Management of pediatric psoriasis with acitretin: A review

Abstract

Psoriasis is a chronic inflammatory disease of the skin which can occur at any age-group. Psoriasis in childhood is not uncommon and has genetic susceptibility but usually, an environmental trigger such as infection is thought to initiate the disease process. Pediatric psoriasis has profound effects on both physical and psychosocial health of the patient. Treatment of mild psoriasis can be done with topical therapies but those which do not respond to topical therapies can be treated with phototherapy and systemic therapies. The use of systemic therapies in childhood is mainly based on the published data, case series, expert opinion and the experience as there is the lack of controlled trials in the age group. Based on the experience retinoids are probably the second line drugs for the treatment of pediatric psoriasis which do not respond to topical therapies and phototherapy. Using acitretin in a low dose and with proper physical examinations and laboratory investigations will reduce the hazard of potential serious adverse events. This article gives the review of the use of acitretin in pediatric psoriasis.

A Metabolic Therapy for Malignant Glioma Requires a Clinical Measure

Abstract

Cancers are "reprogrammed" to use a much higher rate of glycolysis (GLY) relative to oxidative phosphorylation (OXPHOS), even in the presence of adequate amounts of oxygenation. Originally identified by Nobel Laureate Otto Warburg, this hallmark of cancer has recently been termed metabolic reprogramming and represents a way for the cancer tissue to divert carbon skeletons to produce biomass. Understanding the mechanisms that underlie this metabolic shift should lead to better strategies for cancer treatments. Malignant gliomas, cancers that are very resistant to conventional treatments, are highly glycolytic and seem particularly suited to approaches that can subvert this phenotype.

CXCL-10 and Interleukin-6 are Reliable Serum Markers for Vitiligo Activity: A Multicenter Cross-Sectional Study

Summary

This cross-sectional multicenter study aimed to evaluate serum CXCL-10, as an activity marker for vitiligo and compare it with other putative serum and tissue markers. Serum CXCL-10 was compared to interferon gamma (IFN-γ), interleukin 6 (IL-6) and IL-17 using ELISA in 55 non-segmental vitiligo patients (30 active and 25 stable) and 30 healthy controls. Marginal skin biopsy was taken for immunohistochemical evaluation of CD8+T-cells and CXCL-10 +ve cells. Serum levels of CXCL-10, IL-17 and IL-6 were elevated in all vitiligo patients compared to controls (P<0.05). All investigated serum markers were higher in active versus stable vitiligo. Tissue expression of CXCL-10+ve cells and CD8+ve T-cells was stronger in vitiligo patients compared to controls, and tissue CXCL-10 +ve cells expression was stronger in active versus stable cases. Positive correlations were noted between the different serum and tissue markers. CXCL-10 was the most specific whereas IL-6 was the most sensitive serum marker to distinguish active from stable disease.

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Combined aesthetic interventions for prevention of facial ageing, and restoration and beautification of face and body

Reexamining mechanic’s hands as a characteristic skin finding in dermatomyositis

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Josef Symon S. Concha, Joseph F. Merola, David Fiorentino, Victoria P. Werth
Mechanic's hands is a poorly defined clinical finding that has been reported in a variety of rheumatologic diseases. Morphologic descriptions include hyperkeratosis on the sides of the digits that sometimes extends to the distal tips, diffuse palmar scale, and, more recently observed, linear discrete scaly papules in a similar lateral distribution. The association of mechanic's hands with dermatomyositis, although recognized, is still debatable. In this review, most studies have shown that mechanic's hands is commonly associated with dermatomyositis and displays histopathologic findings of interface dermatitis, colloid bodies and interstitial mucin which are consistent with a cutaneous connective tissue disease. A more specific definition of this entity would help to determine its usefulness in classifying and clinically identifying patients with dermatomyositis, with implications related to subsequent screening for associated comorbidities in this setting.

Therapeutic pearl: 5-fluorouracil tattoo for idiopathic guttate hypomelanosis

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Carlos Gustavo Wambier, Sarah Perillo de Farias Wambier, Maria Teresa Pereira Soares, Juliano Breunig, Mark Aaron Cappel, Marina Landau

Cause specific mortality in adults with atopic dermatitis

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Jacob P. Thyssen, Lone Skov, Alexander Egeberg
BackgroundAdult atopic dermatitis (AD) has been associated with several co-morbidities, but cause-specific mortality risk is unknown.ObjectivesTo examine cause-specific death rates and risk in adults with AD.MethodsWe performed cross-linkage of nationwide health care and cause of death registers. Adult patients with AD were matched with 10 controls per study subject. We calculated incidence rates per 1,000 person-years and hazard ratios (HRs) of cause-specific death with 95% confidence intervals (95% CIs) using Cox proportional hazards models.ResultsA total of 8,686 patients and 86,860 matched controls were studied. The risk of death, due to any cause, was significantly increased in patients with AD (HR 1.27, 95%CI 1.11-1.45). Significant causes included cardiovascular (HR 1.45; 95%CI 1.07-1.96), infectious (HR 3.71; 95% CI 1.43-9.60) and urogenital diseases (HR 5.51; 95%CI 1.54-19.80). No increased risk of death due to cancer, endocrine, neurological, psychiatric, respiratory, or gastroenterological disease was observed.LimitationsThe results might not be generalizable to patients seen exclusively by primary care physicians.ConclusionsAdults with atopic dermatitis had slightly increased risk of death during follow-up. While the risk of death from cardiovascular, urogenital, and infectious diseases was slightly elevated among patients with AD, the absolute risk was very low.

Porcine Xenografts for Surgical Defects: A Single Center Experience with 128 Cases

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Sean Marzolf, Divya Srivastava, Rajiv I. Nijhawan

A simple device for ablation of keloidal tissue and serial deposition of intralesional drugs

Publication date: Available online 2 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Savita Yadav, Somesh Gupta

Death and dignity in Catholic Christian thought

Abstract

This article traces the history of the concept of dignity in Western thought, arguing that it became a formal Catholic theological concept only in the late nineteenth century. Three uses of the word are distinguished: intrinsic, attributed, and inflorescent dignity, of which, it is argued, the intrinsic conception is foundational. The moral norms associated with respect for intrinsic dignity are discussed briefly. The scriptural and theological bases for adopting the concept of dignity as a Christian idea are elucidated. The article concludes by discussing the relevance of this concept of dignity to the spiritual and ethical care of the dying.

Islamic perspectives on clinical intervention near the end-of-life: We can but must we?

Abstract

The ever-increasing technological advances of modern medicine have increased physicians' capacity to carry out a wide array of clinical interventions near the end-of-life. These new procedures have resulted in new "types" of living where a patient's cognitive functions are severely diminished although many physiological functions remain active. In this biomedical context, patients, surrogate decision-makers, and clinicians all struggle with decisions about what clinical interventions to pursue and when therapeutic intent should be replaced with palliative goals of care. For some patients and clinicians, religious teachings about the duty to seek medical care and the care of the dying offer ethical guidance when faced with such choices. Accordingly, this paper argues that traditional Sunni Islamic ethico-legal views on the obligation to seek medical care and Islamic theological concepts of human dignity (karāmah) and inviolability (ḥurmah) provide the ethical grounds for non-intervention at the end-of-life and can help calibrate goals of care discussions for Muslim patients. In closing the paper highlights the pressing need to develop a holistic ethics of healthcare of the dying from an Islamic perspective that brings together multiple genres of the Islamic intellectual tradition so that it can meet the needs of the patients, clinicians and Muslim religious leaders interacting with the healthcare system.

Mechanisms of the action of adenine on anti-allergic effects in mast cells

Abstract

Introduction

Mast cells play an important role in allergic responses.

Methods

We herein demonstrated the mechanisms of inhibitory effect of adenine on IgE/antigen-induced degranulation and TNF-α release in mast cells.

Results

We found that these effects were dependent on the amino group of adenine because purine only weakly inhibited degranulation. Adenine also inhibited Ca²⁺ ionophore- and thapsigargin-induced degranulation, however, this inhibitory effect was weaker than that of the antigen. Therefore, the inhibitory effects of adenine on degranulation may be mediated before as well as after the Ca²⁺ raise under the antigen stimulus. Adenine inhibited antigen-induced Syk and the subsequent induction of AKT and ERK activation under FcϵRI-mediated signal. Adenine also attenuated antigen-induced increase in Ca²⁺. Furthermore, adenine inhibited IgE/antigen-induced IKKα/β activation, which is involved in degranulation. Finally, adenine protected mice against anaphylactic allergic responses in vivo.

Conclusions

The present study revealed a key role of adenine in the attenuation of allergic responses through the inhibition of Syk-mediated signal transduction and IKK-mediated degranulation.

We demonstrated the amino group of adenine may play a key role in IgE/antigen-induced degranulation in mast cells. The inhibitory effects of adenine on degranulation may be mediated before as well as after the Ca2+ raise under the antigen stimulus. We also provided key role of adenine in the attenuation of allergic responses through the inhibition of Syk-mediated signal transduction and IKK-mediated degranulation.

A comparison of nanoparticullate CpG immunotherapy with and without allergens in spontaneously equine asthma-affected horses, an animal model

Abstract

Introduction

New therapeutic strategies to modulate the immune response of human and equine allergic asthma are still under extensive investigation. Immunomodulating agents stimulating T-regulatory cells offer new treatment options beyond conventional symptomatic treatment or specific immunotherapy for human and equine allergic airway diseases, with the goal of a homoeostatic T-helper cell balance. The aim of this study was to evaluate the effects of a nebulized gelatin nanoparticle-CpG formulation (CpG-GNP) with and without specific allergens for the treatment of spontaneous allergic equine asthma as a model for human asthma.

