Multiparametric MR imaging of the Prostate

Publication date: Available online 16 December 2017
Source:Radiologic Clinics of North America
Author(s): Stephen Thomas, Aytekin Oto

Teaser

Multiparametric MR imaging is widely embraced for the diagnosis, staging, and surveillance of prostate cancer. However, normal anatomic structures and many benign entities have overlapping imaging features with prostate cancer. Although some of these entities require biopsy and histopathologic diagnosis, some have characteristic imaging features that are suggestive of their diagnosis. Knowledge of these pitfalls is important in establishing a correct diagnosis and avoiding unnecessary biopsies, as these entities are encountered routinely in clinical practice.


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Prostate MR Imaging

Publication date: Available online 16 December 2017
Source:Radiologic Clinics of North America
Author(s): Aytekin Oto




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Circulating tumour DNA, a promising biomarker for the management of colorectal cancer

Publication date: Available online 16 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Shelize Khakoo, Alexandros Georgiou, Marco Gerlinger, David Cunningham, Naureen Starling
Circulating cell free tumour DNA (ctDNA) maintains the same genomic alterations that are present in the corresponding tumour, thereby allowing for quantitative and qualitative real-time evaluation in body fluids as an alternative to onerous repeat biopsies. Improvements in the sensitivity of techniques used to identify ctDNA has led to a surge of research investigating its role in the detection of: early disease, relapse, response to therapy and emerging drug resistance mechanisms. Following curative surgery, ctDNA detection is a promising marker of minimal residual disease and could better select patients for adjuvant chemotherapy. Longitudinal monitoring could help identify early relapse. In metastatic disease, ctDNA can predict response to chemotherapy prior to evidence of disease progression on imaging and investigate novel primary and acquired resistance mechanisms to targeted therapies. More experience in detecting, analysing and interpreting ctDNA within prospective trials, will better define its role for implementation into routine clinical practice.



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A SYSTEMATIC REVIEW OF THE SAFETY PROFILE OF THE DIFFERENT COMBINATIONS OF FLUOROPYRIMIDINES AND OXALIPLATIN IN THE TREATMENT OF COLORECTAL CANCER PATIENTS

Publication date: Available online 16 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Chiara Baratelli, Clizia Zichi, Massimo Di Maio, Maria Pia Brizzi, Cristina Sonetto, Giorgio Vittorio Scagliotti, Marco Tampellini
The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities.The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of "any-grade" and "severe" toxicity for haematological and non-haematological adverse events of each group.We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy.This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity.



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Design, synthesis, and evaluation of polyamine-memantine hybrids as NMDA channel blockers

Publication date: Available online 16 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Takuya Kumamoto, Marie Nakajima, Reina Uga, Naoko Ihayazak, Haruna Kashihara, Kazuaki Katakawa, Tsutomu Ishikawa, Ryotaro Saiki, Kazuhiro Nishimura, Kazuei Igarashi
N-Methyl-D-aspartate (NMDA) receptors have been implicated in learning and memory, and may also play a central role in various conditions leading to neuronal degradation. NMDA receptor antagonists could therefore be of therapeutic benefit for a number of neurological disorders. We have designed hybrid compounds of polyamines and memantine, both of which function as NMDA channel blockers. The triamine derivative with a guanidine moiety showed more potent antagonistic activity than memantine.

Graphical abstract

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Supported carbon dots serve as high-performance adsorbent for the retention of trace cadmium

Publication date: 1 April 2018
Source:Talanta, Volume 180
Author(s): Yi-Kun Li, Ting Yang, Ming-Li Chen, Jian-Hua Wang
Carbon dots were prepared via a one-pot hydrothermal route, and a new solid-phase extraction (SPE) adsorbent was developed by immobilizing the carbon dots on the microcarrier cytopore, shortly termed as C-dots@cytopore. The C-dots@cytopore composites were characterized by means of FT-IR, SEM, XPS and fluorescence spectrometry. The performance of the composites for the adsorption of heavy metals was thoroughly evaluated by using cadmium as a model. The binding of cadmium on C-dots@cytopore fits Langmuir adsorption, and the adsorption dynamic follows pseudo-second-order adsorption kinetics model. The binding of cadmium was pH-dependent, with a maximum adsorption capacity of 2420μgg⁻¹ obtained at pH 4–7. A novel separation and preconcentration procedure was thus developed for trace cadmium using the C-dots@cytopore composites as SPE sorbent. The retained cadmium could be readily eluted and recovered by a 0.1molL⁻¹ HNO3 solution and further quantified with graphite furnace atomic absorption spectrometry (GFAAS). With a sample volume of 1.0mL, an enrichment factor of 17.85 was obtained with a detection limit of 1.8ngL⁻¹ and a RSD value of 2.6% at 0.1μgL⁻¹ (n = 9). The procedure was further validated by analyzing cadmium in certified reference materials and a series of environmental water samples.

Graphical abstract

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Preliminary survey of matrix effects in the Microwave-sustained, Inductively Coupled Atmospheric-pressure Plasma (MICAP)

Publication date: 1 April 2018
Source:Talanta, Volume 180
Author(s): Klemens M. Thaler, Andrew J. Schwartz, Christoph Haisch, Reinhard Niessner, Gary M. Hieftje
Matrix effects caused by Na and Al in the nitrogen Microwave-sustained, Inductively Coupled, Atmospheric-pressure Plasma (MICAP) were investigated. Easily ionizable elements, such as Na, can suppress or enhance the analyte signal; Al is shown here to produce a similar effect. The influence of these matrices was examined for 18 emission lines of 8 analyte atoms and ions having a wide range of excitation and ionization energies. The plasma operating conditions were fixed during all experiments at a total nitrogen flow of 19.4Lmin⁻¹ and a microwave power of 1.5kW. An Fe solution was used to determine the excitation temperature of the plasma by the Boltzmann plot method at selected matrix concentrations. In addition, vertical emission profiles of the plasma were measured. The matrix effect becomes worse at higher concentrations of an easily ionizable element. The effect is caused not only by a shift in ionization equilibrium but also by a possible change in plasma ionization temperature. Correction methods to reduce the matrix effects were tested and are discussed.

Graphical abstract

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Turn-on fluorescent sensor for the detection of glucose using manganese dioxide−phenol formaldehyde resin nanocomposite

Publication date: 1 April 2018
Source:Talanta, Volume 180
Author(s): Zhong Feng Gao, Asmerom Yohannes Ogbe, Ei Ei Sann, Xudong Wang, Fan Xia
Monitoring blood glucose has attracted considerable attention because diabetes mellitus is a global public health problem. Herein, we reported a turn-on fluorescence detection strategy based on manganese dioxide (MnO2)-phenol formaldehyde resin (PFR) nanocomposite for rapid, sensitive, and selective detection of glucose levels in human blood. In this biosensing system, MnO2 nanoshell on the PFR nanoparticle surfaces serve as a quencher. PFR fluorescence can make a recovery in the presence of H2O2, reducing MnO2 to Mn²⁺. The sensor shows a linear range from 50nM to 90μM with a low detection limit of 20nM for H2O2 detection. Thus, the glucose can be detected on the basis of the enzymatic conversion of glucose by glucose oxidase to produce H2O2. This method exhibits a wide linear range from 5μM to 1mM with a low detection limit of 1.5μM. Because of the excellent photostability offered by PFR, the developed strategy has been successfully applied for the diagnosis of diabetes mellitus in human blood samples. Compared with commercial glucometer, our method showed satisfactory results, indicating the significant reliability. The developed turn-on fluorescent sensor might hold great promise in nanomedicine and bioanalysis.

Graphical abstract

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Theta-burst modulation of mid-ventrolateral prefrontal cortex affects salience coding in the human ventral tegmental area

Publication date: 1 April 2018
Source:Appetite, Volume 123
Author(s): Martin Ulrich, Sabrina Lorenz, Markus W. Spitzer, Leon Steigleder, Thomas Kammer, Georg Grön
In the context of hedonic (over-)eating the ventral tegmental area (VTA) as a core part of the dopaminergic reward system plays a central role in coding incentive salience of high-caloric food. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate whether transcranial magnetic theta-burst stimulation (TBS) over the right mid-ventrolateral prefrontal cortex (mid-VLPFC) can induce modulation of calorie-sensitive brain activation in the VTA. The prefrontal location for TBS had been predetermined by seed-based resting-state fMRI with a functionally defined portion of the VTA serving as seed region obtained from an independent second fMRI experiment. In a sample of 15 healthy male participants, modulation of calorie-sensitive VTA activation did not significantly differ between the two TBS protocols. Comparisons with baseline revealed that both TBS protocols significantly affected calorie-sensitive neural processing of the mid-VLPFC in a rather similar way. In the VTA significant modulation of calorie-sensitive activation was observed after continuous TBS, whereas the modulatory effect of intermittent TBS was less reliable but also associated with a decrease of activation for high-caloric food images. Neurostimulation of right mid-VLPFC is suggestive as a main entry point of downstream signal changes for high- and low-caloric food cues that could enforce a shift in valuating stimuli of initially different incentive salience.



