Investigation of the activation of the temporalis and masseter muscles in voluntary and spontaneous smile production

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Jessica E. Steele, Ian R. Woodcock, Adrian D. Murphy, Monique M. Ryan, Tony J. Penington, Christopher J. Coombs

Summary

Introduction

Masticatory muscles or their nerve supply are options for facial reanimation surgery, but their ability to create spontaneous smile has been questioned. This study assessed the percentage of healthy adults who activate the temporalis and masseter muscles during voluntary and spontaneous smile.

Methods

Healthy volunteer adults underwent electromyography (EMG) studies of the temporalis and masseter muscles during voluntary and spontaneous smile. Responses were repeated three times and recorded as negative, weakly positive, or strongly positive according to the activity observed. The best response was used for analysis.

Results

Thirty healthy adults (median age: 34 years, range: 25–69 years) participated. Overall, 92% of the masseter muscles were activated during voluntary smile (22% strong, 70% weak). Seventy-seven percent of the masseter muscles were activated in spontaneous smile (12% strong, 65% weak). The temporalis muscle was activated in 62% of responses in voluntary smile (15% strong, 47% weak) and in 45% of responses in spontaneous smile (13% strong, 32% weak).

No significant difference was found for males vs females or closed vs open mouth smiles. There was no significant difference in responses between voluntary and spontaneous smiles for the temporalis and masseter muscles, and their use in voluntary smile did not predict activity in spontaneous smile.

Conclusions

Our study has shown that masseter and temporalis are active in a high proportion of healthy adults during voluntary and spontaneous smiles. Further work is required to determine the relationship between preoperative donor muscle activation and postoperative spontaneous smile, and whether masticatory muscle activity can be upregulated with appropriate training.

Diagnostic accuracy of bioimpedance spectroscopy in patients with lymphedema: A retrospective cohort analysis

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Evelyn S. Qin, Mindy J. Bowen, Wei F. Chen

Summary

Background

Bioimpedance spectroscopy (BIS) is used by healthcare specialists to diagnose lymphedema. BIS measures limb fluid content by assessing tissue resistance to the flow of electric current. However, there is debate regarding the validity of BIS in diagnosing early lymphedema. Indocyanine green (ICG) lymphography has been established as the most accurate diagnostic modality to date for lymphedema diagnosis. In this retrospective study, we test the sensitivity, specificity, and diagnostic accuracy of BIS in diagnosing lymphedema by referencing its results with ICG lymphography.

Methods

Patients presented to the University of Iowa Lymphedema Center from 2015 to 2017 were evaluated with a standardized protocol that included history and physical examination, a validated lymphedema-specific quality-of-life assessment (LYMQOL), circumference –measurement-based index, BIS, and ICG lymphography. Diagnostic accuracy of BIS was assessed using ICG lymphography as a reference test.

Results

Fifty-eight patients had positive ICG lymphography results, which confirmed the diagnosis of lymphedema. ICG lymphographic findings consistently correlated with clinical examination, LYMQOL evaluation, and lymphedema indices. By contrast, BIS demonstrated a false-negative rate of 36% – 21 out of 58 patients had normal BIS readings, but a positive ICG lymphography result. The 21 false-negative results occurred in patients with early-stage disease. Sensitivity and specificity for BIS were 0.64 and 1, respectively.

Conclusion

BIS carries an excessively high rate of false-negative results to be dependably used as a diagnostic modality for lymphedema. ICG lymphography highly correlates with other tracking modalities, and it remains the most reliable tool for diagnosing lymphedema.

Orthotopic transfer of vascularized groin lymph node flap in the treatment of breast cancer-related lymphedema: Clinical results, lymphoscintigraphy findings, and proposed mechanism

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Hin-Lun Liu, Suet-Ying Pang, Chung-Ching Lee, Melody Man-Kuen Wong, Hon-Ping Chung, Yu-Wai Chan

Summary

Introduction

Vascularized lymph node transfer (VLNT) has become very popular in the treatment of secondary lymphedema. However, the mechanism has not been clearly elucidated.

The purpose of this study was (1) to evaluate the outcome of vascularized groin lymph node (VGLN) transfer using axilla as a recipient site in patients with breast cancer-related lymphedema (BCRL) and (2) to provide radiological evidence of lymphangiogenesis in VLNT.

Methods

Between August 2013 and June 2016, 30 consecutive patients with a mean age of 60 years underwent VGLN transfer for BCRL. A skinless VGLN flap nourished by the superficial circumflex iliac vessels was transferred to the axillary region of the lymphedematous limb. The outcomes were assessed clinically with limb circumference measurement and radiologically with lymphoscintigraphy.

