Microphthalmia with linear skin defects (MLS) syndrome: familial presentation

Linear IgA bullous dermatosis associated with amyotrophic lateral sclerosis

Milia: a useful clinical marker of CYLD mutation carrier status

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Abstract

Background

Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.

Patients and Methods

We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.

Results

Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids, and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (6 grade 1-2, 7 grade 3-4, 1 grade 5 Stevens-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% vs. 28%, p=0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2, 6 grade 3-4). Duration of steroid taper, severity of initial irAEs, and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% vs. 31%, p=0.03).

Conclusions

Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in select patients.

The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established

Interactive effects of PAHs with different rings and As on their uptake, transportation, and localization in As hyperaccumulator

Abstract

In order to illuminate the mechanism of the interaction of polycyclic aromatic hydrocarbon (PAH) with different benzene rings and arsenic (As) in As hyperaccumulator, Pteris vittata L., the uptakes of PAHs were investigated using hydroponics simulation and localizations of PAHs in the plant were determined using two-photon laser scanning confocal microscopy (TPLSCM). The results showed that the total As concentration in different parts of P. vittata decreased in the presence of PAHs with increased numbers of benzene rings: 38.0–47.4% for benzo(a)pyrene (BaP, five rings), 20.5–35.9% for pyrene (PYR, four rings), and 13.7–16.6% for fluorine (FLU, three rings). BaP and PYR concentrations increased, while FLU concentration decreased in the presence of As. The results of TPLSCM revealed that PAHs distributed in epidermal cells of roots, xylem, and endothelial cells of rachis, epidermis, and stomatal cells of pinnae; however, the fluorescence intensity of BaP and PYR were higher than FLU significantly in plant. This study provided important basis to further research on interactive effects of PAHs and As in the P. vittata. These findings were important to understand the mechanisms of PAH and As translocation and distribution by P. vittata.

In search of a comprehensible set of endpoints for the routine monitoring of neurotoxicity in vertebrates: sensory perception and nerve transmission in zebrafish ( Danio rerio ) embryos

Abstract

In order to develop a test battery based on a variety of neurological systems in fish, three sensory systems (vision, olfaction, and lateral line) as well as nerve transmission (acetylcholine esterase) were analyzed in zebrafish (Danio rerio) embryos with respect to their suitability as a model for the screening of neurotoxic trace substances in aquatic ecosystems. As a selection of known or putative neurotoxic compounds, amidotrizoic acid, caffeine, cypermethrin, dichlorvos, 2,4-dinitrotoluene, 2,4-dichlorophenol, 4-nonylphenol, perfluorooctanoic acid, and perfluorooctane sulfonic acid were tested in the fish embryo test (OECD test guideline 236) to determine EC₁₀ values, which were then used as maximum test concentration in subsequent neurotoxicity tests. Whereas inhibition of acetylcholinesterase was investigated biochemically both in vivo and in vitro (ex vivo), the sensory organs were studied in vivo by means of fluorescence microscopy and histopathology in 72- or 96-h-old zebrafish embryos, which are not regarded as protected developmental stages in Europe and thus — at least de jure — represent alternative test methods. Various steps of optimization allowed this neurotoxicity battery to identify neurotoxic potentials for five out of the nine compounds: Cypermethrin and dichlorvos could be shown to specifically modulate acetylcholinesterase activity; dichlorvos, 2,4-dichlorophenol, 4-nonylphenol, and perfluorooctane sulfonic acid led to a degeneration of neuromasts, whereas both vision and olfaction proved quite resistant to concentrations ≤ EC₁₀ of all of the model neurotoxicants tested. Comparison of neurotoxic effects on acetylcholinesterase activity following in vivo and in vitro (ex vivo) exposure to cypermethrin provided hints to a specific enzyme-modulating activity of pyrethroid compounds. Enhancement of the neuromast assay by applying a simultaneous double-staining procedure and implementing a 4-scale scoring system (Stengel et al. 2017) led to reduced variability of results and better statistical resolution and allowed to differentiate location-dependent effects in single neuromasts. Since acetylcholinesterase inhibition and neuromast degeneration can be analyzed in 72- and 96-h-old zebrafish embryos exposed to neurotoxicants according to the standard protocol of the fish embryo toxicity test (OECD TG 236), the fish embryo toxicity test can be enhanced to serve as a sensitive neurotoxicity screening test in non-protected stages of vertebrates.

The addition of PRP to facial lipofilling: a double-blind placebo-controlled randomized trial.

Background: Lipofilling is a treatment modality to restore tissue volume, but may also rejuvenate the aging skin. Platelet-rich plasma has been reported to augment the efficacy of lipofilling, both on graft take and rejuvenation by altering the ADSC. Authors hypothesized that PRP addition would increase the rejuvenating effect while shortening recovery time. Methods: The study conducted was a single-centre, double blinded, placebo-controlled randomized trial (2012-2015). In total, a well-defined cohort of 32 healthy females enrolled in the study, with 25 completing the follow-up. All patients underwent aesthetic facial lipofilling with either saline or PRP added. Outcome was determined by changes in skin elasticity, volumetric changes of the nasolabial fold, recovery time and patient satisfaction during follow-up (1 year). Results: PRP did not improve the outcome of facial lipofilling when looking at skin elasticity improvement, graft volume maintenance in the nasolabial fold or patient satisfaction. Patient recovery after surgery however, dropped significantly. Furthermore, no skin rejuvenation effects from lipofilling could be observed. Conclusion: This study clearly demonstrates that the addition of PRP to the lipograft significantly reduces patient's reported recovery time, but does not significantly improve skin elasticity, volume retention nor overall patient satisfaction as compared to lipofilling alone. Moreover, reported effects of 'normal' (not SVF/ADSC enriched) lipofilling on skin rejuvenation, as has been reported and suggested to be seen in clinical studies when used in combination with facelift surgery, could also not be addressed. (C)2017American Society of Plastic Surgeons

The lateral thigh perforator (LTP) flap for autologous breast reconstruction: A prospective analysis of 138 flaps.

Background: The septocutaneous tensor fasciae latae (sc-TFL) or lateral thigh perforator (LTP) flap was previously introduced by our group as an alternative flap for autologous breast reconstruction when the abdomen is not suitable as a donor site. The aim of this study was to analyze our experience with the LTP flap and to present the surgical refinements that were introduced. Methods: A prospective study was conducted of all LTP flap breast reconstructions performed since September 2012. Patient demographics, operative details, complications and flap re-explorations were recorded. Preoperative imaging with MRA was performed in all patients. Surgical refinements that were introduced during this study included limitation of the flap width and the use of quilting sutures at the donor site. Results: A total of 138 LTP flap breast reconstructions were performed in 86 consecutive patients. Median operation times were 277 minutes (range 196-561) for unilateral and 451 minutes (range 335-710) for bilateral procedures. Median flap weight was 348 grams (range 175-814). Two total flap losses (1.4%) were recorded and eleven flaps (8.0%) required re-exploration, which resulted in viable flaps. The incidence of donor-site complications reduced significantly after the surgical refinements were introduced. Wound problems decreased from 40.0% to 6.3%, seroma from 25.0% to 9.5%, and infection from 27.5% to 9.5%, respectively. Conclusions: The LTP flap is an excellent option for autologous breast reconstruction with minimal recipient-site complications. The surgical refinements resulted in a significant reduction of donor-site complications. Therefore, the LTP flap is currently our second choice after the DIEP flap. (C)2017American Society of Plastic Surgeons

Complications and Patient-Reported Outcomes after Abdominal-Based Breast Reconstruction: Results of the Mastectomy Reconstruction Outcomes Consortium (MROC) Study.

Background: Abdominal flap reconstruction is the most popular form of autologous breast reconstruction. The current study compared complications and patient-reported outcomes (PROs) after pedicled transverse rectus abdominis myocutaneous (PTRAM), free TRAM (FTRAM), deep inferior epigastric perforator (DIEP), and superficial inferior epigastric artery (SIEA) flaps. Methods: Patients having abdominal-based breast reconstruction at 11 centers were prospectively evaluated for abdominal donor-site and breast complications. PROs were measured by the BREAST-Q and PROMIS surveys. Mixed-effects regression models were used to assess the effects of procedure type on outcomes. Results: 720 patients had one-year follow-up and 587 had two-year follow-up. Two years after reconstruction, SIEA compared with DIEP flap was associated with a higher rate of donor-site complications (OR=2.7, p=0.001), however SIEA reported higher BREAST-Q abdominal physical well-being scores than DIEP at one year (mean difference: 4.72, p=0.053, on a scale from 0 to 100). This difference was not significant at two years. Abdominal physical well-being scores at two year post-operatively were lower in PTRAM group by 7.2 points (p=0.006) than DIEP and by 7.8 points (p = 0.03) than SIEA, and in FTRAM group lower by 4.9 points (p = 0.04) than DIEP. Bilateral reconstruction had significantly lower abdominal physical well-being scores compared with unilateral reconstruction. Conclusions: While all abdominal-based flaps are viable breast reconstruction options, DIEP and SIEA flaps are associated with a higher abdominal physical well-being than PTRAM and FTRAM flaps. Although SIEA flaps offer the advantage of not violating the fascia, higher rates of donor-site complications may diminish patient satisfaction. (C)2017American Society of Plastic Surgeons

Bony/Cartilaginous Mismatch: A radiologic investigation into the etiology of tension nose deformity.

