Extracellular ATP signaling and clinical relevance

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Lei Dou, Yi-Fa Chen, Peter J. Cowan, Xiao-ping Chen
Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.



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Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Dino B.A. Tan, Teck-Hui Teo, Abdul M. Setiawan, Nathanael E. Ong, Maja Zimmermann, Alan Chen-Yu Hsu, Peter A.B. Wark, Yuben P. Moodley




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IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis

Publication date: Available online 21 December 2017
Source:Clinical Immunology
Author(s): Mariam Rabani, Benjamin Wilde, Katharina Hübbers, Shilei Xu, Andreas Kribben, Oliver Witzke, Sebastian Dolff
ObjectivesB-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE).MethodsIsolated PBMCs of SLE-patients (n=30) and healthy controls (n=21) were in vitro stimulated with CPG, IgG+IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry.ResultsThe strongest stimulus for Granzyme B secretion of B-cells was IgG+IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B⁺ B-cells in particular SLE-patients with active disease and with lupus nephritis.ConclusionsThe frequency of GrB+ producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.



http://ift.tt/2z7R2Gm

Extracellular ATP signaling and clinical relevance

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Lei Dou, Yi-Fa Chen, Peter J. Cowan, Xiao-ping Chen
Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.



http://ift.tt/2z8GYx1

Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Dino B.A. Tan, Teck-Hui Teo, Abdul M. Setiawan, Nathanael E. Ong, Maja Zimmermann, Alan Chen-Yu Hsu, Peter A.B. Wark, Yuben P. Moodley




http://ift.tt/2Bs4OtK

IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis

Publication date: Available online 21 December 2017
Source:Clinical Immunology
Author(s): Mariam Rabani, Benjamin Wilde, Katharina Hübbers, Shilei Xu, Andreas Kribben, Oliver Witzke, Sebastian Dolff
ObjectivesB-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE).MethodsIsolated PBMCs of SLE-patients (n=30) and healthy controls (n=21) were in vitro stimulated with CPG, IgG+IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry.ResultsThe strongest stimulus for Granzyme B secretion of B-cells was IgG+IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B⁺ B-cells in particular SLE-patients with active disease and with lupus nephritis.ConclusionsThe frequency of GrB+ producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.



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Issue Information - Cover and Editorial Board

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Issue Information - TOC

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Optical properties of implanted Xe color centers in diamond

Publication date: 15 March 2018
Source:Optics Communications, Volume 411
Author(s): Russell Sandstrom, Li Ke, Aiden Martin, Ziyu Wang, Mehran Kianinia, Ben Green, Wei-bo Gao, Igor Aharonovich
Optical properties of color centers in diamond have been the subject of intense research due to their promising applications in quantum photonics. In this work we study the optical properties of Xe related color centers implanted into nitrogen rich (type IIA) and an ultrapure, electronic grade diamond. The Xe defect has two zero phonon lines at ∼794 nm and 811 nm, which can be effectively excited using both green and red excitation, however, its emission in the nitrogen rich diamond is brighter. Near resonant excitation is performed at cryogenic temperatures and luminescence is probed under strong magnetic field. Our results are important towards the understanding of the Xe related defect and other near infrared color centers in diamond.



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Daily conformity drinking motivations are associated with increased odds of consuming alcohol mixed with energy drinks

Publication date: April 2018
Source:Addictive Behaviors, Volume 79
Author(s): Ashley N. Linden-Carmichael, Cathy Lau-Barraco
Recent research indicates that individuals drank more heavily and experienced more harms on days they consumed alcohol mixed with energy drinks (AmEDs). Limited research, thus far, has examined predictors of AmED use on a daily level. Drinking motives, or reasons for drinking, are shown to discern AmED users from non-users, but the extent to which daily drinking motives covary with AmED use has not been tested. The current study used a daily diary design to determine how motives differ between AmED and other drinking occasions. Participants included 122 college students (73.8% women) with a mean age of 20.39years. Participants completed up to 14 daily surveys, resulting in 389 drinking days (40days involved AmED use). Participants reported on their drinking motives at baseline as well as on each drinking day. Multilevel models revealed that, after controlling for other motives, AmED use was more likely on days where conformity motives were higher than usual and was less likely when enhancement motives were higher. Daily social and coping motives as well as all motives measured at baseline were unassociated with AmED use. Our findings suggest that conformity motives, or drinking to fit in with others, are the most salient drinking motive predicting AmED use on a drinking day. Given that conformity motives are often less associated with alcohol use outcomes in general, these findings highlight AmEDs as a unique alcoholic beverage. Clinicians and interventionists working with frequent AmED users should consider the unique conditions under which AmEDs are consumed.



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Case of warty dyskeratoma on the anterior chest: The relationship between its dermoscopic and histopathological findings

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Granulocyte and monocyte adsorption apheresis for palmoplantar pustulosis with extra-palmoplantar lesions and pustulotic arthro-osteitis

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Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies

Publication date: Available online 20 December 2017
Source:Trends in Immunology
Author(s): Shashi Gujar, Jonathan G. Pol, Youra Kim, Patrick W. Lee, Guido Kroemer
Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics. Administration of OVs to cancer-bearing hosts induces two distinct immunities: antiviral and antitumor. While antitumor immunity is beneficial, antiviral immune responses are often considered detrimental for the efficacy of OV-based therapy. The existing dogma postulates that anti-OV immune responses restrict viral replication and spread, and thus reduce direct OV-mediated killing of cancer cells. Accordingly, a myriad of therapeutic strategies aimed at mitigating anti-OV immune responses is presently being tested. Here, we advocate that OV-induced antiviral immune responses hold intrinsic anticancer benefits and are essential for establishing clinically desired antitumor immunity. Thus, to achieve the optimal efficacy of OV-based cancer immunotherapies, strategic management of anti-OV immune responses is of critical importance.



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Epidermal mast cells in the nail matrix of a patient with psoriasis confined to the nails

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Multiple cutaneous and uterine leiomyomata with features of benign metastasing leiomyomatosis: a novel mutation of the fumarate hydratase gene

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Unilesional CD30+ mycosis fungoides with large cell transformation and spontaneous regression, masquerading as verruca vulgaris

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Localized, ovoid urticarial plaques with fine, nonfollicular pustules

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Combination of low-dose total skin electron beam therapy and subsequent localized skin electron beam therapy as a therapeutic option for advanced-stage mycosis fungoides

Summary

Electron beam therapy (EBT) is an established treatment for mycosis fungoides (MF), but evidence for the use of EBT in advanced cutaneous conditions is limited, and optimal scheduling of the regimen for such conditions remains unclear. We report the case of a 44-year-old woman diagnosed with MF with widespread cutaneous lesions, including multiple huge tumours in the craniofacial area. Low-dose total skin (TS)EBT and subsequent localized skin (LS)EBT achieved striking improvements in eruptions. Oral etretinate was also administered during therapy. Our experience implies that combined TSEBT and LSEBT may be worth attempting when a patient presents with both widespread lesions and prominent tumours, even when the tumours are extremely large.

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Mammography screening: A major issue in medicine

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Philippe Autier, Mathieu Boniol
Breast cancer mortality is declining in most high-income countries. The role of mammography screening in these declines is much debated.Screening impacts cancer mortality through decreasing the incidence of number of advanced cancers with poor prognosis, while therapies and patient management impact cancer mortality through decreasing the fatality of cancers. The effectiveness of cancer screening is the ability of a screening method to curb the incidence of advanced cancers in populations. Methods for evaluating cancer screening effectiveness are based on the monitoring of age-adjusted incidence rates of advanced cancers that should decrease after the introduction of screening. Likewise, cancer-specific mortality rates should decline more rapidly in areas with screening than in areas without or with lower levels of screening but where patient management is similar. These two criteria have provided evidence that screening for colorectal and cervical cancer contributes to decreasing the mortality associated with these two cancers. In contrast, screening for neuroblastoma in children was discontinued in the early 2000s because these two criteria were not met. In addition, overdiagnosis – i.e. the detection of non-progressing occult neuroblastoma that would not have been life-threatening during the subject's lifetime – is a major undesirable consequence of screening.Accumulating epidemiological data show that in populations where mammography screening has been widespread for a long time, there has been no or only a modest decline in the incidence of advanced cancers, including that of de novo metastatic (stage IV) cancers at diagnosis. Moreover, breast cancer mortality reductions are similar in areas with early introduction and high penetration of screening and in areas with late introduction and low penetration of screening. Overdiagnosis is commonplace, representing 20% or more of all breast cancers among women invited to screening and 30–50% of screen-detected cancers. Overdiagnosis leads to overtreatment and inflicts considerable physical, psychological and economic harm on many women. Overdiagnosis has also exerted considerable disruptive effects on the interpretation of clinical outcomes expressed in percentages (instead of rates) or as overall survival (instead of mortality rates or stage-specific survival). Rates of radical mastectomies have not decreased following the introduction of screening and keep rising in some countries (e.g. the United States of America (USA)). Hence, the epidemiological picture of mammography screening closely resembles that of screening for neuroblastoma.Reappraisals of Swedish mammography trials demonstrate that the design and statistical analysis of these trials were different from those of all trials on screening for cancers other than breast cancer. We found compelling indications that these trials overestimated reductions in breast cancer mortality associated with screening, in part because of the statistical analyses themselves, in part because of improved therapies and underreporting of breast cancer as the underlying cause of death in screening groups. In this regard, Swedish trials should publish the stage-specific breast cancer mortality rates for the screening and control groups separately. Results of the Greater New York Health Insurance Plan trial are biased because of the underreporting of breast cancer cases and deaths that occurred in women who did not participate in screening. After 17 years of follow-up, the United Kingdom (UK) Age Trial showed no benefit from mammography screening starting at age 39–41.Until around 2005, most proponents of breast screening backed the monitoring of changes in advanced cancer incidence and comparative studies on breast cancer mortality for the evaluation of breast screening effectiveness. However, in an attempt to mitigate the contradictions between results of mammography trials and population data, breast-screening proponents have elected to change the criteria for the evaluation of cancer screening effectiveness, giving precedence to incidence-based mortality (IBM) and case—control studies. But practically all IBM studies on mammography screening have a strong ecological component in their design. The two IBM studies done in Norway that meet all methodological requirements do not document significant reductions in breast cancer mortality associated with mammography screening. Because of their propensity to exaggerate the health benefits of screening, case–control studies may demonstrate that mammography screening could reduce the risk of death from diseases other than breast cancer.Numerous statistical model approaches have been conducted for estimating the contributions of screening and of patient management to reductions in breast cancer mortality. Unverified assumptions are needed for running these models. For instance, many models assume that if screening had not occurred, the majority of screen-detected asymptomatic cancers would have progressed to symptomatic advanced cancers. This assumption is not grounded in evidence because a large proportion of screen-detected breast cancers represent overdiagnosis and hence non-progressing tumours. The accumulation of population data in well-screened populations diminishes the relevance of model approaches.The comparison of the performance of different screening modalities – e.g. mammography, digital mammography, ultrasonography, magnetic resonance imaging (MRI), three-dimensional tomosynthesis (TDT) – concentrates on detection rates, which is the ability of a technique to detect more cancers than other techniques. However, a greater detection rate tells little about the capacity to prevent interval and advanced cancers and could just reflect additional overdiagnosis. Studies based on the incidence of advanced cancers and on the evaluation of overdiagnosis should be conducted before marketing new breast-imaging technologies.Women at high risk of breast cancer (i.e. 30% lifetime risk and more), such as women with BRCA1/2 mutations, require a close breast surveillance. MRI is the preferred imaging method until more radical risk-reduction options are eventually adopted. For women with an intermediate risk of breast cancer (i.e. 10–29% lifetime risk), including women with extremely dense breast at mammography, there is no evidence that more frequent mammography screening or screening with other modalities actually reduces the risk of breast cancer death.A plethora of epidemiological data shows that, since 1985, progress in the management of breast cancer patients has led to marked reductions in stage-specific breast cancer mortality, even for patients with disseminated disease (i.e. stage IV cancer) at diagnosis. In contrast, the epidemiological data point to a marginal contribution of mammography screening in the decline in breast cancer mortality. Moreover, the more effective the treatments, the less favourable are the harm–benefit balance of screening mammography.New, effective methods for breast screening are needed, as well as research on risk-based screening strategies.