Methods

Twenty equine asthma-affected horses were treated either with CpG-GNP alone or CpG-GNP with allergens. Two specific allergens were selected for each horse based on history and an in-vitro test. Each horse received seven administrations of the respective nebulized composition and was examined before treatment, immediately after and 6 weeks after the treatment course.

Results

Clinical parameters such as breathing rate, indirect interpleural measurement, arterial blood gases, amount of tracheal mucus and percentage of neutrophils and cytokines in tracheal washes and serum samples were evaluated. Treatment with CpG-GNP alone as well as in combinations with relevant allergens resulted in clinical improvement of nasal discharge, breathing rate, amount of secretion and viscosity, neutrophil percentage and partial oxygen pressure directly after and 6 weeks after treatment. There were no significant differences between the two treatments in clinical parameters or local cytokine profiles in the tracheal wash fluid (IL-10, IFN-g, and IL-17). IL-4 concentrations decreased significantly in both groups.

Conclusion

Nonspecific CpG-GNP-based immunotherapy shows potential as a treatment for equine and possibly also human allergic asthma.

The aim of this study was to evaluate the effects of a nebulized gelatin nanoparticle-CpG formulation (CpG-GNP) with and without specific allergens for the treatment of spontaneous allergic equine Asthma as a model for human asthma. Immunomodulating agents stimulating T-regulatory cells offer new treatment options beyond conventional symptomatic treatment for human and equine allergic airway diseases, with the goal of a homoeostatic T-helper cell balance. Nonspecific CpG-GNP-based immunotherapy shows potential as a treatment for equine and possibly also human allergic asthma.

Quantitative image analysis of protein expression and colocalization in skin sections

Abstract

Immunofluorescence (IF) and in situ proximity ligation assay (isPLA) are techniques that are used for in situ protein expression and colocalization analysis, respectively. However, an efficient quantitative method to analyze both IF and isPLA staining on skin sections is lacking. Therefore, we developed a new method for semi-automatic quantitative layer-by-layer measurement of protein expression and colocalization in skin sections using the free open-source software CellProfiler. As a proof of principle, IF and isPLA of ichthyosis-related proteins TGm-1 and SDR9C7 were examined. The results indicate that this new method can be used for protein expression and colocalization analysis in skin sections.

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Safety, efficacy, and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis

Abstract

Background

Real-life data on newer biologic and biosimilar agents for moderate-to-severe psoriasis are lacking.

Objectives

To examine safety, efficacy, and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) and compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima).

Methods

The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between January 1^st, 2007 and March 31^st, 2017. We used Kaplan-Meier survival curves and Cox-regression to examine drug survival patterns.

Results

A total of 3495 treatment series (2161 patients) were included (adalimumab n=1332, etanercept n=579, infliximab n=333, ustekinumab n=1055, and secukinumab n=196). Secukinumab had the highest number of PASI100 respondants, but also the lowest drug survival among all biologics. Ustekinumab had the highest drug survival overall. There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept. Treatment with higher-than-approved dosages was frequent for all drugs except for adalimumab and secukinumab. Adverse events (predominantly infections) were most frequent for secukinumab and showed an increased (albeit low) incidence of cardiovascular events compared with the other agents.

Conclusions

Ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, albeit that most patients on secukinumab were non-naïve. Switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable. Adverse events occurred most frequently with secukinumab. Future studies are warranted to assess the long-term safety of novel biologics for psoriasis.

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Population-based Clinical Practice Research Datalink study using algorithm modelling to identify the true burden of hidradenitis suppurativa

Summary

Background

Epidemiology data regarding hidradenitis suppurativa (HS) are conflicting and prevalence estimates vary 80-fold, from 0.05% in a population-based study, to 4%.

Objectives

To assess the hypothesis that previous population-based studies under-estimated true HS prevalence by missing undiagnosed cases.

Methods

We performed a population-based observational and case-control study using the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data. Physician-diagnosed cases in CPRD were identified from specific Read codes. Algorithms identified unrecognised 'proxy' cases, with at least five Read code records for boils in flexural skin sites. Validation of proxy cases was undertaken with General Practitioner questionnaires to confirm criteria-diagnosed cases. A case-control study assessed disease associations.

Results

On 30 June 2013, 23,353 physician-diagnosed HS cases were documented in 4,364,308 research-standard records. 68,890 proxy cases were identified, reduced to 10,146 criteria-diagnosed cases after validation, extrapolated from 107 completed questionnaires (61% return rate). Overall point prevalence was 0.77% (95% CI 0.76% to 0.78%). An additional 18,417 cases had a history of 1-4 flexural skin boils.

In physician-diagnosed cases, ORs for current smoker and obesity (BMI>30) were 3.61 (95% CI 3.44 to 3.79) and 3.29 (95% CI 3.14 to 3.45). HS was associated with type 2 diabetes, Crohn's disease, hyperlipidaemia, acne and depression and not associated with ulcerative colitis or polycystic ovary syndrome.

Conclusions

Contrary to results of previous population-based studies, HS is relatively common, with a UK prevalence of 0.77%, one-third being unrecognised, criteria-diagnosed cases using the most stringent disease definition. If probable cases are included, HS prevalence rises to 1.19%.

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Cuestionarios validados: una potente herramienta para la investigación

Publication date: Available online 1 November 2017
Source:Actas Dermo-Sifiliográficas
Author(s): N. Blázquez Sánchez

Síndrome de Iso-Kikuchi: 3 casos en la edad pediátrica

Publication date: Available online 1 November 2017
Source:Actas Dermo-Sifiliográficas
Author(s): L.L. Tirelli, P.C. Luna, R. Cano, J.P. Giraldo, M. Larralde
El síndrome de Iso-Kikuchi, onicodisplasia congénita del dedo índice, es una entidad poco frecuente caracterizada por la anoniquia total o displasia de la uña del dedo índice, acompañado, en algunas ocasiones, de alteraciones óseas subyacentes, por lo general, en ausencia de otras anomalías. Si bien se han planteado distintas hipótesis fisiopatogénicas, la etiología sigue siendo desconocida.Describimos los casos de 3 pacientes pediátricos, 2 varones y una niña, con alteraciones ungueales y óseas compatibles con el síndrome de Iso-Kikuchi. Destacamos la importancia de reconocer esta entidad tempranamente para evitar la realización de estudios complementarios y terapéuticas innecesarias.Iso-Kikuchi syndrome, or congenital onychodysplasia of the index finger, is an uncommon condition characterized by total anonychia or dysplasia of the nail of the index finger. It is occasionally accompanied by underlying bone abnormalities and is rarely associated with other conditions. Although various hypotheses have been put forward to explain the pathophysiology of the syndrome, its etiology remains unknown.We report the cases of 3 pediatric patients (2 boys and 1 girl) with nail changes and bone abnormalities consistent with Iso-Kikuchi syndrome. We highlight the importance of recognizing this entity early to avoid the need for additional tests and unnecessary treatment.

Leiomiosarcoma cutáneo: características clínicas, histopatológicas y correlación pronóstica en 12 pacientes

Publication date: Available online 1 November 2017
Source:Actas Dermo-Sifiliográficas
Author(s): E. Rodríguez-Lomba, I. Molina-López, V. Parra-Blanco, R. Suárez-Fernández, A. Pulido-Pérez
IntroducciónEl leiomiosarcoma de piel es una neoplasia maligna de estirpe muscular cuya baja incidencia dificulta el desarrollo de protocolos específicos de diagnóstico y manejo terapéutico.ObjetivosDescribir las características clínicas e histopatológicas de una serie de leiomiosarcomas cutáneos primarios y secundarios, junto con su correlación pronóstica.Material y métodosSe realizó un estudio retrospectivo, descriptivo y observacional. Se seleccionaron 17 casos de leiomiosarcoma cutáneo en 12 pacientes, diagnosticados entre el 1 de enero de 2000 y el 31 de diciembre de 2015. Se recogieron sus datos demográficos, características clínicas e histopatológicas, evolución y respuesta al tratamiento.ResultadosSe reclutaron 5 varones y 7 mujeres, todos ellos mayores de 50 años al diagnóstico. Se recogieron 4 leiomiosarcomas dérmicos (4/17, 23%) en 4 pacientes, 2 leiomiosarcomas hipodérmicos (2/17, 11,5%) en 2 pacientes, y 11 metástasis cutáneas de leiomiosarcoma (11/17, 65%) en 6 pacientes. Las localizaciones más frecuentes fueron cuero cabelludo (7/17, 41%), miembros inferiores (3/17, 17%) y tronco (3/17, 17%). Durante el seguimiento, un 50% de leiomiosarcomas dérmicos recidivaron, un 50% de leiomiosarcomas hipodérmicos presentaron metástasis a distancia y 5/6 pacientes con metástasis cutáneas de leiomiosarcoma (83%) fallecieron a causa de su enfermedad.LimitacionesEste estudio es una revisión retrospectiva de una serie de casos de tamaño limitado en un centro único.ConclusionesEl leiomiosarcoma cutáneo es una neoplasia maligna poco frecuente. A la hora de adoptar una actitud diagnóstico-terapéutica en estos pacientes debemos tener en cuenta la marcada heterogeneidad pronóstica entre sus diferentes subtipos.IntroductionCutaneous leiomyosarcoma is a malignant neoplasm derived from smooth muscle cells. Its low incidence hampers the development of specific protocols for diagnosis and treatment.ObjectivesTo describe the clinical and histopathologic characteristics of a series of primary and secondary cutaneous leiomyosarcomas and to determine how these characteristics correlate with prognosis.Material and methodsWe performed an observational, descriptive, retrospective study based on 17 cutaneous leiomyosarcomas in 12 patients diagnosed between January 1, 2000 and December 31, 2015. We recorded demographic data, clinical and histopathologic characteristics, outcome, and response to treatment.ResultsWe included 5 men and 7 women, all aged more than 50 years at diagnosis. There were 4 cutaneous leiomyosarcomas (23%) in 4 patients, 2 subcutaneous leiomyosarcomas (11.5%) in 2 patients, and 11 skin metastases of leiomyosarcoma (65%) in 6 patients. The most frequently affected sites were the scalp (41%), lower limbs (17%), and trunk (17%). During follow-up, 50% of the cutaneous leiomyosarcomas recurred, 50% of the subcutaneous leiomyosarcomas presented distant metastases, and 83% of the patients with skin metastases of leiomyosarcoma died of their disease.LimitationsOurs was a retrospective review of a small case series at a single center.ConclusionsCutaneous leiomyosarcoma is an uncommon malignant neoplasm. Our approach to diagnosis and therapy must take into account the marked heterogeneity in the prognosis of the various subtypes.

