Merkel Cell Carcinoma: Updates on Pathogenesis, Diagnosis, and Management

Abstract

Purpose of Review

To describe updates on the pathogenesis, diagnosis, and management of Merkel cell carcinoma (MCC).

Recent Findings

Sequencing studies revealed that MCCs have either a low mutational burden and integrated Merkel cell polyomavirus (MCPyV), or they have a high number of ultraviolet-associated somatic mutations and no MCPyV. Clinically, prognosis was better for stage III MCC of unknown primary than known primary. Similarly, lack of immunosuppression conferred better prognosis. The immunogenicity of MCC was reflected in high response rates to PD-1/PD-L1 checkpoint inhibitors.

Summary

MCC is a rare but aggressive neuroendocrine skin cancer associated with advanced age and immunosuppression. Approximately 80% of MCCs are MCPyV driven, whereas MCPyV-negative tumors have mutations in genes such as p53 and RB1. MCC is highly immunogenic, and recently, the anti-PD-L1 antibody avelumab was approved to treat metastatic MCC. Here, we summarized features of the pathogenesis, diagnosis, and management of MCC.

Experiencia con vismodegib en carcinoma basocelular avanzado en un centro oncológico

Publication date: Available online 25 July 2018

Source: Actas Dermo-Sifiliográficas

Author(s): E. Bernia, B. Llombart, C. Serra-Guillén, B. Bancalari, E. Nagore, C. Requena, L. Calomarde, A. Diago, J. Lavernia, V. Traves, C. Guillén, O. Sanmartín

Resumen

Introducción y objetivos

Vismodegib es el primer inhibidor selectivo de la vía de la señalización Hedgehog aprobado para el tratamiento del carcinoma basocelular (CBC) localmente avanzado y metastásico. Describimos nuestra experiencia en un centro oncológico con el vismodegib en el tratamiento de pacientes con CBC avanzados y/o múltiples durante un periodo de 5 años.

Material y métodos

Analizamos variables como la edad y el sexo del paciente, la localización, el tamaño, el tipo y las características del tumor, el tiempo de evolución, si son tumores primarios o recidivas, la duración del tratamiento, la respuesta a este (completa, parcial, estabilización o ausencia de respuesta), los efectos secundarios observados y las recidivas.

Resultados

Un total de 22 pacientes fueron tratados, 20 con CBC localmente avanzados y 2 con CBC metastásicos con afectación ganglionar. El tratamiento fue administrado durante 11,8 meses de media. El 41% (9) de los pacientes obtuvieron una respuesta completa al tratamiento, un 45% (10) respuesta parcial y en el 14% (3) de los pacientes el tratamiento consiguió estabilizar la enfermedad. Tras una mediana de 21 meses, 2 casos recidivaron. Los principales efectos secundarios observados fueron disgeusia, alopecia y calambres musculares, todos ellos de carácter leve. Ningún paciente desarrolló un carcinoma epidermoide sobre el área tratada con vismodegib, aunque sí cambios metatípicos tras el tratamiento.

Conclusiones

El vismodegib es un fármaco seguro y eficaz para el tratamiento del CBC localmente avanzado, con un porcentaje de respuesta del 86%. Los efectos adversos deben tenerse en cuenta por su alta frecuencia, aunque estos suelen ser de carácter leve.

Abstract

Introduction and objectives

Vismodegib is the first selective Hedgehog inhibitor approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). In this article, we describe our experience with the use of this drug to treat advanced and/or multiple BCCs at a cancer center over 5 years.

Material and methods

We analyzed the following variables: patient age and sex; tumor location, size, type, and characteristics; time since onset; primary or recurrent status; duration of treatment; response to treatment (complete, partial, stabilization, or absence of response); adverse effects; and recurrences.

Results

We treated 22 patients, of whom 20 had locally advanced BCCs and 2 had metastatic BCCs with lymph node involvement. The treatment was administered over a mean of 11.8 months. Nine patients (41%) achieved complete response and 10 (45%) partial response. The disease was stabilized in 3 (14%). Two patients relapsed after a median of 21 months. The main adverse effects were dysgeusia, alopecia, and muscle cramps, all of which were mild. None of the patients developed squamous cell carcinoma in an area treated with vismodegib, although metatypical changes were observed after treatment.

Conclusions

With a response rate of 96%, vismodegib is a safe and effective treatment for locally advanced BCC. Adverse effects are generally mild but they need to be taken into account owing to their high frequency.

Graphical abstract

Levels and gas-particle partitioning of hexabromocyclododecanes in the urban air of Dalian, China

Abstract

The concentrations of α-, β-, and γ-hexabromocyclododecane diastereomers (HBCDs) in gas phase and particulate phase of Dalian urban air, China, were monitored from September 2016 to August 2017 with high-volume active sampler. The total concentration of ∑HBCDs (gas phase + particulate phase) ranged from 15.47 to 43.57 pg m⁻³, with an average of 27.07 pg m⁻³, and 73.39–96.76% of the total HBCDs were found in the particulate phase. No matter in gas phase or in particulate phase, α-HBCD was the predominant component in all, and there was a good negative correlation between the relative contribution of α-HBCD to ∑HBCDs and that of γ-HBCD to ∑HBCDs. The average ratios of the air concentration of α-HBCD to γ-HBCD were comparable with those found in decorative polystyrene, which indicated that HBCDs in outdoor air of Dalian probably came from indoor air and ventilation air from inside of buildings coupled with the already present contamination in background air. There were clear seasonal differences in the HBCD concentrations. Spearman's rank correlation analysis between the concentrations of HBCDs with meteorological parameters was conducted. The exposure risk of HBCDs was evaluated, which illustrated that the estimated exposure of HBCDs via the outdoor air in Dalian was well below the reference doses (200 ng kg⁻¹ bw day⁻¹) derived by the US National Research Council.

How Differences in Ratings of Odors and Odor Labels Are Associated with Identification Mechanisms

Abstract

Introduction

Odor perception is biased by verbal–semantic processes when cues on an odor's source are readily available from the context. At the same time, olfaction has been characterized as basically sensation driven when this information is absent. In the present study, we examined whether language effects occur when verbal cues are absent and how expectations about an odor's identity shape odor evaluations.

Methods

A total of 56 subjects were asked to rate 20 unlabeled odor samples on perceptual dimensions as well as quality attributes and to eventually provide an odor source name. In a subsequent session, they performed the same rating tasks on a set of written odor labels that was compiled individually for each participant. It included both the 20 correct odor names (true labels) and in any case of incorrect odor naming in the first session, the self–generated labels (identified labels).

Results

We compared odor ratings to ratings of both types of labels to test whether differences between odor and odor label evaluations were rooted in identification mechanisms. In cases of false identifications, we found higher consistencies between the evaluation of an odor and its identified label than between the description of an odor and its true (yet not associated) label.

Conclusions

These results indicate that odor evaluations are strongly affected by the mental image of an odor rather than the actual sensory codes and that this mental image is built spontaneously. Our findings imply that odors and odor labels are evaluated similarly for identical objects and that the differences found in similar studies may have been rooted in different mental representations being evaluated.

Implications

Odor sensations provoke odor naming without explicit demand. These self–generated hypotheses about an odor's source exert a considerable semantic impact on odor perceptual processing, regardless of their accuracy.

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool

Abstract

Background

Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985–2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.

Methods

A multi-institutional retrospective institutional review board–approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.

Results

The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0–1.0, 1.5–2.0, 2.5–3, and 3.5–4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.

Conclusion

The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.

Selective Il-23 Inhibitors: The New Kids on the Block in the Treatment of Psoriasis

Publication date: Available online 25 July 2018

Source: Actas Dermo-Sifiliográficas (English Edition)

Author(s): T. Torres

Técnica de Hughes para la reparación del carcinoma basocelular esclerodermiforme del párpado inferior

Publication date: Available online 25 July 2018

Source: Piel

Author(s): Paula Aguayo-Carreras, Irene Temblador-Barba, Ricardo Ruiz-Villaverde, Carlos Gálvez Prieto-Moreno

The Effects of Telemedicine on Asthma Control and Patients’ Quality of Life In Adults: A Systematic Review and Meta-Analysis

Publication date: Available online 25 July 2018

Source: The Journal of Allergy and Clinical Immunology: In Practice

Author(s): Bunchai Chongmelaxme, Shaun Wen Huey Lee, Teerapon Dhippayom, Surasak Saokaew, Nathorn Chaiyakunapruk, Piyameth Dilokthornsakul

Abstract

Background

Telemedicine is increasingly used to improve health outcomes in asthma. However, it is still inconclusive which telemedicine works effectively.

Objective

This study aimed to determine the effects of telemedicine on asthma control and the quality of life in adults.

Methods

An electronic search was performed from the inception to March 2018 on the following databases: Cochrane CENTRAL, CINAHL, ClinicalTrials.gov, EMBASE, PubMed and Scopus. Randomized controlled trials that assessed the effects of telemedicine in adults with asthma were included in this analysis, and the outcomes of interest were levels of asthma control and quality of life. Random-effects model meta-analyses were performed.

Results

A total of 22 studies (10,281 participants) was included. Each of eleven studies investigated the effects of single-telemedicine, and combined-telemedicine (combinations of telemedicine approaches), and the meta-analyses showed that combined tele-case management could significantly improve asthma control compared with usual care [standardized mean difference (SMD) = 0.78 (95% CI: 0.56, 1.01)]. Combined tele-case management & tele-consultation [SMD = 0.52 (95% CI: 0.13, 0.91)], and combined tele-consultation [SMD = 0.28 (95% CI: 0.13, 0.44)] also significantly improved asthma outcomes, but to a lesser degree. In addition, combined tele-case management [SMD = 0.59 (95% CI: 0.31, 0.88)] was the most effective telemedicine for improving quality of life, followed by combined tele-case management & tele-consultation [SMD = 0.31 (95% CI: 0.03, 0.59)], tele-case management [SMD = 0.30 (95% CI: 0.05, 0.55)], and combined tele-consultation [SMD = 0.27 (95% CI: 0.11, 0.43)], respectively.

