein levels through 67LR/Tollip, decreased MPO activity and inflammatory cytokine levels, supporting EGCG as a potential therapeutic agent for managing acute lung injury induced by H9N2 SIV.



http://ift.tt/2vwdTPc

Alpha-Mangostin protects rat articular chondrocytes against IL-1β-induced inflammation and slows the progression of osteoarthritis in a rat model

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Tianlong Pan, Dengying Wu, Ningyu Cai, Rong Chen, Xuchao Shi, Bin Li, Jun Pan
Osteoarthritis (OA) is a joint disease characterized by inflammation and cartilage degradation. α-Mangostin (α-MG), which can be isolated from the fruit of the tropical evergreen tree Garcinia mangostana-L, is known to have anti-inflammatory properties. The aim of the study was to investigate the use of α-MG in the treatment of OA, using both rat chondrocytes and an OA rat model induced by destabilization of the medial meniscus (DMM). Rat chondrocytes were pretreated with α-MG (0, 1.25, 2.5, and 5.0μg/ml for 24h) prior to stimulation with interleukin-1β (IL-1β) (10ng/ml for 24h). Nitric oxide (NO) production was determined using the Griess method and prostaglandin E2 (PGE2) was assessed using an enzyme-linked immunosorbent assay (ELISA). The expression of inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX-2), matrix metalloproteinase-3, -9, and -13 (MMP-3, MMP-9, and MMP-13), Collagen II, and Aggrecan were detected by both quantitative real-time PCR (qRT-PCR) and a western blot analysis. Nuclear factor-κB (NF-κB) signaling molecules were detected by western blot analysis. Detection of p65 nuclear translocation of NF-κB was examined using immunofluorescence staining. The OA rats received intraperitoneal injections of α-MG (10mg/kg) or saline every other day. Hematoxylin and eosin and Safranin-O-Fast green staining were used to evaluate the severity of cartilage lesions up to 8weeks following surgery. α-MG inhibited the production of NO and PGE2. The elevated expression of INOS, COX-2, MMP-3, MMP-9, and MMP-13, and the degradation of Collagen II and Aggrecan, were reversed by α-MG in IL-1β-stimulated chondrocytes. In addition, IL-1β induced considerable phosphorylation of the NF-kB signaling pathway, which was inhibited by α-MG. Furthermore, the immunofluorescence staining demonstrated that α-MG could suppress IL-1β-induced p65 nuclear translocation. In vivo, cartilage treated with α-MG showed attenuated degeneration and had low Osteoarthritis Research Society International (OARSI) scores compared with the control group. Taken together, these results show that α-MG has potential therapeutic value in the treatment of OA.



http://ift.tt/2wrDJB1

Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Zhi-Jun Liu, Jing Bai, Feng-Li Liu, Xiang-Yang Zhang, Jing-Zhang Wang
3BNC117, which was discovered in 2011, is a broadly neutralizing antibody (bNAb) and specifically neutralizes the human immunodeficiency virus type-1 (HIV-1) by targeting the CD4-binding site. This is the first comprehensive review that focuses on the role of 3BNC117 in the prevention of HIV-1 and acquired immune deficiency syndrome (AIDS). Briefly, 3BNC117 neutralizes many HIV/SHIV strains in vitro, blocks HIV-1 acquisition in animal models via a pre-exposure prophylaxis, alleviates HIV-1-associated viremia via a post-exposure therapeutic effect, prevents the establishment of latent HIV-1 reservoirs, and induces both humoral and cellular anti-HIV immune responses in vivo. The outcomes of Phase I and Phase IIa clinical trials in 2015 and 2016 showed the safety, tolerability, and therapeutic efficacy of 3BNC117 in HIV-1-infected human individuals. Nevertheless, anti-3BNC117 antibodies and HIV-1 strains resistant to 3BNC117 pose clinical challenges to immunotherapy with 3BNC117, so potential strategies for optimizing the potency of 3BNC117 are suggested here. Predictably, HIV-1 prevention and AIDS treatment will benefit from combinational immunotherapies with 3BNC117 and other pharmaceuticals (bNAbs, antiretroviral medicines, viral inducers, etc.) in the near future.

