Alterations of growth rate and gene expression levels of UPEC by antibiotics at sub-MIC

Abstract

The host is the main environment for bacteria, and they also expose to many antibiotics during the treatment of infectious diseases in host body. In this study, it was aimed to investigate possible changes in growth rate and expression levels of three virulence genes (foc/foc, cnf1, and usp) in a uropathogenic E. coli standard strain within the presence of ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. The UPEC C7 strain was grown on tryptic soy broth-TSB (control), TSB + ciprofloxacin, TSB + nitrofurantoin, and TSB + trimethoprim-sulfamethoxazole for determination of both growth rate and gene expression level. Antibiotics were added according to their sub-minimal inhibition concentrations. E-test was used to determine MIC values of antibiotics. Growth changes were measured in absorbance 600 nm during 24-h period. Total RNA isolations were performed after incubation for 24 h at 37 °C. Gene expression levels were determined by quantitative PCR. Tukey's post hoc test was used for statistical analysis. According to absorbance values, it has been shown that only ciprofloxacin and trimethoprim-sulfamethoxazole have lead significant decrease on growth rate. We also detected statistically significant differences in each gene expression levels for all antibiotics via relative quantification analysis. Fold changes in gene expression was found 0.65, 1.42, 0.23 for foc/foc gene; 0.01, 0.01, 2.84 for cnf1 gene; and 0.1, 0.01, 0.01 for usp gene in the presence of ciprofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole, respectively. This investigation has shown that antibiotics can play a role as an environmental factor which may determine the pathogenicity of bacteria in vivo.

Environmental pollutants, pathogens and immune system in earthworms

Abstract

Earthworms also known as farmer's friends are natural tillers of soil. They belong to Phylum Annelida and class Oligochaeta. Acid soils with organic matter and surface humus maintain the largest fauna of worms and earthworms. Due to their habitat in soil, they are constantly exposed to microbes and pollution generated by anthropogenic sources. Studies have revealed that damage of the immune system of earthworms can lead to alterations of both morphological and cellular characteristics of worms, activation of signalling pathways and can strongly influence their survival. Therefore, the understanding of the robust immune system in earthworms has become very important from the point of view of understanding its role in combating pathogens and pollutants and its role in indicating the soil pollution. In this article, we have outlined the (i) components of the immune system and (ii) their function of immunological responses on exposure to pollutants and pathogens. This study finds importance from the point of view of ecotoxicology and monitoring of earthworm health and exploring the scope of earthworm immune system components as biomarkers of pollutants and environmental toxicity. The future scope of this review remains in understanding the earthworm immunobiology and indicating strong biomarkers for pollution.

Neuroimmunomodulators in neuroborreliosis and Lyme encephalopathy

Abstract

Background

Lyme encephalopathy, characterized by non-specific neurobehavioral symptoms including mild cognitive difficulties, may occur in patients with systemic Lyme disease and is often mistakenly attributed to CNS infection. Identical symptoms occur in innumerable other inflammatory states and may reflect the effect of systemic immune mediators on the CNS.

Methods

Multiplex immunoassays were used to characterize the inflammatory profile in serum and CSF from Lyme and non-Lyme patients with a range of symptoms to determine if there are specific markers of active CNS infection (neuroborreliosis), or systemic inflammatory mediators associated with neurobehavioral syndromes.

Results

CSF CXCL13 was elevated dramatically in confirmed neuroborreliosis (n=8) and to a lesser extent in possible neuroborreliosis (n=11) and other neuroinflammatory conditions (n=44). Patients with Lyme (n=63) or non-Lyme (n=8) encephalopathy had normal CSF findings, but had elevated serum levels of IL-7, TSLP, IL-17A, IL-17F, and MIP-1α/CCL3.

Conclusions

CSF CXCL13 is a sensitive and specific marker of neuroborreliosis in individuals with Borrelia-specific intrathecal antibody (ITAb) production. However, CXCL13 does not distinguish individuals strongly suspected of having neuroborreliosis, but lacking confirmatory ITAb, from those with other neuroinflammatory conditions. Patients with mild cognitive symptoms occurring during acute Lyme disease, and/or following appropriate treatment, have normal CSF but elevated serum levels of T-helper 17 markers and T-cell growth factors. These markers are also elevated in non-Lyme disease patients experiencing similar symptoms. Our results support that in the absence of CSF abnormalities, neurobehavioral symptoms are associated with systemic inflammation, not CNS infection or inflammation, and are not specific to Lyme disease.

Effect of Topical Application of Pure Honey in Chemo-radiation-Induced Mucositis and Its Clinical Benefits in Improving Quality of Life in Patients of Oral Squamous Cell Carcinoma

Abstract

Oral cancer is a major health problem in India, and in certain parts, it represents more than 50% of all cancers. Since almost all of these patients receive chemo-radiotherapy with or without surgery for treatment, a vast majority of them also develop oral mucositis, a debilitating adverse effect of chemo-radiation. There have been various reports in the literature regarding the beneficial role of honey in the management of oral mucositis. The objective of this study was to investigate whether the application of honey in mucositis confers any significant improvement in lesions of mucositis and more specifically whether application of honey brings about any improvement in the quality of life of patients suffering from chemo-radiation-induced oral mucositis. If found to be beneficial, honey could provide a simple, elegant and cost-effective solution to a troublesome health problem, thus benefiting a large number of patients.

Chromium(III) release from chromium-tanned leather elicits allergic contact dermatitis: a use test study

Summary

Background

Chromium (Cr) is a common skin sensitizer. The use of Cr(VI) in leather is restricted in the EU, but that of Cr(III) is not.

Objectives

To assess whether prolonged exposure to Cr-tanned leather with mainly Cr(III) release may elicit allergic contact dermatitis in Cr-allergic individuals.

Method

Ten Cr-allergic subjects and 22 controls were patch tested with serial dilutions of Cr(III) and Cr(VI), and with leather samples. They then conducted a use test with a Cr-tanned and a Cr-free leather bracelet over a period of 3 weeks, for 12 h per day. Cr deposited on the skin from the bracelets was measured in the controls, and the diphenylcarbazide test for Cr(VI) and extraction tests for Cr(III) and Cr(VI) were conducted for the different leathers.

Results

Four of 10 Cr-allergic subjects developed positive reactions to the Cr-tanned bracelet within 7–21 days, whereas only 1 of 10 had a positive patch test reaction to this leather. Cr released from the Cr-tanned leather was most probably entirely Cr(III), with a quantifiable amount being deposited on the skin.

Conclusions

This study strongly suggests that prolonged and repeated exposure to Cr-tanned leather with mainly Cr(III) release is capable of eliciting allergic contact dermatitis in Cr-allergic individuals.

Factors associated with p-phenylenediamine sensitization: data from the Information Network of Departments of Dermatology, 2008–2013

Summary

Background

Risk factors for p-phenylenediamine (PPD) sensitization include the use of hair dyes, the application of temporary black henna tattoos, working as a hairdresser, and, possibly, exposure to hair dye pretests.

Objectives

To quantify the impact of these (putative) risk factors on PPD sensitization.

Methods

Six items related to PPD exposure were added to the routine Information Network of Departments of Dermatology questionnaire from 2008 to 2013. A retrospective analysis of data from 4314 patients tested with PPD 1% pet. was conducted.

Results

Of the PPD-positive patients (n = 271), 80% had their hair dyed, and, of these, 57% subsequently developed scalp dermatitis, whereas only 11% had had a henna tattoo. The self-administrated pretest with hair dye was performed by only a few patients, precluding a more detailed analysis. Hair dyeing [odds ratio (OR) 6.0; 95% confidence interval (CI): 3.9–9.4], henna tattoos (OR 2.4; 95%CI: 1.5–3.7) and being a hairdresser (OR 2.1; 95%CI: 1.3–3.2) increased the risk of PPD sensitization. Neither dyeing of own hair nor application of a temporary henna tattoo seemed to affect PPD sensitization in hairdressers. p-Aminoaryl compounds more often gave positive reactions in patients with henna tattoo.

Conclusions

Hair dyeing is the major risk factor for PPD sensitization in this clinical setting, and application of a temporary black henna tattoo may also lead to (strong) PPD sensitization.

The journey from genetic predisposition to medication overuse headache to its acquisition as sequela of chronic migraine

Migraine remains one of the biggest clinical case to be solved among the non-communicable diseases, second to low back pain for disability caused as reported by the Global Burden of Disease Study 2016. Despite...