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Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): K. Strasser-Weippl, G. Sudan, R. Ramjeesingh, L.E. Shepherd, J. O'Shaughnessy, W.R. Parulekar, P.E.R. Liedke, B.E. Chen, P.E. Goss
BackgroundHistological subtype, (invasive ductal breast cancer (IDBC)/invasive lobular breast cancer (ILBC)), might be a marker for differential response to endocrine therapy in breast cancer.MethodsClinical trial MA.27 compared 5 years of adjuvant anastrozole or exemestane in postmenopausal patients with hormone receptor positive early breast cancer. We evaluated IDBC versus ILBC (based on original pathology reports) as predictor for event-free survival (EFS) and overall survival (OS).ResultsA total of 5709 patients (5021 with IDBC and 688 with ILBC) were included (1876 were excluded because of missing or other histological subtype). Median follow-up was 4.1 years. Overall, histological subtype did not influence OS or EFS (HR (hazard ratio) 1.14, 95% confidence interval (CI) [0.79–1.63], P = 0.49 and HR 1.04, 95% CI [0.77–1.41], P = 0.81, respectively). There was no significant difference in OS between treatment with exemestane versus treatment with anastrozole in the IDBC group (HR = 0.92, 95% CI [0.73–1.16], P = 0.46). In the ILBC group, a marginally significant difference in favour of treatment with anastrozole was seen (HR = 1.79, 95% CI [0.98–3.27], P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with ILBC on anastrozole (HR 2.1, 95% CI [0.99–4.29], P = 0.05). After stepwise selection in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, 95% CI [1.00–4.31], P = 0.05).ConclusionOur data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with ILBC cancers had a better OS when treated with anastrozole versus exemestane, whereas no difference was noted for patients with IDBC.Clinical Trial informationNCT00066573.



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The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Eric Van Cutsem, Robert J. Mayer, Stéphanie Laurent, Robert Winkler, Cristina Grávalos, Manuel Benavides, Federico Longo-Munoz, Fabienne Portales, Fortunato Ciardiello, Salvatore Siena, Kensei Yamaguchi, Kei Muro, Tadamichi Denda, Yasushi Tsuji, Lukas Makris, Patrick Loehrer, Heinz-Josef Lenz, Atsushi Ohtsu
BackgroundIn the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups.MethodsPrimary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics.ResultsEight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability.ConclusionsTrifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status.This trial is registered with ClinicalTrials.gov: NCT01607957.



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In reference to should infants who fail their newborn hearing screen undergo cytomegalovirus testing?

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Extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma: The first case report and consideration of histogenesis

Abstract

A 61-year-old man presented with a dome-shaped nodule, 1.2 cm in size, with a central crater covered by keratinous material near the left lateral malleolus. Histological findings demonstrated a basophilic circular cone in the center, surrounded and sharply demarcated by a broad eosinophilic area. The central conical mass was composed mainly of atypical basaloid cells intermingled with scattered atypical sebaceous cells with scalloped nuclei and microvesicular cytoplasms, suggesting sebaceous carcinoma. The peripheral area consisted of atypical keratinizing squamoid cells without sebaceous cells, suggesting invasive squamous cell carcinoma. Atypical sebaceous cells were positive for adipophilin. Atypical basaloid cells were positive for 34βE12 and CAM5.2. Peripheral squamoid cells were positive for 34βB4 and 34βE12 throughout, and were positive for LHP1 in the superficial layer. We herein describe the first case of extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma, which might have arisen from biphasic differentiation of cancer stem cells.

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Endodontic management of taurodontism with a complex root canal anatomy in mandibular posterior teeth

One of the biggest challenges in endodontic treatment is to comprehensively understand the variation of tooth root canal anatomy. To a large degree, the anatomy and furcation distribution of teeth, which vary from nationality and ethnic groups, will influence the clinical diagnosis, treatment plan and even prognosis. Taurodontism, as one of anatomic variation in tooth structures, is relatively hard to be seen in dental clinics. Two special cases of taurodontism with varied root canal anatomies in mandibular second premolar and first molar are reported in this paper.

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Subacute combined degeneration of the spinal cord in vitamin B12 and copper deficiency

Description

A 67-year-old man with a medical history of pancreatoduodenectomy (Whipple procedure) in September 2015 due to a pancreatic cancer was admitted to our department of neurology 1 year later with a progressively disturbed gait. He reported weakness and numbness of both legs. Clinical examination revealed a spastic sensomotoric tetraparesis with ataxia and bladder dysfunction. MRI showed longitudinal myelopathy exactly limited to the posterior tracts (fasciculus gracilis and fasciculus cuneatus) indicating a metabolic origin (subacute combined degeneration of the spinal cord; figure 1A,B).

Figure 1

(A) Axial T2-weighted and (B) sagittal short T1 inversion recovery (STIR) MRI of the cervical spine showing longitudinal myelopathy exactly limited to the posterior tracts (fasciculus gracilis and fasciculus cuneatus, arrows). (C) Sagittal STIR MRI of the cervical spine 4 months later.

Consistently and according to the medical history of the Whipple procedure, a moderate vitamin B₁₂ deficiency...

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Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologists perspective

A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure.

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Deliberate self-poisoning with long-acting anticoagulant rodenticides

Long-acting anticoagulant rodenticides, also called superwarfarins, are known for their greater potency, longer half-life and delayed onset of symptoms. Cases of superwarfarin poisoning can pose a diagnostic and clinical challenge due to a wide array of presentations and prolonged severe coagulopathy requiring months of high-dose oral vitamin K therapy. The most common presentation of long-acting anticoagulant rodenticide poisoning is mucocutaneous bleeding, with other common presentations including haematuria, gingival bleeding, epistaxis and gastrointestinal bleeding. We discuss a case of deliberate self-poisoning with long-acting anticoagulant rodenticides presenting with haematuria and coagulation values above measurable limits. This case is important as it required immediate and maintenance therapy in order to prevent profound bleeding, as well as the evaluation of the patient's psychosocial factors to ensure medical compliance and to prevent refractory complications or repeated self-harm.

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Stenotrophomonas maltophilia: an emerging multidrug-resistant opportunistic pathogen in the immunocompromised host

Stenotrophomonas maltophilia is a multidrug-resistant opportunistic pathogen with increasing prevalence and high morbidity and mortality. In addition to its classic association with pulmonary infections, S. maltophilia can cause skin and soft tissue infections with varying clinical presentations. We describe the case of a man in his 30s with B-cell acute lymphoblastic leukaemia who presented with a solitary patch of faint but tender purpura found to have rapidly progressive S. maltophilia infection diagnosed on skin biopsy. S. maltophilia infection should be considered in the cutaneous evaluation of the immunocompromised host.

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Colonic perforation by an intrathecal baclofen pump catheter causing delayed Escherichia coli meningitis

Intrathecal baclofen (ITB) delivery via an implanted pump is frequently used for the treatment of spasticity. This is an effective and safe neurosurgical and pharmacological intervention associated with an improvement in patient quality of life. There is, however, a risk of device-related infection. We present a patient with pump-site infection and Escherichia coli meningitis secondary to transcolonic perforation of an intrathecal baclofen pump catheter. While this is rare, we review the intraoperative precautions and best practices that should be taken to prevent and manage this unusual complication.