Graphical abstract

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Immunomodulatory effects induced by intramuscular administration of autologous total immunoglobulin G in patients with atopic dermatitis

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Su-Mi Cho, Myoung-Eun Kim, Byul Kwon, Dong-Ho Nahm
BackgroundPolyvalent human immunoglobulin G (IgG) preparations produced from the plasma pools of healthy blood donors have been used for the treatment of various autoimmune diseases and allergic diseases because of their anti-inflammatory and immunomodulatory effects. We hypothesized that intramuscular administration of autologous total IgG would induce immunomodulatory effects in patients with allergic diseases, based on the clinical efficacy of autologous blood therapy in patients with atopic dermatitis (AD).MethodsSixteen adult AD patients with IgE-mediated sensitization to the house dust mite (Dermatophagoides farinae) received intramuscular injections of 50 mg autologous total IgG twice a week for 4 weeks. The serum levels of IgE, IgG, and IgG4 antibodies to the recombinant group 2 major allergen of Dermatophagoides farinae (Der f 2) and serum levels of interleukin (IL)-10, IL-4, IL-12, and interferon gamma (IFN-γ) were measured by enzyme-linked immunosorbent assay at baseline and at weeks 4, 8, and 12.ResultsThe serum level of IgE antibodies to Der f 2 was significantly decreased at 12 weeks compared with baseline (p<0.005). The serum levels of IgG and IgG4 antibodies to Der f 2 were significantly increased at 4, 8, and 12 weeks compared with baseline (p<0.05). The serum levels of IL-10 and IFN-γ were significantly increased at 4, 8, and 12 weeks compared with baseline (p<0.05). There were no significant differences in the serum levels of IL-4 or IL-12 before and after intramuscular administrations of autologous total IgG (p>0.05).ConclusionIntramuscular administration of autologous total IgG induced anti-allergic immunomodulatory effects in AD patients. Further studies are required to evaluate the detailed immunological mechanism underlying these effects.



http://ift.tt/2wrFwWK

IL-17 contributes to the pathogenesis of obliterative bronchiolitis via regulation of M1 macrophages polarization in murine heterotopic trachea transplantation models

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Qingshu Meng, Jie Liu, Fang Lin, Luer Bao, Yuyu Jiang, Liang Zheng, Jinjun Tie, Lin Zhang, Xiaoting Liang, Lu Wei, Yuan Li, Huimin Fan, Xiaohui Zhou
Acute allograft rejection is a principal conundrum in lung obliterative bronchiolitis (OB). Monocytes/macrophages infiltration has been proved to be the main reason for acute rejection. IL-17 contributes to the recruitment and function of macrophages. However, the mechanism of IL-17 underlying OB progression remains elusive. In the present study, we showed that the deficiency of IL-17 attenuated the pathology of murine heterotopic trachea allografts. Compared to WT recipients, IL-17^−/− mice displayed higher frequency of CD206+ cells and lower ratio of CD86+ cells among F4/80+ macrophages in allografts and spleens on day 7 post heterotopic trachea transplantation. Moreover, mRNA levels of pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β decreased in allografts of IL-17^−/− recipients, but these of MRC1 and Arg-1 increased in comparison with WT. IL-17 deficiency can inhibit LPS induced M1 while promote IL-4 induced M2 polarization of bone marrow-derived macrophages. Further data demonstrated that the deficiency of IL-17 suppressed the lipopolysaccharide-induced M1 polarization and function through prevention of phosphorylation of both STAT3 and STAT5. Therefore, IL-17 contributes to OB pathogenesis through regulating macrophages function, thereby it may unravel part of the complexity of IL-17 in OB and enhance future therapeutic development.



http://ift.tt/2vwdRXA

Ethyl pyruvate reverses development of Pseudomonas aeruginosa pneumonia during sepsis-induced immunosuppression