Conclusions

Combined-telemedicine involving tele-case management or tele-consultation appear to be effective telemedicine interventions to improve asthma control and quality of life in adults. Our findings are expected to provide healthcare professionals with current evidence of the effects of telemedicine on asthma control and patients' quality of life.

The density and distribution of acral melanocytic nevi and acral melanomas on the plantar foot

Preservation of Sebaceous Glands and PPARγ Expression in Central Centrifugal Cicatricial Alopecia

Melanoma risk after in vitro fertilization: A review of the literature

The role of female sex hormones in the pathogenesis of malignant melanoma (MM) remains controversial. While melanocytes appear to be hormonally responsive, the effect of estrogen on MM cells is less clear. Available clinical data does not consistently demonstrate that increased endogenous hormones from pregnancy, or increased exogenous hormones from oral contraceptive pills and hormone replacement, impact MM prevalence and outcome.

Practical Needle Driver Cleaning Technique When Using Fast Absorbing Plain Gut Sutures for Facial Defect Repair

Melanoma risk after in vitro fertilization: A review of the literature

Publication date: Available online 25 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Juliana Berk-Krauss, Amy Kalowitz Bieber, Maressa C. Criscito, Jane M. Grant-Kels, Marcia S. Driscoll, Martin Keltz, Miriam Keltz Pomeranz, Kathryn J. Martires, Tracey N. Liebman, Jennifer A. Stein

Abstract

Background

The role of female sex hormones in the pathogenesis of malignant melanoma (MM) remains controversial. While melanocytes appear to be hormonally responsive, the effect of estrogen on MM cells is less clear. Available clinical data does not consistently demonstrate that increased endogenous hormones from pregnancy, or increased exogenous hormones from oral contraceptive pills and hormone replacement, impact MM prevalence and outcome.

Objective

We sought to examine potential associations between in vitro fertilization (IVF) and melanoma.

Methods

A literature review was conducted. Primary outcomes were reported as associations between IVF and melanoma risk, as compared to the general population. Secondary outcomes included associations stratified by type of IVF regimen and subgroup, such as parous versus nulliparous patients.

Results

Eleven studies met our inclusion criteria. Five studies found no increased risk of MM among IVF users as compared to the general population. Two studies found an increase in MM in clomiphene users. Four studies found an increase in MM among patients who were gravid or parous either before or after IVF.

Conclusions

The reviewed studies do not reveal consistent patterns of association between IVF and MM among all infertile women. However, the data indicates that there may be an increased risk of MM in ever-parous patients treated with IVF. High-quality studies, which include a large number of MM cases and control for well-established MM risk factors, are needed to adequately assess the relationship between IVF and MM, particularly among ever-parous women.

Practical Needle Driver Cleaning Technique When Using Fast Absorbing Plain Gut Sutures for Facial Defect Repair

Publication date: Available online 25 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Romi Bloom, Daihung Do

The density and distribution of acral melanocytic nevi and acral melanomas on the plantar foot

Publication date: Available online 25 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Shirin Ghanavatian, Collin M. Costello, Matthew R. Buras, Helen JL. Cumsky, Mark R. Pittelkow, David L. Swanson, Aaron R. Mangold

Preservation of Sebaceous Glands and PPARγ Expression in Central Centrifugal Cicatricial Alopecia

Publication date: Available online 25 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Yemisi Dina, Walaa Borhan, Gulsun Erdag, Ginette A. Okoye, Rajni Sharma, Powell Perng, Crystal Aguh

Bromate removal from aqueous solution with novel flower-like Mg-Al-layered double hydroxides

Abstract

A series of flower-like Mg-Al-layered double hydroxides (FHMA) with four Mg/Al ratios were successfully prepared via a simple method which put the mixed solution of magnesium and aluminum in the mixed solution of water and ethylene glycol (EG). After calcination under 600 °C, the calcination products (CFHMA) were used to adsorb bromate anionic from aqueous solution. The FHMA, CFHMA, and reconstructed CFHMA were characterized by FT-IR, XRD spectra, TG/DTA, N₂ adsorption-desorption isotherm, and SEM. It was found that FHMA had the flower-like morphology when Mg/Al ratio was 2 and 3. Moreover, FHMA lost the layered structures during calcination under 600 °C, but the disappeared structures were reconstructed after adsorption of bromate anionic, which was attributed to the "reformation effect" of FHMA with bromate as an interlayer anion. A series of adsorption studies were performed and the mechanism and reactivity of CFHMA were discussed including the effect of different kind of equilibration conditions, such as initial bromate anionic concentration, adsorbent dosage, contact time, initial solution pH, and co-existing anions. The results of adsorption displayed that the most suitable calcination temperature of FHMA is 600 °C, and the best ratio of Mg/Al is 2:1 to remove bromate anionic pollutant from water. The equilibrium adsorption data of CFHMA revealed a good compliance with the Langmuir model and the experimental data of CFHMA fitted well to the pseudo-second-order kinetic model. The calcination product of FHMA was a decent adsorbent of bromate anionic pollutant.

Endogenous Protection from Ischemic Brain Injury by Preconditioned Monocytes

Exposure to low-dose lipopolysaccharide (LPS) before cerebral ischemia is neuroprotective in stroke models, a phenomenon termed preconditioning (PC). Although it is well established that LPS-PC induces central and peripheral immune responses, the cellular mechanisms modulating ischemic injury remain unclear. Here, we investigated the role of immune cells in the brain protection afforded by PC and tested whether monocytes may be reprogrammed by ex vivo LPS exposure, thus modulating inflammatory injury after cerebral ischemia in male mice. We found that systemic injection of low-dose LPS induces a Ly6C^hi monocyte response that protects the brain after transient middle cerebral artery occlusion (MCAO) in mice. Remarkably, adoptive transfer of monocytes isolated from preconditioned mice into naive mice 7 h after transient MCAO reduced brain injury. Gene expression and functional studies showed that IL-10, inducible nitric oxide synthase, and CCR2 in monocytes are essential for neuroprotection. This protective activity was elicited even if mouse or human monocytes were exposed ex vivo to LPS and then injected into male mice after stroke. Cell-tracking studies showed that protective monocytes are mobilized from the spleen and reach the brain and meninges, where they suppress postischemic inflammation and neutrophil influx into the brain parenchyma. Our findings unveil a previously unrecognized subpopulation of splenic monocytes capable of protecting the brain with an extended therapeutic window and provide the rationale for cell therapies based on the delivery of autologous or allogeneic protective monocytes in patients after ischemic stroke.

SIGNIFICANCE STATEMENT Inflammation is a key component of the pathophysiology of the brain in stroke, a leading cause of death and disability with limited therapeutic options. Here, we investigate endogenous mechanisms of protection against cerebral ischemia. Using lipopolysaccharide (LPS) preconditioning (PC) as an approach to induce ischemic tolerance in mice, we found generation of neuroprotective monocytes within the spleen, from which they traffic to the brain and meninges, suppressing postischemic inflammation. Importantly, systemic LPS-PC can be mimicked by adoptive transfer of in vitro-preconditioned mouse or human monocytes at translational relevant time points after stroke. This model of neuroprotection may facilitate clinical efforts to increase the efficacy of BM mononuclear cell treatments in acute neurological diseases such as cerebral ischemia.

Orbitofrontal Signaling of Future Reward is Associated with Hyperactivity in Attention-Deficit/Hyperactivity Disorder

Alterations in motivated behavior are a hallmark of attention-deficit/hyperactivity disorder (ADHD), one of the most common psychiatric disorders in children and adolescents. The orbitofrontal cortex (OFC) plays a key role in controlling goal-directed behavior, but the link between OFC dysfunction and behavioral deficits in ADHD, particularly in adolescence, remains poorly understood. Here we used advanced high-resolution functional magnetic resonance imaging (fMRI) of the human OFC in adolescents with ADHD and typically developing (TD) controls (N = 39, age 12–16, all male except for one female per group) to study reward-related OFC responses and how they relate to behavioral dysfunction in ADHD. During fMRI data acquisition, participants performed a simple decision-making task, allowing us to image expectation-related responses to small and large monetary outcomes. Across all participants, we observed significant signal increases to large versus small expected rewards in the OFC. These responses were significantly enhanced in ADHD relative to TD participants. Moreover, stronger reward-related activity was correlated with individual differences in hyperactive/impulsive symptoms in the ADHD group, whereas high cognitive ability was associated with normalized OFC responses. These results provide evidence for the importance of OFC dysfunctions in the neuropathology of ADHD, highlighting the role of OFC-dependent goal-directed control mechanisms in this disorder.

SIGNIFICANCE STATEMENT Attention-deficit/hyperactivity disorder (ADHD) is characterized by alterations in motivated behavior which can be understood as diminished goal-directed control. The orbitofrontal cortex (OFC) plays a key role in controlling goal-directed behavior, but its potential contribution to ADHD symptomatology remains poorly understood. Using high-resolution fMRI, we show that adolescent ADHD patients display enhanced OFC signaling of future rewards and that these increased reward-related responses are correlated with the severity of hyperactivity/impulsivity. These findings suggest that an inability to adequately evaluate future outcomes may translate into maladaptive behavior in ADHD patients. They also challenge the idea that dysfunctions in dopaminergic brain areas are the sole contributor to reward-related symptoms in ADHD and point to a central contribution of goal-directed control circuits in hyperactivity.

Stimulation of Individual Neurons Is Sufficient to Influence Sensory-Guided Decision-Making

Aspirin Induces Lysosomal Biogenesis and Attenuates Amyloid Plaque Pathology in a Mouse Model of Alzheimer's Disease via PPAR{alpha}

Lysosomes play a central role in cellular homeostasis by regulating the cellular degradative machinery. Because aberrant lysosomal function has been associated with multiple lysosomal storage and neurodegenerative disorders, enhancement of lysosomal clearance has emerged as an attractive therapeutic strategy. Transcription factor EB (TFEB) is known as a master regulator of lysosomal biogenesis and, here, we reveal that aspirin, one of the most widely used medications in the world, upregulates TFEB and increases lysosomal biogenesis in brain cells. Interestingly, aspirin induced the activation of peroxisome proliferator-activated receptor alpha (PPARα) and stimulated the transcription of Tfeb via PPARα. Finally, oral administration of low-dose aspirin decreased amyloid plaque pathology in both male and female 5X familial Alzheimer's disease (5XFAD) mice in a PPARα-dependent fashion. This study reveals a new function of aspirin in stimulating lysosomal biogenesis via PPARα and suggests that low-dose aspirin may be used in lowering storage materials in Alzheimer's disease and lysosomal storage disorders.