Graphical abstract

Objections to Euvoluntary Exchange Do Not Have “Standing”: Extending Markets Without Limits

A Note From the Editors

Editorial: Innovations in Study Design—A Call for Creative Solutions

Blood Lead, Bone Turnover, and Survival in Amyotrophic Lateral Sclerosis

Abstract

Blood lead and bone turnover may be associated with the risk of amyotrophic lateral sclerosis (ALS). We aimed to assess whether these factors were also associated with time from ALS diagnosis to death through a survival analysis of 145 ALS patients enrolled during 2007 in the National Registry of Veterans with ALS. Associations of survival time with blood lead and plasma biomarkers of bone resorption (C-terminal telopeptides of type I collagen (CTX)) and bone formation (procollagen type I amino-terminal peptide (PINP)) were estimated using Cox models adjusted for age at diagnosis, diagnostic certainty, diagnostic delay, site of onset, and score on the Revised ALS Functional Rating Scale. Hazard ratios were calculated for each doubling of biomarker concentration. Blood lead, plasma CTX, and plasma PINP were mutually adjusted for one another. Increased lead (hazard ratio (HR) = 1.38; 95% confidence interval (CI): 1.03, 1.84) and CTX (HR = 2.03; 95% CI: 1.42, 2.89) were both associated with shorter survival, whereas higher PINP was associated with longer survival (HR = 0.59; 95% CI: 0.42, 0.83), after ALS diagnosis. No interactions were observed between lead or bone turnover and other prognostic indicators. Lead toxicity and bone metabolism may be involved in ALS pathophysiology.

Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population

Abstract

The UK Biobank cohort is a population-based cohort of 500,000 participants recruited in the United Kingdom (UK) between 2006 and 2010. Approximately 9.2 million individuals aged 40–69 years who lived within 25 miles (40 km) of one of 22 assessment centers in England, Wales, and Scotland were invited to enter the cohort, and 5.5% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between nonresponders and responders. Sociodemographic, physical, lifestyle, and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, to be female, and to live in less socioeconomically deprived areas than nonparticipants. Compared with the general population, participants were less likely to be obese, to smoke, and to drink alcohol on a daily basis and had fewer self-reported health conditions. At age 70–74 years, rates of all-cause mortality and total cancer incidence were 46.2% and 11.8% lower, respectively, in men and 55.5% and 18.1% lower, respectively, in women than in the general population of the same age. UK Biobank is not representative of the sampling population; there is evidence of a "healthy volunteer" selection bias. Nonetheless, valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large.

Invited Commentary: Can Estimation of Sodium Intake Be Improved by Borrowing Information From Other Variables?

Abstract

Estimation of dietary sodium intake is problematic. The most accurate measure is average sodium excretion from multiple 24-hour urine collections, but such an approach is impractical. Using data from the Women's Health Initiative, Prentice et al. (Am J Epidemiol. 2017;186(9):1035–1043) assessed the relationship of calibrated estimates of sodium and potassium excretion with cardiovascular outcomes. The calibrated estimates were a function of self-reported sodium-to-potassium ratio from a food frequency questionnaire, age, body mass index, race, supplement use, smoking status, educational level, income, and aspirin use. In general, associations with outcomes using the calibrated estimates were in the expected direction: direct for the sodium-to-potassium ratio and sodium intake and indirect for potassium. The unexpected associations were an increased risk of hemorrhagic stroke with lower sodium-to-potassium ratio and sodium intake and increased risk with higher potassium intake, along with a null relationship of sodium intake with ischemic stroke. Overall, our assessment is that the authors have improved the estimation of mean dietary sodium and potassium intakes. However, more work is needed to show that calibrated estimates actually improve estimation of future clinical events. If this methodological issue can be successfully addressed, their approach has the potential to improve estimation of dietary sodium and potassium intakes in observational studies.

Prentice et al. Respond to “Improving Estimation of Sodium Intake”

Associations of Biomarker-Calibrated Sodium and Potassium Intakes With Cardiovascular Disease Risk Among Postmenopausal Women

Abstract

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.

Mammographic Density Reduction as a Prognostic Marker for Postmenopausal Breast Cancer: Results Using a Joint Longitudinal-Survival Modeling Approach

Abstract

Previous studies have linked reductions in mammographic density after a breast cancer diagnosis to an improved prognosis. These studies focused on short-term change, using a 2-stage process, treating estimated change as a fixed covariate in a survival model. We propose the use of a joint longitudinal-survival model. This enables us to model long-term trends in density while accounting for dropout as well as for measurement error. We studied the change in mammographic density after a breast cancer diagnosis and its association with prognosis (measured by cause-specific mortality), overall and with respect to hormone replacement therapy and tamoxifen treatment. We included 1,740 women aged 50–74 years, diagnosed with breast cancer in Sweden during 1993–1995, with follow-up until 2008. They had a total of 6,317 mammographic density measures available from the first 5 years of follow-up, including baseline measures. We found that the impact of the withdrawal of hormone replacement therapy on density reduction was larger than that of tamoxifen treatment. Unlike previous studies, we found that there was an association between density reduction and survival, both for tamoxifen-treated women and women who were not treated with tamoxifen.

A Multinomial Regression Approach to Model Outcome Heterogeneity

Abstract

When a risk factor affects certain categories of a multinomial outcome but not others, outcome heterogeneity is said to be present. A standard epidemiologic approach for modeling risk factors of a categorical outcome typically entails fitting a polytomous logistic regression via maximum likelihood estimation. In this paper, we show that standard polytomous regression is ill equipped to detect outcome heterogeneity and will generally understate the degree to which such heterogeneity may be present. Specifically, nonsaturated polytomous regression will often a priori rule out the possibility of outcome heterogeneity from its parameter space. As a remedy, we propose to model each category of the outcome as a separate binary regression. For full efficiency, we propose to estimate the collection of regression parameters jointly using a constrained Bayesian approach that ensures that one remains within the multinomial model. The approach is straightforward to implement in standard software for Bayesian estimation.

Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies

Abstract

Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates. We compared several different forms of the standard error for linear and logistic TSRI estimates in simulations and in real-data examples. Among others, we consider standard errors modified from the approach of Newey (1987), Terza (2016), and bootstrapping. In our simulations Newey, Terza, bootstrap, and corrected 2-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real-data examples, the Newey standard errors were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators, respectively. We show that TSRI estimators with modified standard errors have correct type I error under the null. Researchers should report TSRI estimates with modified standard errors instead of reporting unadjusted or heteroscedasticity-robust standard errors.

Comprehensive Analysis of Prevalence, Epidemiologic Characteristics, and Clinical Characteristics of Monoinfection and Coinfection in Diarrheal Diseases in Children in Tanzania

Abstract

The role of interactions between intestinal pathogens in diarrheal disease is uncertain. From August 2010 to July 2011, we collected stool samples from 723 children admitted with diarrhea (cases) to 3 major hospitals in Dar es Salaam, Tanzania, and from 564 nondiarrheic children (controls). We analyzed the samples for 17 pathogens and assessed interactions between coinfections in additive and multiplicative models. At least one pathogen was detected in 86.9% of the cases and 62.8%, of the controls. Prevalence of coinfections was 58.1% in cases and 40.4% in controls. Rotavirus, norovirus genogroup II, Cryptosporidium, and Shigella species/enteroinvasive Escherichia coli were significantly associated with diarrhea both as monoinfections and as coinfections. In the multiplicative interaction model, we found 2 significant positive interactions: rotavirus + Giardia (odds ratio (OR) = 23.91, 95% confidence interval (CI): 1.21, 470.14) and norovirus GII + enteroaggregative E. coli (OR = 3.06, 95% CI: 1.17, 7.98). One significant negative interaction was found between norovirus GII + typical enteropathogenic E. coli (OR = 0.09, 95% CI: 0.01, 0.95). In multivariate analysis, risk factors for death were presence of blood in stool and severe dehydration. In conclusion, coinfections are frequent, and the pathogenicity of each organism appears to be enhanced by some coinfections and weakened by others. Severity of diarrhea was not affected by coinfections.