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The effect of gender, age and product type on the origin induced food product experience among young consumers in Finland

Publication date: 1 April 2018
Source:Appetite, Volume 123
Author(s): Tommi Kumpulainen, Annukka Vainio, Mari Sandell, Anu Hopia
Locally produced and sourced food products are gaining popularity among consumers. The effect of the expectations induced by the origin of the food was studied with 1491 consumers in two separate studies among different age groups. In order to test the consumer response to the product origin neutral, domestic, and local conditions were used. Consumers evaluated the product's pleasantness, their probability to choose it, the overall quality, and their willingness to pay. To gather information on whether the phenomenon was consistent, independent from the product category, three different types of products were tested (meat, bread, and vegetables). Our results show that a closer origin does not necessarily produce a positive response, but that there are several moderating factors such as gender, age, and product type. Female university students responded equally to domestic and local origins in the case of bread, but for meat products, only those of local origin induced a positive reaction. In this study population, the male respondents only reacted to a local origin in the case of bread, while domestic meat products provided similar results to local origins. Among young men consumers in the 7th-9th grades responded to the local origin of vegetables positively, while others among the youngest consumers, the origin did not induce a significant effect. The results indicate that even when the product is not appealing itself, locality can still increase the perceived quality.



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Toward new forms of meal sharing? Collective habits and personal diets

Publication date: 1 April 2018
Source:Appetite, Volume 123
Author(s): Estelle Masson, Sandrine Bubendorff, Christèle Fraïssé
This article sheds light on the fact that the commensality remains a fundamental aspect of eating in French culture. However, at the same time, the expansion of the individualisation and medicalisation of the act of eating during the latest decades impacted the social representations of food.We will first place dietary practices into a general context in which the relationship to food tends to be individualised and in which health-related issues remain an important aspect of the discourse about food on internet.Secondly, we will examine how these practices are (in)compatible with the defining dimensions of the French food model, in particular those relating to commensality (the practice of eating together) and food sharing.It seems that although a personalised diet restricts the objective possibilities of food sharing, it is still central in representations of food and, in some cases, leads to the emergence of associated practices to introduce new forms of social eating behaviours, such as those made possible by the spread of the Internet.



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Editorial Board

Publication date: 1 February 2018
Source:Appetite, Volume 121





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Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila

Publication date: April 2018
Source:Current Opinion in Neurobiology, Volume 49
Author(s): Paola Cognigni, Johannes Felsenberg, Scott Waddell
When animals learn, plasticity in brain networks that respond to specific cues results in a change in the behavior that these cues elicit. Individual network components in the mushroom bodies of the fruit fly Drosophila melanogaster represent cues, learning signals and behavioral outcomes of learned experience. Recent findings have highlighted the importance of dopamine-driven plasticity and activity in feedback and feedforward connections, between various elements of the mushroom body neural network. These computational motifs have been shown to be crucial for long term olfactory memory consolidation, integration of internal states, re-evaluation and updating of learned information. The often recurrent circuit anatomy and a prolonged requirement for activity in parts of these underlying networks, suggest that self-sustained and precisely timed activity is a fundamental feature of network computations in the insect brain. Together these processes allow flies to continuously adjust the content of their learned knowledge and direct their behavior in a way that best represents learned expectations and serves their most pressing current needs.



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The significant prognostic value of circulating tumor cells in colorectal cancer: A systematic review and meta-analysis

Publication date: Available online 29 November 2017
Source:Current Problems in Cancer
Author(s): Yi Tan, Hao Wu
BackgroundCirculating tumor cell (CTC) is a promising candidate biomarker for detection, monitoring and survival prediction of colorectal cancer (CRC). However, the prognostic significance of CTCs in CRC is currently under debate. Here, we performed a meta-analysis to assess the prognostic value of CTC for patients diagnosed with CRC.MethodsA comprehensive literature research had been performed in the Pubmed, Embase Databases, Cochrane Library, Elsevier Science Direct and China National Knowledge Internet for studies reporting prognostic data of CTCs in CRC patients since December 2016. The main outcome measures were overall survival (OS) and progression-free survival (PFS). The hazard ratio (HR) and 95 % confidence interval (95 % CI) were considered to be the effect measures. Subgroup and sensitivity analyses were also performed. We pooled in meta-analysis under a fixed-effect or random-effect model according to heterogeneity.Resultsfifteen published studies containing 3129 patients matched the selection criteria were included in this meta-analysis. Overall analyses revealed that the presence of CTCs was significantly associated with poor mortality (OS: HR 2.36, 95 % CI: [1.87–2.97]; p = 0.006) along with aggressive disease progression (PFS: HR 1.83, 95 % CI: [1.42–2.36]; p < 0.00001). Further subgroup analyses demonstrated that CTC-positive patients also had poor overall survival and disease progression in different subsets, including differences in time points of blood collection, detection methods, median follow-up month and cut-off value of CTC.ConclusionMeta-analysis provides a strong evidence that the presence of CTCs was an independent prognosticator of poor survival outcomes for patients with CRC.



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Breast cancer and synchronous multiple myeloma as a diagnostic challenge: Case report and review of literature

Publication date: Available online 22 November 2017
Source:Current Problems in Cancer
Author(s): Marcin Sokołowski, Grzegorz Mazur, Aleksandra Butrym
Multiple myeloma is a hematological malignancy, which sometimes creates difficulties in diagnosis, based on the presence of monoclonal protein in serum/urine and plasmocyte infiltration in the bone marrow, and on the other hand, synchronous cancers are also a diagnostic challenge. We present a case report of a patient with concurrent breast cancer and multiple myeloma.A 68-year-old woman was admitted to the hospital with diagnosis of left breast cancer in first stage of the disease. In the past, she had had several episodes of thrombocytopenia, leucocytosis, and mild anaemia, which were followed by hematologist in outpatient setting. She was operated and started adjuvant chemotherapy. During treatment, episodes of hematological abnormalities were observed. After completion of the chemotherapy for breast cancer, the patient was observed and short time after that multiple myeloma was diagnosed as a synchronous cancer. Patient was first treated for breast cancer, then subsequently for multiple myeloma (2 lines therapy: CTD and VMP). We describe diagnostic problems with multiple myeloma; however, they could be caused by curation of breast cancer, which might have supressed the proliferation of plasmocytes and could delay the diagnosis. All symptoms of multiple myeloma were interpreted as a secondary effect of chemotherapy. Review of the literature shows the clinical approaches in such situations.



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Hepatocellular carcinoma in the era of immunotherapy

Publication date: Available online 3 November 2017
Source:Current Problems in Cancer
Author(s): Hao-Wen Sim, Jennifer Knox
Hepatocellular carcinoma is a common malignancy which usually emerges on a background of chronic liver disease. Unfortunately, with contemporary management, patients with advanced hepatocellular carcinoma have few treatment options, and prognosis is poor. The emergence of immunotherapy has afforded new therapeutic opportunities. This article reviews the clinical evidence for immunotherapy in advanced hepatocellular carcinoma and presents ideas for future drug development.



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Locally advanced pancreatic cancer: An emerging entity

Publication date: Available online 3 November 2017
Source:Current Problems in Cancer
Author(s): Grainne M. O′Kane, Jennifer J. Knox
Pancreatic adenocarcinoma (PDAC) remains a highly fatal disease that is increasing in incidence. PDAC can be classified according to resectability status with 3 nonmetastatic groups defined: resectable, borderline resectable, and locally advanced PDAC (LAPC). Delineating these subtypes is important with the optimal treatment approach dictated by high-quality CT imaging and multidisciplinary team discussion. Patients with LAPC are thought unresectable and are therefore rarely cured. In these patients, chemotherapy remains the mainstay of treatment. Aggressive approaches in this cohort are increasingly employed. Local therapies after induction chemotherapy including standard fractionation radiation, stereotactic body radiotherapy (SBRT), and irreversible electroporation (IRE) are being investigated in an attempt to improve long-term control. In some cases, responses to neoadjuvant therapy may facilitate surgical resection. Biomarkers that can select patients most likely to benefit from these options are urgently needed. This review aims to highlight the emerging treatment of patients with LAPC and to discuss current trials.



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Is the limit of 60mg of oral morphine equivalent daily dose still actual for the access to rapid onset opioids therapy?

Publication date: Available online 2 November 2017
Source:Current Problems in Cancer
Author(s): Luca Miceli, Rym Bednarova, Luigi Vetrugno, Marco Cascella, Arturo Cuomo




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Meta-analysis of safety and efficacy of rolapitant, NK-1 receptor antagonist for prevention of chemotherapy induced nausea and vomiting☆☆

Publication date: Available online 6 December 2017
Source:Current Problems in Cancer
Author(s): Hussien Ahmed, Ali Mohamed Hammad, Abdelrahman Ibrahim Abushouk, Mohamed Zidan, Mohamed Salem, Ahmed Negida, Mohamed M. Abdel-Daim
Although chemotherapeutic agents represent a cornerstone of cancer treatment, chemotherapy-induced nausea and vomiting (CINV) is one of the most disturbing hazards of cytotoxic therapy that affects the patients' quality of life and basic daily activities. Rolapitant is a novel selective neurokinin-1 receptor antagonist (NK-1 RA), which was clinically approved for prevention of CINV. The aim of the present study is to synthesize evidence about the safety and efficacy of rolapitant in combination with other antiemetic agents for prophylaxis against CINV. We performed a web-based literature search of six authentic databases to identify eligible studies. Safety and efficacy endpoints were extracted and pooled as odds ratios (ORs) in a fixed-effect meta-analysis model, using Comprehensive Meta-Analysis software for windows. Five randomized controlled trials (n=2984) were pooled in the final analysis. Rolapitant (180mg) in combination with a serotonin-3 (5-HT3) receptor antagonist and dexamethasone was superior to placebo plus 5-HT3 receptor antagonist and dexamethasone in term of complete response rate in the acute (OR 1.4, 95% CI [1.16, 1.7]) and the delayed phases (OR 1.68, 95% CI [1.44, 1.96]. Moreover, rates of complete protection were significantly higher with rolapitant 180mg group than placebo in the overall, acute, and delayed phases (OR 1.52, 95% CI [1.3, 1.76]), OR 1.24, 95% CI [1.04, 1.49], OR 1.5, 95% CI [1.29, 1.75]), respectively. It could be concluded that, Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and more effective than 5-HT3 receptor antagonist plus dexamethasone and placebo for the prevention of CINV.