SIGNIFICANCE STATEMENT Developing drugs for the reduction of amyloid β containing senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD), is an important area of research. Aspirin, one of the most widely used medications in the world, activates peroxisome proliferator-activated receptor alpha (PPARα) to upregulate transcription factor EB and increase lysosomal biogenesis in brain cells. Accordingly, low-dose aspirin decreases cerebral plaque load in a mouse model of Alzheimer's disease via PPARα. These results reveal a new mode of action of aspirin that may be beneficial for AD and lysosomal storage disorders.

Feedback and Feedforward Inhibition May Resonate Distinctly in the Ripple Symphony

Cerebellar Learning Properties Are Modulated by the CRF Receptor

Corticotropin-releasing factor (CRF) and its type 1 receptor (CRFR₁) play an important role in the responses to stressful challenges. Despite the well established expression of CRFR₁ in granular cells (GrCs), its role in procedural motor performance and memory formation remains elusive. To investigate the role of CRFR₁ expression in cerebellar GrCs, we used a mouse model depleted of CRFR₁ in these cells. We detected changes in the cellular learning mechanisms in GrCs depleted of CRFR₁ in that they showed changes in intrinsic excitability and long-term synaptic plasticity. Analysis of cerebella transcriptome obtained from KO and control mice detected prominent alterations in the expression of calcium signaling pathways components. Moreover, male mice depleted of CRFR₁ specifically in GrCs showed accelerated Pavlovian associative eye-blink conditioning, but no differences in baseline motor performance, locomotion, or fear and anxiety-related behaviors. Our findings shed light on the interplay between stress-related central mechanisms and cerebellar motor conditioning, highlighting the role of the CRF system in regulating particular forms of cerebellar learning.

SIGNIFICANCE STATEMENT Although it is known that the corticotropin-releasing factor type 1 receptor (CRFR₁) is highly expressed in the cerebellum, little attention has been given to its role in cerebellar functions in the behaving animal. Moreover, most of the attention was directed at the effect of CRF on Purkinje cells at the cellular level and, to this date, almost no data exist on the role of this stress-related receptor in other cerebellar structures. Here, we explored the behavioral and cellular effect of granular cell-specific ablation of CRFR₁. We found a profound effect on learning both at the cellular and behavioral levels without an effect on baseline motor skills.

Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the I_h current they generate contribute to the pathophysiological mechanisms of absence seizures (ASs), but their precise role in neocortical and thalamic neuronal populations, the main components of the network underlying AS generation, remains controversial. In diverse genetic AS models, I_h amplitude is smaller in neocortical neurons and either larger or unchanged in thalamocortical (TC) neurons compared with nonepileptic strains. A lower expression of neocortical HCN subtype 1 channels is present in genetic AS-prone rats, and HCN subtype 2 knock-out mice exhibit ASs. Furthermore, whereas many studies have characterized I_h contribution to "absence-like" paroxysmal activity in vitro, no data are available on the specific role of cortical and thalamic HCN channels in behavioral seizures. Here, we show that the pharmacological block of HCN channels with the antagonist ZD7288 applied via reverse microdialysis in the ventrobasal thalamus (VB) of freely moving male Genetic Absence Epilepsy Rats from Strasbourg decreases TC neuron firing and abolishes spontaneous ASs. A similar effect is observed on -hydroxybutyric acid-elicited ASs in normal male Wistar rats. Moreover, thalamic knockdown of HCN channels via virally delivered shRNA into the VB of male Stargazer mice, another genetic AS model, decreases spontaneous ASs and I_h-dependent electrophysiological properties of VB TC neurons. These findings provide the first evidence that block of TC neuron HCN channels prevents ASs and suggest that any potential anti-absence therapy that targets HCN channels should carefully consider the opposite role for cortical and thalamic I_h in the modulation of absence seizures.

SIGNIFICANCE STATEMENT Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the fine-tuning of cellular and network excitability and have been suggested to be a key element of the pathophysiological mechanism underlying absence seizures. However, the precise contribution of HCN channels in neocortical and thalamic neuronal populations to these nonconvulsive seizures is still controversial. In the present study, pharmacological block and genetic suppression of HCN channels in thalamocortical neurons in the ventrobasal thalamic nucleus leads to a marked reduction in absence seizures in one pharmacological and two genetic rodent models of absence seizures. These results provide the first evidence that block of TC neuron HCN channels prevents absence seizures.

This Week in The Journal

Prostaglandin Signaling Governs Spike Timing-Dependent Plasticity at Sensory Synapses onto Mouse Spinal Projection Neurons

Highly correlated presynaptic and postsynaptic activity evokes spike timing-dependent long-term potentiation (t-LTP) at primary afferent synapses onto spinal projection neurons. While prior evidence indicates that t-LTP depends upon an elevation in intracellular Ca²⁺ within projection neurons, the downstream signaling pathways that trigger the observed increase in glutamate release from sensory neurons remain poorly understood. Using in vitro patch-clamp recordings from female mouse lamina I spino-parabrachial neurons, the present study demonstrates a critical role for prostaglandin synthesis in the generation of t-LTP. Bath application of the selective phospholipase A₂ (PLA₂) inhibitor arachidonyl trifluoromethyl ketone (AACOCF₃) or the cyclooxygenase 2 (Cox-2) inhibitor nimesulide prevented t-LTP at sensory synapses onto spino-parabrachial neurons. Similar results were observed following the block of the EP2 subtype of prostaglandin E₂ (PGE₂) receptor with PF 04418948. Meanwhile, perfusion with PGE₂ or the EP2 agonist butaprost potentiated the amplitude of monosynaptic primary afferent-evoked EPSCs while decreasing the paired-pulse ratio, suggesting a presynaptic site of action. Cox-2 was constitutively expressed in both spinal microglia and lamina I projection neurons within the superficial dorsal horn (SDH). Suppression of microglial activation with minocycline had no effect on the production of t-LTP, suggesting the possibility that prostaglandins produced within projection neurons could contribute to an enhanced probability of glutamate release at primary afferent synapses. Collectively, the results suggest that the amplification of ascending nociceptive transmission by the spinal SDH network is governed by PLA₂–Cox-2–PGE₂ signaling.

SIGNIFICANCE STATEMENT Long-term potentiation (LTP) of primary afferent synapses contributes to the sensitization of spinal nociceptive circuits and has been linked to greater pain sensation in humans. Prior work has implicated elevated glutamate release in the generation of spike timing-dependent LTP (t-LTP) at sensory synapses onto ascending spinal projection neurons, but the underlying mechanisms remain unknown. Here we provide evidence that the activation of EP2 prostaglandin receptors by prostaglandin E₂, occurring downstream of phospholipase A₂ and cyclooxygenase 2 activation, mediates t-LTP at these synapses via changes in presynaptic function. This suggests that prostaglandins can increase the flow of nociceptive information from the spinal cord to the brain independently of their known ability to suppress synaptic inhibition within the dorsal horn.

PTP{sigma} Drives Excitatory Presynaptic Assembly via Various Extracellular and Intracellular Mechanisms

Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are hub proteins that organize excitatory and inhibitory synapse development through binding to various extracellular ligands. Here, we report that knockdown (KD) of the LAR-RPTP family member PTP reduced excitatory synapse number and transmission in cultured rat hippocampal neurons, whereas KD of PTP produced comparable decreases at inhibitory synapses, in both cases without altering expression levels of interacting proteins. An extensive series of rescue experiments revealed that extracellular interactions of PTP with Slitrks are important for excitatory synapse development. These experiments further showed that the intracellular D2 domain of PTP is required for induction of heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic machinery assembly. Consistent with this, double-KD of liprin-α2 and -α3 or KD of PTP substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, PTP-mediated heterologous synapse formation activity. We propose a synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized retrograde signaling cascades, in which both extracellular and intracellular mechanisms are critical in orchestrating distinct synapse types.

SIGNIFICANCE STATEMENT In this study, we sought to test the unproven hypothesis that PTP and PTP are required for excitatory and inhibitory synapse formation/transmission, respectively, in cultured hippocampal neurons, using knockdown-based loss-of-function analyses. We further performed extensive structure–function analyses, focusing on PTP-mediated actions, to address the mechanisms of presynaptic assembly at excitatory synaptic sites. Using interdisciplinary approaches, we systematically applied a varied set of PTP deletion variants, point mutants, and splice variants to demonstrate that both extracellular and intracellular mechanisms are involved in organizing presynaptic assembly. Strikingly, extracellular interactions of PTP with heparan sulfates and Slitrks, intracellular interactions of PTP with liprin-α and its associated proteins through the D2 domain, as well as distinct substrates are all critical.

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.

SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

Galectin-3 in M2 Macrophages Plays a Protective Role in Resolution of Neuropathology in Brain Parasitic Infection by Regulating Neutrophil Turnover

Macrophages/microglia with M2-activation phenotype are thought to play important anti-inflammatory and tissue reparative functions in the brain, yet the molecular bases of their functions in the CNS remain to be clearly defined. In a preclinical model of neurocysticercosis using brain infection with a parasite Mesocestoides corti, we previously reported the presence of large numbers of M2 cells in the CNS. In this study using female mice, we report that M2 macrophages in the parasite-infected brain display abundant galectin-3 expression. Disease severity was increased in Galectin-3^–/– mice correlating with increased neurological defects, augmented cell death and, importantly, massive accumulation of neutrophils and M2 macrophages in the CNS of these mice. Because neutrophil clearance by efferocytosis is an important function of M2 macrophages, we investigated a possible role of galectin-3 in this process. Indeed, galectin-3-deficient M2 macrophages exhibited a defect in efferocytic clearance of neutrophils in vitro. Furthermore, adoptive transfer of M2 macrophages from galectin-3-sufficient WT mice reduced neutrophilia in the CNS and ameliorated disease severity in parasite-infected Galectin-3^–/– mice. Together, these results demonstrate, for the first time, a novel role of galectin-3 in M2 macrophage function in neutrophil turnover and resolution of inflammatory pathology in the CNS. This likely will have implications in neurocysticercosis and neuroinflammatory diseases.