Results

At a mean follow-up of 22.11 ± 7.83 months, 21 (70%) patients had reduction in limb circumference. The mean circumference reduction rate of the lymphedematous limb was 47.06% ± 27.92% (range, 0% to 100%).

Eleven (37%) patients showed radiological improvement in postoperative lymphoscintigraphy that included 7 cases of faster contrast transport and 4 cases of visualization of transplanted lymph node.

Conclusion

Patients with BCRL can benefit from orthotopic VGLN transfer. Lymphangiogenesis is supported by the appearance of transplanted lymph nodes in postoperative lymphoscintigraphy.

Pyoderma gangrenosum after breast surgery: A systematic review

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Denis C. Ehrl, Paul I. Heidekrueger, P. Niclas Broer

Summary

Background

Post-surgical pyoderma gangrenosum (PSPG) is a rare inflammatory skin disorder of unknown aetiology. Given its similar presentation to wound infection and lack of reliable diagnostic tests as well as pathognomonic clinical features, PSPG is difficult to diagnose. The aim of this review was to identify factors contributing to PSPG to aid with timely diagnosis and appropriate therapy.

Methods

A systematic literature review was performed by following PRISMA guidelines, focusing on PSPG after reconstructive and aesthetic breast surgery. The online databases PubMed, Medline, EMBASE, Scopus, and Cochrane were used, and additionally, a Google^© search was performed.

Results

A total of 68 articles describing 87 cases of PSPG following aesthetic and reconstructive breast surgery were found. The majority of PSPG (44%) occurred after breast reduction surgery and microsurgical breast reconstruction (16%). The most common associated conditions were malignancies in 37% and autoimmune deficiencies in 17%. Microbiological examinations were found to have a negative result in 90%. The median time from initial presentation with symptoms to correct diagnosis of PG was on average 12.5 days, with unsuccessful first-line therapy on average for 20.0 days. After the diagnosis of PG, medical therapy most commonly involved steroids in 84% and/or Cyclosporine A in 22% of the cases. On average, the duration of this therapy was 4.7 months.

Conclusion

The diagnosis of PSPG remains a challenging issue. However, according to the presented review, several distinct clinical signs in combination with lack of treatment response should prompt further investigation to promote timely diagnosis and correct treatment of this potentially debilitating disease.

A comparative evaluation of spectrophotometric intracutaneous analysis and laser doppler imaging in the assessment of adult and paediatric burn injuries

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Somy Charuvila, Masha Singh, Declan Collins, Isabel Jones

Summary

Introduction

Clinical assessment of mid-dermal burns can be challenging. Currently, laser Doppler imaging (LDI) is the gold standard adjunct in the assessment of burn injuries. Although LDI has demonstrated reliable accuracy, it poses various limitations in routine use including cost and ease of use. In comparison, spectrophotometric intracutaneous analysis (SIA) is a relatively cheaper technique, which can be carried out using a modified digital camera that enables easy image acquisition. We aim to compare the accuracy of the two modalities in the assessment of mid-dermal burn injuries.

Methods

We recruited 29 patients with mid-dermal burns presenting within 2 to 5 days post burn. Forty-five burn regions of interest were identified, and the patients underwent imaging using both the modalities. Subsequent clinical outcome was followed up and showed that treatment remained unaffected by participation. Two clinicians then independently predicted the healing potential of each burn region retrospectively as per images from either modality.

Results

McNemar's test indicated that there is no significant difference between the accuracy of the two modalities (p = 0.61).

Conclusion

The results suggest that the accuracy of SIA is comparable to that of LDI. Our experience with SIA indicates its potential as a cost-effective and user-friendly adjunct in decision-making.

Tissue expansion in cranioplasty – a collaborative approach for all involved for improved outcomes

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Sarah Williams, Norbert Kang

Abstract

The use of tissue expanders is well established in plastic surgery. However, there are currently no clear indications for tissue expansion as an adjunct to cranioplasty. We present a series of nine patients who underwent tissue expansion prior to cranioplasty after removal of an infected bone flap and/or radiotherapy. Family members of 8 patients were taught how to undertake expansion at home. Two patients experienced exposure and infection of the expander. Post-operatively two patients developed an infection of their cranioplasty implant which was removed. We recommend using tissue expansion for patients who have experienced a long interval (>6 months) after removal of their bone flap to reconstruction. Early involvement of plastic surgeons may be helpful in reducing the risk of re-operation in these complex cases. Tissue expansion done at home appears to be safe.