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Title Page

Publication date: November–December 2017
Source:Current Problems in Cancer, Volume 41, Issue 6





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Information for Readers

Publication date: November–December 2017
Source:Current Problems in Cancer, Volume 41, Issue 6





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Table of Contents

Publication date: November–December 2017
Source:Current Problems in Cancer, Volume 41, Issue 6





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Familial Colorectal Cancer Type X (FCCTX) and the correlation with various genes—A systematic review

Publication date: November–December 2017
Source:Current Problems in Cancer, Volume 41, Issue 6
Author(s): Mahdieh Nejadtaghi, Hamideh Jafari, Effat Farrokhi, Keihan Ghatreh Samani
Familial Colorectal Cancer Type X (FCCTX) is a type of hereditary nonpolyposis colorectal cancer in accordance to Amsterdam criteria-1 for Lynch syndrome, with no related mutation in mismatch repair gene. FCCTX is microsatellite stable and is accounted for 40% of families with Amsterdam criteria-1 with a high age of onset. Thus, the carcinogenesis of FCCTX is different compared to Lynch syndrome. In addition to the microsatellite stability and the presence of less predominant tumors in proximal colon, various clinical features have also been associated with FCCTX in comparison with Lynch syndrome such as no increased risk of extra-colonic cancers, older age of diagnosis and higher adenoma/carcinoma rate. Genetic etiology of this type of cancer which is autosomal dominant is unknown. In this review, we focus on the genes and their variants identified in this type of CRC. In order to find out the correlation between FCCTX and various genes database such as PubMed and PMC, search engine such as Google scholar and portals such as Springer and Elsevier have been searched. Based on our literature search, several studies suggest that FCCTX is a heterogeneous type of disease with different genetic variants. Recent studies describe the correlation between FCCTX and genes such as BRCA2, SEMA4, NTS, RASSF9, GALNT12, KRAS, BRAF, APC, BMPR1A, and RPS20. Considering the fact that BRCA2 has the highest mutation rate (60%) and is one of the most crucial DNA repair genes, it will be considered as a big role player in this type of cancer in comparison with other genes.



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Anti-PD1/PDL1 induced psoriasis

Publication date: November–December 2017
Source:Current Problems in Cancer, Volume 41, Issue 6
Author(s): Dimitra Voudouri, Vasiliki. Nikolaou, Konstantinos Laschos, Andriani Charpidou, Nikolaos Soupos, Ioanna Triantafyllopoulou, Ioanna Panoutsopoulou, Gerasimos Aravantinos, K. Syrigos, A. Stratigos
BackgroundImmune checkpoint inhibitors are novel agents approved for the treatment of late-stage malignancies. Despite its important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects known as immune-related adverse events. Skin toxicities are the most frequent immune-related adverse events during anti-PD1 blockade therapies. Among them, rare cases of psoriasis exacerbation have been reported.MethodsWe present the clinical characteristics of exacerbated psoriasis in 5 patients under anti-PD1/PDL1 therapy.ResultsA total of 5 patients were overall included (4 males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1 (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a strong related family history (3/5 siblings). Four out of 5 patients experienced guttate lesions, though the most severe exacerbation was noted in the durvalumab group. Four out of 5 patients managed to continue treatment after close dermatologic monitoring, whereas 1 patient under durvalumab was forced to treatment delays owing to the severity of the skin reactions. Skin rashes appeared in all patients after the fourth cycle of immunotherapy.ConclusionsBoth anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although more severe flares were noted in patients treated with durvalumab. Not only personal but also related family history of psoriasis are significant risk factors and need to be outlined before treatment initiation. If such related history exists, strict skin surveillance can lead to the early diagnosis and treatment of any psoriatic exacerbations that could otherwise severely affect quality of life or even compromise therapeutic protocols and final prognosis.



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Complications in the treatment of mandibular condylar fractures: Surgical versus conservative treatment

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Iván García-Guerrero, Juan M. Ramírez, Rafael Gómez de Diego, José M. Martínez-González, María S. Poblador, José L. Lancho
ObjectivesIn the present article, we aim to review the main intra- and post-operative complications associated with two different therapeutic approaches for treating mandibular condylar fractures: conservative (CTR) and surgical treatment (ORIF, Open Reduction and Internal Fixation).Material and methodsWe have carried out a retrospective, meta-analytic, observational study using literature review, covering the period between 2000- September 2017. The data obtained were processed using statistical software SPSS v.0.18 and R v.2.11.1. The chi-squared test was used for comparison of relative frequencies for independent samples.ResultsA total of 2458 patients with 2810 fractures were collected for study. Patients treated with CTR and ORIF were an average of 29 years old, of those treated with CTR, 72.37% and 27.63% were male or female respectively and, of those treated with ORIF, 70.36% and 29.64% were male or female respectively. The main complications suffered by CTR and ORIF patients were: asymmetry (10.2%/6.4%), residual pain (6.5%/5.6%), temporomandibular joint and articular imbalance (15.9%/10.3%) and malocclusion (11.1%/4.0%), respectively. We only found significant differences between CTR and ORIF in the number of cases of temporomandibular joint and articular imbalance and malocclusion.Facial nerve damage was found exclusively among ORIF patients (8.6%) of which 8.3% were temporary and 0.3% permanent.ConclusionsThe complications associated with either technique are minimal and infrequent, resulting in successful outcomes with minimal morbidity. CTR are associated with complications deriving from delayed mobilization leading to functional limitation, whereas the main complication associated with ORIF treatment was facial nerve damage.



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Effect of different resistance-training protocols on the extracellular matrix of the calcaneal tendon of rats

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Josete Mazon, Andrea Aparecida de Aro, Priscyla Waleska Simões, Edson Rosa Pimentel
The calcaneal tendon extracellular matrix (ECM) is composed of collagen, non-collagenous glycoproteins and proteoglycans, and able to adapt to various biomechanical stimuli. The objective of this study was to analyze the response of different resistance-training protocols, such as hypertrophy, strength and resistance, on the organization of the calcaneal tendon after training. Wistar rats were divided into four groups: untrained (UT), resistance training (RT), hypertrophy training (HT), and strength training (ST). The protocol in a vertical climbing platform was performed thrice per week over twelve weeks. For biochemical study, the tendons of each group were minced and analyzed for gelatinases, quantification of non-collagenous proteins, sulfated glycosaminoglycans, and hydroxyproline. For morphological analysis, sections were stained with HE and toluidine blue. Non-stained sections were used for birefringence analysis under polarization microscopy. The highest hydroxyproline concentrations were found in HT (154.8±14.2) and RT (173.6±25.2) compared with UT (122.4±27.0). A higher concentration of non-collagenous proteins was detected in the RT group (14.98mg/g) compared with the other groups. In polarization microscopy, major birefringence was observed in HT and the lowest in ST compared with UT, indicating higher organization of collagen bundles in HT. In analysis for zymography, the presence of latent MMP-9 was more prominent in the ST group and the active MMP-9 more prominent in the HT group. For MMP-2, significant differences in the latent isoform between the HT (184,867±6765) and UT (173,018±9696) groups were found. In sections stained with toluidine blue (TB), higher metachromasia was observed in the tendon's distal region in HT and RT groups, indicating a greater amount of proteoglycans. We conclude that the different training protocols produced different responses in the ECM. The remarkable presence of MMP-2 and -9 in the hypertrophy training group may be related to the highest organization of collagen bundles and possibly a more efficient remodeling process, observed in that group, as demonstrated by images and measurements of birefringence.



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Editorial Board

Publication date: January 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 215





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OBC

Publication date: January 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 215





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Ultrasound assessment of soft tissue augmentation around implants in the aesthetic zone using a connective tissue graft and xenogeneic collagen matrix - 1-year randomised follow-up

Publication date: Available online 15 December 2017
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Monika Puzio, Artur Błaszczyszyn, Jakub Hadzik, Marzena Dominiak
PurposeA comparative, ultrasound evaluation of the thickness of keratinized mucosa (TKT) around implants one year after gingival augmentation (GA) by means of a connective tissue graft (CTG) and the xenogeneic collagen matrix (CMX).Materials and methodsA total of 75 bone level tapered implants (Conelog^® Camlog) were inserted in 57 patients in the aesthetic area of both jaws. The patients were divided into 3 groups: control group I- without GA; group II- GA 3 months before implantation, and group III- GA 3 months after implantation. Groups II and III were divided into two subgroups depends on type of material used for GA: a) CMX (Mucograft^®, Geistlich Pharma AG) and b) CTG. The patients underwent a clinical and ultrasound examination before, then after 3 and 12 months following GA respectively to evaluate TKT at two points using ultrasound equipment (Pirop^®, Echoson). Point 1 was considered to be in the middle of the line connecting the cemento-enamel junction (CEJ) to the adjacent teeth, and point 2 on the mucogingival junction (MGJ).ResultsThree months after GA, the highest increase in gingival thickness was noted in group IIIb (point 1-0.95mm, 2- 1.01mm). However, 12 months after GA the highest gingival thickness was observed in group IIb (point 1- 1.76mm, 2- 1.36m) and next IIIb (point 1- 1.52mm, 2- 1.15mm).ConclusionsBoth CTG and Geistlich Mucograft^® increased TKT, but higher values were noted using CTG augmentation before implantation. An ultrasonic device can be used as a non-invasive, reliable, and reproducible method for evaluating TKT.