SIGNIFICANCE STATEMENT Macrophages/microglia with M1-activation phenotype are thought to promote CNS pathology, whereas M2-anti-inflammatory phenotype promote CNS repair. However, the mechanisms regulating M2 cell-protective functions in the CNS microenvironment are undefined. The current study reports that helminth infection of the brain induces an increased expression of galectin-3 in M2 macrophages accumulated in the CNS. Using multiple experimental models in vivo and in vitro, they show that galectin-3 in M2 macrophages functions to clear neutrophils accumulated in the CNS. Importantly, galectin-3 in M2 macrophages plays a central role in the containment of neuropathology and disease severity. These results provide a direct mechanistic evidence of the protective function of M2 macrophages in the CNS.

Behavioral Evidence and Neural Correlates of Perceptual Grouping by Motion in the Barn Owl

Perceiving an object as salient from its surround often requires a preceding process of grouping the object and background elements as perceptual wholes. In humans, motion homogeneity provides a strong cue for grouping, yet it is unknown to what extent this occurs in nonprimate species. To explore this question, we studied the effects of visual motion homogeneity in barn owls of both genders, at the behavioral as well as the neural level. Our data show that the coherency of the background motion modulates the perceived saliency of the target object. An object moving in an odd direction relative to other objects attracted more attention when the other objects moved homogeneously compared with when moved in a variety of directions. A possible neural correlate of this effect may arise in the population activity of the intermediate/deep layers of the optic tectum. In these layers, the neural responses to a moving element in the receptive field were suppressed when additional elements moved in the surround. However, when the surrounding elements all moved in one direction (homogeneously moving), they induced less suppression of the response compared with nonhomogeneously moving elements. Moreover, neural responses were more sensitive to the homogeneity of the background motion than to motion-direction contrasts between the receptive field and the surround. The findings suggest similar principles of saliency-by-motion in an avian species as in humans and show a locus in the optic tectum where the underlying neural circuitry may exist.

SIGNIFICANCE STATEMENT A critical task of the visual system is to arrange incoming visual information to a meaningful scene of objects and background. In humans, elements that move homogeneously are grouped perceptually to form a categorical whole object. We discovered a similar principle in the barn owl's visual system, whereby the homogeneity of the motion of elements in the scene allows perceptually distinguishing an object from its surround. The novel findings of these visual effects in an avian species, which lacks neocortical structure, suggest that our basic visual perception shares more universal principles across species than presently thought, and shed light on possible brain mechanisms for perceptual grouping.

Differential Representation of Landmark and Self-Motion Information along the CA1 Radial Axis: Self-Motion Generated Place Fields Shift toward Landmarks during Septal Inactivation

Spatial location in the environment can be defined in relation to specific landmarks or in relation to the global context, and is estimated from both the sensing of landmarks and the inner sense of cumulated locomotion referred to as path-integration. The respective contribution of landmark and path-integration to place-cell activity in the hippocampus is still unclear and complicated by the fact that the two mechanisms usually overlap. To bias spatial mechanisms toward landmark or path-integration, we use a treadmill equipped with a long belt on which male mice run sequentially through a zone enriched and a zone impoverished in visual-tactile cues. We show that inactivation of the medial septum (MS), which is known to disrupt the periodic activity of grid cells, impairs mice ability to anticipate the delivery of a reward in the cue-impoverished zone and transiently alter the spatial configuration of place fields in the cue-impoverished zone selectively: following MS inactivation, place fields in the cue-impoverished zone progressively shift backward and stabilize near the cues, resulting in the contraction of the spatial representation around cues; following MS recovery, the initial spatial representation is progressively restored. Furthermore, we found that place fields in the cue-rich and cue-impoverished zones are preferentially generated by cells from the deep and superficial sublayers of CA1, respectively. These findings demonstrate with mechanistic insights the contribution of MS to the spread of spatial representations in cue-impoverished zones, and indicate a segregation of landmark-based and path-integration-assisted spatial mechanisms into deep and superficial CA1, respectively.

SIGNIFICANCE STATEMENT Cells encoding a cue-impoverished zone and the vicinity of landmarks responded differentially to septal inactivation and resided in distinct sublayers of CA1. These findings provide new insights on place field mechanisms: septal activity is critical for maintaining the spread of place fields in cue-impoverished areas, but not for the generation of place fields; Following MS inactivation, trial-by-trial network modifications by activity-dependent mechanisms are responsible for the gradual collapse of spatial representations. Furthermore, the findings suggest parallel coding streams for landmark and self-motion information. Superficial CA1 cells are better suited for encoding global position via the assist of path-integration, whereas deep CA1 cells can support spatial memory processes on an object-specific basis.

Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention

Humans possess three genetic isoforms of apolipoprotein E (ApoE)—ApoE2, ApoE3, and ApoE4—that confer differential risk for Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. This study sought to investigate the impact of human ApoE isoforms on brain energy metabolism, an area significantly perturbed in preclinical AD. A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism, focusing on pathways leading to the generation of acetyl-CoA, in human ApoE gene-targeted replacement female mice. Consistent with our previous findings, brains expressing ApoE2 exhibited the most robust profile, whereas brains expressing ApoE4 displayed the most deficient profile on the uptake and metabolism of glucose, the primary fuel for the brain. Specifically, the three ApoE brains differed significantly in facilitated glucose transporters, which mediate the entry of glucose into neurons, and hexokinases, which act as the "gateway enzyme" in glucose metabolism. Interestingly, on the uptake and metabolism of ketone bodies, the secondary energy source for the brain, ApoE2 and ApoE4 brains showed a similar level of robustness, whereas ApoE3 brains presented a relatively deficient profile. Further, ingenuity pathway analysis indicated that the PPAR-/PGC-1α signaling pathway could be activated in the ApoE2 brain and inhibited in the ApoE4 brain. Notably, PGC-1α overexpression ameliorated ApoE4-induced deficits in glycolysis and mitochondrial respiration. Overall, our data provide additional evidence that human ApoE isoforms differentially modulate brain bioenergetic metabolism, which could serve as a potential mechanism contributing to their discrete risk impact in AD.

SIGNIFICANCE STATEMENT We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.

Intranasal wnt3a Attenuates Neuronal Apoptosis through Frz1/PIWIL1a/FOXM1 Pathway in MCAO Rats

After ischemic stroke, apoptosis of neurons is a primary factor in determining outcome. Wnt3a is a naturally occurring protein that has been shown to have protective effects in the brain for traumatic brain injury. Although wnt3a has been investigated in the phenomena of neurogenesis, anti-apoptosis, and anti-inflammation, it has never been investigated as a therapy for stroke. We hypothesized that the potential neuroprotective agent wnt3a would reduce infarction and improve behavior following ischemic stroke by attenuating neuronal apoptosis and promoting cell survival through the Frizzled-1/PIWI1a/FOXM1 pathway in middle cerebral artery occlusion (MCAO) rats. A total of 229 Sprague Dawley rats were assigned to male, female, and 9-month-old male MCAO or sham groups followed by reperfusion 2 h after MCAO. Animals assigned to MCAO were either given wnt3a or its control. To explore the downstream signaling of wnt3a, the following interventions were given: Frizzled-1 siRNA, PIWI1a siRNA, and PIWI1a-clustered regularly interspaced short palindromic repeats, along with the appropriate controls. Post-MCAO assessments included neurobehavioral tests, infarct volume, Western blot, and immunohistochemistry. Endogenous levels of wnt3a and Frizzled-1/PIWI1a/FOXM1 were lowered after MCAO. The administration of intranasal wnt3a, 1 h after MCAO, increased PIWIL1a and FOXM1 expression through Frizzled-1, reducing brain infarction and neurological deficits at 24 and 72 h. Frizzled-1 and PIWI1a siRNAs reversed the protective effects of wnt3a after MCAO. Restoration of PIWI1a after knockdown of Frizzled-1 increased FOXM1 survival protein and reduced cleaved caspase-3 levels. In summary, wnt3a decreases neuronal apoptosis and improves neurological deficits through Frizzled-1/PIWI1a/FOXM1 pathway after MCAO in rats. Therefore, wnt3a is a novel intranasal approach to decrease apoptosis after stroke.

SIGNIFICANCE STATEMENT Only 5% of patients receive recombinant tissue plasminogen activator after stroke, and few qualify for mechanical thrombectomy. No neuroprotective agents have been successfully translated to promote neuronal survival in stroke. Thus, using a clinically relevant rat model of stroke, middle cerebral artery occlusion, we explored a novel intranasal administration of wnt3a. wnt3a naturally occurs in the body and crosses the blood–brain barrier, supporting the clinically translatable approach of intranasal administration. Significant neuronal apoptosis occurs during stroke, and wnt3a shows promise due to its antiapoptotic effects. We investigated whether wnt3a mediates its poststroke effects via Frizzled-1 and the impact on its downstream signaling molecules, PIWI1a and FOXM1, in apoptosis. Elucidating the mechanism of wnt3a will identify additional pharmacological targets and further understanding of stroke.

Subtype-specific signaling pathways and genomic aberrations associated with prognosis of glioblastoma

Abstract

Background

A high heterogeneity and activation of multiple oncogenic pathways have been implicated in failure of targeted therapies in glioblastoma.

Methods

Using TCGA data, we identified subtype-specific prognostic core genes by a combined approach of genome-wide Cox regression and Gene Set Enrichment Analysis. The results were validated with combined eight public datasets containing 608 glioblastomas. We further examined prognostic chromosome aberrations and mutations.