3-Tesla MRI-assisted detection of compression points in ulnar neuropathy at the elbow in correlation with intraoperative findings

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Alina Hold, Michael S. Mayr-Riedler, Thomas Rath, Igor Pona, Patrick Nierlich, Julia Breitenseher, Gregor Kasprian

Summary

Introduction

Releasing the ulnar nerve from all entrapments is the primary objective of every surgical method in ulnar neuropathy at the elbow (UNE). The aim of this retrospective diagnostic study was to validate preoperative 3-Tesla MRI results by comparing the MRI findings with the intraoperative aspects during endoscopic-assisted or open surgery.

Methods

Preoperative MRI studies were assessed by a radiologist not informed about intraoperative findings in request for the exact site of nerve compression. The localizations of compression were then correlated with the intraoperative findings obtained from the operative records. Percent agreement and Cohen's kappa (κ) values were calculated.

Results

From a total of 41 elbows, there was a complete agreement in 27 (65.8%) cases and a partial agreement in another 12 (29.3%) cases. Cohen's kappa showed fair-to-moderate agreement.

Conclusion

High-resolution MRI cannot replace thorough intraoperative visualization of the ulnar nerve and its surrounding structures but may provide valuable information in ambiguous cases or relapses.

A prospective randomised comparison of fixation methods in Tamai's zone I amputation

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Hyung-Sup Shim, Byung Yeun Kwon, Bommie F. Seo, Ho Kwon, Sung-No Jung

Summary

Background

The treatment of choice for fingertip amputation is replantation to restore function and aesthetics. The purpose of this study was to compare the success rates and salvage periods between patients with Tamai's zone I amputation injuries treated with bony fixation and suture fixation.

Methods

Fifty-five patients with Tamai's zone I amputations with bony involvement were included in this study. The patients were allocated randomly to two groups treated by bony fixation with Kirschner (K-)wire and suture fixation, respectively. In the bony fixation group (n = 21), the distal phalangeal bone was fixed with K-wire; in the suture fixation group (n = 34), the amputated portion was fixed with sutures alone. The success rate was defined as the percentage of fully viable replanted cases, and the salvage period was defined as extending from the first postoperative day to the cessation of salvation.

Results

The success rates for the bony and suture fixation groups were 90.0% and 91.1%, respectively, with no significant difference. The average salvage period was longer in the bony fixation group than in the suture fixation group (8.7 ± 1.25 vs. 6.4 ± 0.98 days; P = 0.01). No case of non-union of the distal phalangeal bone, limitation of motion, or disfigurement was observed in either group.

Conclusion

The average salvage period was significantly longer for the bony fixation group, but the success rates did not differ between groups. We suggest that bony fixation is not mandatory in the treatment of Tamai's zone I amputation.

Flap choice does not affect complication rates or functional outcomes following extremity soft tissue sarcoma reconstruction

Publication date: July 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 71, Issue 7

Author(s): Jelena Slump, Stefan O.P. Hofer, Peter C. Ferguson, Jay S. Wunder, Anthony M. Griffin, Harald J. Hoekstra, Esther Bastiaannet, Anne C. O'Neill

Summary

Background

Flap reconstruction plays an essential role in facilitating limb preservation in patients with extremity soft tissue sarcoma (ESTS). However, the effect of flap choice on the rates of postoperative complications and functional outcomes has not been clearly established. This study directly compares the outcomes of free and pedicled flap reconstructions in patients with ESTS.

Methods

Two hundred sixty-six patients who underwent flap reconstruction following ESTS resection were included. Associations between flap type and complications were determined using logistic regression analyses. Functional outcome was evaluated using the Toronto Extremity Salvage Score (TESS) and the Musculoskeletal Tumor Society Scales (MSTS).

Results

There was no significant difference between complication rates in the pedicled and free flap groups (32% vs. 38%, p = 0.38). In the lower limb, pedicled flaps had complication rates similar to those of free flaps on univariate analysis (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 0.56–2.26, p = 0.75). Conversely, in the upper limb, pedicled flaps were associated with fewer complications on univariate analysis (OR = 0.31, 95% CI = 0.11–0.86, p = 0.03), but this was not significant on multivariate analysis (OR = 0.45, 95% CI = 0.13–1.59, p = 0.22). Obesity was a strong predictor of complications in the upper limb group on multivariate analysis (body mass index [BMI] ≥ 30 kg/m², OR = 7.01, 95% CI = 1.28–38.51, p = 0.03). There was no significant difference in functional outcomes between both flap groups in either upper or lower limbs.