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Distribution and neurochemistry of porcine urinary bladder-projecting sensory neurons in subdomains of the dorsal root ganglia: a quantitative analysis

Publication date: Available online 21 November 2017
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Anna Kozłowska, Anita Mikołajczyk, Mariusz Majewski
The aim of the present study has been to verify the inter- and intraganglionic distribution pattern of porcine urinary bladder-projecting (UBP) neurons localized in the sacral dorsal root ganglia (DRGs). The morphology and chemical phenotype of these cells have also been investigated. These neurons were visualized using the fluorescent tracer Fast Blue (FB) which was injected bilaterally into the urinary bladder wall of five juvenile female pigs. The intraganglionic distribution showed that small- and medium-sized FB+ perikarya were mainly located in the central (S3-S4) and periphero-central (S2) region of the ganglia, while large cells were heterogeneously distributed. Immunohistochemistry revealed that the most frequently observed markers in small and medium-sized UBP perikarya were: neurofilament 200, lectin from Bandeiraea simplicifolia (Griffonia simplicifolia) isolectin B4, substance P, calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide and transient receptor potential vanilloid 1. Moreover, UBP neurons containing these substances were also mainly observed in the central and periphero-central region of the ganglion. Differences in the percentage of traced cells and their neuropeptide content were observed between the S2, S3 and S4 DRGs. In conclusion, the present study, for the first time, describes the arrangement of UBP DRGs neurons within particular subdomains of sacral ganglia, taking into account their size and chemical phenotype.



http://ift.tt/2yKbjln

Polymer nanostructures for bioapplications induced by laser treatment

Publication date: Available online 16 December 2017
Source:Biotechnology Advances
Author(s): Petr Slepička, Jakub Siegel, Oleksiy Lyutakov, Nikola Slepičková Kasálková, Zdeňka Kolská, Lucie Bačáková, Václav Švorčík
Modification of polymer substrates can essentially change the properties of material and thereby it allows their usage in attractive fields of material research. Laser treatment can be successfully applied for change in physico-chemical surface properties and/or for selective change of surface morphology with pattern construction. Three major applications of laser induced structures were described, cytocompatibility control, application as anti-bacterial substrate and plasmonic-based detection system. The construction of a second generation antibacterials using the synergic effect of either nanopatterning of polymers by application of a laser or noble metals deposition and consequent modification of nanostructures was presented.



http://ift.tt/2kAQL9O

Effects of Xiao Yao San on Interferon-α-Induced Depression in Mice

Publication date: Available online 16 December 2017
Source:Brain Research Bulletin
Author(s): Mengmeng Wang, Weiliang Huang, Tingting Gao, Xiaoshan Zhao, Zhiping Lv
Background and ObjectiveXiao Yao San (XYS) is a traditional Chinese medicine used to treat depression; however, the mechanism underlying its antidepressant properties remains unclear. The objective of the present study was to investigate the effects and action mechanisms of XYS on interferon-α-induced depression in mice.MethodMice were divided into six groups: control; model; low-, medium-, and high-dose XYS; and escitalopram-treated group. Except for the control mice, all groups of mice were injected with interferon (IFN)-α to establish the depression model. XYS and escitalopram were then administered to the respective mice daily for 21 days. Sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were used to measure behavioral indices. High-performance liquid chromatography (HPLC) was used to measure serotonin (5-HT) concentrations, while western blots were used to examine indoleamine-2,3-dioxygenase 1 (IDO1) expression in the dorsal raphe nucleus (DRN). The number of microglia in the DRN was observed using immunofluorescence.ResultsCompared with that of the control group, the model group showed a significant decrease in sucrose consumption (P < 0.05) and significant increase in the duration of immobility in the FST and TST (P < 0.05). These parameters improved significantly after XYS or escitalopram treatment. There was also a significantly higher and lower expression of IDO1 protein and 5-HT in the mouse DRN, respectively, which were reversed by administering XYS and escitalopram (P < 0.05). Moreover, the number of microglia in the mouse DRN increased significantly and was reduced by XYS and escitalopram (P < 0.05).ConclusionXYS reduced the number of microglia and expression of IDO1, which increased the levels of 5-HT in the mouse DRN and, thereby, improved the depressive behavior of mice. This may explain, at least in part, the antidepressant properties of XYS in patients.



http://ift.tt/2kAOLyu

Role of the orexin receptors within the nucleus accumbens in the drug priming-induced reinstatement of morphine seeking in the food deprived rats

Publication date: Available online 16 December 2017
Source:Brain Research Bulletin
Author(s): Marjan Sahafzadeh, Saeideh Karimi-Haghighi, Zahra Mousavi, Abbas Haghparast
Orexin plays a key role in mediating stress-induced drug relapse. However, the role of different types of orexinergic receptors that modulate stress-induced drug seeking remains unknown. The nucleus accumbens (NAc) has an important role in the reward system and receives orexinergic projections of the lateral hypothalamus. In addition, orexin interacts with other receptors that are involved in drug reinstatement. Therefore, in the present study, the role of orexin receptors in the NAc in morphine priming- induced reinstatement and the effect of food deprivation (FD) on drug reinstatement were examined. The extinguished morphine preference rats were tested for reinstatement following the 24-h FD condition after conditioning was induced. In the other groups, the animals were given intra-accumbal administration of SB334867 (01, 1 and 10 nM/0.5 μl DMSO) as an orexin-1 receptor antagonist and TCSOX229 (1, 5 and 25 nM/0.5 μl DMSO), as an orexin-2 receptor antagonist. The results showed that the blockade of two types of orexin receptors in the NAc remarkably attenuated the effect of FD on the drug reinstatement; however, they were more effective in FD condition. These findings indicate that the NAc is a brain area within which orexin has a fundamental role in the effect of stress on morphine-induced reinstatement and the effect of food deprivation- on the reinstatement of morphine.



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Evaluation of patients' compliance in different age groups: preventive methodology.

Related Articles

Evaluation of patients' compliance in different age groups: preventive methodology.

Minerva Stomatol. 2017 Dec 14;:

Authors: Maspero C, Galbiati G, Giannini L, Zanoni F, Farronato M, Esposito L

Abstract
BACKGROUND: The aim of this work is to evaluate the effectiveness of the SSRD Department of University of Milan PREVENTION PROGRAM between subjects of different sex and ages.
METHODS: PREVENTION PROGRAM is divided into six stages, in which specific and standardized procedures are effected on patient; then checkups are planned after three months. 90 patients (48 females, 42 males) were included. Subjects were divided into three ages groups: 6-9, 10- 12 and over 12 years old. Plaque Index, Bleeding Index, and quantitative and qualitative variations of bacterial plaque were considered.
RESULTS: Remarkable results were obtained regarding both the effective reduction of bacterial oral flora and patient's compliance and learning, especially in the group of patients older than 10 years. The new values of parameters recorded at the end of the study showed that all the subjects included in the sample had an improvement of compliance in oral hygiene, in particular: - P.I. level 3, 10-12 age, sex; - B.I. level 4, males over 10, female 6-9 age; - quantitative and qualitative variations of bacterial plaque, level 4, all groups.
CONCLUSIONS: Patient instruction and motivation allow to obtain optimal results in particular in patients aged more than 10 years.

PMID: 29243447 [PubMed - as supplied by publisher]

http://ift.tt/2AGthH2

Prevalence of dental caries among schoolchildren from North-Eastern Italian population.

Related Articles

Prevalence of dental caries among schoolchildren from North-Eastern Italian population.

Minerva Stomatol. 2017 Dec 14;:

Authors: Dobbiani A, Berton F, Perinetti G, Costantinides F, DI Lenarda R

Abstract
OBJECTIVE: The longitudinal aspect of dental caries has not been previously reported for the Italian population. The primary object of the present study is to collect information of the prevalence of dental decay among the schoolchildren of primary school of Gradisca d'Isonzo (GO) and to analyse the tendency of caries among the students followed since the first year of school.
METHODS: Subsequent examinations hold from 2011 to 2015 has been conducted by two calibrated examiners. Oral hygiene instruction and motivation followed the visits. According to WHO principals DMFT and dmft were recorded. The children in the survey were divided into five groups according to their ages (6, 7, 8 and 9 years), and these groups were considered separately. Descriptive and statistical analysis of the data were conducted.
RESULTS: More than 400 pupils were recruited, resulting in almost 900 examinations during five years. Overall, the %dft ≥ 1 children range from 18.9% (10 years, 2013) to 53.5% (8 years, 2011) across the different age groups. Overall, the %DFT ≥ 1 children range from 8.3% (6 years, 2011) to 44.1% (10 years, 2012) across the different age groups.
CONCLUSIONS: Within the limits of the present study, the WHO goals are still not met, among the population in exam. Our results show a trend of decay diminution that enhances in the cohort of 10-aged children suggesting the importance of dental education. Furthermore, the lack of paediatric initiatives of oral hygiene may be overcome by a national intensive educational program, supported by further scientific evidence.