Background: Tension nose deformity is believed to be due to an "oversized" septal quadrangular cartilage. Prior studies have shown that quadrangular cartilage size is relatively consistent in size in populations. We hypothesize that the tension nose deformity is actually due to an external extrusion of a normal sized septal cartilage from an undersized bony septal encasement. Methods: A retrospective case-control study of sagittal CT scans was conducted, measuring the perimeter and surface area of the quadrangular cartilage and bony septal aperture in tension nose cases and controls. Statistical analysis was performed. Results: Of 23 patients enrolled in the study, 12 patients were sorted into the tension nose group, while 11 patients were considered controls. Both groups had similar perimeter and surface area of their quadrangular cartilage, without statistical difference between the two groups. However, the tension nose group had a statistically significant reduction in bony septal aperture perimeter when compared to controls (p

Outcomes After Phalloplasty: Do Transgender Patients and Multiple Urethral Procedures Carry a Higher Rate of Complication?.

Introduction: Phalloplasty is associated with improved quality-of-life in those with penile defects, and in female-to-male transgender (transmale) patients seeking gender-confirming surgery. However, aggregate complication and outcome data is sparse. This study compares phalloplasty outcomes between transmale and cismale patients and between those with primary versus staged urethroplasty. Methods: A comprehensive literature search of PubMed, MEDLINE, and Google Scholar databases was conducted for studies relating to phalloplasty. Data on techniques, complications, outcomes, and patient demographics were collected. Analysis using the random-effects model with subgroup analyses was performed. Results: A total of 50 studies (1,351 patients) were included; 19 studies (869 patients) for transmale patients and 31 studies (482 patients) for cismale patients. The urethral complication rate in the transmale group was 39.4% (95% CI: 30.6-48.9, p=0.028) compared to 24.8% (95% CI: 16.5-35.4, p

Analysis and experimental evaluation of shunt active power filter for power quality improvement based on predictive direct power control

Abstract

This paper discusses the use of the concept of classical and predictive direct power control for shunt active power filter function. These strategies are used to improve the active power filter performance by compensation of the reactive power and the elimination of the harmonic currents drawn by non-linear loads. A theoretical analysis followed by a simulation using MATLAB/Simulink software for the studied techniques has been established. Moreover, two test benches have been carried out using the dSPACE card 1104 for the classic and predictive DPC control to evaluate the studied methods in real time. Obtained results are presented and compared in this paper to confirm the superiority of the predictive technique. To overcome the pollution problems caused by the consumption of fossil fuels, renewable energies are the alternatives recommended to ensure green energy. In the same context, the tested predictive filter can easily be supplied by a renewable energy source that will give its impact to enhance the power quality.

Effect of an alkaline environment on the engineering behavior of cement-stabilized/solidified Zn-contaminated soils

Abstract

Although the stabilization/solidification method has been widely used for remediation of heavy metal-contaminated soils in recent decades, the engineering behavior and mobility of heavy metal ions under alkaline groundwater conditions are still unclear. Therefore, the unconfined compressive strength test (UCS) combined with toxicity characteristic leaching procedure (TCLP) and general acid neutralization capacity (GANC) was used to investigate the effects of alkalinity (using NaOH to simulate alkalinity in the environment) on the mechanical and leaching characteristics of cement-solidified/stabilized (S/S) Zn-contaminated soils. Moreover, the microstructure was analyzed using the scanning electron microscope (SEM) technology. The results indicated that alkaline environment could accelerate the UCS development compared with specimens without soaking in NaOH solution,, regardless of whether the specimens contained Zn²⁺ or not. And the UCS varied obviously attributed to the variations of both NaOH concentration and soaking time. Except for the specimens soaked for 90 days, the leached Zn²⁺ concentrations were higher than that of without soaking. However, the leachability of Zn²⁺ in all the stabilized specimens is in the regulatory level. ANC results indicated that the Zn²⁺ leaching behavior can be divided into three stages related to the initial leachate pH. Moreover, SEM results proved that the alkaline environment could actually facilitate the cement hydration process. The results proved in the present paper could be useful in treating the heavy metal-contaminated soils involved in the solidification/stabilization technology under alkaline environment.

Photoreduction of Cr(VI) in water using BiVO 4 -Fe 3 O 4 nano-photocatalyst under visible light irradiation

Abstract

The residuals of hexavalent chromium in the aquatic environment have raised much concern for water decontamination. In this study, BiVO₄-Fe₃O₄ was synthesized using a solvothermal method and adopted as a photoreduction catalyst to removal of Cr(VI) in water under visible light irradiation. The physical and chemical properties of BiVO₄-Fe₃O₄ were characterized by UV-vis-DRS, SEM, XRD, FTIR, and BET. The results demonstrated that the band gap for the obtained material is 1.74 eV with an average size of 15 nm and a specific surface area of 55.16 m²/g. A high photocatalytic performance was observed on the photoreduction of Cr(VI) and the removal efficiency was increased in the lower pH condition. The ascending catalyst dosages made the promotion effect, while the increase of Cr(VI) concentration contributed the inhibition for the reduction performance. The structural characteristics of the selected hole scavengers (ethanol, isopropanol, formic acid, citric acid, and oxalic acid) showed the various effects on the reactions due to the amounts of α-OH. For the optimal condition, 79.37% Cr(VI) was removed. Based on the excellent reusability of BiVO₄-Fe₃O₄, this study demonstrated a potential method for the economic-friendly removal of high-valence metals with easier separation in the water.

Pyrosequencing analysis of source water switch and sulfate-induced bacterial community transformation in simulated drinking water distribution pipes

Abstract

Inter-basin water transfer and source water switching will be increasingly launched due to significant population increase and the shortage of the local water resources in cities around the world. Source water switch may cause physiochemical and microbiological de-stabilization of pipe material, biofilms, and loose deposits in drinking water distribution system (DWDS). Great sulfate alteration during source water switch had been deemed as the main cause of a red water case that occurred in a northern China city. To ascertain the relationship between water quality changing and bacterial communities of biofilms in DWDS and possible bacteria risk in a red water case, water quality changing experiments in simulated DWDSs were conducted for approximately 2 years. Twenty-five corrosion scale samples and eight water samples collected from pipe harvest sites or during experimental periods were analyzed for their bacterial community composition by 454-pyrosequencing technology. Taxonomy results together with redundancy analysis (RDA) or canonical correspondence analysis (CCA) and hierarchical cluster analysis all indicated that bacterial community of samples with groundwater (GW) or surface water (SW) supply history and their variations under high sulfate water were rather different owing to different water source histories and the original pipe scale characteristics. Potential opportunistic pathogens: Burkholderia, Escherichia-Shigella, Mycobacterium, Serratia, Ralstonia, Novosphingobium, Flavobacterium, Sphingomonas, and Sphingopyxis were observed in scale or water samples.

The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats

Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors ...

Releasing the “GENI”: Integrating authentic microbial genomics research into the classroom through GENI-ACT.

Abstract

The integration of genomics research into the undergraduate biology curriculum provides students with the opportunity to become familiar with bioinformatics tools and answer original research questions. Our purpose with this research project was to upscale the research experience through integration with classroom experience giving students access to authentic research projects. Students annotated 60 predicted ABC genes of Methanothermobacter thermautotrophicus and Methanobacterium sp. SWAN-1 and they were required to present a research poster to demonstrate their understanding of the project. During this research project a number of tests, assessments and surveys were conducted to assess familiarity with technical and conceptual understanding of genome annotation, satisfaction with annotation instruction, gain in bioinformatics research skills, scientific communications skills and increased student interest in research. We found that students gained significant skills in bioinformatics, specifically genome annotation skills and also gained confidence in their abilities to carry out scientific research. As a result of this authentic undergraduate research experience underrepresented students were motivated to pursue future careers in STEM fields.