Conclusions

Postoperative complications and functional outcomes for patients undergoing free and pedicled flaps are similar in ESTS reconstruction. Selecting the most suitable reconstructive option in each individual case is paramount to preserving function while minimizing postoperative morbidity.

Drug Utilization Patterns and Adherence in Patients on Systemic Medications for the Treatment of Psoriasis: A Retrospective Comparative Cohort Study

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Erica D. Dommasch, Moa P. Lee, Cara J. Joyce, Elizabeth M. Garry, Joshua J. Gagne

Abstract

Background

Non-adherence to systemic treatments for psoriasis leads to treatment failure and increased healthcare utilization.

Objective

Examine drug utilization patterns and adherence for new users of systemic medications for psoriasis.

Methods

We conducted a retrospective comparative cohort study using a large US health insurance claims database including psoriasis patients who were new users of acitretin, adalimumab, etanercept, methotrexate, and ustekinumab. Adherence was measured using proportion of days covered (PDC) dichotomized as adherent (≥0.80) or non-adherent (<0.80). Odds ratios (ORs) and 95% confidence intervals (CIs) comparing adherence to each exposure (acitretin, adalimumab, etanercept, and ustekinumab) to the referent (methotrexate) were estimated via logistic regression, with pairwise 1:1 propensity score (PS) matching to adjust for potential confounders.

Results

22,742 patients were new users of systemic medications. Compared to methotrexate, we report greater adherence among users of adalimumab, etanercept, and ustekinumab [PS-matched OR (95% CI) = 2.24 (2.05, 2.45), 1.77 (1.63, 1.92), and 2.54 (2.24, 2.87), respectively], and lower adherence among new users of acitretin [0.57 (0.50, 0.63)].

Limitations

Unable to evaluate reasons for discontinuation.

Conclusions

We report greater adherence in new users of biologics when compared to methotrexate. Further research is needed to understand overall low adherence to systemic medications for psoriasis.

Clinical Pearls: Fluorescent tattoos as anatomic markers to track trichologic responses

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Kumar Sukhdeo

Skin Confident: A skin health and acne educational intervention to improve Acne Quality of Life measures in adolescents

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Angela Burleigh, Masoud Yousefi, Shannon Humphrey

Comment on “Guidelines of care for the management of basal cell carcinoma”

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Lieke C.J. van Delft, Maud H.E. Jansen, Klara Mosterd, Nicole W.J. Kelleners-Smeets

Atypical Fibroxanthoma: Systematic Review and Meta-analysis of Treatment with Mohs Micrographic Surgery or Excision

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Stanislav N. Tolkachjov, Benjamin F. Kelley, Fares Alahdab, Patricia J. Erwin, Jerry D. Brewer

Abstract

Background

Atypical fibroxanthoma (AFX) is a fibrohistiocytic tumor with relatively high local recurrence rates, but low metastatic potential. Wide local excision (WLE) and Mohs micrographic surgery (MMS) are common treatments, although no consensus exists regarding optimal therapy.

Objective

To systematically review evidence of AFX recurrence and metastatic rates following different surgical modalities.

Methods

Data Sources: Comprehensive search from 1946 or database inception to March 20, 2017.

Study Selection

Included studies had 5 or more patients with atypical fibroxanthoma treated surgically.

Data Extraction and Synthesis

Two reviewers independently abstracted the data. Risk of bias was assessed with Newcastle-Ottawa Scale.

Main Outcomes and Measures

Recurrence and metastasis.

Results

23 studies were selected (907 patients and 914tumors). 175 cases were treated with MMS (recurrence rate, 2.0% [95% CI, 0%-4.1%]; metastatic rate, 1.9% [95% CI, 0.1%-3.8%]). 732 were treated with WLE (recurrence rate, 8.7% [95% CI,5%-12.3%]; metastasis rate, 1% [95% CI, 0.2%-1.9%]). Among immunocompromised patients, no recurrence or metastases developed in the MMS subgroup, whereas 4/10 recurred and 1/10 metastasized in the WLE subgroup.

Limitations

low quality of published studies

Conclusion

MMS for atypical fibroxanthoma is associated with a lower recurrence rate than wide local excision.

Reply to Comment on “Guidelines of Care for the Management of Basal Cell Carcinoma”

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Christopher K. Bichakjian, Murad Alam

A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening

Publication date: Available online 5 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Dayoung Ko, Shari R. Lipner

Chronic Non-Melanoma Skin Cancers and Health Related Impairment: A Case-Control Study

Publication date: Available online 3 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Adam Sutton, Ashley Crew, Shauna Higgins, Andrew Kwong, Ashley Wysong

A Comparison of Skin Cancer Screening and Treatment Costs at a Massachusetts Cancer Center, 2008 versus 2013

Publication date: Available online 3 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Frederick C. Morgan, Juanita Duran, Belen Fraile, Pritesh S. Karia, Jennifer Y. Lin, Patrick A. Ott, Emily Stamell Ruiz, David M. Wang, Yichen Zhang, Chrysalyne D. Schmults

Abstract

Background

Temporal analyses of skin cancer costs are needed to examine how expenditure differences between diagnoses are changing.