PMID: 29243446 [PubMed - as supplied by publisher]

http://ift.tt/2AHNYCI

Disease tolerance: concept and mechanisms

JL McCarville | JS Ayres

http://ift.tt/2BjuBAN

Suppression of NLRP3 attenuates hemorrhagic transformation after delayed rtPA treatment in thromboembolic stroke rats: Involvement of neutrophil recruitment

Publication date: Available online 16 December 2017
Source:Brain Research Bulletin
Author(s): Zhiliang Guo, Shuhong Yu, Xin Chen, Ping Zheng, Ting Hu, Zhenhui Duan, Xiaoyun Liu, Qian Liu, Ruidong Ye, Wusheng Zhu, Xinfeng Liu
BackgroundInflammation and neutrophils play pivotal roles in hemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rtPA) treatment in stroke; however, the contribution of Nod-like receptor protein 3 (NLRP3), a key component of the innate immune system, is not yet known. This study aimed to explore the role of NLRP3 in the delayed rtPA-induced HT and its association with the neutrophil recruitment.MethodsRats were subjected to thromboembolic focal cerebral ischemia and delayed rtPA treatment at 4 h after ischemia to mimic HT. NLRP3 short hairpin RNAs (shRNA) were administered 72 h before ischemia. Additionally, rabbit anti-rat neutrophil serum (inducing neutropenia) was administered before cerebral ischemia. The infarct volume, edema volume, neurological deficit, hemorrhages, blood-brain barrier (BBB) integrity and brain neutrophil recruitment were evaluated at 24 h after cerebral ischemia.ResultsOur results demonstrated that delayed rtPA treatment at 4 h after ischemia promoted the expression of NLRP3 in neurons, microglia and endothelial cells, degradation of BBB components, and HT. NLRP3 knockdown significantly attenuated NLRP3 expression, BBB disruption, and HT. It also improved neurological functions and reduced neutrophil recruitment. Rabbit anti-rat neutrophil serum, like NLRP3 shRNA, reduced hemorrhage score and hemorrhage volumes after rtPA treatment. Furthermore, the anti-rat neutrophil serum combined with NLRP3 shRNA didn't further increase the protective effect on HT compared to rabbit anti-rat neutrophil serum used alone.ConclusionsTogether, our data suggest that NLRP3 inhibition can reduce neutrophil recruitment, which may contribute to the inhibitory effect on HT.



http://ift.tt/2kCci21

A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation

Publication date: Available online 16 December 2017
Source:Brain and Development
Author(s): Yukimune Okubo, Wakaba Endo, Takehiko Inui, Sato Suzuki-Muromoto, Takuya Miyabayashi, Noriko Togashi, Ryo Sato, Natsuko Arai-Ichinoi, Atsuo Kikuchi, Shigeo Kure, Kazuhiro Haginoya
Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous multiple congenital contractures appearing at birth. Mutations in X-linked zinc-finger gene ZC4H2 were recently identified in some families and individuals with variable forms of AMC associated with dysmorphic signs, intellectual disability and spastic paresis. We present a non-consanguineous Japanese female presenting AMC with severe intellectual disability and spastic quadriplegia who also had progressive brain atrophy. Microarray-based comparative genomic hybridization identified 395 kb microdeletions at Xq11.2 which only included ZC4H2 gene. Previous reports showed that affected females have lesser symptoms and slight abnormality on brain MRI compared to male due to X-inactivation. Our case, however, showed severe manifestation than as ever reported as well as progressive diffuse brain atrophy, which implicated contribution of other genetic or environmental factors or extremely skewed X inactivation.



http://ift.tt/2k59fzT

Prevalence of dental caries among schoolchildren from North-Eastern Italian population.

Related Articles

Prevalence of dental caries among schoolchildren from North-Eastern Italian population.

Minerva Stomatol. 2017 Dec 14;:

Authors: Dobbiani A, Berton F, Perinetti G, Costantinides F, DI Lenarda R

Abstract
OBJECTIVE: The longitudinal aspect of dental caries has not been previously reported for the Italian population. The primary object of the present study is to collect information of the prevalence of dental decay among the schoolchildren of primary school of Gradisca d'Isonzo (GO) and to analyse the tendency of caries among the students followed since the first year of school.
METHODS: Subsequent examinations hold from 2011 to 2015 has been conducted by two calibrated examiners. Oral hygiene instruction and motivation followed the visits. According to WHO principals DMFT and dmft were recorded. The children in the survey were divided into five groups according to their ages (6, 7, 8 and 9 years), and these groups were considered separately. Descriptive and statistical analysis of the data were conducted.
RESULTS: More than 400 pupils were recruited, resulting in almost 900 examinations during five years. Overall, the %dft ≥ 1 children range from 18.9% (10 years, 2013) to 53.5% (8 years, 2011) across the different age groups. Overall, the %DFT ≥ 1 children range from 8.3% (6 years, 2011) to 44.1% (10 years, 2012) across the different age groups.
CONCLUSIONS: Within the limits of the present study, the WHO goals are still not met, among the population in exam. Our results show a trend of decay diminution that enhances in the cohort of 10-aged children suggesting the importance of dental education. Furthermore, the lack of paediatric initiatives of oral hygiene may be overcome by a national intensive educational program, supported by further scientific evidence.

PMID: 29243446 [PubMed - as supplied by publisher]

http://ift.tt/2AHNYCI

Opposing Post-transcriptional Control of InR by FMRP and LIN-28 Adjusts Stem Cell-Based Tissue Growth

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Arthur Luhur, Kasun Buddika, Ishara Surangi Ariyapala, Shengyao Chen, Nicholas Samuel Sokol
Although the intrinsic mechanisms that control whether stem cells divide symmetrically or asymmetrically underlie tissue growth and homeostasis, they remain poorly defined. We report that the RNA-binding protein fragile X mental retardation protein (FMRP) limits the symmetric division, and resulting expansion, of the stem cell population during adaptive intestinal growth in Drosophila. The elevated insulin sensitivity that FMRP-deficient progenitor cells display contributes to their accelerated expansion, which is suppressed by the depletion of insulin-signaling components. This FMRP activity is mediated solely via a second conserved RNA-binding protein, LIN-28, known to boost insulin signaling in stem cells. Via LIN-28, FMRP controls progenitor cell behavior by post-transcriptionally repressing the level of insulin receptor (InR). This study identifies the stem cell-based mechanism by which FMRP controls tissue adaptation, and it raises the possibility that defective adaptive growth underlies the accelerated growth, gastrointestinal, and other symptoms that affect fragile X syndrome patients.

Graphical abstract

Teaser

Luhur et al. report that FMRP acts via LIN-28 in progenitor cells to dampen the adaptive expansion of intestinal tissue in the fruit fly, raising the possibility that defective LIN28-mediated adaptive growth underlies some of the symptoms that affect fragile X syndrome patients.


http://ift.tt/2j9dwBB

Integration of GPCR Signaling and Sorting from Very Early Endosomes via Opposing APPL1 Mechanisms

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Silvia Sposini, Frederic G. Jean-Alphonse, Mohammed A. Ayoub, Affiong Oqua, Camilla West, Stuart Lavery, Jan J. Brosens, Eric Reiter, Aylin C. Hanyaloglu
Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized β2-adrenergic receptor. LHR recycling is driven by receptor-mediated Gαs/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. Receptor/Gαs endosomal signaling is localized to microdomains of heterogeneous VEE populations and regulated by APPL1 phosphorylation. Our study uncovers a highly integrated inter-endosomal communication system enabling cells to tightly regulate spatially encoded signaling.

Graphical abstract

Teaser

Sposini et al. report that G-protein signaling from specific GPCRs is spatially restricted in very early endosomes (VEEs), compartments distinct from classic early endosomes. Mechanistically, receptor signaling and sorting from VEEs occur via opposing phosphorylation states of APPL1 adaptor protein, providing novel decoding mechanisms for cells to tightly control signaling.


http://ift.tt/2j7uP62

Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Alasdair W. Jubb, Shelagh Boyle, David A. Hume, Wendy A. Bickmore
Glucocorticoids act by binding to the glucocorticoid receptor (GR), which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH) at loci associated with GR binding. Rapid chromatin decompaction was generally not dependent on transcription at those loci that are known to be inducible in both mouse and human macrophages and was sustained for up to 5 days following ligand removal. Chromatin decompaction was not dependent upon persistent GR binding, which decayed fully after 24 hr. We suggest that sustained large-scale chromatin reorganization forms an important part of the response to glucocorticoid and might contribute to glucocorticoid sensitivity and resistance.

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Teaser

Glucocorticoids are important anti-inflammatory therapeutics. Jubb at al. find that treating primary macrophages with glucocorticoid induces rapid and persistent chromatin reorganization at genes that respond in both mice and humans. Higher-order chromatin structure at these core loci may be involved in the glucocorticoid response and be relevant to resistance.


http://ift.tt/2zfjSrF

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel
Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease.

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Teaser

Soltis et al. performed a systems biology study of obesity-induced hepatic insulin resistance in mice. They collected a variety of omic datasets, including metabolomics, and integrated these into a network model. They tested model predictions and identified widespread hepatocellular injury and enhanced hepatocyte apoptosis as features of hepatic insulin resistance.


http://ift.tt/2zfAeAP

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Andreas S. Puschnik, Caleb D. Marceau, Yaw Shin Ooi, Karim Majzoub, Natalie Rinis, Joseph N. Contessa, Jan E. Carette
The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile, and yellow fever viruses, which pose a serious threat for global health. Recent genetic screens identified endoplasmic reticulum (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST. Viral mutants adapted to replicate in cells deficient of the OST complex showed resistance to NGI-1 treatment, reinforcing the on-target activity of NGI-1. Lastly, we show that NGI-1 also has strong antiviral activity in primary and disease-relevant cell types. This study provides an example for advancing from the identification of genetic determinants of infection to a host-directed antiviral compound with broad activity against flaviviruses.