Results

In Classical and Mesenchymal subtypes, two receptor tyrosine kinases (RTK) (MET and IGF1R), and the genes in RTK downstream pathways such as PI3K/AKT/mTOR, and NF-κB, were commonly detected as prognostic core genes. Classical subtype-specific prognostic core genes included those in cell cycle, DNA repair, and JAK-STAT pathway. Immune-related genes were enriched in the prognostic genes showing negative promoter CpG methylation/expression correlations. Mesenchymal subtype-specific prognostic genes were those related to mesenchymal cell movement, PI3K/AKT, MAPK/ERK, WNT/β-catenin, and WNT/Ca²⁺ pathways. In copy number alterations and mutations, 6p loss and TP53 mutations were associated with poor and good survival respectively in Classical subtype. In Mesenchymal subtype, patients with PIK3R1 or PCLO mutations showed poor prognosis. In G-CIMP subtype, patients harboring 10q loss, 12p gain, or 14q loss exhibited poor survival. Furthermore, 10q loss was significantly associated with recently recognized G-CIMP subclass showing relatively low CpG methylation and poor prognosis.

Conclusions

These subtype-specific alterations have promising potentials of new prognostic biomarkers and therapeutic targets combined with surrogate markers of glioblastoma subtypes. However, considering the small number of events, the results of copy number alterations and mutations require further validations.

Spacetime in String Theory: A Conceptual Clarification

Abstract

In this paper, some conceptual issues are addressed in order to make sense of what string theory is supposed to tell us about spacetime. The dualities in string theory are used as a starting point for our argumentation. We explore the consequences of a standard view towards these dualities, namely that the dual descriptions represent the same physical situation. Given this view, one has to understand string theory in a manner such that what counts as physical spacetime is based only on the shared physical content—or common core—of the dual descriptions. In general such a spatiotemporal picture does not have to agree with, or be similar to, any of the ones suggested by naïve readings of the dual descriptions. However, in certain regimes or limits, one or the other of the initial dual descriptions may give a good effective description of physical spacetime.

Association Between Mediterranean Anti-inflammatory Dietary Profile and Severity of Psoriasis

This cohort study uses a self-completed questionnaire by respondents in the French NutriNet-Santé study to evaluate the association between a Mediterranean anti-inflammatory dietary profile and the severity of psoriasis.

RCM and En Face Histopathologic Correlation of the Dermoscopic “Circle Within a Circle” in LM

This case report describes a process by which the dermoscopic "circle within a circle" feature can be correlated with findings of reflectance confocal microscopic (RCM) and en face histopathologic findings from a lentigo maligna lesion.

Violaceous Patches in the Axilla

A man in his 40s presented with dark red, circular lesions in his right axilla without pain, blisters, or other symptoms; after resolution with a topical cream, similar lesions appeared in his left axilla and inguinal folds 5 months later. What is your diagnosis?

Increasing Minority Representation in the Dermatology Department

This Viewpoint reviews Johns Hopkins' successful experience in increasing the number of faculty physicians in dermatology from groups underrepresented in medicine and suggests steps that other institutions can take to replicate this success.

Facial-Aging App Availability in Waiting Rooms as a Potential Opportunity for Skin Cancer Prevention

This survey study explores whether a single exposure of adult patients in a waiting room to an app that approximates facial UV damage may lead to altered UV protection behavior.

Performance of Dermatology Physician Assistants—Reply

In Reply We thank Marghoob et al for the opportunity to address their concerns regarding our study. Number needed to biopsy (NNB) (or excise) is a well-established measure consistent with prior publications, including studies by Marghoob and colleagues. While NNB can vary with disease prevalence, patients in both cohorts in our study had similar rates of keratinocyte carcinomas and invasive melanomas. Patients were also similarly distributed by age and sex, and our NNB findings remained consistent when patients with a melanoma history were excluded.

Performance of Dermatology Physician Assistants

To the Editor In a recent issue of JAMA Dermatology, Anderson et al aimed to compare skin cancer diagnostic accuracy of physician assistants (PAs) with that of dermatologists (MDs) and used the number needed to biopsy as the main outcome measure.

Characteristics and Skin Cancer Risk Behaviors of US Adult Sunless Tanners

This secondary analysis of a cross-sectional study using data from the 2015 National Health Interview Survey assesses the demographic characteristics and skin cancer risk behaviors of US adults who are sunless tanners.

Incidence of Endemic Human Cutaneous Leishmaniasis in the United States

This observational study reviews cases of endemic human leishmaniasis occurring in the United States, mostly in Texas, over a 10-year period.

Cirugía en tumores malignos del aparato ungueal: si es posible, mejor cirugía funcional

Publication date: Available online 25 July 2018

Source: Actas Dermo-Sifiliográficas

Author(s): J.M. Ródenas

Molecular parts and genetic circuits for metabolic engineering of microorganisms

Abstract

Microbial conversion of biomass into value-added biochemicals is a highly sustainable process compared to petroleum-based production. In this regard, microorganisms have been engineered via simple overexpression or deletion of metabolic genes to facilitate the production. However, the producer microorganisms require complex regulatory circuits to maximize productivity and performance. To address this issue, diverse genetic circuits have been developed that allow cells to minimize their metabolic burden, overcome metabolic imbalances, and respond to a dynamically changing environment. In this review, we briefly explain the basic strategy for constructing genetic circuits by assembling molecular parts such as input, operation, and output modules. Next, we describe recent applications of the circuits in the metabolic engineering of microorganisms to improve biochemical production. Beyond those achievements, genetic circuits will facilitate more innovative approaches to future strain development through mining and engineering new genetic elements and improving the complexity of genetic circuit design.

Multiples Myelom

Moderne Diagnostik des multiplen Myeloms

Zusammenfassung

Hintergrund

Kaum eine Erkrankung in der Hämatologie entwickelt sich so dynamisch wie das multiple Myelom (MM) in den letzten Jahren. Dies betrifft sowohl therapeutische wie auch diagnostische Möglichkeiten.

Ziel

In diesem Übersichtsartikel werden die gegenwärtige Standarddiagnostik des MM dargestellt und ein Ausblick auf zukünftige Diagnostika aufgezeigt.

Ergebnisse und Schlussfolgerung

In absehbarer Zeit wird die Überprüfung einer persistierenden minimalen Resterkrankung nach Therapie sowie der Einsatz funktioneller Bildgebung Einzug in die Standarddiagnostik des MM halten. Die ersten positiven Studienergebnisse für zielgerichtete Therapien für genetisch determinierte Myelomsubgruppen – Venetoclax für t(11;14)-positive Patienten – legen zudem die Notwendigkeit einer Ausweitung der genetischen Diagnostik für MM-Patienten nahe.

Glucosamine abrogates the stem cell factor + endothelin-1-induced stimulation of melanogenesis via a deficiency in MITF expression due to the proteolytic degradation of CREB in human melanocytes

Abstract

We have already reported that glucosamine (GlcN) distinctly abrogates the pigmentation of human epidermal equivalents stimulated by stem cell factor + endothelin-1 (SE). In this study, we characterized the molecular mechanism involved in the anti-melanogenic effects of GlcN using normal human melanocytes (NHMs) in culture. The SE-stimulated gene (12 h) and protein (24 h) expression levels of melanocyte-specific proteins (at the indicated times post-stimulation) were significantly abrogated by pretreatment with GlcN for 72 h. Western blotting analysis of the phosphorylation of intracellular signaling molecules in the MAPK pathway revealed that despite the significantly decreased level of total CREB protein at all times post-stimulation, the SE-stimulated phosphorylation of ERK, CREB and MITF is not attenuated at 15 min post-stimulation in GlcN-treated NHMs. However, the SE-stimulated protein expression level of total MITF at 2 and 6 h post-stimulation was significantly abrogated by 72 h pretreatment with GlcN. Consistently, pretreatment with GlcN for 72 h abrogated the stimulated gene and protein expression levels of MITF at 1 h and 2 h post-stimulation, respectively. Analysis of gene and protein expression levels also demonstrated that pretreatment with GlcN for 72 h significantly reduced the protein levels of CREB and MITF without affecting their gene expression levels prior to the SE stimulation. Silencing with a CREB siRNA distinctly abrogated the SE-stimulated expression of MITF (at 2 h post-stimulation) and melanocyte-specific proteins (at 24 h post-stimulation). Similarly, transfection of MITF siRNA markedly abrogated the SE-stimulated expression of MITF protein and melanocyte-specific proteins at 2 and 24 h post-stimulation, respectively. Finally, the decreased levels of CREB and MITF proteins induced by 72 h pretreatment with GlcN were abrogated by the co-addition of the proteosomal degradation inhibitor MG132. These findings suggest that the anti-melanogenic effect elicited by GlcN is mediated via the decreased expression of MITF which results from the attenuated transcriptional activity of CREB due to proteolytic degradation.

Progress Toward Eliminating Mother to Child Transmission of HIV in Kenya: Review of Treatment Guidelines Uptake and Pediatric Transmission Between 2013 and 2016—A Follow Up

Abstract

Background Prevention of mother to child transmission of HIV (PMTCT) services are critical to achieve national and global targets of 90% antiretroviral therapy (ART) coverage in PMTCT, and mother to child transmission rates less than 5%. In 2012, Kenya adopted WHO's recommended ART regimen for PMTCT "Option B+". Aims This study assesses progress made in adopting these new guidelines and associated outcomes. Methods We analysed programmatic data of 2604 mother–infant pairs enrolled in the HIV Infant Tracking System (HITSystem) at four government hospitals in Kenya between January, 2013 and December, 2016. We then compared PMTCT trends between 2010 and 2012 and 2013–2016 for the same four government hospitals. Results A total of 2,371 (91.1%) received some ART regimen, however; only 911 (56.2%) mothers received ART regimens compliant with WHO Option B+. From 2013 to 2016, the percent of mothers on WHO Option B + doubled from 42 to 84% (p < 0.001), the mean week of ART initiation decreased from 19.0 to 9.7 weeks (p < 0.001), the percent of pregnant women who were already on ART at the time of PMTCT enrolment increased from 5.8 to 31.7% (p < 0.001), and the paediatric transmission rate decreased from 5.9 to 2.5% (p = 0.002). Conclusion Comparing data at these four Kenyan hospitals indicates significant progress has been made from 2010 to 2016. To continue these positive gains, concerted focus will be needed to target and improve the integration of new guidelines into clinical practice at the facility level, adherence to treatment and retention in care.