Degradation of organics extracted from dewatered sludge by alkaline pretreatment in microbial electrolysis cell

Abstract

Waste activated sludge in China are mostly subjected to dewatering process before final disposal without stabilization. This study investigated the feasibility of organics degradation and H₂ production from non-stabilized dewatered sludge (DS) by microbial electrolysis cells (MECs). Alkaline pretreatment was used to disintegrate sludge matrix and solubilize organic matters in DS. Then, the treatment performance of DS supernatant in a single-chamber MEC at various applied voltages was investigated. The COD (chemical oxygen demand) removal rate increased with increasing voltage, which ranged from 26.35 to 44.92% at 0.5–0.9 V. The average coulombic efficiency was 75.6%, while the cathodic hydrogen recovery was not satisfied (15.56–20.05%) with H₂ production rates of 0.027–0.038 m³ H₂/(m³ day). The reasons could be ascribed to the complexity of the substrate, H₂ loss, and the confinement of configuration in scale-up. The organic matter degradation was influenced by the composition of DS. The carbohydrates could be readily used; meanwhile, the major component of the DS supernatant, i.e. proteins, was difficult to be utilized, which resulted from the low biodegradability of the transphilic fractions during the MEC operation.

Response to ‘Serological diagnostics in the detection of IgG autoantibodies against human collagen VII in epidermolysis bullosa acquisita: a multicentre analysis': reply from authors

The Risk of Skin Necrosis Following Hyaluronic Acid Filler Injection in Patients with a History of Cosmetic Rhinoplasty

Abstract

Background

As the number of patients using dermal filler for face augmentation increases, the number of adverse events associated with injection may increase. Unpredictable repositioning of blood vessels and a more tenuous blood supply in the operated nose may increase the risk of ischemia, necrosis and vascular embolism following the filler injection.

Objectives

To highlight the importance of the patient's history of previous cosmetic procedures including rhinoplasty in the emergence of vascular complications.

Methods

Our medical records over a two-year period were reviewed retrospectively to identify all patients who were treated at our center for vascular complications associated with facial hyaluronic acid filler injections. In each case, the subject's demographic data (gender and age), habitual status, past medical and surgical history, the symptoms and clinical presentation at the first visit, the time interval between the injection and the onset of symptoms, injected filler material and brand, injection sites, the introduced treatment, and photographs were reviewed carefully.

Results

A total of seven patients were identified, each developing skin necrosis following injection of the hyaluronic acid filler. All patients reported a cosmetic rhinoplasty more than three years ago.

Conclusions

Our finding confirms the conjecture previously made in the literature and suggests that the distinctive vascularity of the nose and the surrounding area may cause filler augmentation induced vascular complications in patients whose vascular circulation has already been compromised by a previous nose surgery.

Relationship between α-melanocyte stimulating hormone levels and therapeutic outcome of melanocyte transplantation and phototherapy in non-segmental patients with vitiligo: A prospective study

Issue Information

Editorial: Special Issue “Effect-related evaluation of anthropogenic trace substances—concepts for genotoxicity, neurotoxicity and endocrine effects”

Mild Complications or Unusual Persistence of Porcine Collagen and Hyaluronic Acid Gel Following Periocular Filler Injections

The purpose of this study was to describe the histopathologic appearance of dermal eyelid fillers that were unexpectedly encountered in ophthalmic plastic surgery samples from patients with mild eyelid disfigurements, and to review eyelid cases with complications that had previously been described in the literature. A retrospective histopathologic study with Alcian blue, elastic, and Masson trichrome stains of 2 cases that were submitted to the Ocular Pathology Department was conducted, and a critical review of previously published cases of the histopathologic characteristics of dermal filler material in the periocular region was also conducted. Two periocular tissue samples were found to contain dermal filler material. In one case, porcine collagen appeared as amorphous or indistinctly microfibrillar aggregates that stained light blue with the Masson trichrome method. In the other case, hyaluronic acid gel appeared as vivid blue amorphous pools of material in extracellular locules after staining with the Alcian blue method. An inflammatory response was not observed in either case. Patients who undergo facial filler procedures may, at a later time, require a surgical excisional procedure from which a specimen is generated. Previously injected dermal filler that the patient neglected to mention may be present in the pathologic sample, potentially perplexing the unsuspecting pathologist. Both ophthalmic plastic surgeons and ocular pathologists should be aware of the histopathologic features of dermal fillers. It is helpful if a surgeon who submits a specimen to the pathology service makes note of any known prior use of facial filler material or is alert to its possible presence when unfamiliar foreign material is discovered in the dermis of the eyelids. Accepted for publication October 10, 2017. Supported by Heed Fellowship (NW). The authors have no conflicts of interest to disclose. Correspondence address and reprint requests to Frederick A. Jakobiec, M.D., D.Sc., David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, MA 02114. E-mail: Fred_Jakobiec@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Orbital Extranodal Marginal Zone Lymphoma Following Radiotherapy: A Report of 2 Cases

Purpose: To present 2 patients in whom orbital radiation preceded the development of periorbital extranodal marginal zone lymphoma by more than a decade and to investigate the likelihood of this representing irradiation-induced malignancy. Methods: Retrospective chart review and histopathologic study with immunohistochemistry of 2 cases. Results: The first patient was a 58-year-old woman who developed an orbital mass within the vicinity of the lateral rectus muscle 17 years after external beam proton radiation therapy for an inferotemporal choroidal melanoma. The second patient was a 32-year-old woman who developed a mass in the right lacrimal gland 12 years after external beam photon radiation therapy for chronic inflammatory dacryoadenitis. Histopathologic and immunohistochemical studies confirmed orbital extranodal marginal zone lymphoma in both cases. Retrospective review of older histopathologic slides from the second patient revealed underlying immunoglobulin G4–related disease. Discussion: The unusual sequence of events in these 2 cases raises the question of whether orbital radiation may in rare instances promote the development of orbital extranodal marginal zone lymphoma. The literature pertaining to irradiation-induced secondary malignancy in the orbit is reviewed. Conclusions: Clinicians should consider the possibility of a secondary malignancy when evaluating a patient with an orbital mass and a history of prior local radiation exposure. Accepted for publication November 5, 2017. Natalie Wolkow is supported by a Heed Ophthalmic Fellowship. The remaining authors have no conflicts of interest to disclose. Address correspondence and reprint requests to Frederick A. Jakobiec, M.D., D.Sc., Department of Ophthalmology, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, Massachusetts 02114. E-mail: Fred_Jakobiec@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Significance of Early Postoperative Eyelid Position on Late Postoperative Result in Mueller’s Muscle Conjunctival Resection and External Levator Advancement Surgery

Purpose: The purpose of this study was to determine whether advancement of the levator aponeurosis in external levator resection surgery or Mueller's muscle and conjunctiva in Mueller's muscle conjunctival resection (MMCR) surgery has a differential effect on variation in eyelid position during the postoperative period. Methods: In this retrospective observational cohort study, 2 groups of patients were defined. The first underwent MMCR surgery without tarsectomy by surgeon 1. The second underwent external levator resection without dissection posterior to the levator aponeurosis by surgeon 2. Marginal reflex distance (MRD1) was calculated based on digital photographs at baseline, 1 week postoperatively and at 3-month follow up. The primary outcome measure was change in MRD1 over time. The secondary outcome was defined as the proportion of patients with minimal early postoperative change (change of MRD1 less than 0.5 mm at 1 week postoperatively). Repeated measures analysis of variance, t test, and chi-square analyses were performed. Results: Of the 114 eyes in the sample, there were 68 in the MMCR group and 46 in the external levator resection group. A significant interaction between group and time was noted (p 1 mm from the early postoperative to the late postoperative time points. Conclusions: Both external levator resection and MMCR can effectively elevate the eyelid in cases of primary involutional ptosis, and have similar late postoperative results. The authors found that MMCR cases undergo greater change between the early and late postoperative period, suggesting the process of eyelid elevation after MMCR may be dynamic, involving postoperative physiologic modification. Accepted for publication October 29, 2017. Presented at the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO). The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Daniel B. Rootman, M.D., M.S., Doheny and Stein Eye Institutes, Division of Orbital and Oculoplastic Surgery, David Geffen School of Medicine at UCLA, 300 Stein Plaza, University of California, Los Angeles, Los Angeles, CA 90095. E-mail: Rootman@jsei.ucla.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Anomalous Sphenoid Diploe Vein: Case Report Highlighting the Value of Careful CT Evaluation Prior to Decompression Surgery