Graphical abstract

Teaser

The mosquito-borne flaviviruses depend on oligosaccharyltransferase (OST) for replication. Puschnik et al. reveal that the OST inhibitor NGI-1 has pan-flaviviral activity in several disease-relevant cell types. The effect on viral replication acts through OST but appears to be largely independent of blocking catalytic N-glycosylation activity.


http://ift.tt/2zgrZ7F

Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Alfred K. Ramirez, Matthew D. Lynes, Farnaz Shamsi, Ruidan Xue, Yu-Hua Tseng, C. Ronald Kahn, Simon Kasif, Jonathan M. Dreyfuss
White adipocytes are specialized for energy storage, whereas brown adipocytes are specialized for energy expenditure. Explicating this difference can help identify therapeutic targets for obesity. A common tool to assess metabolic differences between such cells is the Seahorse Extracellular Flux (XF) Analyzer, which measures oxygen consumption and media acidification in the presence of different substrates and perturbagens. Here, we integrate the Analyzer's metabolic profile from human white and brown adipocytes with a genome-scale metabolic model to predict flux differences across the metabolic map. Predictions matched experimental data for the metabolite 4-aminobutyrate, the protein ABAT, and the fluxes for glucose, glutamine, and palmitate. We also uncovered a difference in how adipocytes dispose of nitrogenous waste, with brown adipocytes secreting less ammonia and more urea than white adipocytes. Thus, the method and software we developed allow for broader metabolic phenotyping and provide a distinct approach to uncovering metabolic differences.

Graphical abstract

Teaser

Ramirez et al. integrate extracellular flux measurements with a human metabolic model to infer flux differences between brown (energy-burning) and white (energy-storing) adipocytes. Differences are experimentally validated. Brown adipocytes dispose of nitrogenous waste differently than white adipocytes. This method can be applied to any tissue/cell assayed with extracellular analyzers.


http://ift.tt/2zfXrD3

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Katherine R. Singleton, Lorin Crawford, Elizabeth Tsui, Haley E. Manchester, Ophelia Maertens, Xiaojing Liu, Maria V. Liberti, Anniefer N. Magpusao, Elizabeth M. Stein, Jennifer P. Tingley, Dennie T. Frederick, Genevieve M. Boland, Keith T. Flaherty, Shannon J. McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J. Adams, Jason W. Locasale, Karen Cichowski, Sayan Mukherjee, Kris C. Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

Graphical abstract

Teaser

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, but by combining statistical modeling of tumor data with functional interrogation of resistance models, Singleton et al. show that these pathways converge to activate MYC. BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, informing therapies that select against resistance.


http://ift.tt/2j5ZiBi

Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Tania A. Seabrook, Onkar S. Dhande, Nao Ishiko, Victoria P. Wooley, Phong L. Nguyen, Andrew D. Huberman
The use of sensory information to drive specific behaviors relies on circuits spanning long distances that wire up through a range of axon-target recognition events. Mechanisms assembling poly-synaptic circuits and the extent to which parallel pathways can "cross-wire" to compensate for loss of one another remain unclear and are crucial to our understanding of brain development and models of regeneration. In the visual system, specific retinal ganglion cells (RGCs) project to designated midbrain targets connected to downstream circuits driving visuomotor reflexes. Here, we deleted RGCs connecting to pupillary light reflex (PLR) midbrain targets and discovered that axon-target matching is tightly regulated. RGC axons of the eye-reflex pathway avoided vacated PLR targets. Moreover, downstream PLR circuitry is maintained; hindbrain and peripheral components retained their proper connectivity and function. These findings point to a model in which poly-synaptic circuit development reflects independent, highly stringent wiring of each parallel pathway and downstream station.

Graphical abstract

Teaser

Seabrook et al. found using conditional genetic deletion of specific retinal ganglion cell types that retinal innervation of the pretectum is highly regulated and that downstream circuit connections are maintained following removal of peripheral sensory drive.


http://ift.tt/2zg5LCp

ATP Citrate Lyase Regulates Myofiber Differentiation and Increases Regeneration by Altering Histone Acetylation

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Suman Das, Frederic Morvan, Giulio Morozzi, Benjamin Jourde, Giulia C. Minetti, Peter Kahle, Helene Rivet, Pascale Brebbia, Gauthier Toussaint, David J. Glass, Mara Fornaro
ATP citrate lyase (ACL) plays a key role in regulating mitochondrial function, as well as glucose and lipid metabolism in skeletal muscle. We report here that ACL silencing impairs myoblast and satellite cell (SC) differentiation, and it is accompanied by a decrease in fast myosin heavy chain isoforms and MYOD. Conversely, overexpression of ACL enhances MYOD levels and promotes myogenesis. Myogenesis is dependent on transcriptional but also other mechanisms. We show that ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3(K9/14) and H3(K27) at the MYOD locus, thus increasing MYOD expression. ACL overexpression in murine skeletal muscle leads to improved regeneration after cardiotoxin-mediated damage. Thus, our findings suggest a mechanism for regulating SC differentiation and enhancing regeneration, which might be exploited for devising therapeutic approaches for treating skeletal muscle disease.

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Teaser

Das et al. report that ATP citrate lyase (ACL) acts downstream of IGF-1 to stimulate myoblast and satellite cell differentiation. ACL stimulates acetyl-CoA, which is utilized by acetyl transferases (e.g., P300) to enhance Acetyl-H3(K9/14/27) at the MYOD promoter, resulting in increased MYOD expression and improved muscle regeneration following injury.


http://ift.tt/2zgs1fN

Infrabarrels Are Layer 6 Circuit Modules in the Barrel Cortex that Link Long-Range Inputs and Outputs

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Shane R. Crandall, Saundra L. Patrick, Scott J. Cruikshank, Barry W. Connors
The rodent somatosensory cortex includes well-defined examples of cortical columns—the barrel columns—that extend throughout the cortical depth and are defined by discrete clusters of neurons in layer 4 (L4) called barrels. Using the cell-type-specific Ntsr1-Cre mouse line, we found that L6 contains infrabarrels, readily identifiable units that align with the L4 barrels. Corticothalamic (CT) neurons and their local axons cluster within the infrabarrels, whereas corticocortical (CC) neurons are densest between infrabarrels. Optogenetic experiments showed that CC cells received robust input from somatosensory thalamic nuclei, whereas CT cells received much weaker thalamic inputs. We also found that CT neurons are intrinsically less excitable, revealing that both synaptic and intrinsic mechanisms contribute to the low firing rates of CT neurons often reported in vivo. In summary, infrabarrels are discrete cortical circuit modules containing two partially separated excitatory networks that link long-distance thalamic inputs with specific outputs.

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Teaser

Layer 6 is a major input-output layer of neocortex, but key principles of its circuit organization are lacking. Crandall et al. reveal barrel-like structures called infrabarrels that include distinct excitatory circuits linking thalamic inputs with specific outputs, thus providing a framework for understanding the functional organization of layer 6.


http://ift.tt/2zgEVKC

Cell Type of Origin Dictates the Route to Pluripotency

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Christian M. Nefzger, Fernando J. Rossello, Joseph Chen, Xiaodong Liu, Anja S. Knaupp, Jaber Firas, Jacob M. Paynter, Jahnvi Pflueger, Sam Buckberry, Sue Mei Lim, Brenda Williams, Sara Alaei, Keshav Faye-Chauhan, Enrico Petretto, Susan K. Nilsson, Ryan Lister, Mirana Ramialison, David R. Powell, Owen J.L. Rackham, Jose M. Polo
Our current understanding of induced pluripotent stem cell (iPSC) generation has almost entirely been shaped by studies performed on reprogramming fibroblasts. However, whether the resulting model universally applies to the reprogramming process of other cell types is still largely unknown. By characterizing and profiling the reprogramming pathways of fibroblasts, neutrophils, and keratinocytes, we unveil that key events of the process, including loss of original cell identity, mesenchymal to epithelial transition, the extent of developmental reversion, and reactivation of the pluripotency network, are to a large degree cell-type specific. Thus, we reveal limitations for the use of fibroblasts as a universal model for the study of the reprogramming process and provide crucial insights about iPSC generation from alternative cell sources.

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Teaser

Nefzger et al. find that the molecular reprogramming trajectories of fibroblasts, neutrophils, and keratinocytes have a cell-type-specific component that only fully converges in induced pluripotent stem cells. The authors also identify universal changes shared by all three cell types, including two transcriptional waves and a conserved transcriptional program involving Egr1 downregulation.


http://ift.tt/2j8cBkR

Nucleus Accumbens Dopamine Signaling Regulates Sexual Preference for Females in Male Mice

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Yamit Beny-Shefer, Noga Zilkha, Yael Lavi-Avnon, Nadav Bezalel, Ilana Rogachev, Alexander Brandis, Molly Dayan, Tali Kimchi
Sexual preference for the opposite sex is a fundamental behavior underlying reproductive success, but the neural mechanisms remain unclear. Here, we examined the role of dopamine signaling in the nucleus accumbens core (NAcc) in governing chemosensory-mediated preference for females in TrpC2^−/− and wild-type male mice. TrpC2^−/− males, deficient in VNO-mediated signaling, do not display mating or olfactory preference toward females. We found that, during social interaction with females, TrpC2^−/− males do not show increased NAcc dopamine levels, observed in wild-type males. Optogenetic stimulation of VTA-NAcc dopaminergic neurons in TrpC2^−/− males during exposure to a female promoted preference response to female pheromones and elevated copulatory behavior toward females. Additionally, we found that signaling through the D1 receptor in the NAcc is necessary for the olfactory preference for female-soiled bedding. Our study establishes a critical role for the mesolimbic dopaminergic system in governing pheromone-mediated responses and mate choice in male mice.