Sex Differences in the Association Between Pain and Injurious Falls in Older Adults: A Population-Based Longitudinal Study

Abstract

We investigated whether there are sex differences in the association between pain and incident injurious falls. A total of 2,934 people (ages ≥60 years) from the population-based Swedish National Study on Aging and Care in Kungsholmen (2001–2004) participated. Participants were followed up for 3 and 10 years for falls leading to hospitalization or outpatient care. Data were analyzed with flexible parametric survival models that adjusted for potential confounders. During the first 3 years of follow-up, 67 men and 194 women experienced an injurious fall, and over 10 years of follow up, 203 men and 548 women experienced such a fall. In men, the presence of pain, having pain that was at least mild, having pain that affected several daily activities, and having daily pain all significantly increased the likelihood of incurring an injurious fall during the 3-year follow-up period. The multivariate-adjusted hazard ratios ranged from 1.78 (95% confidence interval: 1.00, 3.15) for the presence of pain to 2.89 (95% confidence interval: 1.41, 5.93) for several daily activities' being affected by pain. Results for the 10-year follow-up period were similar. No significant associations were detected in women. Although pain is less prevalent in men than in women, its impact on risk of injurious falls seems to be greater in men.

Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies

Abstract

Detailed metabolic profiling in large-scale epidemiologic studies has uncovered novel biomarkers for cardiometabolic diseases and clarified the molecular associations of established risk factors. A quantitative metabolomics platform based on nuclear magnetic resonance spectroscopy has found widespread use, already profiling over 400,000 blood samples. Over 200 metabolic measures are quantified per sample; in addition to many biomarkers routinely used in epidemiology, the method simultaneously provides fine-grained lipoprotein subclass profiling and quantification of circulating fatty acids, amino acids, gluconeogenesis-related metabolites, and many other molecules from multiple metabolic pathways. Here we focus on applications of magnetic resonance metabolomics for quantifying circulating biomarkers in large-scale epidemiology. We highlight the molecular characterization of risk factors, use of Mendelian randomization, and the key issues of study design and analyses of metabolic profiling for epidemiology. We also detail how integration of metabolic profiling data with genetics can enhance drug development. We discuss why quantitative metabolic profiling is becoming widespread in epidemiology and biobanking. Although large-scale applications of metabolic profiling are still novel, it seems likely that comprehensive biomarker data will contribute to etiologic understanding of various diseases and abilities to predict disease risks, with the potential to translate into multiple clinical settings.

Skin lesions of Birt-Hogg-Dubé syndrome: clinical and histopathological findings in 31 Japanese patients who presented with pneumothorax and/or multiple lung cysts.

Birt-Hogg-Dubé syndrome (BHDS) typically involves fibrofolliculomas (FFs) and trichodiscomas (TDs) of the skin, multiple pulmonary cysts often with pneumothorax, and renal neoplasms [1–4]. Although the FLCN gene located in chromosome 17p11.2, when mutated, causes BHDS [5,6], its onset and conditions vary in each organ. Spontaneous pneumothorax usually develops in 20- to 40-year (yr)-olds, but in few patients over 40 [4], whereas skin lesions are commonly found in those over 25–35 yrs old and renal tumors appear in some over 40.

Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment

Sensitive skin is characterized by the sensations, such as tingling, pricking, heat, burning, pain, or itch with or without erythema. Because of its subjective feeling property, self-assessment may be one of the valuable methods for evaluation of sensitive skin. However, more accurate parameters or objective factors are required for its evaluation [1]. Lactic acid stinging test (LAST) has been widely accepted as an assessment of sensitive skin [2], although the percentage of lactic acid and the evaluation method are different among studies.

Whole Exome Sequencing allows the identification of two novel groups of Xeroderma pigmentosum in Tunisia, XP-D and XP-E: Impact on molecular diagnosis

Skin cancer (SC) represent the most common malignancy worldwide. SC is a complex disease influenced by both external environment and inherent genetics [1]. In Tunisia, SC is relatively frequent, sun exposure constitutes the major factor [2] Hereditary genodermatosis with cancer predisposition are suspected, if there is a family history of SC. Among them, chromosomal breakage diseases characterized by defects in DNA repair pathways or by genomic instability that predispose, also, to internal cancer.

Maintenance of Certification: A Grandfatherly Ethical Analysis

Rosacea comorbidities and future research: The 2017 update by the National Rosacea Society Expert Committee

Although causal relationships have not been determined, many recent studies have uncovered associations between rosacea and increased risk for a variety of systemic disorders, many with potentially serious outcomes (Table I).1-17 This might significantly increase the clinical significance of rosacea because evidence that rosacea might be an outcome of systemic inflammation is mounting. In addition, current scientific knowledge has pointed to a variety of promising research avenues that might help further illuminate rosacea's etiology, pathophysiology, and clinical implications.

Nonbullous cutaneous pemphigoid: a systematic review

Cutaneous pemphigoid (bullous pemphigoid) is an autoimmune bullous disease that typically presents with tense bullae and severe pruritus. However, bullae may be lacking, a subtype termed nonbullous cutaneous pemphigoid.

Merkel Cell Carcinoma: Current United States Incidence and Projected Increases based on Changing Demographics

Merkel cell carcinoma (MCC) incidence rates are rising and strongly age-associated, relevant for an aging population.

Reexamining mechanic’s hands as a characteristic skin finding in dermatomyositis

Mechanic's hands is a poorly defined clinical finding that has been reported in a variety of rheumatologic diseases. Morphologic descriptions include hyperkeratosis on the sides of the digits that sometimes extends to the distal tips, diffuse palmar scale, and, more recently observed, linear discrete scaly papules in a similar lateral distribution. The association of mechanic's hands with dermatomyositis, although recognized, is still debatable. In this review, most studies have shown that mechanic's hands is commonly associated with dermatomyositis and displays histopathologic findings of interface dermatitis, colloid bodies and interstitial mucin which are consistent with a cutaneous connective tissue disease.

The Use of Vessel Loop to Bolster Mattress Sutures and to Prevent Scars

Therapeutic pearl: 5-fluorouracil tattoo for idiopathic guttate hypomelanosis

A simple device for ablation of keloidal tissue and serial deposition of intralesional drugs

Cause specific mortality in adults with atopic dermatitis

Adult atopic dermatitis (AD) has been associated with several co-morbidities, but cause-specific mortality risk is unknown.

Beyond JAAD January 2018

Porcine Xenografts for Surgical Defects: A Single Center Experience with 128 Cases

Autologous breast reconstruction using the immediately lipofilled extended latissimus dorsi flap

–The latissimus dorsi flap is a popular choice for autologous breast reconstruction. To dramatically improve volume, we report our experience of using the immediately lipofilled extended latissimus dorsi flap and show it is a valid option for autologous breast reconstruction.

Optimizing donor site closure following bilateral breast reconstruction with abdominal-based free flaps

The abdomen is the primary donor site for autologous free flap breast reconstruction, but violation of the rectus abdominus complex can result in significant morbidity.1, 2 Abdominal hernias and bulges are the most concerning donor site complications in the long term, but early wound complications also contribute to significant morbidity during the initial postoperative period. In order to minimize the risk of hernias and bulges, reinforcement of the abdominal wall with placement of mesh may be necessary particularly in the setting of bilateral breast reconstruction.

Rectus femoris branch: an alternative blood supply for a distally based anterolateral thigh flap

Successful raising of a distally-based anterolateral thigh (dALT) flap mainly depends on a well-developed lateral circumflex femoral artery (LCFA) descending branch and an intact vascular connection between the descending branch and the vascular network of the knee. However, in some clinical scenarios, the descending branch is hypoplastic or the vascular connection of the knee is compromised. We present six cases of using dALT flaps in soft tissue defect reconstruction of the knee with either of the above-mentioned conditions.

Distally based sural neuro-fasciocutaneous perforator flap for foot and ankle reconstruction: surgical modifications for flap pedicle and donor site closure without skin graft

The conventional procedure of the sural neuro-fasciocutaneous flap enables the supply of blood and venous drainage by increasing the width of the adipofascial tissue and preserving tiny venous return routes. Moreover, skin graft is a common method for donor site closure, which may lead to some complications and influence the aesthetic appearance. We report modifications for a distally based sural neuro-fasciocutaneous perforator flap and a relaying flap for donor site closure without skin graft.

Importance of sentinel lymphatic node biopsy in detection of early micrometastases in patients with cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant skin cancer with a tendency to spread via lymphogenic pathway. Metastases are found in 2% - 6 % of cases. The aim of this study was to determine CSCC micrometastases when non-invasive examination methods do not detect them.

A systematic review of near-infrared spectroscopy in flap monitoring: current basic and clinical evidence and prospects

Recently, near-infrared spectroscopy (NIRS) has been reported to be a reliable non-invasive modality for free flap monitoring; however, the history of its application in flap monitoring is short, and there is no definite consensus regarding its use at present.

Retrobulbar hematoma: a systematic review of factors related to outcomes

Retrobulbar hematoma (RBH), a rare but serious condition, can result in permanent vision loss. Although it is a known complication following trauma or facial fracture reduction, sinus surgery, or blepharoplasty, factors related to patient outcomes are not well-defined. A systematic review was performed to determine the relation of patient/treatment factors to outcomes.

A flap based on the plantar digital artery arch branch to improve appearance of reconstructed fingers: anatomical and clinical application

To investigate blood supply features of the flap based on the plantar digital artery arch and arch branch artery, and the treatment of outcomes of reconstructed fingers by the plantar digital artery arch branch island flap.