Lateral bony decompression may offer several biomechanical advantages and has become a commonly used surgical approach. Preoperative imaging plays a key role in surgical planning by providing information about the locoregional anatomy. The marrow space of the greater wing of the sphenoid is a focal point of the decompression surgery based on the volume that it occupies. Several vessels pass through the sphenoid bone, but most are small caliber vessels. The authors describe a case of an uncommon anatomical variant of the cranial diploic venous system in which the anterior transverse diploic vessel traverses the marrow space of the sphenoid. The vessel was identified on preoperative CT evaluation. Despite anticipation of potential bleeding, lateral decompression was abandoned due to difficulties in maintaining hemostasis which compromised the view for safe surgical progress. Accepted for publication November 5, 2017. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Hamzah Mustak, M.D., Stein Eye Institute, University of California Los Angeles, 300 Stein Plaza, Los Angeles, CA 90095. E-mail: shmustak@hotmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Removal of cadmium in aqueous solution using wheat straw biochar: effect of minerals and mechanism

Abstract

The biochars were produced from wheat straw (WSBC) at different pyrolytic temperatures. Biochars were characterized by multiple instrumental techniques and were applied to remove Cd from aqueous solution. The removal mechanism was explored, and the quantitative information regarding the relative contribution of related mechanisms to Cd sorption on biochars was provided. The results showed that pseudo-second-order kinetic model, TC (two-compartment) model, and Freundlich isotherm could well fit the process of Cd sorption on biochars. The sorption could be divided into fast and slow adsorption stages. The order of the Cd removal capacity by biochar was WSBC700 > WSBC500 > WSBC300. Adsorption amount of Cd by biochar reduced when the biochar was rinsed with 1.0 M HCl, which indicated that acid-soluble minerals in biochar played an important role during the Cd removal process, especially for the biochar obtained at high pyrolytic temperature. Various equipments were used to investigate the interaction mechanism between biochar and Cd. Mineral precipitation, surface complexation, and cation-π interaction were the main mechanisms of Cd sorption on the biochars. The contribution of cation-π mechanism was in the range of 25.42–48.58%, 2.18–19.30% for surface complexation and 32.12–72.41% for mineral precipitation, respectively. The pyrolytic temperature significantly influenced the removal capacity and mechanism of Cd on biochars. The cation-π mechanism was predominant for biochar obtained at lower pyrolytic temperature. However, mineral precipitation mechanism played a crucial role for biochar obtained at high pyrolytic temperature. These results are helpful for the design or screening of "engineered biochar" to act as sorbents to remove or immobilized Cd in polluted soil or water.

Graphical abstract

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Lead, zinc, and cadmium uptake, accumulation, and phytoremediation by plants growing around Tang-e Douzan lead–zinc mine, Iran

Abstract

In the current study, soils of Tang-e Douzan mine, located in Isfahan, Iran, were collected and analyzed for soluble, exchangeable, and total amounts of Pb, Zn, Cd, Ca, and Mg. The maximum Pb, Zn, Cd, Ca, and Mg concentrations in soils were 2500, 1100, 59, 43,800, and 1320 mg/kg for total metals, 86, 83, 6.3, 4650, and 48 mg/kg for their exchangeable fractions, and 59, 3.7, 0.53, 430, and 6.4 mg/kg for their soluble fractions, respectively. All specimens collected, including 69 plant species, were analyzed for Pb, Zn, and Cd. Moreover, their phytoremediation potential was investigated by calculating bioconcentration factors (BCF), translocation factors (TF), and extraction factors (EF) for each heavy metal. Analysis of the leaves for heavy metals showed no metal hyperaccumulation. The highest shoot concentrations of Pb (298 mg/kg) and Zn (740 mg/kg) were found in Roemeria hybrida subsp. dodecandra and Cd (43 mg/kg) in Chenopodium foliosum. Plants having BCFs and TFs > 1 are capable of phytoextraction. Among the analyzed species, four had both TFs and BCFs > 1 for Zn, 13 for Cd, and none for Pb. R. hybrida, Bromus squarrosus, Descurainia sophia, and Poa bulbosa seem to be the best choices for phytoextraction of Zn. Aegilops columnaris, Allium ampeloprasum subsp. iranicum, B. squarrosus, and Cousinia piptocephala are the best choices for phytoextraction of Cd. Plants with BCF > 1 and TF < 1, including Cerastium dichotomum and Muscari neglectum for Pb, Ceratocephala falcata, M. neglectum, Ornithogalum orthophyllum, and Ranunculus arvensis for Zn and C. falcata, M. neglectum, O. orthophyllum, and R. hybrida subsp. dodecandra for Cd, are proposed to be the most efficient species for metal phytostabilization.

Comment on “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”

I read with interest and trepidation "Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee" ¹ —interest because at St Jude we invest significant time and expertise in researching and optimizing pediatric neuro-oncologic imaging; trepidation because I was a member of this committee but felt compelled to withdraw because I felt that 2 recommendations were counter to existing evidence and potentially detrimental to patient care.

A change at the helm of Neuro-Oncology

I would like to begin by congratulating our past Editor-in-Chief, Dr. Patrick Wen, for his outstanding work in evolving Neuro-Oncology to increasing heights in quality and impact. Over the past 4 years, under the tutelage and expert leadership of Patrick, Neuro-Oncology has not only thrived, it has exceeded all of our expectations. Patrick has led our journal to an increase in impact factor and has introduced both new features and a sense of enthusiasm and excitement about the journal. The Journal's loss of Patrick is mitigated by the fact that SNO is fortunate to have him as president, and we wish him well in this endeavor, as he continues to participate in helping with the journal.

Reviewer Lists for Neuro-Oncology

The following lists refer to the number of times reviewed within the 12-month period ending October 31, 2017. The names of Editorial Board members and Editorial Team members are excluded from the lists.

Highlights from the Literature

Forthcoming Meetings

Response to Harreld re: “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”

What is lost in the letter by Harreld is the mandate of the RAPNO committee and the purpose of the proposed recommendations. Our goal, as a committee, was to develop consensus recommendations on the response assessment for use in clinical trials of patients with medulloblastoma and other seeding tumors, which could then be tested prospectively. Committee recommendations were based on scientific justification where this exists in peer-reviewed literature, or based upon the extensive experience of leaders in the field who are members of this group. Rather than recommend advanced imaging sequences utilized in limited institutions, we proposed recommendations that can be utilized at most institutions and that will allow uniformity and quality data collection. This approach is also in line with the Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee and their recommendations. ¹ As such, it required compromise from the committee members in order to be applicable and feasible for the majority of institutions.

Extent of surgery in low-grade gliomas: an old question in a new context

See the article by Wijnenga et al on pages 103–112

Control versus cognition: the changing paradigm of adjuvant therapy for resected brain metastasis

Twenty years ago, Patchell and colleagues¹ demonstrated that whole-brain radiotherapy (WBRT) mitigates relapse both in the surgical bed and elsewhere in the brain and prevents death from neurologic causes in patients with resected brain metastasis. Therefore, postoperative WBRT became the standard of care.

Synergy of vaccination and agonist OX40 treatment—toward a mechanism-driven combination of glioma immunotherapy

See the article by Jahan et al on pages44–54.

The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis

Abstract

Background

Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes.

Methods

We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model.

Results

Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1–5.0 cm³) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002–1.02; P = 0.016) per cm³ increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1–5.0 cm) already negatively affected OS.

Conclusion

Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report

Abstract

Background

Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown.

Methods

Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1–38.9), median age at last evaluation 30.3 years (range, 6.1–56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs.

Results

From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6–16.7; motor impairment HR: 7.6; 95% CI: 5.8–9.9; hearing loss HR: 18.4; 95% CI: 13.1–25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2–3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8–3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9–5.4), and stroke (HR: 14.9; 95% CI: 10.4–21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6–3.2), meningioma (HR: 2.6; 95% CI: 1.1–6.5), and stroke (HR: 2.0; 95% CI: 1.1–3.4).

Conclusions

CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.

Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location

Abstract

Background

The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.

Methods

Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection.

Results

We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival.

Conclusion

These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.

Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma

Abstract

Background

Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials.