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Wei Chen, Jie Lian, Jing-jing Ye, Qing-fei Mo, Jie Qin, Guang-liang Hong, Long-wang Chen, Shao-ce Zhi, Guang-ju Zhao, Zhong-qiu Lu
Sepsis is characterized by an innate immune response and the following immune dysfunction which can increase the emergence of secondary infections. Ethyl pyruvate (EP) has multiple immunoregulation functions in several serious illnesses, such as burn injury, severe sepsis and acute respiratory syndrome. However, little data was shown the effect of EP administration on immunosuppression post-CLP and the following secondary infection. The cecal ligation and puncture (CLP) followed by the induction of Pseudomonas aeruginosa (PA) was used as a clinically relevant two-hit model of sepsis. We assessed the survival rate, lung damage and lung bacterial clearance in vehicle or EP treatment group to demonstrate the lung response to Pseudomonas aeruginosa of septic mice. Then cytokines including lung IL-6, IL-1β, IL-10 and plasma HMGB1, apoptosis of splenic immune cells and Foxp3 level on regulatory T cells (Tregs) were studied to demonstrate the mechanisms of EP administration on two-hit mice. We found that the susceptibility of septic mice to Secondary Pseudomonas aeruginosa pneumonia could be down-regulated by ethyl pyruvate treatment and the protective effects of EP may via decreasing lung IL-10 and plasma HMGB1 expression, inhibiting the function of Tregs and relieving the apoptosis of splenic immune cells. The "immune paralysis" post-sepsis still remains a rigorous challenge for curing sepsis, our study may aid in the development of new therapeutic strategies to this problem.



http://ift.tt/2vOkaRu

The peroxisome proliferator-activated receptor pan-agonist bezafibrate suppresses microvascular inflammatory responses of retinal endothelial cells and vascular endothelial growth factor production in retinal pigmented epithelial cells

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Ayumi Usui-Ouchi, Yasuo Ouchi, Nobuyuki Ebihara
A randomized clinical trial showed the beneficial effects of the selective peroxisome proliferator-activated receptor (PPAR)-α agonist, fenofibrate, in reducing the progression of diabetic retinopathy independent of serum lipid levels. All subtypes of PPAR (PPAR-α, PPAR-γ, and PPAR-β/δ) have been reported to play a key role in microvascular inflammation and angiogenesis. Therefore, the agonistic function of fenofibrate against the PPAR-α has been suggested to contribute to its medicinal effect. Furthermore, bezafibrate is a fibrate drug commonly used as a lipid-lowering agent to treat hyperlipidemia and acts as a pan-agonist of all PPARs subtypes. However, the effects of bezafibrate in diabetic retinopathy remain unclear. Therefore, the purpose of this study was to investigate the effects of bezafibrate on retinal microvascular inflammation. Bezafibrate was not cytotoxic against human retinal microvascular endothelial cells (HRMECs) and human retinal pigment epithelial cells (ARPE-19 cells) treated with <100 and 200μM bezafibrate, respectively. In HRMECs, the expression levels of tumor necrosis factor (TNF)-α-induced monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 were significantly suppressed by bezafibrate in a dose-dependent manner. TNF-α-induced nuclear translocation of nuclear factor (NF)-κB p65 and cell migration were also significantly inhibited in bezafibrate-treated HRMECs. Furthermore, bezafibrate treatment significantly suppressed interleukin (IL)-1β-induced vascular endothelial growth factor (VEGF) production in ARPE-19 cells. These results suggest that bezafibrate has beneficial effects on retinal microvascular inflammation. Our study demonstrates the therapeutic potential of bezafibrate for managing diabetic retinopathy.



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Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

http://ift.tt/2etJb1C

Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

http://ift.tt/2etJb1C

SalivaPRINT Toolkit – Protein profile evaluation and phenotype stratification

Publication date: Available online 31 August 2017
Source:Journal of Proteomics
Author(s): Igor Cruz, Eduardo Esteves, Mónica Fernandes, Nuno Rosa, Maria José Correia, Joel P. Arrais, Marlene Barros
The value of the molecular information obtained from saliva is dependent on the use of in vitro and in silico techniques. The main proteins of saliva when separated by capillary electrophoresis enable the establishment of individual profiles with characteristic patterns reflecting each individual phenotype. Different physiological or pathological conditions may be identified by specific protein profiles. The association of each profile to the particular protein composition provides clues as to which biological processes are compromised in each situation. Patient stratification according to different phenotypes often within a particular disease spectrum is especially important for the management of individuals carrying multiple diseases and requiring personalized interventions. In this work we present the SalivaPRINT Toolkit, which enables the analysis of protein profile patterns and patient phenotyping. Additionally, the SalivaPRINT Toolkit allows the identification of molecular weight ranges altered in a particular condition and therefore potentially involved in the underlying dysregulated mechanisms. This tutorial introduces the use of the SalivaPRINT Toolkit command line interface (http://ift.tt/2vNY3ut) as an independent tool for electrophoretic protein profile evaluation. It provides a detailed overview of its functionalities, illustrated by the application to the analysis of profiles obtained from a healthy population versus a population affected with inflammatory conditions.Biological significanceWe present SalivaPRINT, which serves as a patient characterization tool to identify molecular weights related with particular conditions and, from there, find proteins, which may be involved in the underlying dysregulated cellular mechanisms. The proposed analysis strategy has the potential to boost personalized diagnosis. To our knowledge this is the first independent tool for electrophoretic protein profile evaluation and is crucial when a large number of complex electrophoretic profiles needs to be compared and classified.