Dermoscopy of Pigmented Actinic Keratosis of the Face: A Study of 232 Cases

Publication date: November 2017
Source:Actas Dermo-Sifiliográficas (English Edition), Volume 108, Issue 9
Author(s): A. Kelati, H. Baybay, E. Moscarella, G. Argenziano, S. Gallouj, F.Z. Mernissi
The diagnosis of pigmented actinic keratosis (PAK) is often challenging because of overlapping features with lentigo maligna.ObjectiveTo investigate dermoscopic patterns of PAK according to their different evolutionary stages, and to correlate the pattern with clinical characteristics of the patients.MethodsDescriptive and analytical study of 232 PAK. Dermoscopic patterns were divided into two categories: the follicule surroundings
tm) abnormalities (FSA) and follicular keratosis
tm) abnormalities (FKA).ResultsFSA and FKA dermoscopic patterns were related to male gender, except for star-like appearance, double white clods and dermoscopic horn (p≤0.04). Rhomboidal, annular granular pattern, gray halo, white circle and double clods were dermoscopic pattern significantly related to xeroderma pigmentosum's type of skin. Based on the evolutionary stages of PAK, the jelly sign was significantly related to thin patches of PAK. Central crusts and scales were related to thick plaques and the star-like appearance to hypertrophic PAK. The presence of 2 or more dermoscopic signs in both FSA and FKA was noticed in 99.1% of lesions.ConclusionsThe dermoscopic diagnosis of PAK vary according to the evolutionary stages of the disease, this will increase the diagnosis accuracy, with therapeutic implications.

Graphical abstract

Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway

Abstract

Emerging role of Nrf-2/HO-1 in pathogenesis of diabetic neuropathy has been suggested. Diabetic neuropathy is one of the most common complications of diabetes and more than 50% patients of diabetes develop diabetic neuropathy. Rutin has been well documented to show protective effect in various complications, e.g., diabetic neuropathy. However, its mechanistic insight is still not completely understood. The present study has been designed to explore the protective effect of rutin and its interaction with COX-2 inhibitor, nimesulide in diabetic neuropathy. DN (diabetic neuropathy) rats were maintained with or without rutin (100 and 200 mg/kg), nimesulide (5 and 10 mg/kg), and their combinations for 8 weeks. Body weight, serum glucose, pain assessment (mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia), and motor nerve conduction velocity (MNCV) were measured in all groups. Oxidative damage was assessed through biochemical estimation and mitochondrial ROS production, followed by inflammatory and apoptotic markers (TNF-α, caspase-3, Nrf-2, HO-1, and NF-kBp65) for their activity, protein, and gene expression. The structural changes were also reported through transmission electron microscope. Streptozotocin injection (55 mg/kg) induced diabetes reduced body weight, reduced the threshold for pain in various pain assessment parameters. Oxidative damage (increased MDA, decreased SOD, catalase, and GSH levels) increased mitochondrial ROS production followed by increased expression of inflammatory markers and decreased expression of Nrf-2/HO-1 in sciatic nerve. Treatment with rutin (100 and 200 mg/kg) and nimesulide (5 and 10 mg/kg) significantly attenuates these alterations as compared to DN control rats. Furthermore, combination of rutin (200 mg/kg) and nimesulide (10 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect alone in streptozotocin-treated rats. The present study suggests the involvement of Nrf-2/HO-1 pathway in the protective effect of rutin against streptozotocin-induced diabetic neuropathy.

Multimodal Analgesia in Breast Surgical Procedures: Technical and Pharmacological Considerations for Liposomal Bupivacaine Use

Enhanced recovery after surgery is a multidisciplinary perioperative clinical pathway that uses evidence-based interventions to improve the patient experience as well as increase satisfaction, reduce costs, mitigate the surgical stress response, accelerate functional recovery, and decrease perioperative complications. One of the most important elements of enhanced recovery pathways is multimodal pain management. Herein, aspects relating to multimodal analgesia following breast surgical procedures are discussed with the understanding that treatment decisions should be individualized and guided by sound clinical judgment. A review of liposomal bupivacaine, a prolonged-release formulation of bupivacaine, in the management of postoperative pain following breast surgical procedures is presented, and technical guidance regarding optimal administration of liposomal bupivacaine is provided.

Medical Scribes in an Academic Dermatology Practice

This study examines the implementation of a multipractice quality improvement pilot program evaluating medical scribe impact on dermatologist documentation time and physician satisfaction.

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).

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.

Prescription-Strength Topical Steroids Sold Without Prescription

This case report describes the use of a prescription-strength topical steroids obtained without prescription.

CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension

NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats. The basal amplitude of evoked NMDAR-EPSCs and puff NMDA currents in retrogradely labeled PVN neurons were significantly higher in SHRs than in WKY rats. The CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP) normalized the increased amplitude of NMDAR-EPSCs and puff NMDA currents in labeled PVN neurons in SHRs but had no effect in WKY rats. Treatment with AIP also normalized the higher frequency of NMDAR-mediated miniature EPSCs of PVN neurons in SHRs. CaMKII-mediated phosphorylation level of GluN2B serine 1303 (S1303) in the PVN, but not in the hippocampus and frontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased level of phosphorylated GluN2B S1303 in the PVN. In addition, microinjection of AIP into the PVN significantly reduced arterial blood pressure and lumbar sympathetic nerve discharges in SHRs. Our findings suggest that CaMKII activity is increased in the PVN and contributes to potentiated presynaptic and postsynaptic NMDAR activity to elevate sympathetic vasomotor tone in hypertension.

SIGNIFICANCE STATEMENT Heightened sympathetic vasomotor tone is a major contributor to the development of hypertension. Although glutamate NMDA receptor (NMDAR)-mediated excitatory drive in the hypothalamus plays a critical role in increased sympathetic output in hypertension, the molecular mechanism involved in potentiated NMDAR activity of hypothalamic presympathetic neurons remains unclear. Here we show that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased and plays a key role in the potentiated presynaptic and postsynaptic NMDAR activity of hypothalamic presympathetic neurons in hypertension. Also, the inhibition of CaMKII in the hypothalamus reduces elevated blood pressure and sympathetic nerve discharges in hypertension. This new knowledge extends our understanding of the mechanism of synaptic plasticity in the hypothalamus and suggests new strategies to treat neurogenic hypertension.

Correction: Funk et al., "Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves"

Functional Heterogeneity within Rat Orbitofrontal Cortex in Reward Learning and Decision Making

Rat orbitofrontal cortex (OFC) is located in the dorsal bank of the rhinal sulcus, and is divided into the medial orbital area, ventral orbital area, ventrolateral orbital area, lateral orbital area, dorsolateral orbital area, and agranular insular areas. Over the past 20 years, there has been a marked increase in the number of publications focused on the functions of rat OFC. While collectively this extensive body of work has provided great insight into the functions of OFC, leading to theoretical and computational models of its functions, one issue that has emerged relates to what is defined as OFC because targeting of this region can be quite variable between studies of appetitive behavior, even within the same species. Also apparent is that there is an oversampling and undersampling of certain subregions of rat OFC for study, and this will be demonstrated here. The intent of the Viewpoint is to summarize studies in rat OFC, given the diversity of what groups refer to as "OFC," and to integrate these with the findings of recent anatomical studies. The primary aim is to help discern functions in reward learning and decision-making, clearing the course for future empirical work.

SK Channels Regulate Resting Properties and Signaling Reliability of a Developing Fast-Spiking Neuron

Reliable and precise signal transmission is essential in circuits of the auditory brainstem to encode timing with submillisecond accuracy. Globular bushy cells reliably and faithfully transfer spike signals to the principal neurons of the medial nucleus of the trapezoid body (MNTB) through the giant glutamatergic synapse, the calyx of Held. Thus, the MNTB works as a relay nucleus that preserves the temporal pattern of firing at high frequency. Using whole-cell patch-clamp recordings, we observed a K⁺ conductance mediated by small-conductance calcium-activated potassium (SK) channels in the MNTB neurons from rats of either sex. SK channels were activated by intracellular Ca²⁺ sparks and mediated spontaneous transient outward currents in developing MNTB neurons. SK channels were also activated by Ca²⁺ influx through voltage-gated Ca²⁺ channels and synaptically activated NMDA receptors. Blocking SK channels with apamin depolarized the resting membrane potential, reduced resting conductance, and affected the responsiveness of MNTB neurons to signal inputs. Moreover, SK channels were activated by action potentials and affected the spike afterhyperpolarization. Blocking SK channels disrupted the one-to-one signal transmission from presynaptic calyces to postsynaptic MNTB neurons and induced extra postsynaptic action potentials in response to presynaptic firing. These data reveal that SK channels play crucial roles in regulating the resting properties and maintaining reliable signal transmission of MNTB neurons.

SIGNIFICANCE STATEMENT Reliable and precise signal transmission is required in auditory brainstem circuits to localize the sound source. The calyx of Held synapse in the mammalian medial nucleus of the trapezoid body (MNTB) plays an important role in sound localization. We investigated the potassium channels that shape the reliability of signal transfer across the calyceal synapse and observed a potassium conductance mediated by small-conductance calcium-activated potassium (SK) channels in rat MNTB principal neurons. We found that SK channels are tonically activated and contribute to the resting membrane properties of MNTB neurons. Interestingly, SK channels are transiently activated by calcium sparks and calcium influx during action potentials and control the one-to-one signal transmission from presynaptic calyces to postsynaptic MNTB neurons.

Experience-Dependent Synaptic Plasticity in V1 Occurs without Microglial CX3CR1

Brief monocular deprivation (MD) shifts ocular dominance and reduces the density of thalamic synapses in layer 4 of the mouse primary visual cortex (V1). We found that microglial lysosome content is also increased as a result of MD. Previous studies have shown that the microglial fractalkine receptor CX3CR1 is involved in synaptic development and hippocampal plasticity. We therefore tested the hypothesis that neuron-to-microglial communication via CX3CR1 is an essential component of visual cortical development and plasticity in male mice. Our data show that CX3CR1 is not required for normal development of V1 responses to visual stimulation, multiple forms of experience-dependent plasticity, or the synapse loss that accompanies MD in layer 4. By ruling out an essential role for fractalkine signaling, our study narrows the search for understanding how microglia respond to active synapse modification in the visual cortex.