Thromboprophylaxis in autologous breast reconstruction

Publication date: Available online 10 October 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Sarita Vamadeva, Francis Henry, Judith Hunter, Simon Wood, Navid Jallali

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Sodium Dynamics in Pyramidal Neuron Dendritic Spines: Synaptically Evoked Entry Predominantly through AMPA Receptors and Removal by Diffusion

Dendritic spines are key elements underlying synaptic integration and cellular plasticity, but many features of these important structures are not known or are controversial. We examined these properties using newly developed simultaneous sodium and calcium imaging with single-spine resolution in pyramidal neurons in rat hippocampal slices from either sex. Indicators for both ions were loaded through the somatic patch pipette, which also recorded electrical responses. Fluorescence changes were detected with a high-speed, low-noise CCD camera. Following subthreshold electrical stimulation, postsynaptic sodium entry is almost entirely through AMPA receptors with little contribution from entry through NMDA receptors or voltage-gated sodium channels. Sodium removal from the spine head is through rapid diffusion out to the dendrite through the spine neck with a half-removal time of ~16 ms, which suggests the neck has low resistance. Peak [Na⁺]_i changes during single EPSPs are ~5 mm. Stronger electrical stimulation evoked small plateau potentials that had significant longer-lasting localized [Na⁺]_i increases mediated through NMDA receptors.

SIGNIFICANCE STATEMENT Dendritic spines, small structures that are difficult to investigate, are important elements in the fundamental processes of synaptic integration and plasticity. The main tool for examining these structures has been calcium imaging. However, the kinds of information that calcium imaging reveals is limited. We used newly developed, high-speed, simultaneous sodium and calcium imaging to examine ion dynamics in spines in hippocampal pyramidal neurons. We found that following single subthreshold synaptic activation most sodium entry was through AMPA receptors and not through NMDA receptors or through voltage-gated sodium channels and that the spine neck is not a significant resistance barrier. Most spine mechanisms are linear. However, regenerative NMDA conductances can be activated with stronger stimulation.

Parkinson's Disease Is Not Simply a Prion Disorder

The notion that prion-like spreading of misfolded α-synuclein (α-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD.

Dual Perspectives Companion Paper: Prying into the Prion Hypothesis for Parkinson's Disease, by Patrik Brundin and Ronald Melki

Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (p35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with p35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:p35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.

SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aβ accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the p35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant p35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.

Prying into the Prion Hypothesis for Parkinson's Disease

In Parkinson's disease, intracellular α-synuclein inclusions form in neurons. We suggest that prion-like behavior of α-synuclein is a key component in Parkinson's disease pathogenesis. Although multiple molecular changes are involved in the triggering of the disease process, we propose that neuron-to-neuron transfer is a crucial event that is essential for Lewy pathology to spread from one brain region to another. In this review, we describe key findings in human postmortem brains, cultured cells, and animal models of disease that support the idea that α-synuclein can act as a prion. We consider potential triggers of the α-synuclein misfolding and why the aggregates escape cellular degradation under disease conditions. We also discuss whether different strains of α-synuclein fibrils can underlie differences in cellular and regional distribution of aggregates in different synucleinopathies. Our conclusion is that α-synuclein probably acts as a prion in human diseases, and a deeper understanding of this step in the pathogenesis of Parkinson's disease can facilitate the development of disease-modifying therapies in the future.

Dual Perspectives Companion Paper: Parkinson's Disease Is Not Simply a Prion Disorder, by D. James Surmeier, José A. Obeso, and Glenda M. Halliday

This Week in The Journal

T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice

It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in chronic pain processing. Using an inflammatory (complete Freund's adjuvant) or neuropathic (spared nerve injury) model of persistent pain, we observed that young adult female mice in early pregnancy switch from a microglia-independent to a microglia-dependent pain hypersensitivity mechanism. During late pregnancy, female mice show no evidence of chronic pain whatsoever. This pregnancy-related analgesia is reversible by intrathecal administration of naloxone, suggesting an opioid-mediated mechanism; pharmacological and genetic data suggest the importance of -opioid receptors. We also observe that T-cell-deficient (nude and Rag1-null mutant) pregnant mice do not exhibit pregnancy analgesia, which can be rescued with the adoptive transfer of CD4⁺ or CD8⁺ T cells from late-pregnant wild-type mice. These results suggest that T cells are a mediator of the opioid analgesia exhibited during pregnancy.

SIGNIFICANCE STATEMENT Chronic pain symptoms often subside during pregnancy. This pregnancy-related analgesia has been demonstrated for acute pain in rats. Here, we show that pregnancy analgesia can produce a complete cessation of chronic pain behaviors in mice. We show that the phenomenon is dependent on pregnancy hormones (estrogen and progesterone), -opioid receptors, and T cells of the adaptive immune system. These findings add to the recent but growing evidence of sex-specific T-cell involvement in chronic pain processing.

Oscillatory Reinstatement Enhances Declarative Memory

Declarative memory recall is thought to involve the reinstatement of neural activity patterns that occurred previously during encoding. Consistent with this view, greater similarity between patterns of activity recorded during encoding and retrieval has been found to predict better memory performance in a number of studies. Recent models have argued that neural oscillations may be crucial to reinstatement for successful memory retrieval. However, to date, no causal evidence has been provided to support this theory, nor has the impact of oscillatory electrical brain stimulation during encoding and retrieval been assessed. To explore this we used transcranial alternating current stimulation over the left dorsolateral prefrontal cortex of human participants [n = 70, 45 females; age mean (SD) = 22.12 (2.16)] during a declarative memory task. Participants received either the same frequency during encoding and retrieval (60–60 or 90–90 Hz) or different frequencies (60–90 or 90–60 Hz). When frequencies matched there was a significant memory improvement (at both 60 and 90 Hz) relative to sham stimulation. No improvement occurred when frequencies mismatched. Our results provide support for the role of oscillatory reinstatement in memory retrieval.

SIGNIFICANCE STATEMENT Recent neurobiological models of memory have argued that large-scale neural oscillations are reinstated to support successful memory retrieval. Here we used transcranial alternating current stimulation (tACS) to test these models. tACS has recently been shown to induce neural oscillations at the frequency stimulated. We stimulated over the left dorsolateral prefrontal cortex during a declarative memory task involving learning a set of words. We found that tACS applied at the same frequency during encoding and retrieval enhances memory. We also find no difference between the two applied frequencies. Thus our results are consistent with the proposal that reinstatement of neural oscillations during retrieval supports successful memory retrieval.

Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation

The proper formation of synapses—specialized unitary structures formed between two neurons—is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.

SIGNIFICANCE STATEMENT The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of-function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation.

Domain-General Brain Regions Do Not Track Linguistic Input as Closely as Language-Selective Regions

Language comprehension engages a cortical network of left frontal and temporal regions. Activity in this network is language-selective, showing virtually no modulation by nonlinguistic tasks. In addition, language comprehension engages a second network consisting of bilateral frontal, parietal, cingulate, and insular regions. Activity in this "multiple demand" (MD) network scales with comprehension difficulty, but also with cognitive effort across a wide range of nonlinguistic tasks in a domain-general fashion. Given the functional dissociation between the language and MD networks, their respective contributions to comprehension are likely distinct, yet such differences remain elusive. Prior neuroimaging studies have suggested that activity in each network covaries with some linguistic features that, behaviorally, influence on-line processing and comprehension. This sensitivity of the language and MD networks to local input characteristics has often been interpreted, implicitly or explicitly, as evidence that both networks track linguistic input closely, and in a manner consistent across individuals. Here, we used fMRI to directly test this assumption by comparing the BOLD signal time courses in each network across different people (n = 45, men and women) listening to the same story. Language network activity showed fewer individual differences, indicative of closer input tracking, whereas MD network activity was more idiosyncratic and, moreover, showed lower reliability within an individual across repetitions of a story. These findings constrain cognitive models of language comprehension by suggesting a novel distinction between the processes implemented in the language and MD networks.

SIGNIFICANCE STATEMENT Language comprehension recruits both language-specific mechanisms and domain-general mechanisms that are engaged in many cognitive processes. In the human cortex, language-selective mechanisms are implemented in the left-lateralized "core language network", whereas domain-general mechanisms are implemented in the bilateral "multiple demand" (MD) network. Here, we report the first direct comparison of the respective contributions of these networks to naturalistic story comprehension. Using a novel combination of neuroimaging approaches we find that MD regions track stories less closely than language regions. This finding constrains the possible contributions of the MD network to comprehension, contrasts with accounts positing that this network has continuous access to linguistic input, and suggests a new typology of comprehension processes based on their extent of input tracking.

Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function.

SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction.

Regional Cellular Environment Shapes Phenotypic Variations of Hippocampal and Neocortical Chandelier Cells

Different cortical regions processing distinct information, such as the hippocampus and the neocortex, share common cellular components and circuit motifs but form unique networks by modifying these cardinal units. Cortical circuits include diverse types of GABAergic interneurons (INs) that shape activity of excitatory principal neurons (PNs). Canonical IN types conserved across distinct cortical regions have been defined by their morphological, electrophysiological, and neurochemical properties. However, it remains largely unknown whether canonical IN types undergo specific modifications in distinct cortical regions and display "regional variants." It is also poorly understood whether such phenotypic variations are shaped by early specification or regional cellular environment. The chandelier cell (ChC) is a highly stereotyped IN type that innervates axon initial segments of PNs and thus serves as a good model with which to address this issue. Here, we show that Cadherin-6 (Cdh6), a homophilic cell adhesion molecule, is a reliable marker of ChCs and Cdh6-CreER mice (both sexes) provide genetic access to hippocampal ChCs (h-ChCs). We demonstrate that, compared with neocortical ChCs (nc-ChCs), h-ChCs cover twice as much area and innervate twice as many PNs. Interestingly, a subclass of h-ChCs exhibits calretinin (CR) expression, which is not found in nc-ChCs. Furthermore, we find that h-ChCs appear to be born earlier than nc-ChCs. Surprisingly, despite the difference in temporal origins, ChCs display host-region-dependent axonal/synaptic organization and CR expression when transplanted heterotopically. These results suggest that local cellular environment plays a critical role in shaping terminal phenotypes of regional IN variants in the hippocampus and the neocortex.