Graphical abstract

Teaser

Beny-Shefer et al. find that female-specific pheromone signals detected by the vomeronasal organ induce dopamine release in the nucleus accumbens core (NAcc) of male mice. Optogenetic stimulation of the mesolimbic dopamine system in males during female exposure promotes sexual preference and behavior, whereas blocking NAcc dopamine receptor type 1 obstructs sexual preference.


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Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Lea J. Hachigian, Vitor Carmona, Robert J. Fenster, Ruth Kulicke, Adrian Heilbut, Annie Sittler, Luís Pereira de Almeida, Jill P. Mesirov, Fan Gao, Eric D. Kolaczyk, Myriam Heiman
Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington's disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD.

Graphical abstract

Teaser

Hachigian et al. demonstrate that manipulating levels of the striatum-enriched transcription factor Foxp2 can either rescue or mimic HD-associated behaviors in vivo. They link Foxp2 to the post-developmental regulation of the structure and function of the corticostriatal synapse.


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An Elongin-Cullin-SOCS Box Complex Regulates Stress-Induced Serotonergic Neuromodulation

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Xicotencatl Gracida, Michael F. Dion, Gareth Harris, Yun Zhang, John A. Calarco
Neuromodulatory cells transduce environmental information into long-lasting behavioral responses. However, the mechanisms governing how neuronal cells influence behavioral plasticity are difficult to characterize. Here, we adapted the translating ribosome affinity purification (TRAP) approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing amphid neuron dual ciliated sensory ending (ADF) serotonergic sensory neurons, and we found that it plays a role in mediating a long-lasting change in serotonin-dependent feeding behavior induced by heat stress. We demonstrate that ELC-2 and the von Hippel-Lindau protein VHL-1, components of an Elongin-Cullin-SOCS box (ECS) E3 ubiquitin ligase, modulate this behavior after experiencing stress. Also, heat stress induces a transient redistribution of ELC-2, becoming more nuclearly enriched. Together, our results demonstrate dynamic regulation of an E3 ligase and a role for an ECS complex in neuromodulation and control of lasting behavioral states.

Graphical abstract

Teaser

Neurons integrate and transmit information from the environment to regulate behavior. Using a cell-specific profiling method, Gracida et al. identify a component of an E3 ubiquitin ligase that is required in serotonergic neurons to regulate feeding behavior after experiencing heat stress. This indicates that protein degradation may integrate stimuli to regulate animal states.


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Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Zhenwei Su, Amber L. Alhadeff, J. Nicholas Betley
The brain regulates food intake by processing sensory cues and peripheral physiological signals, but the neural basis of this integration remains unclear. Hypothalamic, agouti-related protein (AgRP)-expressing neurons are critical regulators of food intake. AgRP neuron activity is high during hunger and is rapidly reduced by the sight and smell of food. Here, we reveal two distinct components of AgRP neuron activity regulation: a rapid but transient sensory-driven signal and a slower, sustained calorie-dependent signal. We discovered that nutrients are necessary and sufficient for sustained reductions in AgRP neuron activity and that activity reductions are proportional to the calories obtained. This change in activity is recapitulated by exogenous administration of gut-derived satiation signals. Furthermore, we showed that the nutritive value of food trains sensory systems—in a single trial—to drive rapid, anticipatory AgRP neuron activity inhibition. Together, these data demonstrate that nutrients are the primary regulators of AgRP neuron activity.

Graphical abstract

Teaser

Su et al. demonstrate that nutrient content in the GI tract is rapidly signaled to hypothalamic neurons activated by hunger. This rapid effect is mediated by three satiation signals that synergistically reduce the activity of AgRP neurons. These findings uncover how hunger circuits in the brain are regulated and raise the possibility that hunger can be pharmacologically controlled.


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Functional and Molecular Characterization of Mechanoinsensitive “Silent” Nociceptors

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Vincenzo Prato, Francisco J. Taberner, James R.F. Hockley, Gerard Callejo, Alice Arcourt, Bassim Tazir, Leonie Hammer, Paulina Schad, Paul A. Heppenstall, Ewan S. Smith, Stefan G. Lechner
Mechanical and thermal hyperalgesia (pain hypersensitivity) are cardinal signs of inflammation. Although the mechanism underlying thermal hyperalgesia is well understood, the cellular and molecular basis of mechanical hyperalgesia is poorly described. Here, we have identified a subset of peptidergic C-fiber nociceptors that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli when exposed to the inflammatory mediator nerve growth factor (NGF). Strikingly, NGF did not affect mechanosensitivity of other nociceptors. We show that these mechanoinsensitive "silent" nociceptors are characterized by the expression of the nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) and that the mechanically gated ion channel PIEZO2 mediates NGF-induced mechanosensitivity in these neurons. Retrograde tracing revealed that CHRNA3⁺ nociceptors account for ∼50% of all peptidergic nociceptive afferents innervating visceral organs and deep somatic tissues. Hence, our data suggest that NGF-induced "un-silencing" of CHRNA3⁺ nociceptors significantly contributes to the development of mechanical hyperalgesia during inflammation.

Graphical abstract

Teaser

Prato et al. find that mechanoinsensitive nociceptors account for ∼50% of all nociceptors in visceral organs and deep somatic tissues and are sensitized to mechanical stimuli by the inflammatory mediator NGF, suggesting that they significantly contribute to inflammation-induced mechanical hyperalgesia.


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Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Sara Badodi, Adrian Dubuc, Xinyu Zhang, Gabriel Rosser, Mariane Da Cunha Jaeger, Michelle M. Kameda-Smith, Anca Sorana Morrissy, Paul Guilhamon, Philipp Suetterlin, Xiao-Nan Li, Loredana Guglielmi, Ashirwad Merve, Hamza Farooq, Mathieu Lupien, Sheila K. Singh, M. Albert Basson, Michael D. Taylor, Silvia Marino
We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1^High;CHD7^Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7.

Graphical abstract

Teaser

Badodi et al. find convergence of the chromatin modifiers BMI1 and CHD7 in medulloblastoma pathogenesis, and they show that this pathway regulates tumor proliferation and growth via ERK signaling.


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Ultradeep mapping of neuronal mitochondrial deletions in Parkinson's disease

Publication date: March 2018
Source:Neurobiology of Aging, Volume 63
Author(s): Gonzalo S. Nido, Christian Dölle, Irene Flønes, Helen A. Tuppen, Guido Alves, Ole-Bjørn Tysnes, Kristoffer Haugarvoll, Charalampos Tzoulis
Mitochondrial DNA (mtDNA) deletions accumulate with age in postmitotic cells and are associated with aging and neurodegenerative disorders such as Parkinson's disease. Although the exact mechanisms by which deletions form remain elusive, the dominant theory is that they arise spontaneously at microhomologous sites and undergo clonal expansion. We characterize mtDNA deletions at unprecedented resolution in individual substantia nigra neurons from individuals with Parkinson's disease, using ultradeep sequencing. We show that the number of deleted mtDNA species per neuron is substantially higher than previously reported. Moreover, each deleted mtDNA species shows significant differences in sequence composition compared with the remaining mtDNA population, which is highly consistent with independent segregation and clonal expansion. Deletion breakpoints occur consistently in regions of sequence homology, which may be direct or interrupted stretches of tandem repeats. While our results support a crucial role for misannealing in deletion generation, we find no overrepresentation of the 3′-repeat sequence, an observation that is difficult to reconcile with the current view of replication errors as the source of mtDNA deletions.



http://ift.tt/2kBKmeo

Computer-aided design and manufacture of hyrax devices: Can we really go digital?

Publication date: December 2017
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 152, Issue 6
Author(s): Simon Graf, Marie A. Cornelis, Gustavo Hauber Gameiro, Paolo M. Cattaneo
The aim of this pilot study was to illustrate the feasibility of a new digital procedure to fabricate metallic orthodontic appliances. Hyrax appliances for rapid palatal expansion were produced for 3 patients using a CAD/CAM procedure without physical impressions or printed models. The work flow consisted of intraoral scanning, digital design with incorporation of a scanned prefabricated expansion screw, direct 3-dimensional metal printing via laser melting, welding of an expansion screw, insertion, and finally activation in the patients' mouths. Finite element analyses of the actual hyrax appliances were performed to ensure that the printable material used in combination with the chosen design would withstand the stress generated during activation. The results of these analyses were positive. The clinical results showed that this procedure is an efficient and viable digital way for constructing metallic orthodontic appliances. The flexibility of the digital appliance design, together with the biocompatibility and strength of the chosen material, offers a huge potential for more advanced appliance design.



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IgE promotes type 2 innate lymphoid cells in murine food allergy

Abstract

Background

Mast cells serve an important sentinel function at mucosal barriers and have been implicated as key early inducers of Type 2 immune responses in food allergy. The generation of Th2 and IgE following food allergen ingestion is inhibited in the absence of mast cells. Group 2 innate lymphoid cells are also thought to play an important early role in nascent allergic responses.

Objective

To test whether IgE-mediated mast cell activation promotes intestinal ILC2 responses following ingestion of food allergens and whether ILC2 amplify food allergy.

Methods

Two different mouse models of food allergy, one using intraperitoneally ovalbumin (OVA) primed BALB/c animals and the other using enterally peanut-sensitized inherently atopic IL4raF709 mice, were applied to test the contributions of IgE antibodies and mast cells to ILC2 responses. The effect of ILC2 on mast cell activation and on anaphylaxis was tested.