SIGNIFICANCE STATEMENT Microglia in the visual cortex respond to monocular deprivation with increased lysosome content, but signaling through the fractalkine receptor CX3CR1 is not an essential component in the mechanisms of visual cortical development or experience-dependent synaptic plasticity.

Functional Characterization of 5-HT1B Receptor Drugs in Nonhuman Primates Using Simultaneous PET-MR

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT_1B receptor (5-HT_1BR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates (n = 3), we used positron emission tomography (PET) imaging with the radioligand [¹¹C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT_1BR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT_1BR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT_1BR occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT_1BR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood–brain barrier-permeable 5-HT_1BR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT_1BR cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT_1BR and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin.

SIGNIFICANCE STATEMENT We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT_1B receptor binding and function and determined blood–brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial and temporal effects on brain hemodynamics provide information about pharmacologically driven downstream CNS drug effects; the brain hemodynamic response shows characteristic dose-related effects that differ depending on agonistic or antagonistic drug characteristics and on local 5-HT_1B receptor density. The technique lends itself to a comprehensive in vivo investigation and understanding of drugs' effects in the brain.

The Long 3'UTR mRNA of CaMKII Is Essential for Translation-Dependent Plasticity of Spontaneous Release in Drosophila melanogaster

A null mutation of the Drosophila calcium/calmodulin-dependent protein kinase II gene (CaMKII) was generated using homologous recombination. Null animals survive to larval and pupal stages due to a large maternal contribution of CaMKII mRNA, which consists of a short 3'-untranslated region (UTR) form lacking regulatory elements that guide local translation. The selective loss of the long 3'UTR mRNA in CaMKII-null larvae allows us to test its role in plasticity. Development and evoked function of the larval neuromuscular junction are surprisingly normal, but the resting rate of miniature excitatory junctional potentials (mEJPs) is significantly lower in CaMKII mutants. Mutants also lack the ability to increase mEJP rate in response to spaced depolarization, a type of activity-dependent plasticity shown to require both transcription and translation. Consistent with this, overexpression of miR-289 in wild-type animals blocks plasticity of spontaneous release. In addition to the defects in regulation of mEJP rate, CaMKII protein is largely lost from synapses in the mutant. All phenotypes are non–sex-specific and rescued by a fosmid containing the entire wild-type CaMKII locus, but only viability and CaMKII localization are rescued by genomic fosmids lacking the long 3'UTR. This suggests that synaptic CaMKII accumulates by two distinct mechanisms: local synthesis requiring the long 3'UTR form of CaMKII mRNA and a process that requires zygotic transcription of CaMKII mRNA. The origin of synaptic CaMKII also dictates its functionality. Locally translated CaMKII has a privileged role in regulation of spontaneous release, which cannot be fulfilled by synaptic CaMKII from the other pool.

SIGNIFICANCE STATEMENT As a regulator of synaptic development and plasticity, CaMKII has important roles in both normal and pathological function of the nervous system. CaMKII shows high conservation between Drosophila and humans, underscoring the usefulness of Drosophila in modeling its function. Drosophila CaMKII-null mutants remain viable throughout development, enabling morphological and electrophysiological characterization. Although the structure of the synapse is normal, maternally contributed CaMKII does not localize to synapses. Zygotic production of CaMKII mRNA with a long 3'-untranslated region is necessary for modulating spontaneous neurotransmission in an activity-dependent manner, but not for viability. These data argue that regulation of CaMKII localization and levels by local transcriptional processes is conserved. This is the first demonstration of distinct functions for Drosophila CaMKII mRNA variants.

Unaware Processing of Tools in the Neural System for Object-Directed Action Representation

The hypothesis that the brain constitutively encodes observed manipulable objects for the actions they afford is still debated. Yet, crucial evidence demonstrating that, even in the absence of perceptual awareness, the mere visual appearance of a manipulable object triggers a visuomotor coding in the action representation system including the premotor cortex, has hitherto not been provided. In this fMRI study, we instantiated reliable unaware visual perception conditions by means of continuous flash suppression, and we tested in 24 healthy human participants (13 females) whether the visuomotor object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices is activated even under subliminal perceptual conditions. We found consistent activation in the target visuomotor cortices, both with and without perceptual awareness, specifically for pictures of manipulable versus non-manipulable objects. By means of a multivariate searchlight analysis, we also found that the brain activation patterns in this visuomotor network enabled the decoding of manipulable versus non-manipulable object picture processing, both with and without awareness. These findings demonstrate the intimate neural coupling between visual perception and motor representation that underlies manipulable object processing: manipulable object stimuli specifically engage the visuomotor object-directed action representation system, in a constitutive manner that is independent from perceptual awareness. This perceptuo-motor coupling endows the brain with an efficient mechanism for monitoring and planning reactions to external stimuli in the absence of awareness.

SIGNIFICANCE STATEMENT Our brain constantly encodes the visual information that hits the retina, leading to a stimulus-specific activation of sensory and semantic representations, even for objects that we do not consciously perceive. Do these unconscious representations encompass the motor programming of actions that could be accomplished congruently with the objects' functions? In this fMRI study, we instantiated unaware visual perception conditions, by dynamically suppressing the visibility of manipulable object pictures with mondrian masks. Despite escaping conscious perception, manipulable objects activated an object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices. This demonstrates that visuomotor encoding occurs independently of conscious object perception.

Sex- and Estrus-Dependent Differences in Rat Basolateral Amygdala

Depression and anxiety are diagnosed almost twice as often in women, and the symptomology differs in men and women and is sensitive to sex hormones. The basolateral amygdala (BLA) contributes to emotion-related behaviors that differ between males and females and across the reproductive cycle. This hints at sex- or estrus-dependent features of BLA function, about which very little is known. The purpose of this study was to test whether there are sex differences or estrous cyclicity in rat BLA physiology and to determine their mechanistic correlates. We found substantial sex differences in the activity of neurons in lateral nuclei (LAT) and basal nuclei (BA) of the BLA that were associated with greater excitatory synaptic input in females. We also found strong differences in the activity of LAT and BA neurons across the estrous cycle. These differences were associated with a shift in the inhibition–excitation balance such that LAT had relatively greater inhibition during proestrus which paralleled more rapid cued fear extinction. In contrast, BA had relatively greater inhibition during diestrus that paralleled more rapid contextual fear extinction. These results are the first to demonstrate sex differences in BLA neuronal activity and the impact of estrous cyclicity on these measures. The shift between LAT and BA predominance across the estrous cycle provides a simple construct for understanding the effects of the estrous cycle on BLA-dependent behaviors. These results provide a novel framework to understand the cyclicity of emotional memory and highlight the importance of considering ovarian cycle when studying the BLA of females.

SIGNIFICANCE STATEMENT There are differences in emotional responses and many psychiatric symptoms between males and females. This may point to sex differences in limbic brain regions. Here we demonstrate sex differences in neuronal activity in one key limbic region, the basolateral amygdala (BLA), whose activity fluctuates across the estrous cycle due to a shift in the balance of inhibition and excitation across two BLA regions, the lateral and basal nuclei. By uncovering this push–pull shift between lateral and basal nuclei, these results help to explain disparate findings about the effects of biological sex and estrous cyclicity on emotion and provide a framework for understanding fluctuations in emotional memory and psychiatric symptoms.

Medial Frontal Theta Is Entrained to Rewarded Actions

Rodents lick to consume fluids. The reward value of ingested fluids is likely to be encoded by neuronal activity entrained to the lick cycle. Here, we investigated relationships between licking and reward signaling by the medial frontal cortex (MFC), a key cortical region for reward-guided learning and decision-making. Multielectrode recordings of spike activity and field potentials were made in male rats as they performed an incentive contrast licking task. Rats received access to higher- and lower-value sucrose rewards over alternating 30 s periods. They learned to lick persistently when higher-value rewards were available and to suppress licking when lower-value rewards were available. Spectral analysis of spikes and fields revealed evidence for reward value being encoded by the strength of phase-locking of a 6–12 Hz theta rhythm to the rats' lick cycle. Recordings during the initial acquisition of the task found that the strength of phase-locking to the lick cycle was strengthened with experience. A modification of the task, with a temporal gap of 2 s added between reward deliveries, found that the rhythmic signals persisted during periods of dry licking, a finding that suggests the MFC encodes either the value of the currently available reward or the vigor with which rats act to consume it. Finally, we found that reversible inactivations of the MFC in the opposite hemisphere eliminated the encoding of reward information. Together, our findings establish that a 6–12 Hz theta rhythm, generated by the rodent MFC, is synchronized to rewarded actions.

SIGNIFICANCE STATEMENT The cellular and behavioral mechanisms of reward signaling by the medial frontal cortex (MFC) have not been resolved. We report evidence for a 6–12 Hz theta rhythm that is generated by the MFC and synchronized with ongoing consummatory actions. Previous studies of MFC reward signaling have inferred value coding upon temporally sustained activity during the period of reward consumption. Our findings suggest that MFC activity is temporally sustained due to the consumption of the rewarding fluids, and not necessarily the abstract properties of the rewarding fluid. Two other major findings were that the MFC reward signals persist beyond the period of fluid delivery and are generated by neurons within the MFC.