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A disclosed diagnosis for 24 years unknown illness

IgG4-related disease (IgG4-RD) is a newly described illness over the last several years. A 57-year-old man, who had been followed for chronic kidney disease (CKD), chronic pancreatitis and history of operated cholangitis, was admitted to our hospital for abdominal pain and worsening renal function. Serum levels of IgG and IgG4 were elevated. CT scan showed the characteristic findings of IgG4-related retroperitoneal fibrosis, pancreas and kidney disease. An endoscopic biopsy revealed the finding compatible with IgG4-RD. Steroid therapy led to the remission of his abdominal pain. Patients with CKD of unknown aetiology may have IgG4-RD.

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A surgeons nightmare: pyoderma gangrenosum with pathergy effect mimicking necrotising fasciitis

A 53-year-old woman was admitted for vulval swelling and fever. She was initially diagnosed with vulval cellulitis and given parenteral antibiotics. Within 1 week, she developed necrotic-looking skin lesions extending from her vulva to her buttock. Emergency surgical debridement with diversion colostomy was performed in view of suspected necrotising fasciitis. Shortly after the surgery, she developed necrotic-looking skin lesions at the peripheral venous cannula insertion site, central line insertion site, and around her surgical wounds and stoma. A second surgical debridement was performed and shortly afterwards, similar skin lesions appeared around her surgical wounds. Her clinical progression was suggestive of pyoderma gangrenosum with pathergy effect. Hence, she was started on topical steroid, systemic steroid and immunosuppressant. The skin lesions responded well to medical therapy. Further systemic workup for conditions associated with this disease revealed findings suspicious for myelodysplastic syndrome.

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Management of atypical femoral fracture in a patient with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a generalised connective tissue disorder associated with low bone mass, bone fragility and increased susceptibility to fractures. First-line treatment to improve bone mineral density (BMD) is usually with bisphosphonates but long-term usage has been associated with uncommon complications such as atypical femoral fractures (AFF). Treatment with teriparatide in this situation has been reported with positive outcomes. However, choice of treatment after 2 years of teriparatide has not been well studied or reported. We describe a patient with OI treated with bisphosphonates for 9 years, who then suffered a spontaneous AFF, was subsequently started on teriparatide for 2 years followed by 6 monthly Denosumab. 1 year post-treatment with Denosumab, there was significant improvement in BMD, good fracture healing and no new fractures. This case highlights the potential use of denosumab following 2 years of teriparatide treatment in patients with OI with AFF.

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Spinal cord abscess secondary to infected dorsal dermal sinus in an infant: uncommon presentation of a known entity

Infection along the congenital dermal sinus tract is well known. However, congenital dorsal dermal sinus presenting with intramedullary abscess is quite rare. The sinus tract usually presents in the midline and acts as a portal of entry for infection that may manifest as meningitis, extradural or subdural abscess and may further involve the cord. Surgical drainage of pus and complete excision of the sinus tract is the standard treatment. Here we describe an infant with an infected congenital dorsal dermal sinus with atypical presentation as large paracentral abscess in the upper back. We further highlight the importance of recognising and treating these skin dimples even when clinically silent to avoid catastrophic complications.

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Uvular necrosis following diagnostic gastroscopy

Uvular necrosis is an extremely rare complication of gastroscopy. We describe the fifth published case of uvular necrosis following an uncomplicated diagnostic gastroscopy in a young man. Presentation with severe sore throat and inability to swallow saliva occurred within 24 hours of gastroscopy and resolved with conservative treatment.

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Auditory agnosia caused by bilateral putamen haemorrhage

A 55-year-old right-handed man with a history of hypertension suddenly fell and developed right hemiparesis. Neurological examination revealed that he was alert, but did not appropriately respond to verbal questions and commands. Detailed examination revealed that he could correctly respond to written commands. His speech was almost fluent, showing no paraphasia and normal articulation. His written sentences were legible. Pure tone audiometry showed that his auditory acuity was relatively preserved. His brainstem auditory evoked potential components from I to V were recorded bilaterally with normal latency. Cerebral CT demonstrated fresh bleeding in the left putamen and an old haemorrhage on the opposite side. He was treated by antihypertensive therapy and rehabilitation. Although there remained mild sensory deficit on his right extremities and he felt a slight noise during conversation, he had little difficulty with verbal communication when he was transferred to another hospital on day 38.

http://ift.tt/2Dmb97m

Successful embolisation of an intracranial meningioma via a right-sided aortic arch

Right aortic arch is an unusual arch variation. Supra-aortic neurointervention in such cases has been sparingly reported. This case highlights the unusual association of a left hemispheric convexity meningioma with a right aortic arch which was successfully navigated. Particle embolisation of the meningioma produced good results followed by complete surgical excision and gratifying overall final outcome in this challenging scenario.

http://ift.tt/2oXWVWZ

Primary apocrine carcinoma of an unusual site

Primary apocrine carcinoma is a rare malignancy most commonly occurring in apocrine dense areas like axilla. There are only about 200 cases reported to date. We report a case of primary apocrine carcinoma present at an unusual site, that is, the arm. A wide local excision of the mass was done and was diagnosed as apocrine carcinoma on histopathological examination and was confirmed by immunohistochemistry. Wide local excision is the treatment required.

http://ift.tt/2DjIYpi

Mystery ring: a case of TIPS stent migration

Description

We present a 50-year-old man with history of end-stage liver disease secondary to hepatitis C, who frequently presents to the hospital with ascites. He recently underwent Trans jugular Intrahepatic Portosystemic Shunt (TIPS) stent placement after becoming resistant to diuresis and large volume therapeutic paracentesis. He presented to the emergency room with altered mental status due to hepatic encephalopathy. On physical exam, he was noted to have a systolic murmur; hence, a transthoracic echocardiogram was ordered. It showed an echo dense ring-like shadow in the right atrium close to intra-atrial septum (figure 1). Transoesophageal echocardiogram was obtained for better visualisation, and it showed a migrated TIPS stent entering the right atrium from the inferior vena cava with its cephalad end close to the intra-atrial septum (figure 2). There was no evidence of mechanical complication related to stent migration by echocardiography. The patient declined percutaneous retrieval....

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Ultrawide field imaging with navigable magnifier for diagnosis of diffuse unilateral subacute neuroretinitis

Description

A 52-year-old female presented with painless loss of vision in right eye since 3–4 years. Visual acuity was counting fingers close to face in right eye and 20/20 in left eye. Anterior segment examination and intraocular pressure were normal in both eyes. Right eye had multiple areas of pigment mottling and deep retinal scarring scattered throughout the fundus, along with optic disc atrophy (figure 1). Fundus examination of left eye was unremarkable. Window defects were detected on ultrawide field fluorescein angiography. Diffuse unilateral subacute neuroretinitis (DUSN) was suspected due to the ultrawide field imaging (UWFI) characteristics. The clinical UWFI was scanned with a navigable magnifier available in the software (Optos PLC, Dunfermline, UK). A slender, white-coloured, minimally curved structure was identified in the temporal pre-equatorial region with an adjoining scar (figure 2).

Figure 1

UWFI of the right eye depicting multiple...

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Recurrent lower gastrointestinal bleeding in an 87-year-old woman

Description

An 87-year-old woman presented to an outside hospital with a complaint of bright red blood per rectum (BRBPR), where her haemoglobin was found to be 4.6 g/dL. An extensive gastrointestinal (GI) work was performed, including oesophagogastroduodenoscopy, colonoscopy and a video capsule endoscopy, followed by a superior mesenteric artery (SMA) angiogram which showed no active extravasation. The patient continued to have BRBPR and was transferred to our hospital for further work-up. Her medical history was significant for hypertension, hyperlipidaemia and coronary artery disease. Her surgical history included knee arthroplasty, hernia repair, hysterectomy, cholecystectomy and appendectomy. Physical examination of the abdomen was soft, non-distended and non-tender. On transfer, a CT enterography was obtained and could not identify the source of bleeding but did note some stenosis of the superior mesenteric artery (SMA). A colonoscopy was then performed, which revealed old blood in her colon, but no active bleeding was found. A subsequent nuclear tagged...

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Giant ductal pseudoaneurysm in infancy: a lesson learnt the hard way

Description

A 7-month-old girl, ex-preterm (26-weeker), 4.5 kg, with 4 mm patent ductus arteriosus (PDA) underwent PDA device closure (Amplatzer duct occluder - ADO II 4x6 mm) elsewhere and was readmitted 4 days later with pericardial effusion. Needle pericardiocentesis drained 50 mL of haemorrhagic fluid. Septic screen was negative. Severe dyspnoea ensued 2 weeks later. Chest X-ray excluded lung pathology. Bedside echocardiogram showed PDA device in situ (online ), no residual ductus, vegetation or pericardial recollection, unobstructed flow in the pulmonary artery and descending aorta, normal pulmonary arterial pressures, and normal biventricular function. Curiously, a giant anechoic mass (22x25 mm) (online ) was visualised posteroinferior to the device with its neck communicating with lesser curvature of the thoracic aorta at the level of origin of the left subclavian artery (figure 1A,B). Intra-aneurysmal thrombus or aortic dissection was absent. We diagnosed giant ductal pseudoaneurysm with possible left bronchial compression.

Figure 1

(A) Parasternal short-axis transthoracic two-dimensional echocardiogram...