Methods

A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative.

Results

Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care.

Conclusion

The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.

Prognostic relevance of genetic alterations in diffuse lower-grade gliomas

Abstract

Background

Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown.

Methods

Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA).

Results

In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA.

Conclusions

Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

Agonist OX40 immunotherapy improves survival in glioma-bearing mice and is complementary with vaccination with irradiated GM-CSF–expressing tumor cells

Abstract

Background

Glioma immunotherapy is an active area of clinical investigation. Glioma-associated immunosuppression remains an obstacle to efficacious immunotherapy, and combination approaches are likely necessary for durable success. OX40 is a member of the tumor necrosis factor receptor superfamily that is upregulated on activated lymphocytes, ligation of which results in enhanced activity and may be active against cancer. We sought to confirm the efficacy of agonist anti-OX40 immunotherapy against glioma and hypothesized that it is complementary with irradiated whole tumor cell vaccination.

Methods

GL261 tumor cells were implanted into the right frontal lobes of syngeneic mice, which were then treated with controls, agonist anti-OX40 monoclonal antibody, vaccination with subcutaneous injection of irradiated granulocyte macrophage colony stimulating factor (GM-CSF)–expressing GL261 cells (GVAX), or vaccination + agonist anti-OX40 therapy. Animals were followed for survival. On day 18, splenocytes were harvested for enzyme-linked immunosorbent spot analyses and brains were harvested for immunohistochemistry and flow cytometry analyses of infiltrating lymphocytes.

Results

Combination immunotherapy with GVAX and systemic agonist anti-OX40 monoclonal antibody improved survival by 14 days over controls (median survival 36 vs 22 days, P < 0.00005). Systemically, T helper cell type 1 (Th1) antitumor immunity was enhanced significantly by combination therapy. In the brain, combination immunotherapy increased the percentage of Th1 CD4+ T lymphocytes and reduced the fraction that were Th2. In the brain, vaccination improved the ratio of CD8+ to FoxP3+ T lymphocytes, while combination immunotherapy reversed intracranial T-lymphocyte exhaustion, reducing their coexpression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as well as PD-1 and lymphocyte-activation gene 3 (LAG-3).

Conclusions

Anti-OX40 immunotherapy is active against intracranial glioma and synergizes with GVAX. Vaccination and anti-OX40 immunotherapy are mechanistically complementary, particularly in the glioma microenvironment.

Dissecting human gliomas by single-cell RNA sequencing

Abstract

Diffuse gliomas are the most common human primary brain tumors and remain incurable. They are complex entities in which diverse genetic and nongenetic effects determine tumor biology and clinical course. Our current understanding of gliomas in patients is primarily based on genomic and transcriptomic methods that have profiled them as bulk, providing critical information yet masking the diversity of cells within each tumor. Recent advances in single-cell DNA and RNA profiling have paved the way to studying tumors at cellular resolution. Here, we review initial studies deploying single-cell analysis in clinical glioma samples, with a focus on RNA expression profiling. We highlight how these studies provide new insights into glioma biology, tumor heterogeneity, cancer cell lineages, cancer stem cell programs, the tumor microenvironment, and glioma classification.

Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma

Abstract

Background

Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM.

Methods

Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay. Cell apoptosis was analyzed by TUNEL, annexin V staining, and blotting of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Both subcutaneous xenograft and orthotropic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis; the tumor growth was monitored by bioluminescence imaging, and tumor tissue was analyzed by immunohistochemistry to validate signaling changes.

Results

PI3K inhibition activates WEE1 kinase, which in turn phosphorylates cell division control protein 2 homolog (Cdc2) at Tyr15 and inhibits Cdc2 activity, leading to G2/M arrest in a p53-independent manner. WEE1 inhibition abrogated the G2/M arrest and propelled cells to prematurely enter into mitosis and consequent cell death through mitotic catastrophe and apoptosis. Additionally, combination treatment significantly suppressed tumor growth in a subcutaneous model but not in an intracranial model due to limited blood–brain barrier penetration.

Conclusions

Our findings highlight WEE1 as an adaptive resistant gene activated after PI3K inhibition, and inhibition of WEE1 potentiated the effectiveness of PI3K targeted inhibition, suggesting that a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in GBM.

CD70, a novel target of CAR T-cell therapy for gliomas

Abstract

Background

Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target.

Methods

Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models.

Results

CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect.

Conclusion

These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.

Neurological complications of new chemotherapy agents

Abstract

This last decade has yielded more robust development of cancer treatments and first-in-class agents than ever before. Since 2006, nearly one hundred new drugs have received regulatory approval for the treatment of hematological and solid organ neoplasms. Moreover, older conventional therapies have received approval for new clinical indications and are being used in combination with these newer small-molecule targeted treatments. The nervous system is vulnerable to many of the traditional cancer therapies, manifesting both already well-described acute and chronic toxicities. However, newer agents may produce toxicities that may seem indistinguishable from the underlying cancer. Early recognition of neurotoxicities from new therapeutics is vital to avoid irreversible neurological injury. This review focuses on cancer therapies in use in the last 10 years and approved by the FDA from January 2006 through January 1, 2017.

MerTK as a therapeutic target in glioblastoma

Abstract

Background

Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.

Methods

We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.

Results

MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein–positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%–10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.

Conclusions

These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

Feet in danger: short exposure to contaminated soil causing health damage—an experimental study

Abstract

In this study, hematological and behavioral changes in Wistar rats exposed to soil collected from urban areas next to an industrial complex were investigated. Animals were exposed to soil samples placed at the bottom of cages for 4 days. After this period, behavioral parameters were measured by the open field test and the elevated plus-maze. Blood was collected to measure hematological parameters. The soil from the vicinity of the oil refining industry caused changes in hematological parameters and altered behavioral parameters in both tests. The soil from the vicinity of the petroleum refining industry and fertilizer industries increased the density of white blood cells and decreased exploratory activity in the exposed animals. The results demonstrate that contact with contaminated soils, even for short periods, can cause physiological damage in organisms and that special attention should be given to people who live under constant exposure to these soils.

Contribution of ammonia-oxidizing archaea and ammonia-oxidizing bacteria to ammonia oxidation in two nitrifying reactors

Abstract

In this study, two laboratory nitrifying reactors (NRI and NRII), which were seeded by sludge from different sources and operated under different operating conditions, were found to possess distinct dominant ammonia-oxidizing microorganisms. Ammonia-oxidizing archaeal (AOA) amoA genes outnumbered ammonia-oxidizing bacterial (AOB) amoA genes in reactor NRI, while only AOB amoA genes were detectable in reactor NRII. The AOA amoA gene sequences retrieved from NRI were characterized within the Nitrososphaera sister cluster of the group 1.1b Thaumarchaeota. Two inhibitors for ammonia oxidation, allylthiourea (ATU) and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO), were applied individually and as a mixture to observe the ammonia-oxidizing activity of both microorganisms in the reactors' sludge. The results indicated that AOA and AOB jointly oxidized ammonia in NRI, while AOB played the main role in ammonia oxidation in NRII. DNA-stable isotope probing with labeled ¹³C–HCO₃⁻ was performed on NRI sludge. Incorporation of ¹³C into AOA and AOB implied that both microorganisms may perform autotrophy during ammonia oxidation. Taken together, the results from this study provide direct evidence demonstrating the contribution of AOA and AOB to ammonia oxidation in the nitrifying reactors.

