Probiotic Supplementation for Prevention of Atopic Dermatitis in Infants and Children: A Systematic Review and Meta-analysis

Abstract

Background

Probiotic supplementation in early life may be effective in preventing atopic dermatitis (AD); however, results regarding efficacy have been controversial.

Objective

The aim of our study was to investigate the effect of probiotic supplementation on the risk of AD.

Methods

We systematically searched PubMed, EBSCO, Embase and Web of Science databases up to 8 March 2018 for potentially relevant studies regarding probiotic supplementation and AD. Included infants and children were those with probiotic exposure in utero and/or after birth who were not previously diagnosed with AD. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) and used the Jadad and Newcastle–Ottawa scales to assess methodologic quality.

Results

A total of 28 studies met the inclusion criteria. Compared with controls, probiotic treatment was associated with a reduced risk of AD (OR 0.69; 95% CI 0.58–0.82, P < 0.0001). The use of probiotics during both the prenatal and the postnatal period significantly reduced the incidence of AD (OR 0.67; 95% CI 0.54–0.82); however, analysis of studies of probiotics given prenatally only or postnatally only did not reach statistical significance.

Conclusions

Our meta-analysis showed that probiotic supplementation during both the prenatal and the postnatal period reduced the incidence of AD in infants and children. Our findings suggest that starting probiotic treatment during gestation and continuing through the first 6 months of the infant's life may be of benefit in the prevention of AD.

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Efficacy of axillary versus infraclavicular brachial plexus block in preventing tourniquet pain: A randomised trial

BACKGROUND Axillary and infraclavicular brachial plexus blocks are commonly used for upper limb surgery. Clinicians require information on the relative benefits of each to make a rational selection for specific patients and procedures. OBJECTIVES The main objective of the study was to compare axillary and infraclavicular brachial plexus block in terms of the incidence and severity of tourniquet pain. DESIGN Single blinded, randomised trial. SETTING University affiliated hospital, level-1 trauma centre. PATIENTS Age more than 18 years, ASAI-III patients undergoing orthopaedic surgery distal to the elbow, with an anticipated tourniquet duration of more than 45 min were recruited. INTERVENTIONS Patients underwent either ultrasound guided axillary brachial plexus block or infraclavicular block (ICB). MAIN OUTCOME MEASURES Incidence of tourniquet pain (onset, severity, associated haemodynamic changes) and block characteristics (block performance/onset times, distribution, incidence of adverse events, patient satisfaction) were recorded. RESULTS Eighty two patients (40 in the axillary block and 42 in the ICB group) were recruited. The incidence (5/36 and 3/35; P = 0.71), onset time mean (SD) were 73.0 (14.8) and 86.6 (5.7) min (P = 0.18) and severity (mild/moderate; 4/1 and 1/2; P = 0.51) of tourniquet pain were similar in the two groups. The incidence of paraesthesia during block performance, and block performance time were greater in the axillary block group (P = 0.0054 and 0.012, respectively). The volume of local anaesthetic administered was greater in the ICB group (P 

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Utility of Skin Biopsy and Culture in the Diagnosis and Classification of Chronic Ulcers: A Single-Institution, Retrospective Study

Abstract: In the United States, chronic ulcers affect 6.5 million people, with a cost of ≈$20 million annually. The most common etiology of chronic ulcers in the United States is venous stasis, followed by arterial insufficiency and neuropathic ulcers. Less common causes of chronic ulcers include infection, inflammatory etiologies such as vasculitis and pyoderma gangrenosum, and neoplastic causes. Obtaining skin biopsy and tissue culture can be helpful in diagnosing unusual causes of chronic ulcers; however, there are little data on the diagnostic utility of skin biopsy in rendering a definitive diagnosis of the etiology of chronic ulcers. A retrospective study of all skin ulcers biopsied during a 10-year period at the University of Washington was undertaken. Re-excisions and surgical wounds were excluded. A total of 270 ulcer biopsy specimens were included. In 48% of cases, no specific diagnosis could be rendered histologically. 44.8% of chronic ulcers biopsied were due to atypical causes, with neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma, and cutaneous T-cell lymphoma) being the most common. Vasculitis and pyoderma gangrenosum each represented 1.5% of rendered diagnoses. Concomitant skin culture was performed in 28.9% of cases, and special stains [acid-fast bacilli, Brown and Brenn (B&B), Grocott's methenamine silver, and periodic acid-Schiff stains] were performed in 34.0%. Although more than half (49 of 78) of tissue cultures were positive, only 6.8% (12 of 175) of special stains on tissue sections were positive. We conclude that although the etiology of many ulcers cannot be determined by routine histology alone, skin biopsy of ulcers remains a critical part of the workup given that when a specific cause can be determined, atypical etiologies, including neoplasms, represent a significant proportion of chronic ulcers. Limitations of our study include referral bias. Our results also confirm the higher diagnostic yield of conventional tissue culture compared with special tissue stain biopsies of skin ulcers. Correspondence: Shiva Khoobyari, MD, Department of Pathology, University of Washington Medical Center, Box 357470, 1959 NE Pacific Street, Seattle, WA 98195 (e-mail: Skhoob@uw.edu) S. Khoobyari and T. I. Miller had equal contribution. The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Concurrent Metastatic Merkel Cell Carcinoma and Cutaneous Squamous Cell Carcinoma in the Same Lymph Node