IUCN conservation status does not predict glucocorticoid concentrations in reptiles and birds

Abstract

Circulating glucocorticoids (GCs) are the most commonly used biomarker of stress in wildlife. However, their utility as a tool for identifying and/or managing at-risk species has varied. Here, we took a very broad approach to conservation physiology, asking whether IUCN (International Union for the Conservation of Nature) listing status (concern versus no obvious concern) and/or location within a geographic range (edge versus non-edge) predicted baseline and post-restraint concentrations of corticosterone among many species of birds and reptiles. Even though such an approach can be viewed as coarse, we asked in this analysis whether corticosterone concentrations might be useful to implicate species at risk. Indeed, our effort, relying on HormoneBase, a repository of data on wildlife steroids, complements several other large-scale efforts in this issue to describe and understand GC variation. Using a phylogenetically informed Bayesian approach, we found little evidence that either IUCN status or edge/non-edge location in a geographic distribution were related to GC levels. However, we did confirm patterns described in previous studies, namely that breeding condition and evolutionary relatedness among species predicted some GC variation. Given the broad scope of our work, we are reluctant to conclude that IUCN status and location within a range are unrelated to GC regulation. Indeed, we encourage future more targeted efforts on GCs in at-risk populations to reveal how factors leading to IUCN listing or the environmental conditions at range edges impact individual performance and fitness, particularly in the mammals, amphibians and fish species we could not study here because data are currently unavailable.

A new non-invasive graphical method for quantification of cerebral blood flow with[ $$^{123}\hbox {I}$$ 123 I ] IMP

Abstract

Objective

[ \(^{123}\hbox {I}\) ] N-isopropyl-p-iodoamphetamine ( \(^{123}\hbox {I}\) -IMP) is an ideal perfusion tracer for single photon emission computed tomography, which shows good linearity between cerebral blood flow (CBF) and accumulation. However, quantification of CBF using \(^{123}\hbox {I}\) -IMP without arterial blood sampling has been challenging, with previous methods requiring empirically obtained regression formulae to estimate CBF. Furthermore, the CBF value obtained via some of the previous methods would be affected by the clearance rate of \(^{123}\hbox {I}\) -IMP from the lungs. This paper introduces a new non-invasive quantification method for CBF using \(^{123}\hbox {I}\) -IMP and dynamic planar images.

Methods

We have developed a theory based on Microsphere model. This method does not involve regression formulae for estimation and allows for direct measurement of CBF, considering the clearance rate of \(^{123}\hbox {I}\) -IMP from the lungs. The study method is executed as easily as conventional Graph-Plot method. We compared the CBF values obtained by our study method and the established autoradiograph (ARG) method.

Results

CBF values obtained using the new method demonstrated significant correlation with values determined using ARG method.

Conclusions

The novel method described presents a reliable and more simple way of determining CBF when compared to current methods.

Der Wert Alpiner Forschungseinzugsgebiete im Bereich der Fernerkundung, der Schneedeckenmodellierung und der lokalen Klimamodellierung

Zusammenfassung

Der Hochgebirgsraum ist traditionell ein Raum mit wenigen bis keinen Messstationen. Vorortmessungen sind nur in ausgesuchten Gebieten oder nur punktuell verfügbar. Aus diesem Grund werden Landoberflächenmodelle, regionale Klimamodelle und Fernerkundungsdaten eingesetzt, um die benötigte Information zur erzeugen. Wie diese Daten im Gebirgsraum tatsächlich sind, bleibt dabei oftmals offen, da Evaluationsdatensätze fehlen, oder nur lückenhaft vorhanden sind. Besonders wertvoll sind in diesem Zusammenhang alpine Einzugsgebiete, die – meist aufgrund der Bemühungen von regionalen Gruppen oder Organisationen – einen höheren Grad an Instrumentierung aufweisen. Das vom bayerischen Umweltministerium geförderte Einzugsgebiet um die Umweltforschungsstation Schneefernerhaus an der Zugspitze (D) ist ein solches Gebiet. Die drei diskutierten Fallbeispiele zeigen, mit welchen Unsicherheiten zu rechnen ist, wenn Modelle gänzlich ohne oder mit wenig Basisdaten aus dem Zielgebiet betrieben werden. Weiterhin soll der Nutzen alpiner Forschungseinzugsgebiete im Kontext optimierter Modellsetups, verbesserter Modellergebnisse und abgeleiteter Fernerkundungsprodukte aufgezeigt werden.

The biodiversity hypothesis and immunotolerance in allergy

Abstract

Background

The human immune system is capable of detecting a multitude of substances and organisms in the environment and responding to these in a variety of ways. This includes immune responses to pathogens, on the one hand, and immunotolerance in the form of immunoregulatory responses, resulting in either the termination of immune responses or in tolerance to harmless and endogenous substances, on the other. The development of immunotolerance is an active process that is essentially characterized by interaction with microbiota and environmental components and is primarily mediated by regulatory T cells.

Methods

This article provides an overview of selected scientific articles and is addressed also to non-specialists. It is based on a literature search in PubMed, specialist databases, and guidelines.

Results

According to the diversity hypothesis, exposure in early childhood to broad biodiversity is now considered to reduce the risk of developing allergic diseases.

Conclusion

Therefore, tolerance induction emerges in allergology not only as a potential concept for prevention, but also as a treatment approach in atopic diseases.

Non-celiac gluten/wheat sensitivity (NCGS)—a currently undefined disorder without validated diagnostic criteria and of unknown prevalence

Abstract

Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist's and nutritionist's point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.

SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and more than 10 years of daily practice analyzed in different subgroups

Abstract

Background

Efficacy of house dust mite (HDM) allergen immunotherapy (AIT) in allergic rhinitis and controlled allergic asthma has been documented in controlled trials with adults and children. However, tolerability comparing clinical development and post marketing data, particularly in different subgroups, is missing.

Methods

We performed an analysis of pooled safety data for subcutaneous AIT (SCIT) with a high-dose house dust mite allergoid from 6 randomized, controlled trials (RCT) in HDM allergic respiratory disease (ARD) and of post marketing safety data from more than 10 years including different subgroups (age, gender, asthma status).

Results

In all, 500 patients with ARD were treated in RCTs: 279 received the marketed dose of 1800 protein nitrogen units (PNU) high-dose HDM allergoid AIT (214 double-blind placebo controlled [HDM-DBPC], 65 children/adolescents usual care controlled [HDM-RCT(UC)]), and 221 placebo (PL). 38.8% adverse events (AEs) were observed with 1800 PNU in HDM-DBPC (31.2% PL, 35.5% HDM-ALL [1800 PNU]); the difference was primarily because of local reactions; there was no difference in systemic reactions (10.9% PL, 11.2% HDM-DBPC, 11.2% HDM-ALL); one out of 279 high-dose HDM allergoid-treated patients had a serious adverse event (SAE).

Children (n = 39)/adolescents (n = 26) had fewer related AEs and local reactions compared to adults; systemic reactions: children 12.8%, adults 11.2% adolescents 7.7%. Females had slightly more AEs. Treatment was well tolerated in asthmatic patients (n = 267; GINA I n = 32, II n = 104, III n = 17, 114 no classification).

In more than 10 years more than 100,000 patients were treated with high-dose HDM allergoid (1800 PNU) under daily practice conditions. Adverse drug reactions (ADRs) were reported in 0.5% of patients. 94.6% of these ADRs were expected.

Conclusion

SCIT with the marketed dose of high-dose HDM allergoid was well tolerated in clinical development and in daily practice. There was no increased risk for the investigated patient subgroups. Tolerability was comparable to HDM sublingual immunotherapy (SLIT) tablets.

Fragrances as allergens

Abstract

Contact allergies due to fragrances are common. If one adds up the reaction incidences of the indicators of fragrance allergy (fragrance mix [FM] I + II, balsam of Peru and turpentine), these reach 17% in a hospital collective (Information Network of Departments of Dermatology [IVDK] data 2016) and are thus higher than those for nickel allergy (approximately 16%). In the case of positive reactions to FM I, >50% do not react to one of the components. This type of reaction should be interpreted as allergic with caution, unless other data (e. g., positive history, application test) support this interpretation. FM-I-positive individuals often react to oak moss (27.2%) and isoeugenol (18.2%). These are followed by hydroxycitronellal (10.9%), cinnamal (10.6%), cinnamyl alcohol (8.4%), eugenol (7.3%), geraniol (5.5%), and amyl cinnamal (1.5%). The frequency of sensitization (SF) to the individual fragrances depends on their allergenic potency (measured using the local lymph node assay, LLNA) and the frequency of use (extent of exposure). The relationship between SF and exposure is described by the sensitization exposure quotient (SEQ). The SEQ is a measure of the risk of sensitization. In general, it correlates with the SF on the one hand and with the allergenic potency (hazard) on the other. Exceptions to this rule indicate a newly recognized problem: (1) Although methyl 2-octynoate plays no role in SH statistics, it came third after tree moss and oak moss with its SEQ (=risk); (2) despite its low potency, hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral®) had a relatively high risk. In this particular case, potency (the inherent hazard) was not the determinant of risk, but rather the overly high doses used. Allergy monitoring by clinical epidemiology needs to be more heavily supplemented by data on exposure.

Comparative physiological behaviors of Ulva lactuca and Gracilariopsis lemaneiformis in responses to elevated atmospheric CO 2 and temperature

Abstract

Physiological metabolisms of seaweeds usually suffered climate changes in the field. Gracilariopsis lemaneiformis and Ulva lactuca, collected from Nan'ao Island, Shantou, China, were cultured under ambient and elevated CO₂ supply (390 and 800 μl L⁻¹), with low and high temperatures (15 °C and 25 °C) for 2 weeks, aiming to compare the difference of the main physiological metabolism between two seaweed species in response to the elevated CO₂ and high temperature. At 15 °C, the pH reduction in the culture medium caused by elevated CO₂ was larger in G. lemaneiformis than in U. lactuca. At 25 °C, elevated CO₂ significantly increased photosynthetic rates (P_n or P_g) and maintained constant respiratory rates (R_d) in G. lemaneiformis. However, for 25 °C-grown U. lactuca, the increment of CO₂ did not enhance the P_n (P_g) rates but rapidly decreased the R_d rates itself. With the higher R_d/P_g ratios in G. lemaneiformis than U. lactuca, the warming thereby promoted more allocation of photosynthetic products to respiratory consumption in G. lemaneiformis. Both P_g and R_d rates exhibited lower temperature acclimation in two seaweeds. In addition, elevated CO₂ markedly increased the relative growth rate (RGR) and phycobiliprotein (PB) contents at 25 °C, but exhibited no enhancement of chlorophyll a (Chl a), carotenoids (Car), soluble carbohydrate (SC), and soluble protein (SP) contents in G. lemaneiformis, with the reduction of SC when temperature increased only. We suggested that climate changes were probably a more benefit to U. lactuca than to G. lemaneiformis, inherently justifying the metabolism during G. lemaneiformis maricultivation.