SIGNIFICANCE STATEMENT Canonical interneuron (IN) types conserved across distinct cortical regions such as the hippocampus and the neocortex are defined by morphology, physiology, and gene expression. However, it remains unknown whether they display phenotypic variations in different cortical regions. In addition, it is unclear whether terminal phenotypes of regional IN variants belonging to a canonical IN type are determined intrinsically or extrinsically. Our results provide evidence of striking differences in axonal/synaptic organization and calretinin expression between hippocampal chandelier cells (ChCs) and neocortical ChCs. They also reveal that local cellular environment in distinct cortical regions regulates these terminal phenotypes. Therefore, our study suggests that local cortical environment shapes the phenotypes of regional IN variants, which may be required for unique circuit operations in distinct cortical regions.

Astrocyte-Mediated Neuronal Synchronization Properties Revealed by False Gliotransmitter Release

Astrocytes spontaneously release glutamate (Glut) as a gliotransmitter (GT), resulting in the generation of extrasynaptic NMDAR-mediated slow inward currents (SICs) in neighboring neurons, which can increase local neuronal excitability. However, there is a deficit in our knowledge of the factors that control spontaneous astrocyte GT release and the extent of its influence. We found that, in rat brain slices, increasing the supply of the physiological transmitter Glut increased the frequency and signaling charge of SICs over an extended period. This phenomenon was replicated by exogenous preexposure to the amino acid D-aspartate (D-Asp). Using D-Asp as a "false" GT, we determined the extent of local neuron excitation by GT release in ventrobasal thalamus, CA1 hippocampus, and somatosensory cortex. By analyzing synchronized neuronal NMDAR-mediated excitation, we found that the properties of the excitation were conserved in different brain areas. In the three areas, astrocyte-derived GT release synchronized groups of neurons at distances of >;200 μm. Individual neurons participated in more than one synchronized population, indicating that individual neurons can be excited by more than one astrocyte and that individual astrocytes may determine a neuron's synchronized network. The results confirm that astrocytes can act as excitatory nodes that can influence neurons over a significant range in a number of brain regions. Our findings further suggest that chronic elevation of ambient Glut levels can lead to increased GT Glut release, which may be relevant in some pathological states.

SIGNIFICANCE STATEMENT Astrocytes spontaneously release glutamate (Glut) and other gliotransmitters (GTs) that can modify neuronal activity. Exposing brain slices to Glut and D-aspartate (D-Asp) before recording resulted in an increase in frequency of GT-mediated astrocyte–neuron signaling. Using D-Asp, it was possible to investigate the effects of specific GT release at neuronal NMDARs. Calcium imaging showed synchronized activity in groups of neurons in cortex, hippocampus, and thalamus. The size of these populations was similar in all areas and some neurons were involved in more than one synchronous group. The findings show that GT release is supply dependent and that the properties of the signaling and activated networks are largely conserved between different brain areas.

GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of Protein Kinase A: Implications for Multiple Sclerosis

Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting disease progression. Our previous findings suggest that fibronectin aggregates, as an environmental factor, contribute to remyelination failure by perturbing oligodendrocyte progenitor cell (OPC) maturation. Here, we aim at elucidating whether exogenously added gangliosides (i.e., cell surface lipids with a potential to modulate signaling pathways) could counteract fibronectin-mediated inhibition of OPC maturation. Exclusive exposure of rat oligodendrocytes to GD1a, but not other gangliosides, overcomes aggregated fibronectin-induced inhibition of myelin membrane formation, in vitro, and OPC differentiation in fibronectin aggregate containing cuprizone-induced demyelinated lesions in male mice. GD1a exerts its effect on OPCs by inducing their proliferation and, at a late stage, by modulating OPC maturation. Kinase activity profiling revealed that GD1a activated a protein kinase A (PKA)-dependent signaling pathway and increased phosphorylation of the transcription factor cAMP response element-binding protein. Consistently, the effect of GD1a in restoring myelin membrane formation in the presence of fibronectin aggregates was abolished by the PKA inhibitor H89, whereas the effect of GD1a was mimicked by the PKA activator dibutyryl-cAMP. Together, GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation by activating a PKA-dependent signaling pathway. Given the persistent presence of fibronectin aggregates in MS lesions, ganglioside GD1a might act as a potential novel therapeutic tool to selectively modulate the detrimental signaling environment that precludes remyelination.

SIGNIFICANCE STATEMENT As an environmental factor, aggregates of the extracellular matrix protein fibronectin perturb the maturation of oligodendrocyte progenitor cells (OPCs), thereby impeding remyelination, in the demyelinating disease multiple sclerosis (MS). Here we demonstrate that exogenous addition of ganglioside GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation, both in vitro and in vivo, by activating a PKA-dependent signaling pathway. We propose that targeted delivery of GD1a to MS lesions may act as a potential novel molecular tool to boost maturation of resident OPCs to overcome remyelination failure and halt disease progression.

Visual Responses in FEF, Unlike V1, Primarily Reflect When the Visual Context Renders a Receptive Field Salient

When light falls within a neuronal visual receptive field (RF) the resulting activity is referred to as the visual response. Recent work suggests this activity is in response to both the visual stimulation and the abrupt appearance, or salience, of the presentation. Here we present a novel method for distinguishing the two, based on the timing of random and nonrandom presentations. We examined these contributions in frontal eye field (FEF; N = 51) and as a comparison, an early stage in the primary visual cortex (V1; N = 15) of male monkeys (Macaca mulatta). An array of identical stimuli was presented within and outside the neuronal RF while we manipulated salience by varying the time between stimulus presentations. We hypothesized that the rapid presentation would reduce salience (the sudden appearance within the visual field) of a stimulus at any one location, and thus decrease responses driven by salience in the RF. We found that when the interstimulus interval decreased from 500 to 16 ms there was an approximate 79% reduction in the FEF response compared with an estimated 17% decrease in V1. This reduction in FEF response for rapid presentation was evident even when the random sequence preceding a stimulus did not stimulate the RF for 500 ms. The time course of these response changes in FEF suggest that salience is represented much earlier (<100 ms following stimulus onset) than previously estimated. Our results suggest that the contribution of salience dominates at higher levels of the visual system.

SIGNIFICANCE STATEMENT The neuronal responses in early visual processing [e.g., primary visual cortex (V1)] reflect primarily the retinal stimulus. Processing in higher visual areas is modulated by a combination of the visual stimulation and contextual factors, such as salience, but identifying these components separately has been difficult. Here we quantified these contributions at a late stage of visual processing [frontal eye field (FEF)] and as a comparison, an early stage in V1. Our results suggest that as visual information continues through higher levels of processing the neural responses are no longer driven primarily by the visual stimulus in the receptive field, but by the broader context that stimulus defines—very different from current views about visual signals in FEF.

MAP1B Light Chain Modulates Synaptic Transmission via AMPA Receptor Intracellular Trapping

The regulated transport of AMPA-type glutamate receptors (AMPARs) to the synaptic membrane is a key mechanism to determine the strength of excitatory synaptic transmission in the brain. In this work, we uncovered a new role for the microtubule-associated protein MAP1B in modulating access of AMPARs to the postsynaptic membrane. Using mice and rats of either sex, we show that MAP1B light chain (LC) accumulates in the somatodendritic compartment of hippocampal neurons, where it forms immobile complexes on microtubules that limit vesicular transport. These complexes restrict AMPAR dendritic mobility, leading to the intracellular trapping of receptors and impairing their access to the dendritic surface and spines. Accordingly, increasing MAP1B-LC expression depresses AMPAR-mediated synaptic transmission. This effect is specific for the GluA2 subunit of the AMPAR and requires glutamate receptor interacting protein 1 (GRIP1) interaction with MAP1B-LC. Therefore, MAP1B-LC represents an alternative link between GRIP1-AMPARs and microtubules that does not result in productive transport, but rather limits AMPAR availability for synaptic insertion, with a direct impact on synaptic transmission.