Effect of inorganic and organic solutes on zero-valent aluminum-activated hydrogen peroxide and persulfate oxidation of bisphenol A

Abstract

The effect of varying inorganic (chloride, nitrate, sulfate, and phosphate) and organic (represented by humic acid) solutes on the removal of aqueous micropollutant bisphenol A (BPA; 8.8 μM; 2 mg/L) with the oxidizing agents hydrogen peroxide (HP; 0.25 mM) and persulfate (PS; 0.25 mM) activated using zero-valent aluminum (ZVA) nanoparticles (1 g/L) was investigated at a pH of 3. In the absence of the solutes, the PS/ZVA treatment system was superior to the HP/ZVA system in terms of BPA removal rates and kinetics. Further, the HP/ZVA process was not affected by nitrate (50 mg/L) addition, whereas chloride (250 mg/L) exhibited no effect on the PS/ZVA process. The negative effect of inorganic anions on BPA removal generally speaking increased with increasing charge in the following order: NO₃⁻ (no inhibition) < Cl⁻ (250 mg/L) = SO₄²⁻ < PO₄³⁻ for HP/ZVA and Cl⁻ (250 mg/L; no inhibition) < NO₃⁻ < SO₄²⁻ < PO₄³⁻ for PS/ZVA. Upon addition of 20 mg/L humic acid representing natural organic matter, BPA removals decreased from 72 and 100% in the absence of solutes to 24 and 57% for HP/ZVA and PS/ZVA treatments, respectively. The solute mixture containing all inorganic and organic solutes together partly suppressed the inhibitory effects of phosphate and humic acid on BPA removals decreasing to 46 and 43% after HP/ZVA and PS/ZVA treatments, respectively. Dissolved organic carbon removals were obtained in the range of 30 and 47% (the HP/ZVA process), as well as 47 and 57% (the PS/ZVA process) for the experiments in the presence of 20 mg/L humic acid and solute mixture, respectively. The relative Vibrio fischeri photoluminescence inhibition decreased particularly for the PS/ZVA treatment system, which exhibited a higher treatment performance than the HP/ZVA treatment system.

The Bow and Arrow and Early Human Sociality: an Enactive Perspective on Communities and Technical Practice in the Middle Stone Age

Abstract

In this paper, I draw on postphenomenology and material engagement theory to consider the material and emergent character of sociality in Homo faber. I approach this through the context of the bow and arrow, which is a technology that has received recent attention in cognitive archeology as a proxy for assessing criteria that made early human cognition distinct from that of other hominins. Through an ethnographic case study, I scrutinize the forms of knowledge that are required to use the technology in the dynamic field of environmental practices that constitute the hunt. I demonstrate that the learning of the skill is a transformational process where beginners develop self and intentionality by attuning subjective capacities for sensory awareness and creative responsiveness. Through mutual participation, the bow and arrow aligns disposition and rapport among those whose life processes are shaped by the skill. As a mechanism of shared experience, the bow and arrow generates a community can together perceive and act creatively in an impermanent world. Through these observations, I argue that early human sociality was built not on a pre-evolved capacity for symbolic representation but on technical experience, and I consider important questions this raises about the nature of evolutionary processes at work in the development of communities through time.

Commiserating with Devastated Things: Milan Kundera and the Entitlement of Thinking

Commiserating with Devastated Things: Milan Kundera and the Entitlement of ThinkingWIRTHJASON M.fordham university press. 2016. pp. 227227. £54.00. (hbk).

Management of Morgellons Disease With Low-Dose Trifluoperazine

This medical record review examines the novel use of low-dose trifluoperazine, a high-potency typical antipsychotic, in a cohort of patients with Morgellons disease.

Diagnosis of Neurofibromatosis Type 2 From Congenital Skin Plaques

This genetic testing study reports a case of an early diagnosis of neurofibromatosis type 2 (NF2) in a child after genetic analysis of congenital skin plaques, with confirmation of these findings by analysis of skin plaques from 6 unrelated patients with NF2.

Intertriginous Condyloma-like Plaques and Ulcers

A woman in her 50s with a medical history of hypertension and depression was evaluated by the inpatient dermatology consult service for a 1.5-year history of painful intertriginous wounds; she was previously diagnosed with hidradenitis suppurativa. What is your diagnosis?

Human Herpesvirus 8–Associated Inflammatory Cytokine Syndrome

This case report describes a patient with human herpesvirus 8–associated inflammatory cytokine syndrome.

Comorbidity Development in Children With Psoriasis

This cohort study examines the risk ocomorbidities in children with and without psoriasis, after accounting for obesity.

Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep–wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep–wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep–wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3–36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep–wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep.

SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY_3–36 can reverse this neurochemical imbalance and acutely restore sleep composition. These findings add insight into how innate behaviors such as feeding and sleep are integrated and suggest a novel mechanism through which diet-induced obesity during puberty imposes its long-lasting effects on sleep–wake behavior.

Cognitive Control, the Anterior Cingulate, and Nicotinic Receptors: A Case of Heterozygote Advantage

A Critical Role for Dopamine D5 Receptors in Pain Chronicity in Male Mice

Dopaminergic modulation of spinal cord plasticity has long been recognized, but circuits affected by this system and the precise receptor subtypes involved in this modulation have not been defined. Dopaminergic modulation from the A11 nucleus of the hypothalamus contributes to plasticity in a model of chronic pain called hyperalgesic priming. Here we tested the hypothesis that the key receptor subtype mediating this effect is the D5 receptor (D5R). We find that a spinally directed lesion of dopaminergic neurons reverses hyperalgesic priming in both sexes and that a D1/D5 antagonist transiently inhibits neuropathic pain. We used mice lacking D5Rs (DRD5KO mice) to show that carrageenan, interleukin 6, as well as BDNF-induced hyperalgesia and priming are reduced specifically in male mice. These male DRD5KO mice also show reduced formalin pain responses and decreased heat pain. To characterize the subtypes of dorsal horn neurons engaged by dopamine signaling in the hyperalgesic priming model, we used c-fos labeling. We find that a mixed D1/D5 agonist given spinally to primed mice activates a subset of neurons in lamina III and IV of the dorsal horn that coexpress PAX2, a transcription factor for GABAergic interneurons. In line with this, we show that gabazine, a GABA-A receptor antagonist, is antihyperalgesic in primed mice exposed to spinal administration of a D1/D5 agonist. Therefore, the D5R, in males, and the D1R, in females, exert a powerful influence over spinal cord circuitry in pathological pain likely via modulation of deep dorsal horn GABAergic neurons.

SIGNIFICANCE STATEMENT Pain is the most prominent reason why people seek medical attention, and chronic pain incidence worldwide has been estimated to be as high as 33%. This study provides new insight into how descending dopamine controls pathological pain states. Our work demonstrates that dopaminergic spinal projections are necessary for the maintenance of a chronic pain state in both sexes; however, D5 receptors seem to play a critical role in males whereas females rely more heavily on D1 receptors, an effect that could be explained by sexual dimorphisms in receptor expression levels. Collectively, our work provides new insights into how the dopaminergic system interacts with spinal circuits to promote pain plasticity.

Does Auditory Cortex Code Temporal Information from Acoustic and Cochlear Implant Stimulation in a Similar Way?

Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation

Cocaine abuse disrupts dopamine system function, and reduces cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criterion for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were twofold; we sought to (1) identify the molecular mechanisms by which cocaine exposure produces tolerance and (2) determine whether amphetamine-induced reductions in cocaine intake are connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats, we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed cocaine tolerance. Amphetamine treatment also reversed escalated cocaine intake and decreased motivation to obtain cocaine as measured in a behavioral economics task, thereby linking tolerance to multiple facets of cocaine use. Finally, using fluorescence resonance energy transfer imaging, we found that cocaine tolerance is associated with the formation of DAT-DAT complexes, and that amphetamine disperses these complexes. In addition to extending our basic understanding of DATs and their role in cocaine reinforcement, we serendipitously identified a novel therapeutic target: DAT oligomer complexes. We show that dispersion of oligomers is concomitant with reduced cocaine intake, and propose that pharmacotherapeutics aimed at these complexes may have potential for cocaine addiction treatment.

SIGNIFICANCE STATEMENT Tolerance to cocaine's subjective effects is a cardinal symptom of cocaine addiction and a DSM-V criterion for substance abuse disorders. However, elucidating the molecular adaptions that produce tolerance and determining its behavioral impact have proven difficult. Using cocaine self-administration in rats, we link tolerance to cocaine effects at the dopamine transporter (DAT) with aberrant cocaine-taking behaviors. Further, tolerance was associated with multi-DAT complexes, which formed after cocaine exposure. Treatment with amphetamine deconstructed DAT complexes, reversed tolerance, and decreased cocaine seeking. These data describe the behavioral consequence of cocaine tolerance, provide a putative mechanism for its development, and suggest that compounds that disperse DAT complexes may be efficacious treatments for cocaine addiction.