Abstract: The coexistence of Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) in the same cutaneous lesion is well known. The pathogenesis is believed to be distinct from conventional polyomavirus-related MCC, and it has a more aggressive course. Metastasis of MCC and SCC to the same lymph node is exceedingly rare with only one previously reported case in the English literature. To the best of our knowledge, this is the second case of MCC and SCC with metastasis to the same lymph node. Our case demonstrates the aggressive nature of the combined MCC and SCC in the setting of immunosuppression. Correspondence: Lubna Suaiti, MBChB, MSc, Department of Pathology/Dermatopathology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1072 (e-mail: lsuaiti@gmail.com). The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Linear IgA Bullous Dermatosis Preceding the Diagnosis of Primary Sclerosing Cholangitis and Ulcerative Colitis: A Case Report

Abstract: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder seen in the pediatric and adult populations that is often linked to a medication, infection, or underlying gastrointestinal, hepatobiliary, or autoimmune disease. In this study, we describe the case of a 23-year-old white man whose presentation and diagnosis of LABD ultimately led to the discovery of underlying primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). His dermatitis resolved with topical steroids and dapsone, and he is undergoing systemic treatment for his UC and PSC. This exceptional case further validates the association between LABD with UC, strengthens that with PSC, and underscores the importance of alerting clinicians to consider conducting a systemic workup in addition to thorough medication history on making the diagnosis of LABD. Correspondence: Jaroslaw Jedrych, MD, PhD, UPMC Dermatology, 3708 Fifth Avenue Fifth Floor, Suite 500.68, Pittsburgh, PA 15213 (e-mail: jedrychj@upmc.edu). The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Late-Onset Nevus Comedonicus With Follicular Epidermolytic Hyperkeratosis—Case Report and Review of the Literature

Abstract: Nevus comedonicus is a rare cutaneous follicular hamartoma, characterized by the clustering of papules with firm, blackened horny buffers. It is usually present at birth or during childhood, although few cases of late-onset disease have been described. We present a case of postmenopausal-onset nevus comedonicus in a 55-year-old white woman without relevant medical history. Skin biopsy showed the typical features of several cyst-dilated follicular structures occupied by keratotic material and the peculiar finding of epidermolytic hyperkeratosis of the follicular epithelial walls. A brief review of the clinical and histological features of other similar cases published in the literature is performed. Correspondence: Ramona Zanniello, MD, Section of Dermatology, University of Cagliari, via Ospedale 54, 09124 Cagliari, Italy (e-mail: ramonazanniello@gmail.com). The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Positive Antinucleolar Antibodies on Direct Immunofluorescence of Lesional Skin of a Patient With Limited Systemic Sclerosis

No abstract available

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Proliferating Neurocristic Hamartoma Arising in a Giant Congenital Nevus: Comparative Genomic Hybridization Findings