Pollution assessment of heavy metal accumulation in the farmland soils of Beijing’s suburbs

Abstract

In this study, we used GIS to assess heavy metal concentrations and their spatial variations in Beijing's suburban farmlands. The Beijing soil heavy metal background values (background values), the primary standard of the Chinese Environmental Quality Standard of Soil (primary standard), and the Environmental Quality Standard of Green Food Production Site (green standard) were used as the standards for assessing soil heavy metals. Results showed that the average Hg value was higher than that of the primary standard. The Ni and Pb values were lower than the corresponding background values. From the percentage area, the concentration is 100% area with As, more than 93% area with Cr, Cu, Pb and Zn, and 67% area with Cd and Hg, meeting the primary standard; over 97% area met the green standard. The calculated Nemerow index showed that less than 3% of the samples were slightly polluted, indicating good environmental quality. But the accumulated pollution of Cd and Hg was relatively high in some areas which was mainly affected by the high density of the industry. The farmland soils in Beijing suburbs were found to be suitable for farming, but a small percentage of the soils exceeded the green standard; Cd and Hg levels require special attention.

Usurpation of the role of the plastic surgeon as a public health problem in Mexico: Reflections on a case.

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Usurpation of the role of the plastic surgeon as a public health problem in Mexico: Reflections on a case.

Arch Plast Surg. 2018 Jul;45(4):390-392

Authors: Garcia-Espinoza JA, García-Manzano RA, Aguilar-Aragón VB

PMID: 30037204 [PubMed]

Giant extraskeletal chondroma of the hand: A rare case.

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Giant extraskeletal chondroma of the hand: A rare case.

Arch Plast Surg. 2018 Jul;45(4):388-389

Authors: Wenny R, Pollhammer MS, Duscher D, Aitzetmueller MM, Haslhofer DJ, Huemer GM, Schmidt M

PMID: 30037203 [PubMed]

Primary angle-closure glaucoma, a rare but severe complication after blepharoplasty: Case report and review of the literature.

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Primary angle-closure glaucoma, a rare but severe complication after blepharoplasty: Case report and review of the literature.

Arch Plast Surg. 2018 Jul;45(4):384-387

Authors: Kappen IFPM, Nguyen DT, Vos A, van Tits HWHJ

Abstract
Blepharoplasty is one of the most commonly performed aesthetic procedures. Surgical complications are rare, but can have severe consequences, such as permanent vision loss. In this report, we describe a patient who developed primary angle-closure glaucoma (ACG) with associated vision loss after a oculoplastic procedure using local anesthesia. So far, six similar cases have been described in the literature. It is believed that acute ACG is triggered by the surgical procedure in patients with predisposing risk factors such as a cataract. Surgical triggering factors include the use of buffered lidocaine/xylocaine with adrenaline/epinephrine, stress, and coverage of the eyes postoperatively. Due to postoperative analgesic use, the clinical presentation can be mild and atypical, leading to a significant diagnostic delay. Acute ACG should therefore be excluded in each patient with postoperative complaints by assessing pupillary reactions. If a fixed mid-wide pupil is observed in an ophthalmologic examination, an immediate ophthalmology referral is warranted. Surgeons should be aware of this rare complication in order to offer treatment at an early stage and to minimize the chance of irreversible vision loss.

PMID: 30037202 [PubMed]

Traumatic cerebrospinal fluid leakage following septorhinoplasty.

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Traumatic cerebrospinal fluid leakage following septorhinoplasty.

Arch Plast Surg. 2018 Jul;45(4):379-383

Authors: Youssef A, Ahmed S, Ibrahim AA, Daniel M, Abdelfattah HM, Morsi H

Abstract
Septoplasty/septorhinoplasty is a common ear, nose and throat procedure offered for those patients with deviated septum who are suffering from nasal obstruction and functional or cosmetic problems. Although it is a basic and simple procedure, it could lead to catastrophic complications including major skull base injuries which result in cerebrospinal fluid (CSF) leaks. We describe two different cases of traumatic CSF leaks following septoplasty/septorhinoplasty at two different sites. The first patient suffered a CSF leak following septoplasty and presented to Alexandria University Hospital. The leak was still active at presentation and identified as coming from a defect in the roof of the sphenoid sinus and was repaired surgically. The second patient presented 4 days after her cosmetic septorhinoplasty with a CSF leak and significant pneumocephalus. She was managed conservatively. Understanding the anatomical variations of the paranasal sinuses and implementing proper surgical techniques are crucial in preventing intracranial complications when performing either septoplasty or septorhinoplasty. A good quality computed tomography of the nose and paranasal sinuses is a valuable investigation to avoid major complications especially CSF leaks following either procedure.

PMID: 30037201 [PubMed]

Successful treatment of a bowel fistula in the open abdomen by perforator flaps and an aponeurosis plug.

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Successful treatment of a bowel fistula in the open abdomen by perforator flaps and an aponeurosis plug.

Arch Plast Surg. 2018 Jul;45(4):375-378

Authors: Sashida Y, Kayo M, Hachiman H, Hori K, Kanda Y, Nagoya A

Abstract
In this report, we present a case of successful treatment of a bowel fistula in the open abdomen by perforator flaps and an aponeurosis plug. A 70-year-old man underwent total gastrectomy and developed anastomotic leakage and dehiscence of the abdominal wound a week later. He was dependent upon extracorporeal membrane oxygenation, continuous hemodiafiltration, and a respirator. Bowel fluids contaminated the open abdomen. Two months after the gastric operation, a plastic surgery team, in consultation with general surgeons, performed perforator flaps on both sides and constructed, as it were, a bridge of skin sealing the orifice of the fistula. The aponeurosis of the external oblique muscle was elevated with the flap to be used as a plug. The perforators of the flaps were identified on preoperative and intraoperative ultrasonography. This modality allowed us to locate the perforators precisely and to evaluate the perforators by assessing their diameters and performing a waveform analysis. The contamination decreased dramatically afterwards. The bare areas were gradually covered by skin grafts. The fistula was closed completely 18 days after the perforator flap. An ultrasoundguided perforator flap with an aponeurosis plug can be an option for patients suffering from an open abdomen with a bowel fistula.

PMID: 30037200 [PubMed]

Breast augmentation surgery using an inframammary fold incision in Southeast Asian women: Patient-reported outcomes.

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Breast augmentation surgery using an inframammary fold incision in Southeast Asian women: Patient-reported outcomes.

Arch Plast Surg. 2018 Jul;45(4):367-374

Authors: Randquist C, Por YC, Yeow V, Maglambayan J, Simonyi S

Abstract
Background: This analysis presents patient-reported outcomes of breast augmentation procedures performed in Singapore using an inframammary fold incision and the "5 Ps" best practice principles for breast augmentation. These data are the first of their kind in Southeast Asian patients.
Methods: Through a retrospective chart review, patients who underwent primary breast augmentation with anatomical form-stable silicone gel breast implants using an inframammary fold incision were followed for ≥6 months postoperatively. The BREAST-Q Augmentation Module (scores standardized to 0 [worst] - 100 [best]) and Patient and Observer Scar Assessment Scale (POSAS; 1 [normal skin] to 10 [worst scar imaginable]) were administered. Responses were summarized using descriptive statistics. Patient-reported events were collected.
Results: Twenty-two Southeast Asian patients (mean age, 35.1 years) completed ≥1 postoperative BREAST-Q and POSAS assessment and were assessed 11 months to 5.5 years postoperatively. The mean postoperative BREAST-Q satisfaction with breasts and psychosocial well-being scores were 69.2 and 84.0, respectively. The mean POSAS score for their overall opinion of the scar was 4.2; the mean scores for all scar characteristics ranged from 1.2 to 4.2. Over 90% of patients (20/22) said that they would recommend the procedure. Patient complaints following surgery included anisomastia (possibly pre-existing; n=2), sensory loss at the nipple (n=2) or around the nipple (n=3), scarring (n=4), and slight capsular contracture (n=1). No patients required reoperation.
Conclusions: Southeast Asian patients reported high long-term satisfaction scores on the BREAST-Q scale and with their scar characteristics following breast augmentation using an inframammary fold incision, and nearly all said they would recommend this procedure. No reoperations were necessary in patients assessed for up to 5.5 years postoperatively.

PMID: 30037199 [PubMed]

Camptodactyly: An unsolved area of plastic surgery.

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Camptodactyly: An unsolved area of plastic surgery.

Arch Plast Surg. 2018 Jul;45(4):363-366

Authors: Singh V, Haq A, Priyadarshini P, Kumar P

Abstract
Background: Camptodactyly refers to permanent flexion contracture at the proximal interphalangeal joint. Most cases are limited to fifth-finger involvement. Although common, the treatment of camptodactyly is controversial. Many published studies have emphasized conservative treatment, while others have described surgical procedures. The problem with this deformity is that it presents in several forms, which means that there is no single model for effective treatment. The aim of this paper is to present the difficulties encountered with this condition and the management thereof on an individual basis.
Methods: This is a case series of 14 patients (nine males, five females) who underwent surgical treatment. The results were classified using the method from Mayo Clinic as excellent, good, fair, and poor.
Results: Fourteen patients with 15 fingers underwent surgery, and the results achieved were as follows: excellent, 0; good, 1; fair, 6; poor, 8. The treatment of camptodactyly still remains controversial, and hence proper planning individualized to each patient is needed to achieve the maximal improvement with realistic goals.
Conclusions: Although we performed individualised surgery, our careful follow-up was not able to identify any method as superior over another with respect to gain in extension and loss of flexion. We therefore propose that the extensor mechanism should not be disturbed during surgery to treat camptodactyly cases.