Behavioral, Modeling, and Electrophysiological Evidence for Supramodality in Human Metacognition

Human metacognition, or the capacity to introspect on one's own mental states, has been mostly characterized through confidence reports in visual tasks. A pressing question is to what extent results from visual studies generalize to other domains. Answering this question allows determining whether metacognition operates through shared, supramodal mechanisms or through idiosyncratic, modality-specific mechanisms. Here, we report three new lines of evidence for decisional and postdecisional mechanisms arguing for the supramodality of metacognition. First, metacognitive efficiency correlated among auditory, tactile, visual, and audiovisual tasks. Second, confidence in an audiovisual task was best modeled using supramodal formats based on integrated representations of auditory and visual signals. Third, confidence in correct responses involved similar electrophysiological markers for visual and audiovisual tasks that are associated with motor preparation preceding the perceptual judgment. We conclude that the supramodality of metacognition relies on supramodal confidence estimates and decisional signals that are shared across sensory modalities.

SIGNIFICANCE STATEMENT Metacognitive monitoring is the capacity to access, report, and regulate one's own mental states. In perception, this allows rating our confidence in what we have seen, heard, or touched. Although metacognitive monitoring can operate on different cognitive domains, we ignore whether it involves a single supramodal mechanism common to multiple cognitive domains or modality-specific mechanisms idiosyncratic to each domain. Here, we bring evidence in favor of the supramodality hypothesis by showing that participants with high metacognitive performance in one modality are likely to perform well in other modalities. Based on computational modeling and electrophysiology, we propose that supramodality can be explained by the existence of supramodal confidence estimates and by the influence of decisional cues on confidence estimates.

Dissociable Decoding of Spatial Attention and Working Memory from EEG Oscillations and Sustained Potentials

In human scalp EEG recordings, both sustained potentials and alpha-band oscillations are present during the delay period of working memory tasks and may therefore reflect the representation of information in working memory. However, these signals may instead reflect support mechanisms rather than the actual contents of memory. In particular, alpha-band oscillations have been tightly tied to spatial attention and may not reflect location-independent memory representations per se. To determine how sustained and oscillating EEG signals are related to attention and working memory, we attempted to decode which of 16 orientations was being held in working memory by human observers (both women and men). We found that sustained EEG activity could be used to decode the remembered orientation of a stimulus, even when the orientation of the stimulus varied independently of its location. Alpha-band oscillations also carried clear information about the location of the stimulus, but they provided little or no information about orientation independently of location. Thus, sustained potentials contain information about the object properties being maintained in working memory, consistent with previous evidence of a tight link between these potentials and working memory capacity. In contrast, alpha-band oscillations primarily carry location information, consistent with their link to spatial attention.

SIGNIFICANCE STATEMENT Working memory plays a key role in cognition, and working memory is impaired in several neurological and psychiatric disorders. Previous research has suggested that human scalp EEG recordings contain signals that reflect the neural representation of information in working memory. However, to conclude that a neural signal actually represents the object being remembered, it is necessary to show that the signal contains fine-grained information about that object. Here, we show that sustained voltages in human EEG recordings contain fine-grained information about the orientation of an object being held in memory, consistent with a memory storage signal.

The Role of Cysteine String Protein {alpha} Phosphorylation at Serine 10 and 34 by Protein Kinase C{gamma} for Presynaptic Maintenance

Protein kinase C (PKC) knock-out (KO) animals exhibit symptoms of Parkinson's disease (PD), including dopaminergic neuronal loss in the substantia nigra. However, the PKC substrates responsible for the survival of dopaminergic neurons in vivo have not yet been elucidated. Previously, we found 10 potent substrates in the striatum of PKC-KO mice. Here, we focused on cysteine string protein α (CSPα), a protein from the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles. We found that in cultured cells, PKC phosphorylates CSPα at serine (Ser) 10 and Ser34. Additionally, apoptosis was found to have been enhanced by the overexpression of a phosphorylation-null mutant of CSPα, CSPα(S10A/S34A). Compared with wild-type (WT) CSPα, the CSPα(S10A/S34A) mutant had a weaker interaction with HSP70. However, in sharp contrast, a phosphomimetic CSPα(S10D/S34D) mutant, compared with WT CSPα, had a stronger interaction with HSP70. In addition, total levels of synaptosomal-associated protein (SNAP) 25, a main downstream target of the HSC70/HSP70 chaperone complex, were found to have decreased by the CSPα(S10A/S34A) mutant through increased ubiquitination of SNAP25 in PC12 cells. In the striatum of 2-year-old male PKC-KO mice, decreased phosphorylation levels of CSPα and decreased SNAP25 protein levels were observed. These findings indicate the phosphorylation of CSPα by PKC may protect the presynaptic terminal from neurodegeneration. The PKC–CSPα–HSC70/HSP70–SNAP25 axis, because of its role in protecting the presynaptic terminal, may provide a new therapeutic target for the treatment of PD.

SIGNIFICANCE STATEMENT Cysteine string protein α (CSPα) is a protein belonging to the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles, which maintain the presynaptic terminal. However, the function of CSPα phosphorylation by protein kinase C (PKC) for neuronal cell survival remains unclear. The experiments presented here demonstrate that PKC phosphorylates CSPα at serine (Ser) 10 and Ser34. CSPα phosphorylation at Ser10 and Ser34 by PKC protects the presynaptic terminal by promoting HSP70 chaperone activity. This report suggests that CSPα phosphorylation, because of its role in modulating HSP70 chaperone activity, may be a target for the treatment of neurodegeneration.

Brainstem Pain-Control Circuitry Connectivity in Chronic Neuropathic Pain

Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top–down engagement of the circuitry alongside altered reward processing in pain conditions.

SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain-modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain-modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative for the development of more efficacious therapies.

The Microtubule-Associated Protein Tau Mediates the Organization of Microtubules and Their Dynamic Exploration of Actin-Rich Lamellipodia and Filopodia of Cortical Growth Cones

Proper organization and dynamics of the actin and microtubule (MT) cytoskeleton are essential for growth cone behaviors during axon growth and guidance. The MT-associated protein tau is known to mediate actin/MT interactions in cell-free systems but the role of tau in regulating cytoskeletal dynamics in living neurons is unknown. We used cultures of cortical neurons from postnatal day (P)0–P2 golden Syrian hamsters (Mesocricetus auratus) of either sex to study the role of tau in the organization and dynamics of the axonal growth cone cytoskeleton. Here, using super resolution microscopy of fixed growth cones, we found that tau colocalizes with MTs and actin filaments and is also located at the interface between actin filament bundles and dynamic MTs in filopodia, suggesting that tau links these two cytoskeletons. Live cell imaging in concert with shRNA tau knockdown revealed that reducing tau expression disrupts MT bundling in the growth cone central domain, misdirects trajectories of MTs in the transition region and prevents single dynamic MTs from extending into growth cone filopodia along actin filament bundles. Rescue experiments with human tau expression restored MT bundling, MT penetration into the growth cone periphery and close MT apposition to actin filaments in filopodia. Importantly, we found that tau knockdown reduced axon outgrowth and growth cone turning in Wnt5a gradients, likely due to disorganized MTs that failed to extend into the peripheral domain and enter filopodia. These results suggest an important role for tau in regulating cytoskeletal organization and dynamics during growth cone behaviors.

SIGNIFICANCE STATEMENT Growth cones are the motile tips of growing axons whose guidance behaviors require interaction of the dynamic actin and microtubule cytoskeleton. Tau is a microtubule-associated protein that stabilizes microtubules in neurons and in cell-free systems regulates actin–microtubule interaction. Here, using super resolution microscopy, live-cell imaging, and tau knockdown, we show for the first time in living axonal growth cones that tau is important for microtubule bundling and microtubule exploration of the actin-rich growth cone periphery. Importantly tau knockdown reduced axon outgrowth and growth cone turning, due to disorganized microtubules that fail to enter filopodia and co-align with actin filaments. Understanding normal tau functions will be important for identifying mechanisms of tau in neurodegenerative diseases such as Alzheimer's.