Fremanezumab--A Humanized Monoclonal Anti-CGRP Antibody--Inhibits Thinly Myelinated (A{delta}) But Not Unmyelinated (C) Meningeal Nociceptors

Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of A neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify A meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A- input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients.

SIGNIFICANCE STATEMENT Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of A but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for A-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the A-HT pain pathway may be sufficient for the generation of headache perception.

This Week in The Journal

Activity-Dependence of Synaptic Vesicle Dynamics

The proper function of synapses relies on efficient recycling of synaptic vesicles. The small size of synaptic boutons has hampered efforts to define the dynamical states of vesicles during recycling. Moreover, whether vesicle motion during recycling is regulated by neural activity remains largely unknown. We combined nanoscale-resolution tracking of individual synaptic vesicles in cultured hippocampal neurons from rats of both sexes with advanced motion analyses to demonstrate that the majority of recently endocytosed vesicles undergo sequences of transient dynamical states including epochs of directed, diffusional, and stalled motion. We observed that vesicle motion is modulated in an activity-dependent manner, with dynamical changes apparent in ~20% of observed boutons. Within this subpopulation of boutons, 35% of observed vesicles exhibited acceleration and 65% exhibited deceleration, accompanied by corresponding changes in directed motion. Individual vesicles observed in the remaining ~80% of boutons did not exhibit apparent dynamical changes in response to stimulation. More quantitative transient motion analyses revealed that the overall reduction of vesicle mobility, and specifically of the directed motion component, is the predominant activity-evoked change across the entire bouton population. Activity-dependent modulation of vesicle mobility may represent an important mechanism controlling vesicle availability and neurotransmitter release.

SIGNIFICANCE STATEMENT Mechanisms governing synaptic vesicle dynamics during recycling remain poorly understood. Using nanoscale resolution tracking of individual synaptic vesicles in hippocampal synapses and advanced motion analysis tools we demonstrate that synaptic vesicles undergo complex sets of dynamical states that include epochs of directed, diffusive, and stalled motion. Most importantly, our analyses revealed that vesicle motion is modulated in an activity-dependent manner apparent as the reduction in overall vesicle mobility in response to stimulation. These results define the vesicle dynamical states during recycling and reveal their activity-dependent modulation. Our study thus provides fundamental new insights into the principles governing synaptic function.

Submillisecond Optogenetic Control of Neuronal Firing with Two-Photon Holographic Photoactivation of Chronos

Optogenetic neuronal network manipulation promises to unravel a long-standing mystery in neuroscience: how does microcircuit activity relate causally to behavioral and pathological states? The challenge to evoke spikes with high spatial and temporal complexity necessitates further joint development of light-delivery approaches and custom opsins. Two-photon (2P) light-targeting strategies demonstrated in-depth generation of action potentials in photosensitive neurons both in vitro and in vivo, but thus far lack the temporal precision necessary to induce precisely timed spiking events. Here, we show that efficient current integration enabled by 2P holographic amplified laser illumination of Chronos, a highly light-sensitive and fast opsin, can evoke spikes with submillisecond precision and repeated firing up to 100 Hz in brain slices from Swiss male mice. These results pave the way for optogenetic manipulation with the spatial and temporal sophistication necessary to mimic natural microcircuit activity.

SIGNIFICANCE STATEMENT To reveal causal links between neuronal activity and behavior, it is necessary to develop experimental strategies to induce spatially and temporally sophisticated perturbation of network microcircuits. Two-photon computer generated holography (2P-CGH) recently demonstrated 3D optogenetic control of selected pools of neurons with single-cell accuracy in depth in the brain. Here, we show that exciting the fast opsin Chronos with amplified laser 2P-CGH enables cellular-resolution targeting with unprecedented temporal control, driving spiking up to 100 Hz with submillisecond onset precision using low laser power densities. This system achieves a unique combination of spatial flexibility and temporal precision needed to pattern optogenetically inputs that mimic natural neuronal network activity patterns.

Zic-Proteins Are Repressors of Dopaminergic Forebrain Fate in Mice and C. elegans

In the postnatal forebrain regionalized neural stem cells along the ventricular walls produce olfactory bulb (OB) interneurons with varying neurotransmitter phenotypes and positions. To understand the molecular basis of this region-specific variability we analyzed gene expression in the postnatal dorsal and lateral lineages in mice of both sexes from stem cells to neurons. We show that both lineages maintain transcription factor signatures of their embryonic site of origin, the pallium and subpallium. However, additional factors, including Zic1 and Zic2, are postnatally expressed in the dorsal stem cell compartment and maintained in the lineage that generates calretinin-positive GABAergic neurons for the OB. Functionally, we show that Zic1 and Zic2 induce the generation of calretinin-positive neurons while suppressing dopaminergic fate in the postnatal dorsal lineage. We investigated the evolutionary conservation of the dopaminergic repressor function of Zic proteins and show that it is already present in C. elegans.

SIGNIFICANCE STATEMENT The vertebrate brain generates thousands of different neuron types. In this work we investigate the molecular mechanisms underlying this variability. Using a genomics approach we identify the transcription factor signatures of defined neural stem cells and neuron populations. Based thereon we show that two related transcription factors, Zic1 and Zic2, are essential to control the balance between two defined neuron types in the postnatal brain. We show that this mechanism is conserved in evolutionary very distant species.

Activity Patterns Elicited by Airflow in the Olfactory Bulb and Their Possible Functions

Olfactory sensory neurons (OSNs) can sense both odorants and airflows. In the olfactory bulb (OB), the coding of odor information has been well studied, but the coding of mechanical stimulation is rarely investigated. Unlike odor-sensing functions of OSNs, the airflow-sensing functions of OSNs are also largely unknown. Here, the activity patterns elicited by mechanical airflow in male rat OBs were mapped using fMRI and correlated with local field potential recordings. In an attempt to reveal possible functions of airflow sensing, the relationship between airflow patterns and physiological parameters was also examined. We found the following: (1) the activity pattern in the OB evoked by airflow in the nasal cavity was more broadly distributed than patterns evoked by odors; (2) the pattern intensity increases with total airflow, while the pattern topography with total airflow remains almost unchanged; and (3) the heart rate, spontaneous respiratory rate, and electroencephalograph power in the β band decreased with regular mechanical airflow in the nasal cavity. The mapping results provide evidence that the signals elicited by mechanical airflow in OSNs are transmitted to the OB, and that the OB has the potential to code and process mechanical information. Our functional data indicate that airflow rhythm in the olfactory system can regulate the physiological and brain states, providing an explanation for the effects of breath control in meditation, yoga, and Taoism practices.

SIGNIFICANCE STATEMENT Presentation of odor information in the olfactory bulb has been well studied, but studies about breathing features are rare. Here, using blood oxygen level-dependent functional MRI for the first time in such an investigation, we explored the global activity patterns in the rat olfactory bulb elicited by airflow in the nasal cavity. We found that the activity pattern elicited by airflow is broadly distributed, with increasing pattern intensity and similar topography under increasing total airflow. Further, heart rate, spontaneous respiratory rate in the lung, and electroencephalograph power in the β band decreased with regular airflow in the nasal cavity. Our study provides further understanding of the airflow map in the olfactory bulb in vivo, and evidence for the possible mechanosensitivity functions of olfactory sensory neurons.

Interneurons in the Honeybee Primary Auditory Center Responding to Waggle Dance-Like Vibration Pulses

Female honeybees use the "waggle dance" to communicate the location of nectar sources to their hive mates. Distance information is encoded in the duration of the waggle phase (von Frisch, 1967). During the waggle phase, the dancer produces trains of vibration pulses, which are detected by the follower bees via Johnston's organ located on the antennae. To uncover the neural mechanisms underlying the encoding of distance information in the waggle dance follower, we investigated morphology, physiology, and immunohistochemistry of interneurons arborizing in the primary auditory center of the honeybee (Apis mellifera). We identified major interneuron types, named DL-Int-1, DL-Int-2, and bilateral DL-dSEG-LP, that responded with different spiking patterns to vibration pulses applied to the antennae. Experimental and computational analyses suggest that inhibitory connection plays a role in encoding and processing the duration of vibration pulse trains in the primary auditory center of the honeybee.

SIGNIFICANCE STATEMENT The waggle dance represents a form of symbolic communication used by honeybees to convey the location of food sources via species-specific sound. The brain mechanisms used to decipher this symbolic information are unknown. We examined interneurons in the honeybee primary auditory center and identified different neuron types with specific properties. The results of our computational analyses suggest that inhibitory connection plays a role in encoding waggle dance signals. Our results are critical for understanding how the honeybee deciphers information from the sound produced by the waggle dance and provide new insights regarding how common neural mechanisms are used by different species to achieve communication.

Neural Signature of Value-Based Sensorimotor Prioritization in Humans

In situations in which impending sensory events demand fast action choices, we must be ready to prioritize higher-value courses of action to avoid missed opportunities. When such a situation first presents itself, stimulus–action contingencies and their relative value must be encoded to establish a value-biased state of preparation for an impending sensorimotor decision. Here, we sought to identify neurophysiological signatures of such processes in the human brain (both female and male). We devised a task requiring fast action choices based on the discrimination of a simple visual cue in which the differently valued sensory alternatives were presented 750–800 ms before as peripheral "targets" that specified the stimulus–action mapping for the upcoming decision. In response to the targets, we identified a discrete, transient, spatially selective signal in the event-related potential (ERP), which scaled with relative value and strongly predicted the degree of behavioral bias in the upcoming decision both across and within subjects. This signal is not compatible with any hitherto known ERP signature of spatial selection and also bears novel distinctions with respect to characterizations of value-sensitive, spatially selective activity found in sensorimotor areas of nonhuman primates. Specifically, a series of follow-up experiments revealed that the signal was reliably invoked regardless of response laterality, response modality, sensory feature, and reward valence. It was absent, however, when the response deadline was relaxed and the strategic need for biasing removed. Therefore, more than passively representing value or salience, the signal appears to play a versatile and active role in adaptive sensorimotor prioritization.