Abstract: Neurocristic cutaneous hamartomas (NCHs) are rarely reported tumors with divergent differentiation derived from persistently active pluripotent cells from the neural crest. They result from aberrant development of the neuromesenchyme, and they can express fibrogenic, melanocytic, and/or neurosustentacular differentiation. Thus, congenital melanocytic nevus also represents a neurocristic dysplasia of the skin in which cells are melanogenic cells arrested in development located in the reticular dermis, and nodular proliferative neurocristic hamartoma may arise within a congenital melanocytic nevus. The real importance of NCHs is that, although few cases have been reported in the literature, some cases have shown development of melanoma. Moreover, the only previously reported case of a similar "proliferative neurocristic nodule" analyzed with comparative genomic hybridization showed an aberration pattern similar to melanoma. We present a rare case of NCH associated with a congenital nevus in a 7-year-old boy, with classical histological and immunohistochemical features suggesting a "proliferative neurocristic hamartoma". Comparative genomic hybridization assay showed that chromosomal aberrations were absent in the congenital nevus, whereas, interestingly, the proliferative neurocristic proliferation had an aberration pattern similar to proliferative nodules with gains or losses of entire chromosomes only, similar to typical proliferative nodules and supporting the benign behavior of this lesion. Correspondence: Maria Concepcion Garrido, MD, PhD, Dpto. de Anatomía Patológica, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041 Madrid, Spain (e-mail: mariagarridoruiz@gmail.com). The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Helicobacter pylori antimicrobial resistance during a 5‐year period (2013‐2017) in northern Spain and its relationship with the eradication therapies

Abstract

Background

Antibiotic resistance is the main cause for Helicobacter pylori therapy failure. Frequently, empirical regimens have been recommended in patients with various H. pylori eradication failures. In patients with H. pylori‐resistant to various families of antibiotics, the treatment guided by antimicrobial susceptibility testing allows the achievement of good eradication rates.

Aim

To evaluate the effectiveness of susceptibility‐guided antimicrobial treatment for H. pylori infection in patients with resistance to one or various families of antibiotics.

Methods

A total of 3170 consecutive patients infected by H. pylori during 2013‐2017 were tested for antimicrobial susceptibility. 66.6% patients showed resistance to one antimicrobial, 18.9% to two, and 2.4% to three families of antibiotics. A cohort of 162 H. pylori‐positive patients were enrolled in this study. Forty‐three with single H. pylori resistance to clarithromycin (CLR) were treated with omeprazole (PPI), amoxicillin (AMX), and levofloxacin (LVX)—OAL (31 subjects) or omeprazole, AMX, and metronidazole (MTZ)—OAM (12 patients) and 77 patients with dual H. pylori resistance (51 to CLR and MTZ, 12 to CLR plus LVX, and 14 to MTZ plus LVX) received OAL or OBTM (PPI, bismuth subcitrate, tetracycline, and MTZ), OAM, and OAC, respectively. Other 42 patients with triple H. pylori resistance (CLR, LVX, and MTZ) were treated with PPI, AMX, and rifabutin—OAR (18 subjects), PPI, AMX, and doxycycline—OAD (8), OADB (7), OBTM (6), and ODBR (3). All subjects received standard doses for 10 days. Eradication rate was confirmed by ¹³C‐UBT. Adverse events were assessed by a questionnaire.

Results

Intention‐to‐treat analysis demonstrates that eradication rates using triple therapies in patients with H. pylori resistance to one and to two families of antibiotics were 93% and 94.8%, respectively. In subjects with H. pylori‐resistant to three families of antibiotics, cure rate was higher in naïve patients treated with OAR‐10 days compared to those treated with bismuth‐containing quadruple therapies (90% vs 75%). Adverse events were limited (18 of 162, 11.1%), all of them mild‐moderate.

Conclusions

The implementation of susceptibility‐guided triple therapy for 10 days leads to eradication rate ≥95% in naïve patients with H. pylori resistance to one or two families of antimicrobials. In naïve patients with H. pylori resistance to three families, OAR treatment achieved a 90% of eradication.

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Association of Modified‐FOLFIRINOX‐Regimen‐Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population

AbstractLessons Learned. Modification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer.Patients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery.Background.The objective of this study was to evaluate the efficacy of modified‐FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX‐based neoadjuvant therapy (LAPC‐N) and patients with LAPC who underwent upfront surgery (LAPC‐S).Methods.Forty‐one patients with LAPC‐N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy‐four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC‐S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC‐N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC‐N patients who were not deemed resectable after treatment, and the response was re‐evaluated every 2 months.Results.Forty‐one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX‐based neoadjuvant therapy contributed to a remarkable decrease in CA19‐9 level and tumor diameter. Fourteen LAPC‐N patients underwent surgery (LAPC‐N‐S) after downstaging. Compared with LAPC‐N‐S cases, LAPC‐S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression‐free survival (PFS) of LAPC‐N‐S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC‐S (8.9 months and 7.6 months), respectively.Conclusion.Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC‐N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC‐S cohort, who did not undergo neoadjuvant therapy.