This Week in The Journal

CD44 Signaling Mediates High Molecular Weight Hyaluronan-Induced Antihyperalgesia

We studied, in male Sprague Dawley rats, the role of the cognate hyaluronan receptor, CD44 signaling in the antihyperalgesia induced by high molecular weight hyaluronan (HMWH). Low molecular weight hyaluronan (LMWH) acts at both peptidergic and nonpeptidergic nociceptors to induce mechanical hyperalgesia that is prevented by intrathecal oligodeoxynucleotide antisense to CD44 mRNA, which also prevents hyperalgesia induced by a CD44 receptor agonist, A6. Ongoing LMWH and A6 hyperalgesia are reversed by HMWH. HMWH also reverses the hyperalgesia induced by diverse pronociceptive mediators, prostaglandin E₂, epinephrine, TNFα, and interleukin-6, and the neuropathic pain induced by the cancer chemotherapy paclitaxel. Although CD44 antisense has no effect on the hyperalgesia induced by inflammatory mediators or paclitaxel, it eliminates the antihyperalgesic effect of HMWH. HMWH also reverses the hyperalgesia induced by activation of intracellular second messengers, PKA and PKC, indicating that HMWH-induced antihyperalgesia, although dependent on CD44, is mediated by an intracellular signaling pathway rather than as a competitive receptor antagonist. Sensitization of cultured small-diameter DRG neurons by prostaglandin E₂ is also prevented and reversed by HMWH. These results demonstrate the central role of CD44 signaling in HMWH-induced antihyperalgesia, and establish it as a therapeutic target against inflammatory and neuropathic pain.

SIGNIFICANCE STATEMENT We demonstrate that hyaluronan (HA) with different molecular weights produces opposing nociceptive effects. While low molecular weight HA increases sensitivity to mechanical stimulation, high molecular weight HA reduces sensitization, attenuating inflammatory and neuropathic hyperalgesia. Both pronociceptive and antinociceptive effects of HA are mediated by activation of signaling pathways downstream CD44, the cognate HA receptor, in nociceptors. These results contribute to our understanding of the role of the extracellular matrix in pain, and indicate CD44 as a potential therapeutic target to alleviate inflammatory and neuropathic pain.

Inverted Encoding Models of Human Population Response Conflate Noise and Neural Tuning Width

Channel-encoding models offer the ability to bridge different scales of neuronal measurement by interpreting population responses, typically measured with BOLD imaging in humans, as linear sums of groups of neurons (channels) tuned for visual stimulus properties. Inverting these models to form predicted channel responses from population measurements in humans seemingly offers the potential to infer neuronal tuning properties. Here, we test the ability to make inferences about neural tuning width from inverted encoding models. We examined contrast invariance of orientation selectivity in human V1 (both sexes) and found that inverting the encoding model resulted in channel response functions that became broader with lower contrast, thus apparently violating contrast invariance. Simulations showed that this broadening could be explained by contrast-invariant single-unit tuning with the measured decrease in response amplitude at lower contrast. The decrease in response lowers the signal-to-noise ratio of population responses that results in poorer population representation of orientation. Simulations further showed that increasing signal to noise makes channel response functions less sensitive to underlying neural tuning width, and in the limit of zero noise will reconstruct the channel function assumed by the model regardless of the bandwidth of single units. We conclude that our data are consistent with contrast-invariant orientation tuning in human V1. More generally, our results demonstrate that population selectivity measures obtained by encoding models can deviate substantially from the behavior of single units because they conflate neural tuning width and noise and are therefore better used to estimate the uncertainty of decoded stimulus properties.

SIGNIFICANCE STATEMENT It is widely recognized that perceptual experience arises from large populations of neurons, rather than a few single units. Yet, much theory and experiment have examined links between single units and perception. Encoding models offer a way to bridge this gap by explicitly interpreting population activity as the aggregate response of many single neurons with known tuning properties. Here we use this approach to examine contrast-invariant orientation tuning of human V1. We show with experiment and modeling that due to lower signal to noise, contrast-invariant orientation tuning of single units manifests in population response functions that broaden at lower contrast, rather than remain contrast-invariant. These results highlight the need for explicit quantitative modeling when making a reverse inference from population response profiles to single-unit responses.

Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla

Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action. Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB₁ receptors by the acetaminophen metabolite and endocannabinoid reuptake inhibitor AM 404. However, the contribution of the cannabinoid system to antihyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB₁ receptors have remained elusive. Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent antihyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their antihyperalgesic activity in CB₁^–/– mice, confirming the involvement of the cannabinoid system. Consistent with a mechanism downstream of proinflammatory prostaglandin formation, acetaminophen also reversed hyperalgesia induced by intrathecal prostaglandin E₂. To distinguish between a peripheral/spinal and a supraspinal action, we administered acetaminophen and AM 404 to hoxB8-CB₁^–/– mice, which lack CB₁ receptors from the peripheral nervous system and the spinal cord. These mice exhibited unchanged antihyperalgesia indicating a supraspinal site of action. Accordingly, local injection of the CB₁ receptor antagonist rimonabant into the rostral ventromedial medulla blocked acetaminophen-induced antihyperalgesia, while local rostral ventromedial medulla injection of AM 404 reduced hyperalgesia in wild-type mice but not in CB₁^–/– mice. Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB₁ receptors reside in the rostral ventromedial medulla.

SIGNIFICANCE STATEMENT Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action, including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue-specific CB₁ receptor-deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.

Modulation of Ether-a-Go-Go Related Gene (ERG) Current Governs Intrinsic Persistent Activity in Rodent Neocortical Pyramidal Cells

While cholinergic receptor activation has long been known to dramatically enhance the excitability of cortical neurons, the cellular mechanisms responsible for this effect are not well understood. We used intracellular recordings in rat (both sexes) neocortical brain slices to assess the ionic mechanisms supporting persistent firing modes triggered by depolarizing stimuli following cholinergic receptor activation. We found multiple lines of evidence suggesting that a component of the underlying hyperexcitability associated with persistent firing reflects a reduction in the standing (leak) K⁺ current mediated by Ether-a-go-go-Related Gene (ERG) channels. Three chemically diverse ERG channel blockers (terfenadine, ErgToxin-1, and E-4031) abolished persistent firing and the underlying increase in input resistance in deep pyramidal cells in temporal and prefrontal association neocortex. Calcium accumulation during triggering stimuli appears to attenuate ERG currents, leading to membrane potential depolarization and increased input resistance, two critical elements generating persistent firing. Our results also suggest that ERG current normally governs cortical neuron responses to depolarizing stimuli by opposing prolonged discharges and by enhancing the poststimulus repolarization. The broad expression of ERG channels and the ability of ERG blocks to abolish persistent firing evoked by both synaptic and intracellular step stimuli suggest that modulation of ERG channels may underlie many forms of persistent activity observed in vivo.

SIGNIFICANCE STATEMENT Persistent activity, where spiking continues beyond the triggering stimulus, is a common phenomenon observed in many types of neurons. Identifying the mechanism underlying this elementary process of memory is a step forward in understanding higher cognitive function including short-term memory. Our results suggest that a reduction in the currents normally mediated by Ether-a-go-go-Related Gene (ERG) K⁺ channels contributes to persistent firing in neocortical pyramidal cells. ERG currents have been previously studied primarily in the heart; relatively little is known about ERG function in the brain, although mutations in ERG channels have recently been linked to schizophrenia. The present study is among the first to describe its role in neocortex in relation to biophysical correlates of memory function.

Tonotopic Variation of the T-Type Ca2+ Current in Avian Auditory Coincidence Detector Neurons

Neurons in avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and are characterized by striking structural variations in dendrites and axon initial segment (AIS) according to their acoustic tuning [characteristic frequency (CF)]. T-type Ca²⁺ (CaT) channels regulate synaptic integration and firing behavior at these neuronal structures. However, whether or how CaT channels contribute to the signal processing in NL neurons is not known. In this study, we addressed this issue with whole-cell recording and two-photon Ca²⁺ imaging in brain slices of posthatch chicks of both sexes. We found that the CaT current was prominent in low-CF neurons, whereas it was almost absent in higher-CF neurons. In addition, a large Ca²⁺ transient occurred at the dendrites and the AIS of low-CF neurons, indicating a localization of CaT channels at these structures in the neurons. Because low-CF neurons have long dendrites, dendritic CaT channels may compensate for the attenuation of EPSPs at dendrites. Furthermore, the short distance of AIS from the soma may accelerate activation of axonal CaT current in the neurons and help EPSPs reach spike threshold. Indeed, the CaT current was activated by EPSPs and augmented the synaptic response and spike generation of the neurons. Notably, the CaT current was inactivated during repetitive inputs, and these augmenting effects predominated at the initial phase of synaptic activity. These results suggested that dendritic and axonal CaT channels increase the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation in low-CF NL neurons.