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Sensory neuronopathy associated with cholangiocarcinoma diagnosed 6 years after symptom onset

A pure sensory neuronopathy (also referred to as a sensory ganglionopathy) is one of a handful of classical neurological paraneoplastic syndromes. Current guidelines recommend that in cases of sensory neuronopathy, a search for an underlying malignancy be pursued for up to 4 years. We report the case of a 52-year-old woman with a sensory neuronopathy who was eventually diagnosed with a cholangiocarcinoma 6 years after the onset of her disease. A CT fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed 18 and 24 months after disease onset failed to identify an underlying neoplasm. Immunomodulatory treatment with corticosteroids, intravenous immunoglobulins and plasma exchange were ineffective. Investigations for Sjogren's disease were negative. A third FDG-PET performed 6 years after symptom onset identified a cholangiocarcinoma, which was confirmed histologically following open resection. Since the tumour was removed, our patient's condition has not progressed, but there has been no improvement and she remains severely disabled.

http://ift.tt/2p0Ck4h

Nasal tip schwannoma mimicking rhinophyma

Description

Rhinophyma meaning 'nose growth' in Greek is a relatively common condition that describes thickening of the nasal skin with enlargement of the sebaceous glands. While not fully understood, it is believed to be a result of vascular instability causing leakage of fluid into the tissues. This subsequently triggers inflammation and scarring.1 Treatment is initially medical; systemic isotretinoin has been shown to reduce the bulk of rhinophyma. Many surgical techniques have also been described, all of which involve tissue removal. Previous literature has demonstrated other skin conditions mimicking this diagnosis including angiosarcoma, squamous cell carcinoma and sarcoidosis.2

A 52-year-old woman was referred to ear, nose and throat (ENT) from dermatology for surgical management of rhinophyma. She described a 3-year history of an increasing swelling on the tip of her nose (figure 1). During this time, she underwent extensive conservative treatment with...

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miRNA delivery for skin wound healing

Publication date: Available online 19 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Zhao Meng, Dezhong Zhou, Yongsheng Gao, Ming Zeng, Wenxin Wang
The wound healing has remained a worldwide challenge as one of significant public health problems. Pathological scars and chronic wounds caused by injury, aging or diabetes lead to impaired tissue repair and regeneration. Due to the unique biological wound environment, the wound healing is a highly complicated process, efficient and targeted treatments are still lacking. Hence, research-driven to discover more efficient therapeutics is a highly urgent demand. Recently, the research results have revealed that microRNA (miRNA) is a promising tool in therapeutic and diagnostic fields because miRNA is an essential regulator in cellular physiology and pathology. Therefore, new technologies for wound healing based on miRNA have been developed and miRNA delivery has become a significant research topic in the field of gene delivery.

Graphical abstract

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The influence of developmental timing on B cell diversity

Trine A Kristiansen | Stijn Vanhee | Joan Yuan

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Considering factors affecting the connectome-based identification process: Comment on Waller et al.

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Corey Horien, Stephanie Noble, Emily S. Finn, Xilin Shen, Dustin Scheinost, R. Todd Constable
A recent study by Waller and colleagues evaluated the reliability, specificity, and generalizability of using functional connectivity data to identify individuals from a group. The authors note they were able to replicate identification rates in a larger version of the original Human Connectome Project (HCP) dataset. However, they also report lower identification accuracies when using historical neuroimaging acquisitions with low spatial and temporal resolution. The authors suggest that their results indicate connectomes derived from historical imaging data may be similar across individuals, to the extent that this connectome-based approach may be inappropriate for precision psychiatry and the goal of drawing inferences based on subject-level data. Here we note that the authors did not take into account factors affecting data quality and hence identification rates, independent of whether a low spatiotemporal resolution acquisition or a high spatiotemporal resolution acquisition is used. Specifically, we show here that the amount of data collected per subject and in-scanner motion are the predominant factors influencing identification rates, not the spatiotemporal resolution of the acquisition. To do this, we investigated identification rates in the HCP dataset as a function of the amount of data and motion. Using a dataset from the Consortium for Reliability and Reproducibility (CoRR), we investigated the impact of multiband versus non-multiband imaging parameters; that is, high spatiotemporal resolution versus low spatiotemporal resolution acquisitions. We show scan length and motion affect identification, whereas the imaging protocol does not affect these rates. Our results suggest that motion and amount of data per subject are the primary factors impacting individual connectivity profiles, but that within these constraints, individual differences in the connectome are readily observable.



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Gas-free calibrated fMRI with a correction for vessel-size sensitivity

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Avery J.L. Berman, Erin L. Mazerolle, M. Ethan MacDonald, Nicholas P. Blockley, Wen-Ming Luh, G. Bruce Pike
Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology.



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Affective value, intensity and quality of liquid tastants/food discernment in the human brain: An activation likelihood estimation meta-analysis

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Andy Wai Kan Yeung, Tazuko K. Goto, W. Keung Leung
The primary dimensions of taste are affective value, intensity and quality. Numerous studies have reported the role of the insula in evaluating these dimensions of taste; however, the results were inconsistent. Therefore, in the current study, we performed meta-analyses of published data to identify locations consistently activated across studies and evaluate whether different regions of the human brain could be responsible for processing different dimensions of taste. Meta-analyses were performed on 39 experiments, with 846 total healthy subjects (without psychiatric/neurological disorders) in 34 studies reporting whole-brain results. The aim was to establish the activation likelihood estimation (ALE) of taste-mediated regional activation across the whole brain. Apart from one meta-analysis for all studies in general, three analyses were performed to reveal the clusters of activation that were attributable to processing the affective value (data from 323 foci), intensity (data from 43 foci) and quality (data from 45 foci) of taste. The ALE revealed eight clusters of activation outside the insula for processing affective value, covering the middle and posterior cingulate, pre-/post-central gyrus, caudate and thalamus. The affective value had four clusters of activation (two in each hemisphere) in the insula. The intensity and quality activated only the insula, each with one cluster on the right. The concurrence between studies was moderate; at best, 53% of the experiments contributed to the significant clusters attributable to the affective value, 60% to intensity and 50% to quality. The affective value was processed bilaterally in the anterior to middle insula, whereas intensity was processed in the right antero-middle insula, and quality was processed in the right middle insula. The right middle dorsal insula was responsible for processing both the affective value and quality of taste. The exploratory analysis on taste quality did not have a significant result if the studies using liquid food stimuli were excluded. Results from the meta-analyses on studies involving the oral delivery of liquid tastants or liquid food stimuli confirmed that the insula is involved in processing all three dimensions of taste. More experimental studies are required to investigate whether brain activations differ between liquid tastants and food. The coordinates of activated brain areas and brain maps are provided to serve as references for future taste/food studies.



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Contrasting functional imaging parametric maps: The mislocation problem and alternative solutions

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Mathieu Bourguignon, Nicola Molinaro, Vincent Wens
In the field of neuroimaging, researchers often resort to contrasting parametric maps to identify differences between conditions or populations. Unfortunately, contrast patterns mix effects related to amplitude and location differences and tend to peak away from sources of genuine brain activity to an extent that scales with the smoothness of the maps. Here, we illustrate this mislocation problem on source maps reconstructed from magnetoencephalographic recordings and propose a novel, dedicated location-comparison method. In realistic simulations, contrast mislocation was on average ∼10 mm when genuine sources were placed at the same location, and was still above 5 mm when sources were 20 mm apart. The dedicated location-comparison method achieved a sensitivity of ∼90% when inter-source distance was 12 mm. Its benefit is also illustrated on real brain-speech entrainment data. In conclusion, contrasts of parametric maps provide precarious information for source location. To specifically address the question of location difference, one should turn to dedicated methods as the one proposed here.



http://ift.tt/2kuTOkK

Early use of 80 Hz subthalamic stimulation in Parkinson's disease as an alternative for High-frequency stimulation induced gait changes and postural instability

Publication date: Available online 20 December 2017
Source:Brain Stimulation
Author(s): Marcelo D. Mendonça, Raquel Barbosa, Alexandra Seromenho-Santos, Carla Reizinho, Paulo Bugalho




http://ift.tt/2CNpHf4

Vestibulo-cochlear function in inflammatory neuropathies

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): Marisa Blanquet, Jens A. Petersen, Antonella Palla, Dorothe Veraguth, Konrad P. Weber, Dominik Straumann, Alexander A. Tarnutzer, Hans H. Jung
ObjectiveWe aimed to quantify peripheral-vestibular deficits that may contribute to imbalanced stance/gait in patients with inflammatory neuropathies.MethodsTwenty-one patients (58±15y [mean age±1SD]; chronic-inflammatory-demyelinating-polyneuropathy=10, Guillain-Barré Syndrome=5, Anti-MAG peripheral neuropathy=2, multifocal-motor-neuropathy=4) were compared with 26 healthy controls. All subjects received video-head-impulse testing (vHIT), caloric irrigation and cervical/ocular vestibular-evoked myogenic-potentials (VEMPs). The Yardley vertigo-symptom-scale (VSS) was used to assess vertigo/dizziness. Postural stability was assessed using the functional gait-assessment (FGA). Pure-tone audiograms (n=18), otoacoustic emissions (n=12) and auditory brainstem responses were obtained (n=12).ResultsSemicircular-canal hypofunction was noted in 9/21 (43%) patients (vHIT=6; caloric irrigation=5), whereas otolith function was impaired in 12/21 (57%) (oVEMPs=8; cVEMPs=5), resulting in vestibular impairment of at least one sensor in 13/21 (62%). On average, 2.4±1.1 vestibular end organs (each side: anterior/posterior/horizontal canal, utriculus, sacculus; total=10) were affected. The VSS-scores were higher in patients (16.8±8.6 vs. 9.5±6.2, p=0.002) but did not correlate with the number of affected organs. Auditory neuropathy was found in 1/12 (8%) patients.ConclusionImpairment of one or more vestibular end organs was frequent, but usually mild, possibly contributing to imbalance of stance/gait in inflammatory neuropathies.SignificanceWhile our data does not support routine vestibular testing in inflammatory neuropathies, this may be considered in selected cases.