Results

ILC2 responses were significantly impaired in both models of food allergy in Igh7^-/- mice harboring a targeted deletion of the gene encoding IgE. A similar reduction in food allergen-induced ILC2 was observed in mast cell deficient Il4raF709 Kit^W-sh mice and this was partially corrected by reconstituting these animals using cultured bone marrow mast cells. Mast cells activated ILC2 for IL-13 production in an IL-4Rα-dependent manner. Activated ILC2 amplified systemic anaphylaxis by increasing target tissue sensitivity to mast cell mediators.

Conclusions & clinical relevance

These findings support an important role for IgE-activated mast cells in driving intestinal ILC2 expansion in food allergy and reveal that ILC2, in turn, can enhance responsiveness to the mediators of anaphylaxis produced by mast cells. Strategies designed to inhibit IgE signaling or mast cell activation are likely to inhibit both Type 2 immunity and immediate hypersensitivity in food allergy.

This article is protected by copyright. All rights reserved.

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Typical sensory organization test findings and clinical implication in acute vestibular neuritis

Sensory organization test (SOT) is used to evaluate postural instability. We wanted to characterize the SOT findings in patients with acute vestibular neuritis (VN).

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Mixed messages

Publication date: December 2017
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 152, Issue 6
Author(s): Peter M. Greco




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The Burden of Inbox-Messaging Systems and Its Effect on Work-Life Balance in Dermatology

http://ift.tt/2j97q45

Fibrous Cephalic Plaques in Tuberous Sclerosis Complex

Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of tuberous sclerosis complex (TSC) patients. They constitute a major feature for TSC diagnosis, and may present before other TSC-related cutaneous hamartomas.

http://ift.tt/2zhWxFV

A systematic review of validated sinus surgery simulators

Abstract

Background

Simulation provides a safe and effective opportunity to develop surgical skills. A variety of endoscopic sinus surgery (ESS) simulators have been described in the literature. Validation of these simulators allows for effective utilisation in training.

Objective of review

To conduct a systematic review of the published literature to analyse the evidence for validated ESS simulation.

Search strategy

Pubmed, Embase, Cochrane and Cinahl were searched from inception of the databases to January 11^th, 2017.

Evaluation method

12,516 articles were retrieved of which 10,112 were screened following the removal of duplicates. 38 full text articles were reviewed after meeting the search criteria. Evidence of face, content, construct, discriminant and predictive validity was extracted.

Results

20 articles were included in the analysis describing 12 ESS simulators. 11 of these simulators had undergone validation; 3 virtual reality, 7 physical bench models and 1 cadaveric simulator. 7 of the simulators were shown to have face validity, 7 had construct validity and 1 had predictive validity. None of the simulators demonstrated discriminate validity.

Conclusion

This systematic review demonstrates that a number of ESS simulators have been comprehensively validated. Many of the validation processes, however, lack standardisation in outcome reporting, thus limiting a meta-analysis comparison between simulators.

This article is protected by copyright. All rights reserved.

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Prevalence of skin disease in a population based sample of adults out of five European countries

Abstract

Background

There is a lack of prevalence data on skin diseases in the general adult population, most studies were carried out in small, national or consecutive clinical samples.

Objectives

To determine the prevalence of common skin disease in the general European population and to additionally assess differences in the characteristics of treatment between countries.

Methods

A random sample consisting out of 12,377 subjects aged 18 to 74 years was drawn from the general population of five European countries (Germany, Italy, The Netherlands, Portugal and Sweden). This was a cross-sectional study and all participants were interviewed with a standardized questionnaire assessing the occurrence of 10 common skin diseases during lifetime, past year and past month. If a skin disease was reported we additionally assessed who performed diagnosis and treatment and if drugs were prescribed.

Results

The most common skin disease was warts (41.3%) followed by acne (19.2%) and contact dermatitis (15.0%). In general females were more often affected by skin diseases compared to males, only in skin cancer the prevalence in males was slightly higher. The prevalence of skin diseases in northern countries (Germany, Netherlands & Sweden) was in general higher than in the southern countries (Italy & Spain). In the Netherlands the treatment of skin diseases was less often performed by a dermatologist compared to the other countries.

Conclusion

The prevalence estimates reported in this study are derived from a representative sample of the general population. Data assessment was performed comprehensively across countries, thus country specific prevalence estimates are comparable.

This article is protected by copyright. All rights reserved.

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Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): Dilia Giuggioli, Andreina Manfredi, Federica Lumetti, Michele Colaci, Clodoveo Ferri
BackgroundSkin ulcers (SU) are one of the most frequent manifestations of systemic sclerosis (SSc). SSc-SU are very painful, often persistent and recurrent; they may lead to marked impairment of patient's activities and quality of life. Despite their severe impact on the whole SSc patient's management, the proposed definition, classification criteria, and therapeutic strategies of SSc-SU are still controversial.ObjectiveThe present study aimed to elaborate a comprehensive proposal of definition, classification, and therapeutic strategy of SSc-SU on the basis of our long-term single center experience along with a careful revision of the world literature on the same topic.MethodsA series of 282 SSc patients (254 females and 28 males; 84% with limited and 16% diffuse cutaneous SSc; mean age of 51.5±13.9SD at SSc onset; mean follow-up 5.8±4.6SDyears) enrolled during the last decade at our Rheumatology Unit were retrospectively evaluated with specific attention to SSc-SU. The SSc-SU were classified in 5 subtypes according to prominent pathogenetic mechanism(s) and localization, namely 1. digital ulcers (DU) of the hands or feet, 2. SU on bony prominence, 3. SU on calcinosis, 4. SU of lower limbs, and 5. DU presenting with gangrene. This latter is a very harmful evolution of both DU of the hands and feet needing a differential diagnosis with critical limb ischemia.ResultsDuring the follow up period, one or more episodes of SSc-SU were recorded in over half patients (156/282, 55%); skin lesions were often recurrent and difficult-to-heal because of local complications, mainly infections (67.3%), in some cases associated to osteomyelitis (19.2%), gangrene (16%), and/or amputation (11.5%). SSc-SU were significantly associated with lower patients' mean age at the disease onset (p=0.024), male gender (p=0.03), diffuse cutaneous subset (p=0.015), calcinosis (p=0.002), telangiectasia (p=0.008), melanodermia (p<0.001), abnormal PAPs (p=0.036), and/or altered inflammation reactant (CRP, p=0.001).Therapeutic strategy of SSc-SU included both systemic and local pharmacological treatments with particular attention to complicating infections and chronic/procedural pain, as well as a number of non-pharmacological measures. Integrated local treatments were often decisive for the SSc-SU healing; they were mainly based on the wound bed preparation principles that are summarized in the acronym TIME (necrotic Tissue, Infection/Inflammation, Moisture balance, and Epithelization).The updated review of the literature focusing on this challenging issue was analyzed in comparison with our experience.ConclusionsThe recent advancement of knowledge and management strategies of SSc-SU achieved during the last years lead to the clear-cut improvement of patients' quality of life and reduced long-term disability.



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Clinical and immunological aspects of anti-peptidylarginine deiminase type 4 (anti-PAD4) autoantibodies in rheumatoid arthritis

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): Zyanya Reyes-Castillo, José Francisco Muñoz-Valle, Mara A. Llamas-Covarrubias
Rheumatoid arthritis (RA) is the most common rheumatic autoimmune disease worldwide, which causes progressive joint damage and can lead to functional disability. Despite prominent advances in RA diagnosis and treatment during the last 20years, there is still a need for novel biomarkers that aid in diagnosis and prognosis of this heterogeneous disease. Citrullination is a key post-translational modification implicated on anti-citrullinated protein/peptide antibodies (ACPA) production in RA, catalyzed by human peptidylarginine deiminases (PADs). Among these enzymes, PAD4 has been recognized as an important player in RA pathogenesis and the enzyme itself is a target of autoantibodies (anti-PAD4) in a subgroup of RA patients. Accumulating evidence suggests that anti-PAD4 autoantibodies may be useful as a severity biomarker in RA and recent studies have also shed light on the functional significance of these autoantibodies. This review summarizes the evidence on anti-PAD4 autoantibodies in RA, and addresses its usefulness for disease diagnosis and prognosis. Novel immunological aspects of anti-PAD4 antibodies and their relevance to RA pathogenesis are also discussed.



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Pitfalls in the detection of citrullination and carbamylation

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): M.K. Verheul, P.A. van Veelen, M.A.M. van Delft, A. de Ru, G.M.C. Janssen, T. Rispens, R.E.M. Toes, L.A. Trouw
Carbamylation and citrullination are both post-translational modifications against which (auto)antibodies can be detected in sera of rheumatoid arthritis (RA) patients. Carbamylation is the chemical modification of a lysine into a homocitrulline, whereas citrullination is an enzymatic conversion of an arginine into a citrulline. It is difficult to distinguish between the two resulting amino acids due to similarities in structure. However, differentiation between citrulline and homocitrulline is important to understand the antigens that induce antibody production and to determine which modified antigens are present in target tissues.We have observed in literature that conclusions are frequently drawn regarding the citrullination or carbamylation of proteins based on reagents that are not able to distinguish between these two modifications. Therefore, we have analyzed a wide spectrum of methods and describe here which method we consider most optimal to distinguish between citrulline and homocitrulline.We have produced several carbamylated and citrullinated proteins and investigated the specificity of (commercial) antibodies by both ELISA and western blot. Furthermore, detection methods based on chemical modifications, such as the anti-modified citrulline-"Senshu" method and also mass spectrometry were investigated for their capacity to distinguish between carbamylation and citrullination.We observed that some antibodies are able to distinguish between carbamylation and citrullination, but an overlap in reactivity is often present in the commercially available anti-citrulline antibodies. Finally, we conclude that the use of mass spectrometry is currently essential to differentiate between citrullinated and carbamylated proteins present in complex biological samples.



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