SIGNIFICANCE STATEMENT Neurons in nucleus laminaris are binaural coincidence detectors for sound localization. We report that T-type Ca²⁺ (CaT) current was prominent at dendrites and the axonal trigger zone in neurons tuned to low-frequency sound. Because these neurons have long dendrites and a closer trigger zone compared with those tuned to higher-frequency sound, the CaT current augmented EPSPs at dendrites and accelerated spike triggers in the neurons, implying a strategic arrangement of the current within the nucleus. This effect was limited to the onset of repetitive inputs due to progressive inactivation of CaT current. The results suggested that the CaT current increases the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation of low-frequency sound.

Disrupted Neuroglial Metabolic Coupling after Peripheral Surgery

Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction.

SIGNIFICANCE STATEMENT A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.

The Mouse Pulvinar Nucleus Links the Lateral Extrastriate Cortex, Striatum, and Amygdala

The pulvinar nucleus is a large thalamic structure involved in the integration of visual and motor signals. The pulvinar forms extensive connections with striate and extrastriate cortical areas, but the impact of these connections on cortical circuits has not previously been directly tested. Using a variety of anatomical, optogenetic, and in vitro physiological techniques in male and female mice, we show that pulvinocortical terminals are densely distributed in the extrastriate cortex where they form synaptic connections with spines and small-diameter dendrites. Optogenetic activation of these synapses in vitro evoked large excitatory postsynaptic responses in the majority of pyramidal cells, spiny stellate cells, and interneurons within the extrastriate cortex. However, specificity in pulvinar targeting was revealed when recordings were targeted to projection neuron subtypes. The neurons most responsive to pulvinar input were those that project to the striatum and amygdala (76% responsive) or V1 (55%), whereas neurons that project to the superior colliculus were rarely responsive (6%). Because the pulvinar also projects directly to the striatum and amygdala, these results establish the pulvinar nucleus as a hub linking the visual cortex with subcortical regions involved in the initiation and control of movement. We suggest that these circuits may be particularly important for coordinating body movements and visual perception.

SIGNIFICANCE STATEMENT We found that the pulvinar nucleus can strongly influence extrastriate cortical circuits and exerts a particularly strong impact on the activity of extrastriate neurons that project to the striatum and amygdala. Our results suggest that the conventional hierarchical view of visual cortical processing may not apply to the mouse visual cortex. Instead, our results establish the pulvinar nucleus as a hub linking the visual cortex with subcortical regions involved in the initiation and control of movement, and predict that the execution of visually guided movements relies on this network.

Zinc Inhibits TRPV1 to Alleviate Chemotherapy-Induced Neuropathic Pain

Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1.

SIGNIFICANCE STATEMENT The chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.

The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization

UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs). However, the underlying cellular and molecular neurobiology remains less clear. Here we report the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites. This remodeling effect is mediated by the ubiquitination and degradation of XIAP (X-linked inhibitors of aptosis protein) by E6AP, which leads to activation of caspase-3 and cleavage of microtubules. In vivo, male and female Ube3A 2X ASD mice show decreased XIAP levels, increased caspase-3 activation, and elevated levels of tubulin cleavage. Consistently, dendritic branching and spine density are reduced in cortical neurons of Ube3A 2X ASD mice. In revealing an important role for Ube3A/E6AP in ASD-related developmental alteration in dendritic arborization and synapse formation, our findings provide new insights into the pathogenesis of Ube3A/E6AP-dependent ASD.

SIGNIFICANCE STATEMENT Copy number variation of the UBE3A gene and aberrant overexpression of the gene product E6AP protein is a common cause of autism spectrum disorders (ASDs). During brain development, dendritic growth and remodeling play crucial roles in neuronal connectivity and information integration. We found that in primary neurons and in Ube3A transgenic autism mouse brain, overexpression of E6AP leads to significant loss of dendritic arborization. This effect is mediated by the ubiquitination of XIAP (X-linked inhibitor of aptosis protein) by E6AP, subsequent activation of caspases, and the eventual cleavage of microtubules, leading to local degeneration and retraction at the tips of dendritic branches. These findings demonstrate dysregulation in neuronal structural stability as a major cellular neuropathology in ASD.

Chronisch spontane Urtikaria

Operative Behandlungsoptionen bei Hidradenitis suppurativa/Acne inversa

Zusammenfassung

Hidradenitis suppurativa/Acne inversa (HS/AI) ist eine chronisch inflammatorische Hauterkrankung, für deren Behandlung konservative und operative Therapieoptionen zur Verfügung stehen. Im Hurley-Stadium II und III stellt die operative Sanierung von irreversibel destruiertem Gewebe die Methode der Wahl dar. Resektionstechniken unterschiedlicher Invasivität werden in der Literatur beschrieben. Bisher herrscht kein allgemein akzeptierter Konsens über den Einsatz verschiedener Resektions- und Rekonstruktionstechniken sowie die postoperative Nachbehandlung. Die Beurteilung von Rezidiven nach chirurgischer Intervention wird durch fehlende Rezidivdefinitionen sowie eine heterogene Studienlage erschwert.

Panorama Dermatologische Praxis

Allergen Concerns and Popular Skin Care Products

To the Editor We read with great interest the article by Xu et al published in a recent issue of JAMA Dermatology highlighting the high prevalence of contact allergens in common moisturizers. Their data mirror similar results in our recent study investigating contact allergens in pediatric personal care products marketed as hypoallergenic, dermatologist recommended and/or tested, fragrance free, or paraben free. Similar to the study by Xu et al, which found that 88% of common moisturizers contained at least 1 common contact allergen, we found that 167 of 187 of our selection of pediatric products (89%) contained at least 1 allergen.

Vegetating Darier Disease Treated With Botulinum Toxin

This case report describes a patient with vegetating Darier disease treated with botulinum toxin.

Dermatology Practice Consolidation Fueled by Private Equity Investment

This Viewpoint discusses the consolidation of dermatology practices facilitated by private equity investment and the potential consequences for the specialty and patients.

Dermatology’s Grandest Piano

This is a story about a piano that played a small but special role in dermatology's history. It belonged to Stephen Rothman, MD (1894-1963), one of the most influential dermatologists of the 20th century. He was also an accomplished pianist.

The Importance of Population-Based Estimates of Melanocytic Pathology

In this issue of JAMA Dermatology, Lott et al describe a novel and innovative approach to estimating the prevalence of different types of melanocytic lesions in all adults undergoing skin biopsies in a population. Using an automated natural language processing tool, they analyzed 80 368 written pathology reports of skin biopsies from 47 529 adult patients drawn from an underlying health system patient population, which was representative of the general adult population. For analysis of each pathology report, the diagnosis was first dichotomized as either a melanocytic or nonmelanocytic lesion. For melanocytic lesions, the cases were then assigned to 1 of 4 diagnostic categories based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx), with differing management implications: class I, benign lesion requiring no further treatment; class II, low-risk lesion requiring complete excision with narrow (<5-mm) margins; class III, higher-risk lesion such as melanoma in situ requiring reexcision with 5-mm to 1-cm margins; and class IV/V, invasive melanoma requiring wide reexcision with 1-cm margins or greater. Approximately one-quarter of all skin biopsies were of melanocytic lesions. Of these, over 90% were benign or low risk (class I or II); 4.5% were melanoma in situ or similar-risk lesion (class III); and 4.1% were invasive melanoma (class IV/V).

Hair Repigmentation With Anti–PD-1 and Anti–PD-L1 Immunotherapy

To the Editor We read with great interest the article by Rivera and colleagues reporting on hair repigmentation in patients receiving immunotherapy with anti–programmed cell death 1 (PD-1) and anti–programmed cell death 1 ligand 1 (PD-L1) immunotherapy.

Population-Based Frequencies and Distribution of Melanocytic Lesions

This large-scale analysis of pathology reports in electronic medical records, using the natural language processing technique, evaluates population-based distributions and pathologic characteristics of melanocytic proliferations.

Spanish Fly—Cantharidin’s Alter Ego

Cantharidin, derived from the Greek word for beetle, kantharis, is an odorless, colorless terpenoid produced by up to 2000 species of beetles collectively referred to as blister beetles. Male blister beetles synthesize and use cantharidin as a defensive chemical and nuptial gift. Females receive cantharidin during mating and use the compound to coat their eggs to ward off predators. It functions as a potent vesicant on skin contact, but it is also a systemic poison if ingested, with toxic effects comparable with those of strychnine and cyanide. If properly dosed and applied, however, its blistering properties can be used therapeutically.