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Evidence Underlying Recommendations and Payments from Industry to Authors of the National Comprehensive Cancer Network Guidelines

AbstractBackground.The National Comprehensive Cancer Network (NCCN) guidelines are among the most widely used guidance in oncology. It is critical to understand the extent to which the recommendations in these guidelines are supported by evidence and to investigate whether these recommendations have been influenced by payments from industry to authors.Materials and Methods.We examined the quality and consistency of evidence, as scored by guidelines authors, for systemic treatment incorporated in the NCCN guidelines. Payments data in 2015 were manually abstracted using the Open Payments database, which discloses all payments between the industry and American physicians. Correlations between the percentage of authors who received payments and the proportion of recommendations developed from low‐level evidence per guideline were calculated using Spearman rank correlation.Results.In total, 1,782 recommendations were identified in 29 guidelines, of which 1,282 (71.9%) were based on low‐quality or low‐consistency evidence (low‐level evidence), including "case reports or clinical experience only" (18.9%). A substantial proportion (31/143, 21.7%) of category 1 (the highest level) recommendations were based on low‐level evidence. The majority of authors (87.1%) received payments from industry. However, no association was found between the prevalence of payments among authors and the percentage of recommendations developed from low‐level evidence per guideline.Conclusion.The majority of systemic treatment recommendations in the NCCN guidelines are based on low‐level evidence, including more than one in five category 1 recommendations. Payments from industry were prevalent among authors. However, industrial payments among authors were not associated with inclusion of regimen/agent for which there is no conclusive evidence in the guidelines.Implications for Practice.The authors found that the majority (71.9%) of systemic treatment recommendations issued in the current National Comprehensive Cancer Network guidelines were based on low‐level evidence. Physicians should remain cautious when using current guidelines as the sole source guiding patient care decisions.

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Gastroesophageal Reflux in Asymptomatic Patients with Diabetes: An Impedance Study Diabetes, Obesity and Gastroesophageal Reflux

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0783-2327

Introduction Gastroesophageal reflux disease (GERD) is more frequent in patients with diabetes mellitus (DM).The aim of the present study was to evaluate GER in asymptomatic patients with DM using 24-h pH impedance. Materials and Methods 19 healthy controls and 35 patients with DM without typical GERD symptoms were enrolled in the study. A 24-h pH-impedance study, esophageal manometry and gastroscopy were performed on all patients with DM. In the control group, an impedance study was performed on all subjects, and gastroscopy and esophageal manometry were performed on those who consented to the procedures.Patients with diabetes were categorized as obese [body mass index (BMI)>30 kg/m2] or non-obese (BMI<30 kg/m2) and both groups were compared with healthy controls. Results The mean BMI was similar in the control group (27.3±2.6 kg/m2) and the diabetic group (28.7±5 kg/m2)(p>0.05).Erosive esophagitis was found in 7.5% of the DM group. Esophageal dysmotility was higher in diabetics compared to the control group (45.5 vs. 11%, p=0.04). Neuropathy was found to be an independent risk factor for dysmotility. The mean DeMeester score (DMS) (25.6±32.5 vs. 11.2±17, p=0.01) and bolus exposure time (2.1±1.3 vs.1.3±1.3 min, p=0.009) were higher in the DM group compared with the control group.The difference was mainly observed between obese diabetics and the control group (p<0.05). The mean DMS, pathologic acid reflux, and esophageal dysmotility rate were higher in patients without complications of DM (p<0.05). BMI was higher in these patients than in patients with complications. Conclusion Acid reflux is common in patients with diabetes.GER is associated with the existence of obesity rather than hyperglycemia.
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© Georg Thieme Verlag KG Stuttgart · New York

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Clinical Thyroidology®for the Public – Highlighted Article

From Clinical Thyroidology^® for the Public: Thyroid hormones have major effects on the heart and palpitations and irregular heart rhythms are frequent symptoms caused by hyperthyroidism. Because of this, hyperthyroidism is associated with increased cardiac problems. Read More…

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A Sensorimotor View of Verbal Working Memory

Publication date: Available online 20 November 2018

Source: Cortex

Author(s): Bradley R. Buchsbaum, Mark D'Esposito

https://ift.tt/2PG2TJ2

Space counts! Brain correlates of spatial and numerical representations in synaesthesia