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Spectral and temporal electroencephalography measures reveal distinct neural networks for the acquisition, consolidation, and interlimb transfer of motor skills in healthy young adults

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): M.P. Veldman, N.M. Maurits, M.A.M. Nijland, N.E. Wolters, J.C. Mizelle, T. Hortobágyi
ObjectivePlasticity of the central nervous system likely underlies motor learning. It is however unclear, whether plasticity in cortical motor networks is motor learning stage-, activity-, or connectivity-dependent.MethodsFrom electroencephalography (EEG) data, we quantified effective connectivity by the phase slope index (PSI), neuronal activity by event-related desynchronization, and sensorimotor integration by N30 during the stages of visuomotor skill acquisition, consolidation, and interlimb transfer.ResultsAlthough N30 amplitudes and event-related desynchronization in parietal electrodes increased with skill acquisition, changes in PSI correlated most with motor performance in all stages of motor learning. Specifically, changes in PSI between the premotor, supplementary motor, and primary motor cortex (M1) electrodes correlated with skill acquisition, whereas changes in PSI between electrodes representing M1 and the parietal and primary sensory cortex (S1) correlated with skill consolidation. The magnitude of consolidated interlimb transfer correlated with PSI between bilateral M1s and between S1 and M1 in the non-practiced hemisphere.ConclusionsSpectral and temporal EEG measures but especially PSI correlated with improvements in complex motor behavior and revealed distinct neural networks in the acquisition, consolidation, and interlimb transfer of motor skills.SignificanceA complete understanding of the neuronal mechanisms underlying motor learning can contribute to optimizing rehabilitation protocols



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Cortical sources of resting state electroencephalographic rhythms probe brain function in naïve HIV individuals

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): Claudio Babiloni, Giuseppe Noce, Alfredo Pennica, Paolo Onorati, Paolo Capotosto, Claudio Del Percio, Paolo Roma, Valentina Correr, Elisa Piccinni, Ginevra Toma, Andrea Soricelli, Francesco Di Campli, Laura Gianserra, Lorenzo Ciullini, Antonio Aceti, Elisabetta Teti, Loredana Sarmati, Gloria Crocetti, Raffaele Ferri, Valentina Catania, Maria Teresa Pascarelli, Massimo Andreoni, Stefano Ferracuti
ObjectiveHere we evaluated the hypothesis that resting state electroencephalographic (EEG) cortical sources correlated with cognitive functions and discriminated asymptomatic treatment-naïve HIV subjects (no AIDS).MethodsEEG, clinical, and neuropsychological data were collected in 103 treatment-naïve HIV subjects (88 males; mean age 39.8 years ± 1.1 standard error of the mean, SE). An age-matched group of 70 cognitively normal and HIV-negative (Healthy; 56 males; 39.0 years ± 2.0 SE) subjects, selected from a local university archive, was used for control purposes. LORETA freeware was used for EEG source estimation in fronto-central, temporal, and parieto-occipital regions of interest.ResultsWidespread sources of delta (< 4 Hz) and alpha (8-12 Hz) rhythms were abnormal in the treatment-naïve HIV group. Fronto-central delta source activity showed a slight but significant (p < 0.05, corrected) negative correlation with verbal and semantic test scores. So did parieto-occipital delta/alpha source ratio with memory and composite cognitive scores. These sources allowed a moderate classification accuracy between HIV and control individuals (area under the ROC curves of 70-75%).ConclusionsRegional EEG abnormalities in quiet wakefulness characterized treatment-naïve HIV subjects at the individual level.SignificanceThis EEG approach may contribute to the management of treatment-naïve HIV subjects at risk of cognitive deficits.



http://ift.tt/2z7C4QR

Rattle-type Au@Cu2−xS hollow mesoporous nanocrystals with enhanced photothermal efficiency for intracellular oncogenic microRNA detection and chemo-photothermal therapy

Publication date: March 2018
Source:Biomaterials, Volume 158
Author(s): Yu Cao, Shuzhou Li, Chao Chen, Dongdong Wang, Tingting Wu, Haifeng Dong, Xueji Zhang
The coupling of the localized surface plasma resonance (LSPR) between noble metals of Au, Ag and Cu and semiconductors of Cu2−xE (E = S, Se, Te) opens new regime to design photothermal (PT) agents with enhanced PT conversion efficiency. However, it is rarely explored on fabricating of engineered dual plasmonic hybrid nanosystem for combinatory therapeutic-diagnostic applications. Herein, rattle-type Au@Cu2−xS hollow mesoporous nanoparitcles with advanced PT conversion efficiency are designed for cellular vehicles and chemo-photothermal synergistic therapy platform. The LSPR coupling between the Au core and Cu2−xS shell are investigated experimentally and theoretically to generate a PT conversion efficiency high to 35.2% and enhanced by 11.3% than that of Cu2−xS. By conjugating microRNA (miRNA) gene probe on the surface, it can realize the intracellular oncogenic miRNA detection. After loading of anticancer drug doxorubicin into the cavity of the Au@Cu2−xS, the antitumor therapy efficacy is greatly enhanced in vitro and in vivo due to the NIR photoactivation chemo- and photothermal synergistic therapy. The rattle-type metal-semiconductor hollow mesoporous nanostructure with efficient LSPR coupling and high cargo loading capability will be beneficial to future design of LSPR-based photothermal agents for a broad range of biomedical application.



http://ift.tt/2BPcIwH

Microenvironments to study migration and somal translocation in cortical neurons

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Shifang Zhao, Wenqiang Fan, Xiang Guo, Longjian Xue, Benedikt Berninger, Marcelo J. Salierno, Aránzazu del Campo
Migrating post-mitotic neurons of the developing cerebral cortex undergo terminal somal translocation (ST) when they reach their final destination in the cortical plate. This process is crucial for proper cortical layering and its perturbation can lead to brain dysfunction. Here we present a reductionist biomaterials platform that faithfully supports and controls the distinct phases of terminal ST in vitro. We developed microenvironments with different adhesive molecules to support neuronal attachment, neurite extension, and migration in distinct manners. Efficient ST occurred when the leading process of migratory neurons crossed from low-to high-adhesive areas on a substrate, promoting spreading of the leading growth cone. Our results indicate that elementary adhesive cell-substrate interactions strongly influence migratory behavior and the final positioning of neurons during their developmental journey. This in vitro model allows advanced experimentation to reveal the microenvironmental requirements underlying cortical layer development and disorders.



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Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Marta Overchuk, Gang Zheng
Despite rapid advancements in the field of nanotechnology, there is mounting frustration in the scientific community regarding the translational impact of nanomedicine. Modest therapeutic performance of FDA-approved nanomedicines combined with multiple disappointing clinical trials (such as phase III HEAT trial) have raised questions about the future of nanomedicine. Encouraging breakthroughs, however, have been made in the last few years towards the development of new classes of nanoparticles that can respond to tumor microenvironmental conditions and successfully deliver therapeutic agents to cancer cells. Concurrently, a great deal of effort has also been devoted to alter various parameters of tumor pathophysiology to pre-treat tumors before nanoparticles are administered. Such 'priming' treatments improve access of the systemically administered agents to the tumor and promote drug penetration into the deeper layers of tumor tissue. This review will highlight recent advances in cancer nanomedicine exploiting both nanoparticle design and tumor microenvironment modification; and provide a critical perspective on the future development of nanomedicine delivery in oncology.

Graphical abstract

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Thrombolytic therapy based on fucoidan-functionalized polymer nanoparticles targeting P-selectin

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Maya Juenet, Rachida Aid-Launais, Bo Li, Alice Berger, Joël Aerts, Véronique Ollivier, Antonino Nicoletti, Didier Letourneur, Cédric Chauvierre
Injection of recombinant tissue plasminogen activator (rt-PA) is the standard drug treatment for thrombolysis. However, rt-PA shows risk of hemorrhages and limited efficiency even at high doses. Polysaccharide-poly(isobutylcyanoacrylate) nanoparticles functionalized with fucoidan and loaded with rt-PA were designed to accumulate on the thrombus. Fucoidan has a nanomolar affinity for the P-selectin expressed by activated platelets in the thrombus. Solid spherical fluorescent nanoparticles with a hydrodynamic diameter of 136 ± 4 nm were synthesized by redox radical emulsion polymerization. The clinical rt-PA formulation was successfully loaded by adsorption on aminated nanoparticles and able to be released in vitro. We validated the in vitro fibrinolytic activity and binding under flow to both recombinant P-selectin and activated platelet aggregates. The thrombolysis efficiency was demonstrated in a mouse model of venous thrombosis by monitoring the platelet density with intravital microscopy. This study supports the hypothesis that fucoidan-nanoparticles improve the rt-PA efficiency. This work establishes the proof-of-concept of fucoidan-based carriers for targeted thrombolysis.

Graphical abstract

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A decade of progress in liver regenerative medicine

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Jingwei Zhang, Xin Zhao, Liguo Liang, Jun Li, Utkan Demirci, ShuQi Wang
Liver diseases can be caused by viral infection, metabolic disorder, alcohol consumption, carcinoma or injury, chronically progressing to end-stage liver disease or rapidly resulting in acute liver failure. In either situation, liver transplantation is most often sought for life saving, which is, however, significantly limited by severe shortage of organ donors. Until now, tremendous multi-disciplinary efforts have been dedicated to liver regenerative medicine, aiming at providing transplantable cells, microtissues, or bioengineered whole liver via tissue engineering, or maintaining partial liver functions via extracorporeal support. In both directions, new compatible biomaterials, stem cell sources, and bioengineering approaches have fast-forwarded liver regenerative medicine towards potential clinical applications. Another important progress in this field is the development of liver-on-a-chip technologies, which enable tissue engineering, disease modeling, and drug testing under biomimetic extracellular conditions. In this review, we aim to highlight the last decade's progress in liver regenerative medicine from liver tissue engineering, bioartificial liver devices (BAL), to liver-on-a-chip platforms, and then to present challenges ahead for further advancement.