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Performance on a clinical quadriceps activation battery is related to a laboratory measure of activation and recovery after total knee arthroplasty

Publication date: Available online 31 August 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Michael Bade, Tamara Struessel, Roger Paxton, Joshua Winters, Carol Baym, Jennifer Stevens-Lapsley
ObjectiveTo determine the relationship between performance on a clinical quadriceps activation battery (QAB) with 1) activation measured by doublet interpolation and 2) recovery of quadriceps strength and functional performance following total knee arthroplasty (TKA).DesignThis was a planned secondary analysis of a randomized controlled trialSettingUniversity research laboratoryParticipantsOne hundred sixty-two patients (aged 63 ± 7 (mean ± sd) years; 89 females) undergoing TKA participated.Outcome MeasuresPatients were classified as HIGH (QAB ≥ 4/6) or LOW (QAB ≤3/6) based upon performance on the QAB measured 4 days after TKA. Differences between groups in activation and recovery at 1, 2, 3, 6, and 12 months after TKA were compared using a repeated measures maximum likelihood model.ResultsThe LOW QAB group demonstrated poorer quadriceps activation via doublet interpolation (p=0.01), greater quadriceps strength loss (p=0.01), and greater functional performance decline (all p<0.001) at 1 month after TKA compared to the HIGH QAB group. Differences between LOW and HIGH QAB groups on all measures did not persist at 3 and 12 months (all p>0.05).ConclusionPoor performance on the QAB early after TKA is related to poor quadriceps activation and poor recovery in the early postoperative period. Patients in the LOW QAB group took 3 months to recover to the same level as the HIGH QAB group. The QAB may be useful in identifying individuals who need specific interventions to target activation deficits or different care pathways in the early postoperative period to speed recovery after TKA.



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Outcomes of Advanced Gastric Cancer Patients Treated with at Least Three Lines of Systemic Chemotherapy

AbstractBackground.Second‐line therapy has consistently demonstrated survival benefit if compared with best supportive care; however, there is limited evidence whether further lines of treatment may improve the prognosis of advanced gastric cancer (AGC) patients.Materials and Methods.Starting from a real‐world cohort of 868 AGC patients, we retrospectively analyzed baseline parameters, tumor characteristics, and treatment data of those treated with at least three lines. Categorical features were described through cross‐tables and chi‐square test. We explored the impact of treatment intensity and progression‐free survival (PFS) experienced in previous lines on PFS and overall survival in third‐line by uni‐ and multivariate Cox regression models and described by Kaplan‐Meier estimator plot with log‐rank test.Results.Overall, 300 patients were included in the analysis. The most common site of primary tumor was gastric body; 45.3% of cancers had an intestinal histotype, 14% were human epidermal growth receptor 2 positive. In third‐line, 45.7% of patients received a single‐agent chemotherapy, 49.7% a combination regimen. Patients who had experienced a first‐line PFS ≥6.9 months had a better prognosis compared with those who had achieved a shorter one. Consistently, a second‐line PFS ≥3.5 months positively influenced the prognosis. Patients receiving a third‐line combination regimen had better outcomes compared with those treated with a single‐agent chemotherapy.Conclusion.Our real‐world study confirms that selected AGC patients may receive third‐line treatment. Longer PFS in previous lines or a more intense third‐line treatment positively influenced prognosis. Further efforts are warranted to define the best therapeutic sequences, and to identify the optimal candidate for treatment beyond second‐line.Implications for Practice.The benefit of third‐line treatment to advanced gastric cancer patients is controversial. Our study depicts a real scenario of the clinical practice in Italy, confirming that a non‐negligible proportion of patients receive a third‐line therapy. Longer progression‐free survival in previous treatment lines or higher third‐line treatment intensity positively influenced prognosis. Including a large number of real‐world patients, our study provides information on third‐line treatment from the daily clinical practice; moreover, its results help in defining the best therapeutic sequence and offer some hints to select the optimal candidate for treatment beyond second‐line.