PMID: 30037198 [PubMed]

The effect of increasing the contact surface on tendon healing.

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The effect of increasing the contact surface on tendon healing.

Arch Plast Surg. 2018 Jul;45(4):357-362

Authors: Bilgen F, Duman Y, Bulut Ö, Bekerecioğlu M

Abstract
Background: The most common complication after tendon repair is the development of adhesion, with subsequent rupture.
Methods: In this study, we present a new method in which the tendon healing contact surface is increased to reduce these complications. The tendons of chickens in groups 1, 3, and 5 were transversely cut and repaired with in the traditional fashion with double-modified Kessler method and 5/0 polypropylene. In the other groups, 3 mm of the tendon was removed from the proximal half of the upper end and from the distal half of the lower end of the tendon, and they were repaired with the modified Kessler method. The tendons of the chickens in groups 1 and 2 were evaluated immediatelly after surgery. Groups 3 and 4 were evaluated at 4 weeks after surgery. Groups 5 and 6 were evaluated at 6 weeks.
Results: Increases in transient inflammation and connective tissue formation were observed more clearly in the group treated with the new method in histopathological investigations at weeks 4 and 6. The stretching test showed statistically significant differences between groups 3 and 4 (P<0.05) and groups 5 and 6 (P<0.05).
Conclusions: When repairing tendons with the new method, the healing surface increases and the direction of collagen fibers at the surface changes. Because of these effects, the strength of the tendon healing line increases; we therefore expect that this technique will enable patients to safely engage in early active exercise after the operation, with less risk of tendon rupture.

PMID: 30037197 [PubMed]

Extension block and direct pinning methods for mallet fracture: A comparative study.

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Extension block and direct pinning methods for mallet fracture: A comparative study.

Arch Plast Surg. 2018 Jul;45(4):351-356

Authors: Han HH, Cho HJ, Kim SY, Oh DY

Abstract
Background: Mallet fracture can easily occur during sports activities or in daily life; however, the principles and methods of treatment for such fractures remain debated. Among the surgical treatments, various methods of closed reduction have been proposed. We treated patients with the extension block method (EBM) and the direct pinning method (DPM), and then compared the results. We assessed differences in range of motion and measurements of finger movement after surgery.
Methods: A total of 41 patients who underwent surgery from August 2013 to September 2015 were evaluated retrospectively. Among them, 21 patients were treated with the EBM and 20 patients were treated with the DPM. We then compared extensor lag, range of motion, and outcomes according to Crawford's criteria between before surgery and at 6 to 8 months postoperatively.
Results: The postoperative extensor lag improvement was 4.28° and 10.73°, and the postoperative arc of motion was 55.76° and 61.17° in the EBM and DPM groups, respectively. The Crawford assessment showed no statistically significant difference between the groups, although the score in the DPM group was higher than that in the EBM group (3.5 vs. 3.1).
Conclusions: As closed reduction methods for the treatment of mallet fracture, both the EBM and DPM showed good results. However, the DPM proved to be superior to the EBM in that it produced greater improvements in extensor lag and range of motion.

PMID: 30037196 [PubMed]

Reducing the donor site morbidity in radial forearm free flaps by utilizing a narrow radial forearm free flap.

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Reducing the donor site morbidity in radial forearm free flaps by utilizing a narrow radial forearm free flap.

Arch Plast Surg. 2018 Jul;45(4):345-350

Authors: Shaikh SA, Bawa A, Shahzad N, Yousufzai Z, Ghani MS

Abstract
Background: The radial forearm free flap (RFFF) has remained a leading choice of many plastic surgeons as a fasciocutaneous flap due to its versatility, pedicle length, and simple elevation technique. However, donor site morbidity has led many reconstructive surgeons to limit their use of the RFFF and to use other flaps instead. We propose that using a narrow RFFF (nRFFF) decreases the aesthetic and functional morbidity of the donor site.
Methods: We report our experiences with the nRFFF from April 2012 through May 2015 at the Department of Plastic, Reconstructive, and Hand Surgery at Liaquat National Hospital, Karachi. The donor defects were closed primarily. The Stony Brook Scar Evaluation Scale and comparison with the contralateral hand were used to assess aesthetic and functional outcomes, respectively.
Results: A total of 24 patients underwent nRFFF procedures during the study period. The donor arm showed excellent motor function in 22 cases (91.7%), and very good function in the remaining two cases (8.3%). The aesthetic outcomes were excellent in four patients (16.6%), very good in eight patients (33.3%), good in 10 patients (41.6%), and fair in two patients (8.3%) who developed a hypertrophic scar. All flaps were successful and there were no cases of partial or complete loss.
Conclusions: For small to medium-sized soft tissue defects, the nRFFF had acceptable outcomes due to its thinness, pliability, and major reduction in donor site aesthetic and functional morbidity.

PMID: 30037195 [PubMed]

The efficacy of elongated axillary incision on extended latissimus dorsi flap for immediate breast reconstruction.

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The efficacy of elongated axillary incision on extended latissimus dorsi flap for immediate breast reconstruction.

Arch Plast Surg. 2018 Jul;45(4):340-344

Authors: Park TS, Nam SB, Choi JY, Bae SH, Lee JW, Kim HY

Abstract
Background: In performing extended latissimus dorsi (ELD) flap procedures, a skin paddle design on the bra line helps reduce visible scarring. This improves the patient's satisfaction with the outcome. However, such a design leads to a longer operation time and increased fatigue of the surgeon due to the narrow operative field. In this study, the authors propose a method that elongates the axillary incision line posteriorly by 1.5 cm from the lateral border of the latissimus dorsi muscle. We examined whether this method could shorten the operation time and compared the incidence of complications between patients who underwent this novel procedure and patients who underwent the traditional procedure.
Methods: In this study of patients who underwent ELD flap procedures for immediate breast reconstruction, 89 underwent surgery with the elongated axillary incision and 45 underwent surgery without the elongated incision. The total operation time and complications were retrospectively examined based on the patients' medical records, and we examined whether there was any statistically significant difference in the total operation time.
Results: In the experimental group with the elongated axillary incision, the operation time ranged from 125 to 255 minutes (median, 175 minutes). In contrast, in the control group without the elongated axillary incision, the operation time ranged from 142 and 340 minutes (median, 205 minutes). The operation time was statistically significantly different between the two groups, and no significant complications were observed in the experimental group.
Conclusions: Elongation of the axillary incision alone may shorten the operation time of the ELD flap procedure without causing additional complications.

PMID: 30037194 [PubMed]

A simple calculation for the preoperative estimation of transverse rectus abdominis myocutaneous free flap volume in 2-stage breast reconstruction using a tissue expander.

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A simple calculation for the preoperative estimation of transverse rectus abdominis myocutaneous free flap volume in 2-stage breast reconstruction using a tissue expander.

Arch Plast Surg. 2018 Jul;45(4):333-339

Authors: Kono H, Ishii N, Takayama M, Takemaru M, Kishi K

Abstract
Background: Flap volume is an important factor for obtaining satisfactory symmetry in breast reconstruction with a transverse rectus abdominis myocutaneous (TRAM) free flap. We aimed to develop an easy and simple method to estimate flap volume.
Methods: We performed a preoperative estimation of the TRAM flap volume in five patients with breast cancer who underwent 2-stage breast reconstruction following an immediate tissue expander operation after a simple mastectomy. We measured the height and width of each flap zone using a ruler and measured the tissue thickness by ultrasound. The volume of each zone, approximated as a triangular or square prism, was then calculated. The zone volumes were summed to obtain the total calculated volume of the TRAM flap. We then determined the width of zone II, so that the calculated flap volume was equal to the required flap volume (1.2×1.05×the weight of the resected mastectomy tissue). The TRAM flap was transferred vertically so that zone III was located on the upper side, and zone II was trimmed in the sitting position after vascular anastomosis. We compared the estimated flap width of zone II (=X) with the actual flap width of zone II.
Results: X was similar to the actual measured width. Accurate volume replacement with the TRAM flap resulted in good symmetry in all cases.
Conclusions: The volume of a free TRAM flap can be straightforwardly estimated preoperatively using the method presented here, with ultrasound, ruler, and simple calculations, and this technique may help reduced the time required for precise flap tailoring.

PMID: 30037193 [PubMed]

Open reduction of zygoma fractures with the extended transconjunctival approach and T-bar screw reduction.

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Open reduction of zygoma fractures with the extended transconjunctival approach and T-bar screw reduction.

Arch Plast Surg. 2018 Jul;45(4):325-332

Authors: Song SH, Kwon H, Oh SH, Kim SJ, Park J, Kim SI

Abstract
Background: Zygomaticomaxillary complex (ZMC) fractures mostly occur in the form of tripod fractures. The surgical field is accessed using a combination of three classic approaches. However, the subciliary incision may have unfavorable aesthetic results. Herein, the authors report the advantages of the extended transconjunctival approach (ETA) combined with T-bar screw reduction in minimizing scarring and complications for the treatment of ZMC fractures.
Methods: A total of 26 patients underwent ZMC reduction through the ETA and intraoral approach. A skin incision measuring roughly 5 to 8 mm in length was placed following the lateral canthal skin crease. After releasing the inferior crus of the lateral canthal tendon for canthotomy, the medial periosteum of the lateral orbital rim was preserved for canthal reattachment. A limited subperiosteal dissection and partial relaxing incision of the orbicularis oculi were performed to expose the fracture line of the inferior orbital rim and zygomaticofrontal suture. Reduction was performed using a T-bar screw through the transconjunctival incision and an elevator through the intraoral incision.
Results: The aesthetic and functional results were excellent. Successful reduction was achieved and the skin incision was less than 8 mm in 20 cases (76.9%). Only six patients had an additional skin incision (less than 5 mm) to achieve reduction. No cases of ectropion, entropion, or excessive scarring were noted.
Conclusions: The ETA using a T-bar screw is a useful method for maximizing aesthetic results in ZMC fractures, with the advantages of minimal scarring, faster recovery, and maintenance of pretarsal fullness.

PMID: 30037192 [PubMed]