Publication date: Available online 20 November 2018

Source: Cortex

Author(s): Isabel Arend, Kenneth Yuen, Sarit Ashkenazi, Avishai Henik

Abstract

Over-learned semantic representations, such as numbers, are strongly associated with space in normal cognition, and in the phenomenon called number-space synaesthesia. In number-space synaesthesia, numbers are linked to spatial locations in an idiosyncratic way. Synaesthetes report numbers as belonging to a specific location, or feelings that a specific location is the right location for that number. What does really differentiate synaesthetes from non-synaesthetes with respect to their number-space representation? Here we present a number-space synaesthete, MkM, whose number-space representation dramatically differs from that of controls. We examined the impact of spatial distance with respect to MkM's mental number line, and numerical distance with respect to the conceptualized horizontal representation of numbers. In a behavioural experiment, MkM and controls performed number comparison tasks in which they reported either the larger numerical value (number task) or the larger stimulus (physical task) (Experiment 1). A spatial distance effect was found only for MkM. In a brain imaging experiment, MkM and controls compared a single presented digit with an internal reference (Experiment 2). Consistent with the behavioural results, spatial distance elicited significant brain activations only for MkM in different cortical sites including the left supramarginal gyrus. Numerical distance elicited significant brain activations only for controls in the left somatosensory cortex and in the right operculum. We propose that two types of representation are accessed in synaesthesia: one derived by the semantic coding of numbers across space (described by the mental number line), and an explicit spatial representation derived from the position of number within the synaesthetic association. The level of overlap between these two forms of representation depends on the shape of the synaesthetic number-space association.

https://ift.tt/2R3BIER

Meta-analysis of the visuospatial aftereffects of prism adaptation, with two novel experiments

Publication date: Available online 19 November 2018

Source: Cortex

Author(s): Robert D. McIntosh, Bethany MA. Brown, Louise Young

Abstract

We present a meta-analysis of the effects of visuomotor adaptation to leftward displacing prisms on visuospatial judgements in healthy people, as assessed by perceptual (landmark) and manual versions of the line bisection task. To supplement previously published datasets, we report two novel experiments: Experiment 1 (n=12) found null effects of adaptation to 10° leftward prisms on spatial bias in the landmark task, and Experiment 2 (n=24) found null effects of 12° leftward prisms on spatial bias in a computerised line bisection task. Including these data, we considered 17 experiments for the landmark task (total n = 256), and 12 experiments for line bisection (total n = 172), in which participants were adapted for between 7 and 20 minutes to prism strengths from 8 to 17°. A random-effects meta-analysis, with prism strength and exposure duration as moderators, confirmed robust rightward shifts in visuospatial judgements following leftward prism adaptation. The average standardised effect sizes (Cohen's d) were similar between tasks, increasing by around 0.1 per degree of prismatic displacement, and being boosted by a long (10 minute +) period of exposure. However, the quality of evidence and precision of prediction was superior for the landmark task, with a higher signal-to-noise ratio within studies, and less heterogeneity between studies. We suggest that line bisection responses may be contaminated by sensorimotor aftereffects, and that the landmark task is a more suitable method for measuring true visuospatial aftereffects of prism adaptation. To harness these effects, we recommend that researchers should expose participants to 15° (or higher) leftward prisms for more than ten minutes, with upwards of 250 pointing movements. Power calculations should take account of heterogeneity in the true effect size between studies; and further investigation of the factors underlying this heterogeneity will help to refine optimally-effective methods.

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Using tDCS to facilitate motor learning in speech production: The role of timing

Publication date: Available online 19 November 2018

Source: Cortex

Author(s): Adam Buchwald, Holly Calhoun, Stacey Rimikis, Mara Steinberg Lowe, Rebecca Wellner, Dylan Edwards

Abstract

There exists debate regarding the extent to which transcranial direct current stimulation (tDCS) can affect or enhance human behavior. Here, we examined a previously unexplored domain: speech motor learning. We investigated whether speech motor learning in unimpaired participants can be enhanced using a single-session tDCS experiment, and investigated whether the timing of tDCS relative to a behavioral task affected performance. Participants (N=80) performed a twenty minute learning task with nonwords containing non-native consonant clusters (e.g., GDEEVOO), and were assigned to groups receiving either sham or active tDCS either immediately before or during the task. Both accuracy and properties of errors were examined throughout the course of the practice task, and then practice was compared to a retention period 30 minutes later (R1) and two days later (R2). For cluster and whole-(non)word accuracy measures, acquisition was observed for all groups during the practice session. Compared to the beginning of practice, the tDCS-Before group showed significantly greater improvement than both the sham group and the tDCS-During group at R1. An effect was also observed for vowel duration in errors (/gdivu/→ [gədivu]), with the tDCS-Before group showing significant shortening of vowel errors throughout practice. Overall, the findings suggest that tDCS can improve speech motor learning, and that the improvement may be greater when tDCS is applied immediately before practice, warranting further exploration of this new domain for tDCS research.