SIGNIFICANCE STATEMENT In many situations such as fast-moving sports, we must be ready to act fast in response to sensory events and, in our preparation, prioritize courses of action that lead to greater rewards. Although behavioral effects of value biases in sensorimotor decision making have been widely studied, little is known about the neural processes that set these biases in place beforehand. Here, we report the discovery of a transient, spatially selective neural signal in humans that encodes the relative value of competing decision alternatives and strongly predicts behavioral value biases in decisions made ~500 ms later. Follow-up manipulations of value differential, reward valence, response modality, sensory features, and time constraints establish that the signal reflects an active, feature- and effector-general preparatory mechanism for value-based prioritization.

The Role of Oscillatory Phase in Determining the Temporal Organization of Perception: Evidence from Sensory Entrainment

Recent behavioral, neuroimaging, and neurophysiological studies have renewed the idea that the information processing within different temporal windows is linked to the phase and/or frequency of the ongoing oscillations, predominantly in the theta/alpha band (~4–7 and 8–12 Hz, respectively). However, being correlational in nature, this evidence might reflect a nonfunctional byproduct rather than having a causal role. A more direct link can be shown with methods that manipulate oscillatory activity. Here, we used audiovisual entrainment at different frequencies in the prestimulus period of a temporal integration/segregation task. We hypothesized that entrainment would align ongoing oscillations and drive them toward the stimulation frequency. To reveal behavioral oscillations in temporal perception after the entrainment, we sampled the segregation/integration performance densely in time. In Experiment 1, two groups of human participants (both males and females) received stimulation either at the lower or the upper boundary of the alpha band (~8.5 vs 11.5 Hz). For both entrainment frequencies, we found a phase alignment of the perceptual oscillation across subjects, but with two different power spectra that peaked near the entrainment frequency. These results were confirmed when perceptual oscillations were characterized in the time domain with sinusoidal fittings. In Experiment 2, we replicated the findings in a within-subject design, extending the results for frequencies in the theta (~6.5 Hz), but not in the beta (~15 Hz), range. Overall, these findings show that temporal segregation can be modified by sensory entrainment, providing evidence for a critical role of ongoing oscillations in the temporal organization of perception.

SIGNIFICANCE STATEMENT The continuous flow of sensory input is not processed in an analog fashion, but rather is grouped by the perceptual system over time. Recent studies pinpointed the phase and/or frequency of the neural oscillations in the theta/alpha band (~4–12 Hz) as possible mechanisms underlying temporal windows in perception. Here, we combined two innovative methodologies to provide more direct support for this evidence. We used sensory entrainment to align neural oscillations to different frequencies and then characterized the resultant perceptual oscillation with a temporal dense sampling of the integration/segregation performance. Our results provide the first evidence that the frequency of temporal segregation can be modified by sensory entrainment, supporting a critical role of ongoing oscillations in the integration/segregation of information over time.

AQP4e-Based Orthogonal Arrays Regulate Rapid Cell Volume Changes in Astrocytes

Water channel aquaporin 4 (AQP4) plays a key role in the regulation of water homeostasis in the brain. It is predominantly expressed in astrocytes at the blood–brain and blood–liquor interfaces. Although several AQP4 isoforms have been identified in the mammalian brain, two, AQP4a (M1) and AQP4c (M23), have been confirmed to cluster into plasma membrane supramolecular structures, termed orthogonal arrays of particles (OAPs) and to enhance water transport through the plasma membrane. However, the role of the newly described water-conductive mammalian isoform AQP4e is unknown. Here, the dynamics of AQP4e aggregation into OAPs and its role in the regulation of astrocyte water homeostasis have been studied. Using super-resolution structured illumination, atomic force, and confocal microscopies, the results revealed that, in female rat astrocytes, AQP4e isoform colocalizes with OAPs, affecting its structural dynamics. In hypoosmotic conditions, which elicit cell edema, OAP formation was considerably enhanced by overexpressed AQP4e. Moreover, the kinetics of the cell swelling and of the regulatory volume decrease was faster in astrocytes overexpressing AQP4e compared with untransfected controls. Furthermore, the increase in maximal cell volume elicited by hypoosmotic stimulation was significantly smaller in AQP4e-overexpressing astrocytes. For the first time, this study demonstrates an active role of AQP4e in the regulation of OAP structural dynamics and in water homeostasis.

SIGNIFICANCE STATEMENT Water channel aquaporin 4 (AQP4) plays a key role in the regulation of water homeostasis in the brain. To date, only AQP4a and AQP4c isoforms have been confirmed to enhance water transport through plasmalemma and to cluster into orthogonal arrays of particles (OAPs). We here studied the dynamics, aggregation, and role in the regulation of astrocyte water homeostasis of the newly described water-conductive mammalian isoform AQP4e. Our main findings are as follows: brain edema mimicking hypoosmotic conditions stimulates the formation of new OAPs with larger diameters, due to the incorporation of additional cytoplasmic AQP4 channels and the redistribution of AQP4 channels of the existing OAPs; and AQP4e affects the dynamics of cell swelling and regulatory volume decrease in astrocytes exposed to hypoosmotic conditions.

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In This Issue

Anti-tumor immunity via the superoxide-eosinophil axis induced by a lipophilic component of Mycobacterium lipomannan

Abstract

Mycobacterium bovis Bacille Calmette–Guérin (BCG) has been shown to possess potent anti-tumor activity particularly in various animal models, while the cellular and molecular mechanisms underlying its activity are not well understood. We found that lipomannan (BCG-LM), a lipophilic component of the mycobacterial cell envelope, specifically inhibits tumor growth and induces the infiltration of eosinophils at local tumor invasion sites. In contrast, neither lipoarabinomannan (BCG-LAM) nor the cell wall of Mycobacterium bovis BCG (BCG-CW) exerted anti-tumor immunity. BCG-LM enhances cytotoxic activity of eosinophils via the increased production of superoxide. Global transcriptomic analyses of BCG-LM-pulsed dendritic cells identified C-C motif ligand (CCL) 5 as a crucial chemokine for the anti-tumor immunity induced by BCG-LM, indicating that CCL5 plays an important role for the accumulation of eosinophils in the tumor microenvironment. Furthermore, BCG-LM and memory T_h2 cells exerted a synergetic effect on tumor progression by cooperatively enhancing the eosinophil function. Thus, this study revealed an un-identified BCG-LM-mediated anti-tumor mechanism via superoxide produced by infiltrated eosinophils in the tumor microenvironment. Since BCG-LM activates this unique pathway, it may have potent therapeutic potential as immune cell therapy for cancer patients.

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Involvement of Zizimin2/3 in the age-related defect of peritoneal B-1a cells as a source of anti-bacterial IgM

Abstract

Zizimin2 (Ziz2), also known as dedicator of cytokinesis 11 (DOCK11), is a guanine nucleotide exchange factor that is predominantly expressed in lymphoid tissues. Recent findings demonstrated that Ziz2 is involved in the development of B cells, including germinal centre B cells and marginal zone B cells. However, limited information is currently available on the roles of Ziz2 in B-1 cells, a B-cell subset that resides in body cavities and contributes to protection against foreign pathogens in a T-cell-independent manner. We herein show that Ziz2 and its widely expressed isoform Ziz3 (also known as DOCK10) may be involved in defective production of anti-bacterial IgM by aged B-1a cells, a CD5⁺ subset of B-1 cells. Natural IgM against typical bacterial epitopes was defectively produced by peritoneal B-1a cells from aged mice. The down-regulation of Ziz2/3 in B-1a cells appeared to be responsible for this defective IgM production, as demonstrated by Ziz2/3 double-knockout mice. Mechanistically, lower levels of basal AKT phosphorylation did not allow for the differentiation of Ziz2/3-deficient B-1a cells into plasma cells. Defective production of anti-bacterial IgM was not fully rescued by immunization, resulting in slightly weaker protection in Ziz2/3-deficient mice. Thus, the down-regulation of Ziz2/3 in B-1a cells may at least partly account for defective protection in aged mice.

Expression of KIR2DS1 does not significantly contribute to NK cell cytotoxicity in HLA-C1/C2 heterozygous haplotype B donors

Abstract

NK cells are functionally controlled by the killer immunoglobulin-like receptor (KIR) family that comprises inhibitory (iKIR) and activating (aKIR) members. Genetic association studies suggest that donors expressing aKIRs next to iKIRs will be superior donors in the setting of hematopoietic stem cell transplantation of patients with leukemia. However, contrary evidence states that aKIR expression may be irrelevant or even detrimental. Using a complex methodology incorporating KIR-Q-PCR, double fluorescence and viSNE analysis, we characterized subset distribution patterns and functionality in haplotype A donors which lack aKIRs and haplotype B donors that express a variety of B-specific genes. Here, we show that the alloreactive KIR2DS1⁺ NK cell subset in HLA-C1/C2 donors is highly responsive towards C2-expressing targets but quantitatively small and as such does not significantly contribute to cytotoxicity. Thus, we fail to find a direct link between haplotype allocation status and NK cell cytotoxicity at least in HLA-C1/C2 heterozygous donors.

Hyperferritinemia and inflammation

Abstract

Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an 'innocent bystander' biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.