SIGNIFICANCE STATEMENT The ability of neurons to modify their synaptic connections, known as synaptic plasticity, is accepted as the cellular basis for learning and memory. One mechanism for synaptic plasticity is the regulated addition and removal of AMPA-type glutamate receptors (AMPARs) at excitatory synapses. In this study, we found that a microtubule-associated protein, MAP1B light chain (MAP1B-LC), participates in this process. MAP1B-LC forms immobile complexes along dendrites. These complexes limit intracellular vesicular trafficking and trap AMPARs inside the dendritic shaft. In this manner, MAP1B restricts the access of AMPARs to dendritic spines and the postsynaptic membrane, contributing to downregulating synaptic transmission.

Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome

Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivo.

SIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo. This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.

A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations

Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical–basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (~1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15–30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits.

SIGNIFICANCE STATEMENT Chronic depletion of dopamine from the striatum, a part of the basal ganglia, causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters striatal neuron firing in vivo, with an emphasis on defining whether and how spiny projection neurons (SPNs) engage in the synchronized beta-frequency (15–30 Hz) oscillations that become pathologically exaggerated throughout basal ganglia circuits in parkinsonism. We discovered that a select population of so-called "indirect pathway" SPNs not only fire at abnormally high rates, but are also particularly prone to being recruited to exaggerated beta oscillations. Our results provide an important link between two complementary theories that explain the presentation of disease symptoms on the basis of changes in firing rate or firing synchronization/rhythmicity.

The TRPM1 Channel Is Required for Development of the Rod ON Bipolar Cell-AII Amacrine Cell Pathway in the Retinal Circuit

Neurotransmission plays an essential role in neural circuit formation in the central nervous system (CNS). Although neurotransmission has been recently clarified as a key modulator of retinal circuit development, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we investigated the role of neurotransmission from photoreceptor cells to ON bipolar cells in development using mutant mouse lines of both sexes in which this transmission is abrogated. We found that deletion of the ON bipolar cation channel TRPM1 results in the abnormal contraction of rod bipolar terminals and a decreased number of their synaptic connections with amacrine cells. In contrast, these histological alterations were not caused by a disruption of total glutamate transmission due to loss of the ON bipolar glutamate receptor mGluR6 or the photoreceptor glutamate transporter VGluT1. In addition, TRPM1 deficiency led to the reduction of total dendritic length, branch numbers, and cell body size in AII amacrine cells. Activated Goα, known to close the TRPM1 channel, interacted with TRPM1 and induced the contraction of rod bipolar terminals. Furthermore, overexpression of Channelrhodopsin-2 partially rescued rod bipolar cell development in the TRPM1^–/– retina, whereas the rescue effect by a constitutively closed form of TRPM1 was lower than that by the native form. Our results suggest that TRPM1 channel opening is essential for rod bipolar pathway establishment in development.

SIGNIFICANCE STATEMENT Neurotransmission has been recognized recently as a key modulator of retinal circuit development in the CNS. However, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we focused on neurotransmission between rod photoreceptor cells and rod bipolar cells in the retina. We used genetically modified mouse models which abrogate each step of neurotransmission: presynaptic glutamate release, postsynaptic glutamate reception, or transduction channel function. We found that the TRPM1 transduction channel is required for the development of rod bipolar cells and their synaptic formation with subsequent neurons, independently of glutamate transmission. This study advances our understanding of neurotransmission-mediated retinal circuit refinement.

Adaptation of Thalamic Neurons Provides Information about the Spatiotemporal Context of Stimulus History

Adaptation of neural responses due to the history of sensory input has been observed across all sensory modalities. However, the computational role of adaptation is not fully understood, especially when one considers neural coding problems in which adaptation increases the ambiguity of the neural responses to simple stimuli. To address this, we quantified the impact of adaptation on the information conveyed by thalamic neurons about paired whisker stimuli in male rat. At the single neuron level, although paired-pulse adaptation reduces the information about the present stimulus, the information per spike increases. Moreover, the adapted response can convey significant amounts of information about whether, when and where a previous stimulus occurred. At the population level, ambiguity of the adapted responses about the present stimulus can be compensated for by large numbers of neurons. Therefore, paired-pulse adaptation does not reduce the discriminability of simple stimuli. It provides information about the spatiotemporal context of stimulus history.

SIGNIFICANCE STATEMENT The present work provides a computational framework that demonstrates how adaptation allows neurons to encode spatiotemporal dynamics of stimulus history.

Incidental skin malignancies in teledermatology and in-person cohorts in the Veterans Affairs Health System

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Vasken Keleshian, Alex G. Ortega-Loayza, Phillip Tarkington

The doll hairline: A clue for the diagnosis of frontal fibrosing alopecia

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Nicolò Brandi, Michela Starace, Aurora Alessandrini, Francesca Bruni, Bianca Maria Piraccini

Table of Contents

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

Prevalence of pediatric alopecia areata among 572,617 dermatology patients

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Chauncey C. Caldwell, Sami K. Saikaly, Robert P. Dellavalle, James A. Solomon

Information for Readers

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

A meta-analysis of nevus-associated melanoma: Prevalence and practical implications

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Riccardo Pampena, Athanassios Kyrgidis, Aimilios Lallas, Elvira Moscarella, Giuseppe Argenziano, Caterina Longo
The reported prevalence of nevus-associated melanoma varies substantially. We performed a systematic review and meta-analysis to determine the incidence and prevalence of this disease; we also performed subanalyses considering age, tumor thickness, and nevus-type classification. In 38 observational cohort and case–control studies, 29.1% of melanomas likely arose from a preexisting nevus and 70.9% de novo. Any given melanoma was 64% less likely to be nevus-associated than de novo (risk ratio 0.36, 95% confidence interval [CI] 0.29-0.44; P < .001; I² = 99%); nevus-associated melanomas had a lower mean Breslow thickness than de novo melanomas (mean difference –0.39 mm; 95% CI –0.60 to –0.18; P = .0003; I² = 66%). No significant differences were noted regarding the association of nevus-associated melanomas with nondysplastic nevi or dysplastic nevi (risk ratio 0.77, 95% CI 0.49-1.20; P = .24; I² = 98%).

JAAD Case Reports Article List

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

Vancomycin and DRESS: A retrospective chart review of 32 cases in Los Angeles, California

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Barbara D. Lam, Melanie M. Miller, Adam V. Sutton, David Peng, Ashley B. Crew

Journal Based CME Instructions and Information

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

The specimen that did not survive processing: Ethical considerations pertaining to open disclosure

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Nikki R. Adler, Catriona A. McLean, Douglas Gin

Spectrum of orocutaneous disease associations

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Jeffrey D. Cizenski, Pablo Michel, Ian T. Watson, Jillian Frieder, Elizabeth G. Wilder, John M. Wright, M. Alan Menter
There are a number of diseases that manifest both on the skin and the oral mucosa, and therefore the importance for dermatologists in clinical practice to be aware of these associations is paramount. In the following continuing medical education series, we outline orocutaneous disease associations with both immunologic and inflammatory etiologies.

Editorial Board

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

CME examination

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

Atypical features and systemic associations in extensive cases of Grover disease: A systematic review

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Madeleine Gantz, Daniel Butler, Matthew Goldberg, Jubin Ryu, Timothy McCalmont, Kanade Shinkai
BackgroundGrover disease is an acantholytic disorder that typically occurs on the trunk of older individuals, primarily white men, in association with heat and xerosis. Cases with extensive and/or atypical distributions have been reported.ObjectiveTo review the literature characterizing the population, morphology, associations, and disease course of extensive or atypical eruptions of Grover disease.MethodsA systematic literature review identified 50 articles with 69 cases.ResultsPatient age ranged from 14 to 83 years (mean age, 56 ± 15), with 71% of patients being male and 29% female. Areas of involvement included the trunk (90%), upper and lower extremities (63% and 61%, respectively), face/scalp (28%), neck (21%), groin (11%), buttocks (8%), and axillae (6%). The most common associations included a history of malignancy (61%), recent chemotherapy (38%), and recent transplant (20%).LimitationsExtensive cases with typical clinical morphology may not have been examined by biopsy or reported; thus, this review may have publication bias toward more severe or atypical presentations.ConclusionsGreater variability exists among patients affected by extensive or atypical Grover disease than among those with typical disease. Malignancy is a common association, and there may be a role for immunosuppression in the pathogenesis of extensive or atypical Grover disease.

Answers to CME examination

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

High prevalence of combination tanning among undergraduates: Survey at a southeastern US university

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Marcus C.B. Tan, Natalie R. Gassman, Alyssa M. Fernandez, Sejong Bae, Casey L. Daniel

Spectrum of orocutaneous disease associations

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Elizabeth G. Wilder, Jillian Frieder, Suraj Sulhan, Pablo Michel, Jeffrey D. Cizenski, John M. Wright, M. Alan Menter
The oral cavity and cutaneous organ systems share a close embryologic origin. Therefore, there are numerous dermatologic conditions presenting with concomitant oral findings of which the dermatologist must be aware. The second article in this continuing medical education series reviews inflammatory orocutaneous conditions and a number of genodermatoses. It is essential for dermatologists to be familiar with oral cavity manifestations associated with dermatologic diseases for prompt diagnosis, management, and appropriate referral to stomatology and dentistry.