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Metacognition and self-awareness in Multiple Sclerosis

Publication date: Available online 19 November 2018

Source: Cortex

Author(s): Audrey Mazancieux, Céline Souchay, Olivier Casez, Chris J.A. Moulin

Abstract

Although a large range of literature on awareness and metacognition focuses on different neurological populations, little attention has been paid to Multiple Sclerosis (MS). This paper gathers literatures related to studies of anosognosia and the theoretical construct of metacognition which both offer a means to operationalize and measure awareness in MS. We focused on both a clinical concern, regarding the relationship between subjective and objective evolution of cognitive performance, and the theoretical issue of metacognitive processes implicated in disease awareness. We identified 26 papers with findings related to awareness of cognitive impairment in MS using questionnaire-based or performance-based methods. We found support for the idea that the relationship between subjective evaluation and neuropsychological evaluation depends on disease duration and is strongly modulated by other variables, such as mood state. We propose that the metacognitive deficit for memory tasks in this population arises from memory impairment. Finally, we discuss methodological issues, variability in MS patients, and the domain specificity of metacognitive impairment.

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Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice

Publication date: Available online 19 November 2018

Source: Journal of Autoimmunity

Author(s): Anje Cauwels, Sandra Van Lint, Dominiek Catteeuw, Shengru Pang, Franciane Paul, Elke Rogge, Annick Verhee, Marco Prinz, Niko Kley, Gilles Uzé, Jan Tavernier

Abstract

Type I Interferon (IFN) is widely used for multiple sclerosis (MS) treatment, but its side effects are limiting and its mechanism of action still unknown. Furthermore, 30–50% of MS patients are unresponsive, and IFN can even induce relapses. Fundamental understanding of the cellular target(s) of IFN will help to optimize treatments by reducing side effects and separating beneficial from detrimental effects. To improve clinical systemic IFN usage, we are developing AcTaferons (Activity-on-Target IFNs = AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting.

In experimental autoimmune encephalitis (EAE) in mice, high dose WT mIFNα could delay disease, but caused mortality and severe hematological deficits. In contrast, AFN targeted to dendritic cells (DC, via Clec9A) protected without mortality or hematological consequences. Conversely, CD8-targeted AFN did not protect and exacerbated weight loss, indicating the presence of both protective and unfavorable IFN effects in EAE. Comparing Clec9A-, XCR1-and SiglecH-targeting, we found that targeting AFN to plasmacytoid (p) and conventional (c) DC is superior and non-toxic compared to WT mIFN. DC-targeted AFN increased pDC numbers and their tolerogenic potential, evidenced by increased TGFβ and IDO synthesis and regulatory T cell induction. In addition, both regulatory T and B cells produced significantly more immunosuppressive TGFβ and IL-10.

In conclusion, specific DC-targeting of IFN activity induces a robust in vivo tolerization, efficiently protecting against EAE, without noticeable side effects. Thus, dissecting positive and negative IFN effects via cell-specific targeting may result in better and safer MS therapy and response rates.

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Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis

Publication date: Available online 19 November 2018

Source: Magnetic Resonance Imaging

Author(s): Tomomi Yamada, Yuto Kashiwagi, Takemi Rokugawa, Hideaki Kato, Haruyo Konishi, Tadateru Hamada, Ryohei Nagai, Yusaku Masago, Michiko Itoh, Takayoshi Suganami, Yoshihiro Ogawa, Kohji Abe

Abstract

Introduction

Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA).

Materials and methods

Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (T_max), and the half-life of RE elimination (T_1/2) were calculated. Histopathological analysis was then performed.

Results

Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that T_max and T_1/2 were significantly longer in MC4R-KO mice fed an HFD compared with wild type (WT) mice (T_max, WT, 3.9 ± 0.4 min; MC4R-KO, 7.4 ± 1.5 min; T_1/2, WT, 23.7 ± 1.9 min; MC4R-KO, 62.5 ± 18.5 min). T_max and T_1/2 were significantly correlated with histopathologic score (steatosis vs. Tmax, rho = 0.48, P = 0.04; steatosis vs. T_1/2, rho = 0.50, P = 0.03; inflammation vs. Tmax, rho = 0.55, P = 0.02; inflammation vs. T_1/2, rho = 0.61, P < 0.01; ballooning vs. T_1/2, rho = 0.51, P = 0.03;fibrosis vs T_max, rho = 0.72, P < 0.01; fibrosis vs T_1/2, rho = 0.75, P < 0.01).