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Improved Detection of Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasms

AbstractBackground.Recent work has demonstrated early shedding of circulating epithelial cells (CECs) from premalignant intraductal papillary mucinous neoplasms (IPMNs). However, the potential use of CECs as a "liquid biopsy" for patients with IPMNs has been limited by antigen dependence of CEC isolation devices and the lack of robust detection biomarkers across CEC phenotypes.Materials and Methods.We utilized a negative depletion microfluidic platform to purify CECs from contaminating leukocytes and coupled this platform with immunofluorescence, RNA in situ hybridization, and RNA sequencing (RNA‐seq) detection and enumeration.Results.Using established protein (EpCAM, cytokeratins) and novel noncoding RNA (HSATII, cytokeratins) biomarkers, we detected CECs in 88% of patients bearing IPMN lesions. RNA‐seq analysis for MUC genes confirm the likely origin of these CECs from pancreatic lesions.Conclusion.Our findings increase the sensitivity of detection of these cells and therefore could have clinical implications for cancer risk stratification.Implications for Practice.This work describes a high‐sensitivity platform for detection of epithelial cells shed from preneoplastic lesions at high risk of malignant transformation. Further research efforts are underway to define the transcriptional programs that might allow discrimination between circulating cells released from tumors that will become malignant and cells released from tumors that will not. After further refinement, this combination of technologies could be deployed for monitoring and early detection of patients at high risk for developing new or recurrent pancreatic malignancies.

http://ift.tt/2wn0qIo

Next‐Generation Sequencing for Patients with Sarcoma: A Single Center Experience

AbstractBackground.Sarcomas comprise over 50 subtypes of mesenchymal cancers. For the majority of sarcomas, the driver mutations remain unknown. In this article, we describe our experience with a targeted next‐generation sequencing (NGS) platform in clinic patients.Materials and Methods.We retrospectively analyzed results of NGS using 133 tumor samples from patients diagnosed with a variety of sarcomas that were analyzed with targeted NGS covering over 400 cancer‐related genes (405 DNA, 265 RNA) on a commercially available platform.Results.An average of two gene alterations were identified per tumor sample (range 0–14), and a total of 342 DNA mutations were detected. Eight‐eight percent of samples had at least one detected mutation. The most common mutations were in the cell cycle, including TP53 (n = 35), CDKN2A/B (n = 23), and RB1 (n = 19). Twenty‐seven PI3‐kinase pathway alterations were observed, including PTEN (n = 14), PIK3Ca (n = 4), TSC1 (n = 1), TSC2 (n = 3), STK11 (n = 1), mTOR (n = 3), and RICTOR (n = 2). There were 75 mutations in genes that are targetable with existing drugs (excluding KIT in gastrointestinal stromal tumor) that would allow enrollment onto clinical trials. In general, the estimated tumor mutation burden was low, in particular for those with disease‐defining gene fusions or genetic alterations. Microsatellite instability (MSI) data were available for 50 patients, and all were MSI stable.Conclusion.Our study describes a single‐center experience with targeted NGS for patients with sarcoma. Mutations were readily detected and 75 (representing 40% of patients) were testable for therapeutic effect using existing drugs within the confines of a clinical trial. These data indicate that targeted NGS is a useful tool in potentially routing patients to mutation‐specific clinical trials. Further study will be required to determine if these mutations are clinically meaningful drug targets in sarcoma.Implications for Practice.The sarcomas are a heterogenous family of over 50 different mesenchymal tumors. Current practice for metastatic disease involves systemic chemotherapy or nonspecific kinase inhibitors such as pazopanib. Sarcomas typically lack the classic kinase alterations seen in many carcinomas. The role of next‐generation sequencing in sarcoma clinical practice remains undefined.

http://ift.tt/2vO99j6