Assessment of dermatology clinic resources at safety-net hospitals: Results from a national survey

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Neeta Malviya, Joerg Albrecht, Erin Amerson, Roy Colven, Sylvia Hsu, Toby Maurer, Beth McLellan, Miriam Pomeranz, Benjamin F. Chong

CME examination

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5

Recurrence of genital aphthosis in girls: A retrospective analysis

Publication date: November 2017
Source:Journal of the American Academy of Dermatology, Volume 77, Issue 5
Author(s): Saranya P. Wyles, Julia S. Lehman, Christine M. Lohse, Alison J. Bruce, Rochelle R. Torgerson

Diagnostik und operative Therapie des muskelinvasiven Harnblasenkarzinoms

Zusammenfassung

Hintergrund

Das muskelinvasive Harnblasenkarzinom (MIBC) stellt sowohl diagnostisch als auch therapeutisch eine große Herausforderung dar.

Ziel

Aktuelle Empfehlungen zur Diagnostik und operativen Therapie des MIBC sollen dargestellt werden.

Material und Methode

Empfehlungen der S3-Leitline Harnblasenkarzinom werden vorgestellt und eine selektive Literaturrecherche in PubMed ausgewertet.

Ergebnisse und Diskussion

Histologisch lässt sich das MIBC zwar in der Regel eindeutig vom prognostisch deutlich günstigeren nichtmuskelinvasiven Harnblasenkarzinom abgrenzen, eine präoperative Bestimmung des tatsächlichen Tumorstadiums und damit eine weitere Risikostratifizierung ist mit den heute üblichen diagnostischen Maßnahmen aber nur bedingt möglich. Durch eine radikale Zystektomie (RC, in Kombination mit einer perioperativen Systemtherapie) kann selbst bei Tumoren, die bereits die Organgrenzen erreicht oder überschritten haben, eine gute lokale Tumorkontrolle gewährleistet werden. Dennoch kommt es bei einer Vielzahl der Patienten innerhalb der ersten Jahre nach RC zu einem in der Regel nur palliativ zu behandelnden Rezidiv. Während der diagnostische Wert für eine begleitende systematische pelvine Lymphadenektomie unumstritten ist, ist der therapeutische Nutzen mit Verbesserung der postoperativen Prognose noch nicht sicher belegt. Unklar ist weiterhin, ob sich neue minimalinvasive Operationstechniken hinsichtlich der onkologischen Qualität vom klassisch offen-operativen Vorgehen wesentlich unterscheiden. Auch heute noch ist die RC mit einer relativ hohen Morbidität und einer signifikanten Mortalität, insbesondere bei älteren Patienten, behaftet. Eine Optimierung des perioperativen Managements (z. B. Fast-Track-Protokolle) kann die Morbidität nachweisbar reduzieren.

Stochastic evaluation of annual micropollutant loads and their uncertainties in separate storm sewers

Abstract

This article describes a stochastic method to calculate the annual pollutant loads and its application over several years at the outlet of three catchments drained by separate storm sewers. A stochastic methodology using Monte Carlo simulations is proposed for assessing annual pollutant load, as well as the associated uncertainties, from a few event sampling campaigns and/or continuous turbidity measurements (representative of the total suspended solids concentration (TSS)). Indeed, in the latter case, the proposed method takes into account the correlation between pollutants and TSS. The developed method was applied to data acquired within the French research project "INOGEV" (innovations for a sustainable management of urban water) at the outlet of three urban catchments drained by separate storm sewers. Ten or so event sampling campaigns for a large range of pollutants (46 pollutants and 2 conventional water quality parameters: TSS and total organic carbon (TOC)) are combined with hundreds of rainfall events for which, at least one among three continuously monitored parameters (rainfall intensity, flow rate, and turbidity) is available. Results obtained for the three catchments show that the annual pollutant loads can be estimated with uncertainties ranging from 10 to 60%, and the added value of turbidity monitoring for lowering the uncertainty is demonstrated. A low inter-annual and inter-site variability of pollutant loads, for many of studied pollutants, is observed with respect to the estimated uncertainties, and can be explained mainly by annual precipitation.

Quantifying the potential export flows of used electronic products in Macau: a case study of PCs

Abstract

The used electronic product (UEP) has attracted the worldwide attentions because part of e-waste may be exported from developed countries to developing countries in the name of UEP. On the basis of large foreign trade data of electronic products (e-products), this study adopted the trade data approach (TDA) to quantify the potential exports of UEP in Macau, taking a case study of personal computers (PCs). The results show that the desktop mainframes, LCD monitors, and CRT monitors have more low-unit-value trades with higher trade volumes in the past 10 years, while the laptop and tablet PCs, as the newer technologies, owned the higher ratios of the high-unit-value trades. During the period of 2005–2015, the total mean exports for used laptop and tablet PCs, desktop mainframes, and LCD monitors were approximately 18,592, 79,957, and 43,177 units, respectively, while the possible export volume of used CRT monitors was higher, up to 430,098 units in 2000–2010. Noticed that these potential export volumes could be the lower bound because not all used PCs may be shipped using the PC trade code. For all the four kinds of used PCs, the majority (61.6–98.82%) of the export volumes have gone to Hong Kong, followed by Mainland China and Taiwan. Since 2011, there was no CRT monitor export; however, the other kinds of used PC exports will still exist in Macau in the future. The outcomes are helpful to understand and manage the current export situations of used products in Macau, and can also provide a reference for other countries and regions.

Eppur Si Muove: Ferritin is essential in modulating inflammation

Summary

Ferritin, which was only discovered in the last century has stirred a formidable debate.. For long, Ferritin was appreciated as a non-specific acute phase reactant. Several years ago, we hypothesized the contributory role of ferritin as a pathogenic molecule rather than being a product of inflammation. Latest emerging evidence provide support to this notion. Such revelation provides a step forward toward the understanding of disease conditions associated with hyperferritenemia, and hence provide new targets for treatment modalities. This article is protected by copyright. All rights reserved.

Pigmentstörungen

News

News

Treatment of chronic Q fever: clinical efficacy and toxicity of antibiotic regimens

Abstract

Background

Evidence on effectivity of first line treatment for chronic Q fever, tetracyclines (TET) plus hydroxychloroquine (HCQ), and potential alternatives is scarce.

Methods

We performed a retrospective, observational cohort study to assess efficacy of treatment with TET plus quinolones (QNL), TET plus QNL plus HCQ, QNL monotherapy or TET monotherapy compared to TET plus HCQ in chronic Q fever patients. We used a time-dependent Cox proportional hazards model to assess our primary (all-cause mortality) and secondary outcomes (first disease-related event and therapy failure).

Results

We assessed 322 chronic Q fever patients: 276 (86%) received antibiotics. Compared to TET plus HCQ (n=254;92%), treatment with TET plus QNL (n=49;17%), TET plus QNL plus HCQ (n=29, 10%), QNL monotherapy (n = 93;34%) or TET monotherapy (n=54;20%) were not associated with primary or secondary outcomes. QNL and TET monotherapy were frequently discontinued due to insufficient clinical response. (n=27;29% and n=32;59%). TET plus HCQ, TET plus QNL, and TET plus QNL plus HCQ were most frequently discontinued due to side effects (n=110;43%, n=13;27% and n=12;41%).

Conclusions

Treatment of chronic Q fever with TET plus QNL appears to be a safe alternative for TET plus HCQ, for example if TET plus HCQ cannot be tolerated due to side effects. Treatment with TET plus QNL plus HCQ was not superior to treatment with TET plus HCQ, although this may be caused by confounding by indication. Treatment with TET or QNL monotherapy should be avoided, switches because of subjective insufficient clinical response were frequently observed.

High rates of human fecal carriage of mcr-1 -positive multi-drug resistant Enterobacteriaceae isolates emerge in China in association with successful plasmid families

Abstract

Objectives

mcr-1-mediated colistin resistance in Enterobacteriaceae is concerning, as colistin is used in treating multidrug-resistant Enterobacteriaceae infections. Rates of human mcr-1 gastrointestinal carriage have historically been low. We identified trends in human fecal mcr-1-positivity rates and colonization with mcr-1-positive+third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae in Guangzhou, China, and investigated the genetic contexts of mcr-1 in a subset of mcr-1-positive+3GC-R strains.

Methods

Fecal samples were collected from in-patients and out-patients submitting specimens to three hospitals (2011-2016). mcr-1 carriage trends were assessed using iterative sequential regression. A subset of mcr-1-positive isolates was sequenced (whole genome sequencing [WGS], Illumina), and genetic contexts (flanking regions, plasmids) of mcr-1 characterized.