Conclusions

MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH.

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Comparison of dynamic contrast-enhanced magnetic resonance imaging and contrast-enhanced ultrasound for evaluation of the effects of sorafenib in a rat model of hepatocellular carcinoma

Publication date: Available online 19 November 2018

Source: Magnetic Resonance Imaging

Author(s): Nina M. Muñoz, Adeeb A. Minhaj, Kiersten L. Maldonado, Charles V. Kingsley, Andrea C. Cortes, Houra Taghavi, Urszula Polak, Jennifer M. Mitchell, Joe E. Ensor, James A. Bankson, Asif Rashid, Rony Avritscher

Abstract

Objectives

To compare the accuracy of contrast-enhanced ultrasound (CEUS) and Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the assessment of changes in tissue vascularization as result of sorafenib treatment in a rat model of hepatocellular carcinoma (HCC).

Methods

Male Buffalo rats with orthotopic liver tumors treated daily with 7.5 mg/kg sorafenib via oral gavage for 2 weeks (n = 9) were subject to DCE-MRI and CEUS 2 weeks after tumor implantation - right before treatment initiation - and also after treatment completion - right before tumor harvest. Untreated animals (n = 10) were used as control. Tumor tissue sections were stained for hematoxylin-eosin, pimonidazole, and CD34 for quantitative assessment of necrosis, hypoxia, and microvessel density (MVD), respectively.

Results

Of all the DCE-MRI parameters that were evaluated, only volume transfer constant (K^trans) measurements were significantly lower in sorafenib-treated tumors (0.18 vs 0.33 min⁻¹, p < 0.01), indicating a substantial decrease in vascular permeability caused by the therapy. This reduction was associated with decreased MVD (3.9 vs 10.8% CD34+ cells, p < 0.01), higher tumor necrosis (31.9 vs 21.8%, p < 0.001) and hypoxia (19.7 vs 10.5% pimonidazole binding, p < 0.01). Moreover, statistical analysis demonstrate significant correlation of DCE-MRI K^trans with histopathologic tissue necrosis (r = −0.537, p < 0.05) and MVD (r = 0.599, p < 0.05). Interestingly, none of the CEUS measurements were significantly different between the control and treatment groups, and did not show statistical correlation with any of the histopathological parameters assessed (p > 0.05).

Conclusions

Sorafenib-induced reduction in vascular permeability in this preclinical model of HCC is detected more accurately through DCE-MRI than CEUS, and DCE-MRI parameters strongly correlate with histopathological changes in tissue vascularization and tissue necrosis.

https://ift.tt/2OSbfbe

Leukoderma induced by Rhododendrol is different from leukoderma of vitiligo in pathogenesis: a novel comparative morphological study

Background

Rhododendrol (Rhododenol®), an inhibitor of tyrosinase activity, is used as a skin‐whitening component. Many cases of leukoderma after the application have been reported, termed Rhododenol‐induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo.

Methods

We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, 6 cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy.

Results

There were common findings in RIL and vitiligo at the light‐microscopic level: a) vacuolar changes in the dermoepidermal junction, b) melanophages in the papillary dermis, c) perifollicular lymphocyte infiltration, d) loss or decrease of basal melanin pigment and e) decrease of melanocytes in the lesions. The ultrastructural observations demonstrated specific findings of RIL: 1) remaining melanocytes in depigmented lesions, 2) inhomogeneous melanization in melanocytes and 3) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases.

Conclusions

Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.

This article is protected by copyright. All rights reserved.