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Cold atmospheric plasma (CAP), a novel physicochemical source, induces neural differentiation through cross-talk between the specific RONS cascade and Trk/Ras/ERK signaling pathway

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Ja-Young Jang, Young June Hong, Junsup Lim, Jin Sung Choi, Eun Ha Choi, Seongman Kang, Hyangshuk Rhim
Plasma, formed by ionization of gas molecules or atoms, is the most abundant form of matter and consists of highly reactive physicochemical species. In the physics and chemistry fields, plasma has been extensively studied; however, the exact action mechanisms of plasma on biological systems, including cells and humans, are not well known. Recent evidence suggests that cold atmospheric plasma (CAP), which refers to plasma used in the biomedical field, may regulate diverse cellular processes, including neural differentiation. However, the mechanism by which these physicochemical signals, elicited by reactive oxygen and nitrogen species (RONS), are transmitted to biological system remains elusive. In this study, we elucidated the physicochemical and biological (PCB) connection between the CAP cascade and Trk/Ras/ERK signaling pathway, which resulted in neural differentiation. Excited atomic oxygen in the plasma phase led to the formation of RONS in the PCB network, which then interacted with reactive atoms in the extracellular liquid phase to form nitric oxide (NO). Production of large amounts of superoxide radical (O2⁻) in the mitochondria of cells exposed to CAP demonstrated that extracellular NO induced the reversible inhibition of mitochondrial complex IV. We also demonstrated that cytosolic hydrogen peroxide, formed by O2⁻ dismutation, act as an intracellular messenger to specifically activate the Trk/Ras/ERK signaling pathway. This study is the first to elucidate the mechanism linking physicochemical signals from the CAP cascade to the intracellular neural differentiation signaling pathway, providing physical, chemical and biological insights into the development of therapeutic techniques to treat neurological diseases.



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Editorial Board

Publication date: February 2018
Source:Biomaterials, Volume 156





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Nanoantagonists with nanophase-segregated surfaces for improved cancer immunotherapy

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Yang Ma, Sheng-Lin Qiao, Yi Wang, Yao-Xin Lin, Hong-Wei An, Xiao-Chun Wu, Lei Wang, Hao Wang
The blockade of PD-1/PD-L1 interaction by peptide antagonists can unleash and enhance pre-existing anti-cancer immune responses of T cells to eradicate cancer cells. However, low proteolytic stability is the "Achilles' Heel" of peptides. Here, we first report a nanoantagonist with a physiological temperature sensitive nanophase-segregated surface that exhibits significantly enhanced blood circulation, peptide stability and PD-L1 immune checkpoint blockade efficacy. Thermosensitive polymers with different phase transition temperatures (Tt) are used to form the nanophase-segregated surface on an Au nanorod core. Importantly, the nanophase-segregated surface aids the nanoantagonist to resist protein adsorption and enhance the systemic stability of the linked peptides. Finally, the as-designed nanoantagonist effectively blocks PD-1/PD-L1 interaction in vitro and in vivo, enhances the pre-existing CD8⁺ T cell tumor destruction capability and inhibits tumor growth. This study offers a new strategy for designing nano-formulations for cancer immunotherapy.



http://ift.tt/2BQw6cG

The opportunistic human fungal pathogen Candida albicans promotes the growth and proliferation of commensal Escherichia coli through an iron-responsive pathway

Publication date: Available online 20 December 2017
Source:Microbiological Research
Author(s): Shanshan Li, Xiaoyu Yu, Wenjuan Wu, Daniel Z. Chen, Ming Xiao, Xinhua Huang
Candida albicans is a commensal fungal species that commonly colonizes a heterogeneous mixture of human body where it intimately interacts with other microbes in the host environment such as the gastrointestinal (GI) tract. Most studies in fungal-bacterial interactions are about synergistic or antagonistic effects of bacterial functions on fungal physiological activities including pathogenicity. Very few studies have been demonstrated about the role of fungi on bacteria. In this study, we investigated the interactions between C. albicans and the bacterium Escherichia coli and unexpectedly observed that C. albicans enhances growth and proliferation of Escherichia coli strain K12 by facilitating its cell division. Importantly, we found, based on our genetic screens, that both fungus- and bacterium-derived factors, including the iron-responsive transcription factors Sef1 and Sfu1 in C. albicans and the siderophere enterobactin transporters FepD and FepG in E. coli, actively contribute to this transkingdom interaction. Deletion of SFU1 or SEF1 caused a dramatic reduction in growth enhancement of E. coli. Compared to the wild type E. coli, the enhanced growth of both fepD and fepG null mutants were largely dampened. However, the E. coli mutant lacking entB, a key enzyme catalyzing the biosynthesis of siderophore enterobactin, showed similar growth enhancement as the wild type when co-inoculated with C. albicans. C. albicans promotes growth and proliferation of the commensal bacterium E. coli and an iron-responsive signaling pathway appears to be required. C. albicans may act to supply a siderophere-like molecule that captures the environmental iron to promote the growth of E. coli. Our studies gave insight into a novel interacting mechanism operative in interspecies communication that occurs when bacteria and fungi co-exist.



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Comparative transcriptomic analysis of Cerrena unicolor revealed differential expression of genes engaged in degradation of various kinds of wood

Publication date: Available online 20 December 2017
Source:Microbiological Research
Author(s): Grzegorz Janusz, Andrzej Mazur, Jerzy Wielbo, Piotr Koper, Kamil Żebracki, Anna Pawlik, Beata Ciołek, Andrzej Paszczyński, Agnieszka Kubik-Komar
To explore the number of enzymes engaged by Cerrena unicolor FCL139 for wood degradation, the transcriptomes of the fungus growing on birch, ash, maple sawdust and the control liquid medium were analyzed. Among 12,966 gene models predicted for the C. unicolor genome, 10,396 all-unigenes were detected, of which 9,567 were found to be expressed in each of the tested growth media. The highest number (107) of unique transcripts was detected during fungus growth in the control liquid medium, while the lowest number (11) – in the fungal culture comprising maple saw dust. Analysis of C. unicolor transcriptomes identified numerous genes whose expression differed substantially between the mycelia growing in control medium and each of the sawdust media used, with the highest number (828) of upregulated transcripts observed during the fungus growth on the ash medium. Among the 294 genes that were potentially engaged in wood degradation, the expression of 59 was significantly (p < .01) changed in the tested conditions. The transcripts of 37 of those genes were at least four times more abundant in the cells grown in all sawdust media when compared to the control medium. Upregulated genes coding for cellulases and, to a lower extent, hemicellulases predominated during fungus growth on sawdust. Transcripts encoding cellulolytic enzymes were the most abundant in mycelia grown on birch and maple while lower number of such transcripts was detected in fungus growing on ash. The expression pattern of lignolytic activities-coding genes was strongly dependent on the type of sawdust applied for fungus growth medium.



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Is tracheotomy on the decline in otolaryngology? A single institutional analysis

A recent study reported decreasing trends in tracheotomy procedures by its otolaryngology service. We set out to determine whether the previously reported decrease in otolaryngology performed tracheotomies by one institution is a local or generalizable phenomenon.

http://ift.tt/2BULyEm

Safety and efficacy of intratympanic ciprofloxacin otic suspension post-tubes in a real-world pediatric population

Otorrhea frequently follows tympanostomy tube (TT) placement. We evaluated otorrhea following single 6mg OTO-201 (OTIPRIO®, ciprofloxacin otic suspension 6%) intraoperative injection into each middle ear in a variety of effusion types and concurrent procedures in children undergoing TT placement. Secondary objective: Efficacy based on Medicaid status and safety.

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A new method for removal of eyelid-margin-molluscum

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Faster suction blister formation using two hair dryers

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Solvent effects on the fluorescence and effective three-photon absorption of a Zn(II)-[meso-tetrakis(4-octyloxyphenyl)porphyrin]

Publication date: June 2018
Source:Optics & Laser Technology, Volume 102
Author(s): Yong Wan, Yuxiong Xue, Ning Sheng, Guanghao Rui, Changgui Lv, Jun He, Bing Gu, Yiping Cui
The fluorescence and effective three-photon absorption (3PA) properties of Zn(II)-[meso-tetrakis(4-octyloxyphenyl)porphyrin] (labeled Zn(II)-porphyrin) dissolved in three different polar solvents were systematically investigated. The electrochemical and photophysical properties of Zn(II)-porphyrin were investigated by ¹H NMR spectra, IR spectra, mass spectroscopy, and electronic absorption spectra. The fluorescence emission of Zn(II)-porphyrin in three different solvents excited at the wavelengths of 420 nm (Soret band) and 550 nm (Q-band) were analyzed. By performing Z-scan experiments with femtosecond laser pulses at a wavelength of 800 nm, the effective 3PA process of Zn(II)-porphyrin in three different solvents was observed and the underlying mechanism was discussed in detail. It is found that the fluorescence spectra slightly depend on the polarity of the solvent. Interestingly, the effective 3PA properties of Zn(II)-porphyrin strongly depend on the solvent polarity. The lower the solvent polarity is, the larger effective 3PA cross-section is. Low polar solvents are beneficial to applications of Zn(II)-porphyrin in optical limiting, photodynamic therapy, etc.