Results

Of 8,022 fecal samples collected, 497 (6.2%) were mcr-1-positive, and 182 (2.3%) harbored mcr-1-positive+3GC-R Enterobacteriaceae. We observed marked increases in mcr-1 (0% [Apr/2011] to 31% [Mar/2016]) and more recent (since January 2014; 0% [Apr/2011] to 15% [Mar/2016]) increases in human colonization with mcr-1-positive+3GC-R Enterobacteriaceae (p<0.001). mcr-1-positive+3GC-R isolates were commonly multi-drug resistant.WGS of mcr-1-positive+3GC-R isolates (70 Escherichia coli, 3 Klebsiella pneumoniae) demonstrated bacterial strain diversity (48 E. coli sequence types); mcr-1 in association with common plasmid backbones (IncI, IncHI2/HI2A, IncX4) and sometimes in multiple plasmids; frequent mcr-1 chromosomal integration; and high mobility of the mcr-1-associated insertion sequence ISApl1. Sequence similarity with published mcr-1 plasmid sequences was consistent with spread amongst animal/human reservoirs.

Conclusions

The high prevalence of mcr-1 in multidrug-resistant E. coli colonizing humans is a clinical threat; diverse genetic mechanisms (strains/plasmids/insertion sequences) have contributed to the dissemination of mcr-1, and will facilitate its persistence.

In- and Out-of-hospital Mortality Associated with Seasonal and Pandemic Influenza and Respiratory Syncytial Virus in South Africa, 2009–2013

Abstract

Background

Estimates of influenza- and respiratory syncytial virus (RSV)-associated mortality burden are important to guide policy for control. Data are limited on the contribution of out-of-hospital deaths to this mortality.

Methods

We modeled excess mortality attributable to influenza and RSV infection by applying regression models to weekly deaths from national vital statistics from 2009 through 2013, using influenza and RSV laboratory surveillance data as covariates. We fitted separate models for in- and out-of-hospital deaths.

Results

There were 509791 average annual deaths in South Africa, of which 44% (95% confidence interval [CI] 43%–45%) occurred out-of-hospital. Seasonal influenza and RSV all-cause mortality rates were 23.0 (95% CI 11.0–30.6) and 13.2 (95% CI 6.4–33.8) per 100000 population annually (2.3% [95%CI 2.3%–2.4%] and 1.3% [95% CI 1.2%–1.4%] of all deaths respectively). The peak mortality rate was in individuals aged ≥75 years (386.0; 95% CI 176.5–466.3) for influenza and in infants (143.4; 95% CI 0–194.8) for RSV. Overall, 63% (95% CI 62%–-65%) of seasonal influenza and 48% (95% CI 47%–49%) of RSV-associated deaths occurred out-of-hospital. Among children aged <5 years, RSV-associated deaths were more likely to occur in-hospital, whereas influenza-associated deaths were more likely to occur out-of-hospital. The mortality rate was 6.7 (95% CI 6.4–33.8) in the first influenza A(H1N1)pdm09 wave in 2009 and 20.9 (95% CI 6.4–33.8) in the second wave in 2011, with 30% (95% CI 29%–32%) of A(H1N1)pdm09-associated deaths in 2009 occurring out-of-hospital.

Discussion

More than 45% of seasonal influenza- and RSV-associated deaths occur out-of-hospital in South Africa. These data suggest that hospital-based studies may substantially underestimate mortality burden.

Dropped-head syndrome in a patient under treatment with the MEK inhibitor trametinib for NRAS-mutated metastatic melanoma

Efficacy and tolerability of liposomal polyvinylpyrrolidone-iodine hydrogel for the localized treatment of chronic infective, inflammatory, dermatoses: an uncontrolled pilot study.

Efficacy and tolerability of liposomal polyvinylpyrrolidone-iodine hydrogel for the localized treatment of chronic infective, inflammatory, dermatoses: an uncontrolled pilot study.

Clin Cosmet Investig Dermatol. 2017;10:373-384

Authors: Augustin M, Goepel L, Jacobi A, Bosse B, Mueller S, Hopp M

Abstract
Infection is common in many chronic, inflammatory skin conditions but is often difficult to treat, in part due to growing bacterial resistance to antibiotics. Liposomal polyvinyl-pyrrolidone (PVP)-iodine hydrogel has a unique mode of action, combining the antiseptic and anti-inflammatory actions of PVP-iodine with the drug delivery and moisturizing properties of liposomes. We investigated the utility of liposomal PVP-iodine to treat infective dermatoses. In this prospective, single-arm (uncontrolled), open-label Phase II pilot study, patients with acne vulgaris (n=30), atopic dermatitis (n=20), impetigo contagiosa (n=10), and rosacea (n=10) received PVP-iodine (3%) hydrogel for ≤4 weeks. Global Clinical Severity score improved for all dermatoses (range: 0.5 for acne vulgaris [p<0.001] to 1.0 for impetigo contagiosa [p=0.011]). Improvements in pain, quality of life, (Freiburg Life Quality Assessment), and Eczema Area and Severity Index scores were also seen. Treatment was well tolerated; most frequent adverse events were burning (14%) or itching (9%) sensations. Thus, liposomal PVP-iodine hydrogel has potential utility as an effective treatment for inflammatory skin conditions associated with bacterial colonization.

PMID: 28989281 [PubMed]

Collective narratives, false memories, and the origins of autobiographical memory

Abstract

Building on Dor's theory of language as a social technology for the instruction of imagination, I suggest that autobiographical memory evolved culturally as a response to the problems of false memory and deliberate deceit that were introduced by that technology. I propose that sapiens' linguistic communication about past and future events initially occurred in small groups, and this helped to correct individual memory defects. However, when human groups grew in size and became more socially differentiated, and movement between groups prevented story-verification, misattributions of events became more common. In such conditions individuals with better autobiographical memory had an advantage because they could evaluate their own contents and sources of information, as well as that of others, more accurately; this not only benefitted them directly, but also improved their reliability as social partners. Autobiographical memory thus evolved in the context of human linguistic communication through selection for communicative reliability. However, the advantages of imagination, which enables forward-planning and decision-Making, meant that memory distortions, although controlled and moderated by autobiographical memory, could not be totally eradicated. This may have driven the evolution of additional forms of memory control involving social and linguistic norms. I interpret the language and the social norms of the Pirahã as the outcome of the cultural-evolutionary control of memory distortions. Some ways of testing aspects of this proposal are outlined.

Missempfindungen und Schwellungszustände der Zunge

Issue Information - TOC

Abstracts - Oral and Poster Presentations from the XII International Congress of Dermatology April 18-22, 2017 - Buenos Aires, Argentina

Identification of novel homozygous SLURP1 mutation in a Javanese family with Mal de Meleda

Abstract

Background

Mal de Meleda (OMIM# 248300; keratosis palmoplantaris transgrediens) is an autosomal recessive form of palmoplantar keratoderma, clinically characterized by sharp demarcated erythema and hyperkeratosis of the palms and soles that progress with age and extend to the dorsal aspects of the hands and feet. The mal de Meleda is caused by mutations in the SLURP1 gene that encodes secreted lymphocyte antigen 6/urokinase-type plasminogen receptor-related protein 1 (SLURP1). To date no reported cases from Indonesia. The aims of the study were to describe the typical features of mal de Meleda cases in a Javanese family in Indonesia and identify the mutation in the ARS B gene which encodes SLURP1.

Patients and Methods

In this study, three Javanese patients, siblings from nonconsanguineous nonaffected parents, presented with classical symptoms of mal de Meleda. Genetic analysis screening SLURP1 gene was conducted for the specimens from the patients and other family members.

Results

A novel homozygous three-nucleotide deletion in exon 3, i.e. c.271-273TCTdel, was identified in the patients. Subcloning and sequencing revealed both parents (I.2 and I.3) and one of the father's siblings (I.1) carry heterozygous c.271-273TCTdel, while the other father's sibling (I.2), the mother's sister (I.4), and a healthy control matched the ethnicity of the family, showing normal sequence of the entire SLURP1.

Conclusion

This is the first mal de Meleda case of Javanese ethnicity to be documented, and the unique mutation has not previously been reported. The finding supports the notion that despite the rarity, SLURP1 mutation causing mal de Meleda is ubiquitous.

Teaching & Learning Tips 1: Teaching perspectives – an introduction

Abstract

Challenge: Clinical and research responsibilities often leave little or no time to plan thoughtful teaching encounters with trainees. This "Teaching & Learning Tips" series is designed to be an accessible guide for dermatologists who want to improve their teaching skills. It is comprised of 12 articles about how to enhance teaching in various settings informed by research about how people learn and expert-derived or data-driven best practices for teaching. The series begins with a review of principles to optimize learning in any setting, including cognitive load theory, active learning strategies, and the impact of motivation and emotion on learning. It transitions into a practical "how to" guide format for common teaching scenarios in dermatology, such as lecturing, case-based teaching, and teaching procedures, among others. Herein, we kickoff the series by unpacking assumptions about teaching and learning. What does it mean to teach and learn?