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The Concurrence of Cortical Surface Area Expansion and White Matter Myelination in Human Brain Development

Abstract

The human brain undergoes dramatic structural changes during childhood that co-occur with behavioral development. These age-related changes are documented for the brain's gray matter and white matter. However, their interrelation is largely unknown. In this study, we investigated age-related effects in cortical thickness (CT) and in cortical surface area (SA) as parts of the gray matter volume as well as age effects in T₁ relaxation times in the white matter. Data from N = 170 children between the ages of 3 and 7 years contributed to the sample. We found a high spatial overlap of age-related correlations between SA and T₁ relaxation times of the corresponding white matter connections, but no such relation between SA and CT. These results indicate that during childhood the developmental expansion of the cortical surface goes hand-in-hand with age-related increase of white matter fiber connections terminating in the cortical surface.

https://ift.tt/2OUiPlQ

Person-Based Brain Morphometric Similarity is Heritable and Correlates With Biological Features

Abstract

The characterization of the functional significance of interindividual variation in brain morphometry is a core aim of cognitive neuroscience. Prior research has focused on interindividual variation at the level of regional brain measures thus overlooking the fact that each individual brain is a person-specific ensemble of interdependent regions. To expand this line of inquiry we introduce the person-based similarity index (PBSI) for brain morphometry. The conceptual unit of the PBSI is the individual person's brain structural profile which considers all relevant morphometric measures as features of a single vector. In 2 independent cohorts (total of 1756 healthy participants), we demonstrate the foundational validity of this approach by affirming that the PBSI scores for subcortical volume and cortical thickness in healthy individuals differ between men and women, are heritable, and robust to variation in neuroimaging parameters, sample composition, and regional brain morphometry. Moreover, the PBSI scores correlate with age, body mass index, and fluid intelligence. Collectively, these results suggest that the person-based measures of brain morphometry are biologically and functionally meaningful and have the potential to advance the study of human variation in multivariate brain imaging phenotypes in healthy and clinical populations.

https://ift.tt/2zgM0ug

Voluntary Wheel Running Exercise Evoked by Food-Restriction Stress Exacerbates Weight Loss of Adolescent Female Rats But Also Promotes Resilience by Enhancing GABAergic Inhibition of Pyramidal Neurons in the Dorsal Hippocampus

Abstract

Adolescence is marked by increased vulnerability to mental disorders and maladaptive behaviors, including anorexia nervosa. Food-restriction (FR) stress evokes foraging, which translates to increased wheel running exercise (EX) for caged rodents, a maladaptive behavior, since it does not improve food access and exacerbates weight loss. While almost all adolescent rodents increase EX following FR, some then become resilient by suppressing EX by the second–fourth FR day, which minimizes weight loss. We asked whether GABAergic plasticity in the hippocampus may underlie this gain in resilience. In vitro slice physiology revealed doubling of pyramidal neurons' GABA response in the dorsal hippocampus of food-restricted animals with wheel access (FR + EX for 4 days), but without increase of mIPSC amplitudes. mIPSC frequency increased by 46%, but electron microscopy revealed no increase in axosomatic GABAergic synapse number onto pyramidal cells and only a modest increase (26%) of GABAergic synapse lengths. These changes suggest increase of vesicular release probability and extrasynaptic GABA_A receptors and unsilencing of GABAergic synapses. GABAergic synapse lengths correlated with individual's suppression of wheel running and weight loss. These analyses indicate that EX can have dual roles—exacerbate weight loss but also promote resilience to some by dampening hippocampal excitability.

https://ift.tt/2OUGL8u

Silent Synapse Unsilencing in Hippocampal CA1 Neurons for Associative Fear Memory Storage

Abstract

Clarifying learning-induced synaptic plasticity in hippocampal circuits is critical for understanding hippocampal mechanisms of memory acquisition and storage. Many in vitro studies have demonstrated learning-associated plasticity at hippocampal synapses. However, as a neural basis of memory encoding, the nature of synaptic plasticity underlying hippocampal neuronal responses to memorized stimulation remains elusive. Using in vivo whole-cell recording in anaesthetized adult rats and mice, we investigated synaptic activity of hippocampal CA1 pyramidal cells (PCs) in response to a flash of visual stimulation as the conditioned stimulus (CS) in associative fear conditioning. We found that shortly (<3 days) after conditioning, excitatory synaptic responses and spiking responses to the flash CS emerged in a large number (~70%) of CA1 PCs, a neuronal population previously unresponsive to the flash before conditioning. The learning-induced CA1 excitatory responsiveness was further indicated to result from postsynaptic unsilencing at flash-associated silent synapses, with NMDA receptor-gated responses we recently reported in naive animals. Our findings suggest that associative fear learning can induce excitatory responsiveness to the memorized CS in a large population of CA1 neurons, via a process of postsynaptic unsilencing at CA1 silent synapses, which may be critical for hippocampal acquisition and storage of associative memory.

https://ift.tt/2ze9eRN

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