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Age-related changes of CD4+ T cell migration and cytokine expression in germ-free and SPF mice periodontium

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Koichiro Irie, Takaaki Tomofuji, Daisuke Ekuni, Daiki Fukuhara, Yoko Uchida, Kota Kataoka, Shuichiro Kobayashi, Takeshi Kikuchi, Akio Mitani, Yoshihiro Shimazaki, Manabu Morita
ObjectiveIncreasing age is a potential risk factor for periodontal tissue breakdown, which may be affected by commensal flora. The aim of this study evaluated age-related changes in CD4⁺ T cells, C-C chemokine ligand 5 (CCL5), interleukin (IL)-17A, and receptor activator of nuclear factor-kappa B ligand (RANKL) expression using germ-free (GF) and conventionally reared (SPF) mice.DesignGF and SPF mice at 8 (n = 6/group) and 22 weeks old (n = 6/group) were used. Immunohistochemical analyses were performed to determine the effects of aging on protein expression in periodontal tissues. Age-related changes in alveolar bone were quantified using micro-CT analysis.ResultsSPF mice, but not GF mice, showed an age-related increase in alveolar bone loss (P < 0.01). SPF mice at 22 weeks of age increased expression of CD4⁺ T cells, CCL5, IL-17A, and RANKL compared to those at 8 weeks of age in connective tissue and alveolar bone surface (P < 0.01). Furthermore, there was increased CD4⁺ T cells, which were co-expressed with IL-17A and RANKL in SPF mice at 22 weeks of age. On the other hand, the GF mice did not show any significant differences in CD4⁺ T cells, CCL5, IL-17A and RANKL expression between the two age groups.ConclusionsSPF mice induced an age-related increase in CD4⁺ T cells co- expressed with IL-17A and RANKL, with occurring alveolar bone loss. In contrast, GF mice did not show age-related changes in CD4⁺ T cell migration and cytokine expression.



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Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial

Publication date: Available online 20 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Lars Norgren, Manesh R. Patel, William R. Hiatt, Daniel M. Wojdyla, F. Gerry R. Fowkes, Iris Baumgartner, Kenneth W. Mahaffey, Jeffrey S. Berger, W. Schuyler Jones, Brian G. Katona, Peter Held, Juuso I. Blomster, Frank W. Rockhold, Martin Björck
ObjectivesCritical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established.Design, Materials, MethodsThe EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss.ResultsIn EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16–1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13–1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI.ConclusionsNearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI.ClinicalTrials.govNCT01732822.



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Surgical management of inverted papilloma; a single-center analysis of 247 patients with long follow-up

Our aim was to review our management of inverted papilloma (IP), perform a recurrence analysis, and review the literature.

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Reduced methicillin-resistant Staphylococcus aureus biofilm formation in bone cavities by photodynamic therapy

Publication date: Available online 20 December 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Thalita Santos Dantas Araújo, Paôlla Layanna Fernandes Rodrigues, Mariana Sousa Santos, Janeide Muritiba de Oliveira, Luciano Pereira Rosa, Vanderlei Salvador Bagnato, Kate Cristina Blanco, Francine Cristina da Silva
Photodynamic Therapy (PDT) is a promising alternative for the treatment of infectious bone lesions in the oral cavity. The objective of this study was to evaluate the antimicrobial effectiveness of PDT using blue LED associated with curcumin in methicillin-resistant Staphylococcus aureus biofilms (MRSA) in bovine bone cavities by fluorescence spectroscopy. Standardized suspensions of MRSA culture were inoculated into bone lesions to form biofilm. Forty bone species were distributed in three distinct groups: L-C- (control); L + C- (LED for 5 min.); L-C+ (curcumin incubation for 5 min) and L + C+ (PDT). Aliquots of 100 μl were collected from the bone cavities after the treatments and were cultived in BHI for 24 h at 36 °C ± 1 and bacterial colonies counting were performed. Statistical analysis were performed using the paired t-test and analysis of variance (ANOVA) for the variables studied. Results: The control and PDT groups presented statistically significant differences (p< 0.001). It was possible to reduce 3.666 log10 CFU/mL of MRSA and a reduction in the fluorescence emitted after the treatments was observed. The MRSA reduction in biofilms by PDT was the most efficient treatmnent. There was a significant reduction of biofilms in the L + C- and non-PDT groups by fluorescence spectroscopy images.



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Reconstruction of a skull base defect after endoscopic endonasal resection of a pituitary adenoma: Sphenoid mucosal flaps

Publication date: Available online 20 December 2017
Source:American Journal of Otolaryngology
Author(s): Erden Goljo, Eliezer Kinberg, Katelyn Stepan, Jill K. Gregory, Alfred M. Iloreta, Satish Govindaraj, Hongyan Zou
This report describes a bilateral sphenoid sinus mucosal flap for the repair of a sellar floor defect and CSF leak following endoscopic endonasal skull base surgery. The key advantage of this technique is enabling the sphenoid mucosal flaps to remain vascularized, which reduces postoperative complications including CSF leakage, recurrent sinusitis, meningitis, encephalitis and pneumocephalus. The use of this technique is a viable and possibly favorable alternative to free grafts in the reconstruction of small to medium sized sellar defects with low flow or absent CSF leaks base surgery.



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An algorithm for the classification of mRNA patters in eosinophilic esophagitis: integration of machine learning

Publication date: Available online 19 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Benjamin F. Sallis, Lena Erkert, Sherezade Moñino-Romero, Utkucan Acar, Rina Wu, Liza Konnikova, Willem S. Lexmond, Matthew J. Hamilton, W. Augustine Dunn, Zsolt Szepfalusi, Jon A. Vanderhoof, Scott B. Snapper, Jerrold R. Turner, Jeffrey D. Goldsmith, Lisa A. Spencer, Samuel Nurko, Edda Fiebiger
BackgroundDiagnostic evaluation of eosinophilic esophagitis (EoE) remains difficult, particularly the assessment of the patient's allergic status.ObjectiveEstablish an automated medical algorithm to assist in the evaluation of EoE.MethodsMachine learning techniques were used to establish a diagnostic probability score for EoE (pEoE) based on esophageal mRNA transcript patterns from biopsies of patients with EoE, gastroesophageal reflux disease, and controls. Dimensionality reduction in the training set established weighted factors, which were confirmed by immunohistochemistry. Following weighted factor analysis, p(EoE) was determined by Random Forest classification. Accuracy was tested in an external test set and predictive power was assessed with equivocal patients. Esophageal IgE production was quantified with epsilon germ line (IGHE) transcripts and correlated with serum IgE and the Th2-type mRNA profile to establish an IGHE-score for tissue allergy.ResultsIn the primary analysis, a three-class statistical model generated a p(EoE) score based on common characteristics of the inflammatory EoE profile. A p(EoE) ≥25 successfully identified EoE with high accuracy (sensitivity 94.4%, specificity 92.9%, AUC 0.985) and improved diagnosis of equivocal cases by 84.6%. The p(EoE) changed in response to therapy. A secondary analysis loop in EoE patients defined an IGHE-score≥37.5 for a patient subpopulation with increased esophageal allergic inflammation.ConclusionThe development of intelligent data analysis from a machine learning perspective provides exciting opportunities to improve diagnostic precision and improve patient care in EoE. The p(EoE) and the IGHE-score are steps towards the development of decision trees to define EoE subpopulations and, consequently, will facilitate individualized therapy.

Graphical abstract

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Zika Virus: An Emerging Infectious Disease with Serious Perinatal and Neurologic Complications

Publication date: Available online 19 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Thomas B. Casale, Michael N. Teng, Jamie P. Morano, Thomas Unnasch, Charles J. Lockwood
Zika virus (ZIKV) is a flavivirus that is primarily transmitted by Aedes aegypti, the mosquito vector also important in the transmission of the flaviviruses responsible for dengue fever, yellow fever and chikungunya. Due to occurrence in the same geographic regions, serological cross-reactivity, and similar, albeit often less severe clinical manifestations as dengue and chikungunya infections, ZIKV infection likely went undetected and/or misdiagnosed for many years. ZIKV is somewhat unique among flaviviruses in its ability to also be transmitted via sexual contact, non-sexual body fluids and perinatally. The relatively recent detection of the link between ZIKV infection and Guillain-Barré syndrome and fetal neurological defects including microcephaly has prompted intense efforts aimed at the development of new and specific diagnostic tests. Infection with ZIKV has been postulated to lead to a more severe clinical course from other structurally related viruses, especially dengue, and vice versa, due to a phenomenon termed antibody-dependent enhancement. Inactivated whole virus, DNA, RNA and vectored vaccine approaches to prevent ZIKV infection are in development as are treatments for active disease that are safe in pregnant women. Here we summarize the important epidemiologic and clinical features of ZIKV infection as well as the progress and challenges in developing rapid point of care diagnostic tests and vaccines to prevent disease. We used electronic databases to identify relevant published data regarding ZIKV MeSH searches.



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Immediate Stress Echocardiography for Low-Risk Chest Pain Patients in the Emergency Department: A Prospective Observational Cohort Study

Publication date: Available online 20 December 2017
Source:The Journal of Emergency Medicine
Author(s): Gregory Jasani, Mia Papas, Avkash J. Patel, Neil Jasani, Brian Levine, Yuanyuan Zhang, Erik S. Marshall
BackgroundEvaluation and disposition of low-risk chest pain (CP) patients in the emergency department (ED) is time consuming and expensive. Low-risk CP often results in hospital admission to rule out myocardial infarction, which leads to additional costs and delays.ObjectiveOur aim was to assess whether an immediate exercise stress echocardiogram (IESE) in the ED will allow safe, efficient, and cost-effective evaluation and discharge of patients with low-risk CP.MethodsLow-risk CP patients (TIMI [Thrombolysis in Myocardial Infarction] score 0–1) presenting to the ED with normal electrocardiogram, no history of coronary artery disease, and negative troponin T received IESE. We followed these patients for major adverse cardiac events and compared them to a control cohort of similar-risk patients admitted with traditional care at 1 and 6 months.ResultsWe enrolled 216 patients, 117 IESE and 109 control. We obtained follow-up at 1 and 6 months in 94% of the IESE group and 88% in the control group. There was no difference in diagnostic catheterization or percutaneous coronary intervention between the 2 groups (6.0% and 1.7% vs. 6.4% and 1.8%; p = 0.89). Median time from triage to discharge was significantly shorter with IESE (572.6 min vs. 1466.0 min), resulting in significantly lower cost ($4380.50 vs. $6191.70). There were no adverse events related to IESE or early discharge.ConclusionsIn our study, IESE for low-risk CP patients presenting to the ED has the potential to be equally safe, more expeditious, and more cost effective than admission to an observation unit.