Staphylococcus lugdunensis Infections of the Skin and Soft Tissue: A Case Series and Review

Abstract

Introduction

Staphylococcus lugdunensis (S. lugdunensis) is a coagulase-negative, Gram-positive bacterium that can be isolated as a component of normal skin flora in humans. However, more recently, it has also been documented as a culprit in skin and soft tissue infections. We describe the clinical features of five individuals with S. lugdunensis-associated skin infections. We review the characteristics of other patients that were previously described with this organism as the causative agent of skin infection.

Methods

Staphylococcus lugdunensis was correlated with the development of significant skin and soft tissue infections in five patients. The Pubmed database was used to search for the following terms: "abscess," "cellulitis," "cutaneous," "lugdunensis," "paronychia," "skin," "soft," "staphylococcus," and "tissue." The relevant and reference papers generated by the search were reviewed.

Results

One woman and four men developed S. lugdunensis-related skin infections from February 19, 2015 to May 30, 2017. The patients' ages at the onset of the infection ranged from 30 to 82 years; the median age was 70 years. Four patients were older than 65 years. The back was the most common location for the infection, followed by digits. The infection presented as cystic lesions with cellulitis or periungual abscesses. The lesions were incised or spontaneously ruptured. Patients were empirically treated with oral antibiotics; if necessary, the management was adjusted based on the culture-derived sensitivities of the organisms. The infections resolved within 10–30 days after commencing treatment.

Conclusion

Staphylococcus lugdunensis has previously been considered as a nonpathogenic organism and to be a component of normal skin flora. However, S. lugdunensis can result in significant skin and soft tissue infections, perhaps more frequently in older individuals. Its antibiotic sensitivities appear to be similar to those of methicillin-susceptible Staphylococcus aureus.

Occurrence of selected elements (Ti, Sr, Ba, V, Ga, Sn, Tl, and Sb) in deposited dust and human hair samples: implications for human health in Pakistan

Abstract

The current study determined, for the first time, the levels of titanium (Ti), strontium (Sr), barium (Ba), vanadium (V), gallium (Ga), tin (Sn), thallium (Tl), and antinomy (Sb), in deposited dust, and human hair collected from general population of different geographical areas of Pakistan. All the samples were prepared by microwave digestion and measured by ICP-MS. The results showed that on deposited dust samples, the detected elements followed the descending trend as: Ti > Sr > Ba > V > Ga > Sn > Tl > Sb similar to the upper continental crust. The deposited dust samples from low elevation areas exhibited highest levels of all studied elements (except antimony which was higher in soil samples from mountainous areas), followed by rive plains, mountainous areas, and highland valleys. In contrast, on human hair samples, the elements followed the descending trend as: Sr > Ba > Ti > Ga > V > Sn > Sb > Tl respectively. Ba, Ga, and V concentrations were higher in soil samples from lower elevation Indus plain, and Sr, Tl, Sb, and Ti were higher in samples from mountainous areas. The bioaccumulation trend of all studied elements was in descending order as follows: Sb, Ga, Sn, Ba, Sr, Ti, V, Tl, respectively. Principal component analysis (PCA) and correlation matrix evidenced both geological influences and anthropogenic activities as potential sources of these studied elements. On the other hand, the risk estimation (HI > 1) concluded that population were at higher health risk (non-carcinogenic) for Ga and Ti. All other studied rare elements were within safe limit for humans from all zones.

Debating social egg freezing: arguments from phases of life

Abstract

So-called "social egg freezing" allows a woman to retain the possibility of trying to have a child with her own oocytes later in life, even after having become infertile in the strict sense of the word (that is, infertile without assistance in reproduction).There is a debate about whether it is morally permissible at all, the extent to which it should be permitted legally or even supported, and whether it is ethically desirable. This paper contributes some thoughts to the issue of ethical desirability. More precisely it deals with the question of whether there is any valuable argument to be made on the basis of the idea of life phases and normative expectations related to them. So the question is: Is there a right time in life to have a child, and does this speak against or in favor of social freezing? This question is answered in three steps. First, I will give an overview of ethical arguments that are mostly put forward in favor or against the use of social egg freezing and show that and why the question of life phases should be taken into account. Second, I will sketch what I understand by phases of life, more precisely, what I understand by normatively conceptualized life stages, that are to be distinguished from other kinds of life phases, and how they relate to a good life. Third, I will present two arguments that rely on the idea of life stages and speak against social egg freezing. However, I will criticize them and instead show that from the perspective of life stages nothing speaks against using the technique within certain limits.

Comparison of injection site reactions between the etanercept biosimilar SB4 and the reference etanercept in patients with rheumatoid arthritis from a Phase III study

Abstract

Injection site reactions (ISRs) are common adverse reactions to biologic drugs, consisting of itching, erythema, and induration at the injection site¹. ISRs usually appear within 24-48 hours after injection and subside within a few days. They typically occur in the first two months of treatment and subsequently decrease in frequency; incidence varies by drug. While ISRs seldom result in discontinuation of treatment, ISRs remain a safety concern when using biologic drugs.

This article is protected by copyright. All rights reserved.

Urticaria vasculítica: ¿cuándo sospechar enfermedad sistémica?

Publication date: Available online 11 October 2017
Source:Piel
Author(s): Felipe Ruiz, María González-Aspillaga, María Cárdenas, María A. Macías

Surgical Morbidity and Mortality in Patients after Microvascular Reconstruction for Head and Neck Cancer

Abstract

Objectives

The aim was to evaluate the importance of clinical factors in the prediction of postoperative complications in patients with microvascular reconstruction for head and neck squamous cell cancer (HNSCC).

Design

A retrospective review of case notes was performed.

Setting

Patients treated at a single institute.

Participants

The present study included 259 patients with HNSCC treated with radical surgery and microvascular reconstruction between 1993 and 2014.

Main outcome measures

We allocated the patients to three groups using a preoperative comorbidity score based on risk factors: group A (≥ 3 risk factors, n=16), group B (2 risk factors, n=49), and group C (0 or 1 risk factor, n=194).

Results

Surgical mortality in this cohort was 1.9% (5 of 259 patients). The preoperative comorbidity score was associated with surgical mortality (p<0.001). Pharyngocutaneous fistula (p=0.001) and flap compromise (p=0.023) were more frequent as preoperative comorbidity score increased. Preoperative comorbidity score (p<0.001), advanced age (p=0.007), advanced pathologic T stage (p=0.028), advanced pathologic N stage (p=0.005), preoperative (chemo)radiotherapy (p<0.001), history of cardiovascular disease (p=0.015) and pulmonary disease (p=0.007), and diabetes (p<0.001) had significant adverse effects on 5-year disease-specific survival (DSS) in a univariate analysis. The 5-DSS rates of groups A, B, and C were 30%, 37%, and 70%, respectively. Multivariate analysis showed that preoperative comorbidity score was significantly correlated with 5-year DSS (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.81—6.99; p<0.001 for group A and HR, 1.91; 95% CI, 1.15—3.18; p=0.013 for group B compared with group C).

Conclusion

Patients with a high preoperative comorbidity score have an increased risk of surgical mortality and morbidity after microvascular reconstruction for HNSCC.

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Eight weeks of omeprazole 20 mg significantly reduces both laryngopharyngeal reflux and comorbid chronic rhinosinusitis signs and symptoms: randomized, double blind, placebo controlled trial

Abstract

Objectives

Gastroesophageal reflux recommended treatment (dose and duration) with proton pump inhibitor (PPI) compared to placebo significantly reduces the signs and symptoms of laryngopharyngeal reflux (LPR) and comorbid chronic rhinosinusitis (CRS).

Design

Double blind randomized placebo controlled trial.

Setting

Eight weeks of treatment with omeprazole 20 mg once daily (OD).

Participants

60 patients (28 women, aged 19-87 years) with diagnosed LPR and comorbid CRS.

Main outcome measures

Significant reduction of signs and symptoms (reflux symptom index (RSI) score as subjective, and reflux finding score (RFS) as objective measure) of LPR after 8 weeks of treatment with omeprazole 20 mg OD when compared to placebo. Secondary objectives were significant reduction of signs and symptoms of comorbid CRS after 8 weeks of treatment with omeprazole 20 mg OD when compared to placebo; and the association of the severity of signs and symptoms of LPR with the ones of CRS.

Results

RSI and RFS decreased significantly more in the active treatment group after 8 weeks compared to placebo (p<0.001 for both). CRS and endoscopy scoring decreased both significantly more in the active group after 8 weeks compared to placebo (p<0.001 for both). CRS scoring significantly correlated with RSI (R=0.312, p=0.015) but not with RFS (R=0.199, p=0.127).

Conclusions

The results of our trial suggest that omeprazole 20 mg OD for 8 weeks was effective in reducing signs and symptoms of both LPR and CRS, although in most patients still present at the end of the trial.

This article is protected by copyright. All rights reserved.