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D2A-Ala PEPTIDE DERIVED FROM THE UROKINASE RECEPTOR EXERTS ANTI-TUMOURAL EFFECTS IN VITRO AND IN VIVO

Publication date: Available online 19 December 2017
Source:Peptides
Author(s): Federico Furlan, Gabriele Eden, Marco Archinti, Ralitsa Arnaudova, Giuseppina Andreotti, Valentina Citro, Maria Vittoria Cubellis, Andrea Motta, Bernard Degryse
D2A-Ala is a synthetic peptide that has been created by introducing mutations in the original D2A sequence, ¹³⁰IQEGEEGRPKDDR¹⁴² of human urokinase receptor (uPAR). In vitro, D2A-Ala peptide displays strong anti-tumoural properties inhibiting EGF-induced chemotaxis, invasion and proliferation of a human fibrosarcoma cell line, HT 1080, and a human colorectal adenocarcinoma cell line, HT 29. D2A-Ala exerts its effects by preventing EGF receptor (EGFR) phosphorylation.To test D2A-Ala in vivo, this peptide was PEGylated generating polyethyleneglycol (PEG)-D2A-Ala peptide. PEGylation did not alter the inhibitory properties of D2A-Ala. Human tumour xenografts in the immunodeficient nude mice using HT 1080 and HT 29 cell lines showed that PEG-D2A-Ala significantly prevents tumour growth decreasing size, weight and density of tumours. The most efficient doses of the peptide were 5 and 10 mg/kg, thereby relevant for possible development of the peptide into a drug against cancer in particular tumours expressing EGFR.



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Predicting hypoxia status using a combination of contrast-enhanced computed tomography and [18F]-Fluorodeoxyglucose positron emission tomography radiomics features

Publication date: Available online 19 December 2017
Source:Radiotherapy and Oncology
Author(s): Mireia Crispin-Ortuzar, Aditya Apte, Milan Grkovski, Jung Hun Oh, Nancy Y. Lee, Heiko Schöder, John L. Humm, Joseph O. Deasy
Background and purposeHypoxia is a known prognostic factor in head and neck cancer. Hypoxia imaging PET radiotracers such as ¹⁸F-FMISO are promising but not widely available. The aim of this study was therefore to design a surrogate for ¹⁸F-FMISO TBRmax based on ¹⁸F-FDG PET and contrast-enhanced CT radiomics features, and to study its performance in the context of hypoxia-based patient stratification.Methods121 lesions from 75 head and neck cancer patients were used in the analysis. Patients received pre-treatment ¹⁸F-FDG and ¹⁸F-FMISO PET/CT scans. 79 lesions were used to train a cross-validated LASSO regression model based on radiomics features, while the remaining 42 were held out as an internal test subset.ResultsIn the training subset, the highest AUC (0.873±0.008) was obtained from a signature combining CT and ¹⁸F-FDG PET features. The best performance on the unseen test subset was also obtained from the combined signature, with an AUC of 0.833, while the model based on the 90th percentile of ¹⁸F-FDG uptake had a test AUC of 0.756.ConclusionA radiomics signature built from ¹⁸F-FDG PET and contrast-enhanced CT features correlates with ¹⁸F-FMISO TBRmax in head and neck cancer patients, providing significantly better performance with respect to models based on ¹⁸F-FDG PET only. Such a biomarker could potentially be useful to personalize head and neck cancer treatment at centers for which dedicated hypoxia imaging PET radiotracers are unavailable.



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Genotype-driven phase I study of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation for locally advanced rectal cancer

Publication date: Available online 19 December 2017
Source:Radiotherapy and Oncology
Author(s): Ji Zhu, Xinxiang Li, Yunzhu Shen, Yun Guan, Weilie Gu, Peng Lian, Weiqi Sheng, Sanjun Cai, Zhen Zhang
PurposeWe aimed to identify the maximum tolerated dose (MTD) of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation according to the UGT1A1∗28 genotype in patients with locally advanced rectal cancer.Patients and methodsPatients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy were screened for the UGT1A1∗28 genotype. Twenty-six patients with either the ∗1∗1 or ∗1∗28 genotype were eligible for dose escalation of irinotecan, and patients with a ∗28∗28 genotype were excluded. The starting dose of weekly irinotecan was 50 mg/m² for the two genotype groups, whereas the dose of capecitabine was fixed at 625 mg/m². Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis (total dose of 50 Gy in 25 fractions).ResultsThe dose of weekly irinotecan was escalated to 95 mg/m² in patients with the ∗1∗1 genotype and to 80 mg/m² in those with the ∗1∗28 genotype. Dose-limiting toxicities (DLTs) were observed in 2/2 ∗1∗1 patients at 95 mg/m² and 2/3 ∗1∗28 patients at 80 mg/m². No DLT cases were observed among the three ∗1∗1 patients at 80 mg/m², and one DLT case was observed among the six patients with ∗1∗28 at 65 mg/m². Hence, 80 mg/m² and 65 mg/m² were the MTDs for the two groups. The most common grade 3 to 4 toxicities were neutropenia and diarrhea.ConclusionA higher dose of weekly irinotecan in combination with capecitabine-based CRT is feasible under the guidance of the UGT1A1∗28 genotype. Further clinical trials at these dose levels are warranted.



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What is Botox for hair and what does it do?

Botox for hair may refer to a topical cream or scalp injections, both with the aim of improving the look and health of hair. Learn more about them here.

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Effect of tooth substrate and porcelain thickness on porcelain veneer failure loads in vitro

Publication date: Available online 19 December 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Chunling Ge, Chad C. Green, Dalene A. Sederstrom, Edward A. McLaren, James A. Chalfant, Shane N. White
Statement of problemBonded porcelain veneers are widely used esthetic restorations. High success and survival rates have been reported, but failures do occur. Fractures are the commonest failure mode. Minimally invasive or thin veneers have gained popularity. Increased enamel and porcelain thickness improve the strength of veneers bonded to enamel, but less is known about dentin or mixed substrates.PurposeThe purpose of this in vitro study was to measure the influences of tooth substrate type (all-enamel, all-dentin, or half-dentin-half-enamel) and veneer thickness on the loads needed to cause initial and catastrophic porcelain veneer failure.Material and methodsModel discoid porcelain veneer specimens of varying thicknesses were bonded to the flattened facial surfaces of incisors with different enamel and dentin tooth substrates, artificially aged, and loaded to failure with a small sphere. Initial and catastrophic fracture events were identified and analyzed statistically and fractographically.ResultsFracture events included initial Hertzian cracks, intermediate radial cracks, and catastrophic gross failure. All specimens retained some porcelain after catastrophic failure. Cement failure occurred at the cement–porcelain interface not at the cement–tooth interface. Porcelain veneers bonded to enamel were substantially stronger and more damage-tolerant than those bonded to dentin or mixed substrates. Increased porcelain thickness substantially raised the loads to catastrophic failure on enamel substrates but only moderately raised the loads to catastrophic failure on dentin or mixed substrates. The veneers bonded to half-dentin-half-enamel behaved remarkably like those bonded wholly to dentin.ConclusionsPorcelain veneers bonded to enamel were substantially stronger and more damage-tolerant than those bonded to dentin or half-enamel-half dentin.



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Long Noncoding RNA in Cancer: Wiring Signaling Circuitry

Publication date: Available online 20 December 2017
Source:Trends in Cell Biology
Author(s): Chunru Lin, Liuqing Yang
Long noncoding RNAs (lncRNAs), which are encoded by a vast less explored region of the human genome, may hold missing drivers of cancer and have gained attention recently as a potentially crucial layer of cancer cell regulation. lncRNAs are aberrantly expressed in a broad spectrum of cancers, and they play key roles in promoting and maintaining tumor initiation and progression, demonstrating their clinical potential as biomarkers and therapeutic targets. Recent discoveries have revealed that lncRNAs act as key signal transduction mediators in cancer signaling pathways by interacting with proteins, RNA, and lipids. Here, we review the mechanisms by which lncRNAs regulate cellular responses to extracellular signals and discuss their clinical potential as diagnostic indicators, stratification markers, and therapeutic targets of combinatorial treatments.



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The visual attention span deficit in Chinese children with reading fluency difficulty

Publication date: February 2018
Source:Research in Developmental Disabilities, Volume 73
Author(s): Jing Zhao, Menglian Liu, Hanlong Liu, Chen Huang
With reading development, some children fail to learn to read fluently. However, reading fluency difficulty (RFD) has not been fully investigated. The present study explored the underlying mechanism of RFD from the aspect of visual attention span. Fourteen Chinese children with RFD and fourteen age-matched normal readers participated. The visual 1-back task was adopted to examine visual attention span. Reaction time and accuracy were recorded, and relevant d-prime (d') scores were computed. Results showed that children with RFD exhibited lower accuracy and lower d' values than the controls did in the visual 1-back task, revealing a visual attention span deficit. Further analyses on d' values revealed that the attention distribution seemed to exhibit an inverted U-shaped pattern without lateralization for normal readers, but a W-shaped pattern with a rightward bias for children with RFD, which was discussed based on between-group variation in reading strategies. Results of the correlation analyses showed that visual attention span was associated with reading fluency at the sentence level for normal readers, but was related to reading fluency at the single-character level for children with RFD. The different patterns in correlations between groups revealed that visual attention span might be affected by the variation in reading strategies. The current findings extend previous data from alphabetic languages to Chinese, a logographic language with a particularly deep orthography, and have implications for reading-dysfluency remediation.



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