Objective

To tabulate the costs of skin cancer-related care (SCRC), including both screening and treatment, at an academic cancer center at two time points.

Methods

Cost data (insurance and patient payments) at an academic cancer center from 2008 and 2013 were queried for International Classification of Diseases, Ninth Revision (ICD-9) codes pertaining to skin cancer. Screening costs were separated from treatment costs through associated Current Procedure Terminology (CPT) codes.

Results

The total annual cost of SCRC increased by 64%, the number of patients receiving SCRC increased by 45%, and the mean cost per patient treated increased by 13%. Screening accounted for 17% and 16% of total annual costs in 2008 and 2013, respectively. The mean cost per melanoma patient increased by 84%, which was the largest increase among skin cancer diagnoses. In 2013, the few melanoma patients treated with ipilimumab (n=48, 4% of melanoma patients) accounted for 42% of melanoma treatment costs and 20% of SCRC costs.

Limitations

Prescription costs were unavailable

Conclusion

Melanoma costs increased due to the introduction of ipilimumab. Ongoing studies are needed to monitor SCRC cost-effectiveness at a national level.

Apremilast for moderate hidradenitis suppurativa: results of a randomized controlled trial

Publication date: Available online 3 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Allard R.J.V. Vossen, M.B.A. van Doorn, Hessel H. van der Zee, Errol P. Prens

Abstract

Background

Effective anti-inflammatory treatments for hidradenitis suppurativa (HS) are limited.

Objective

To evaluate the efficacy and short-term safety of apremilast in patients with moderate HS.

Methods

Twenty patients with moderate HS were randomised in a 3 : 1 ratio, to receive blinded treatment with apremilast 30 mg twice daily or placebo for 16 weeks. The primary outcome was the Hidradenitis Suppurativa Clinical Response (HiSCR) at week 16. Linear mixed effects modeling (ANCOVA) was used to assess secondary clinical outcomes between treatment groups.

Results

The HiSCR was met in 8 of 15 (53.3%) patients in the apremilast group and none of 5 patients (0%) in the placebo group (P=0.055) at week 16. Moreover, apremilast-treated patients showed a significantly lower abscess and nodule count (mean difference -2.6; 95% confidence interval -6.0, -0.9; P=0.011), NRS for pain (-2.7; -4.5, -0.9; P=0.009) and itch (-2.8; -5.0, -0.6; P=0.015) over 16 weeks compared with placebo-treated patients. There was no significant difference in the DLQI over time between the two treatment groups (-3.4; -9.0, 2.3; P=0.230). The most frequently reported adverse events in the apremilast-treated patients were mild to moderate headache and gastro-intestinal symptoms, which have not resulted in drop-outs.

Limitations

Small number of patients, relatively short study duration.

Conclusion

Apremilast at a dose of 30 mg twice daily demonstrated clinically meaningful efficacy and was generally well tolerated in patients with moderate HS.

A Phase 2, Randomized Dose-Finding Study of Tapinarof (GSK2894512 Cream) for the Treatment of Atopic Dermatitis

Publication date: Available online 3 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Johnny Peppers, Amy S. Paller, Tomoko Maeda-Chubachi, Sterling Wu, Kevin Robbins, Kelly Gallagher, John E. Kraus

Abstract

Background

Safe and efficacious topical treatments are needed for atopic dermatitis (AD).

Objective

We assessed the safety and efficacy of tapinarof cream (2 concentrations; 2 application frequencies) in patients with AD.

Methods

Double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients aged 12-65 years, with body surface area (BSA) involvement ≥5% and ≤35% and Investigator Global Assessment (IGA) ≥3 (moderate-severe) at Baseline. Primary endpoint included IGA score of clear or almost clear (0 or 1), and minimum 2-grade improvement ("treatment success") at Week 12. Secondary analyses: ≥ 75% improvement in Eczema Area Severity Index (EASI 75), reduction of numeric rating scale (NRS) Itch from Baseline, and other prespecified endpoints.

Results

Treatment success rates at Week 12 were: 53% [1% BID]; 46% [1% QD]; 37% [0.5% BID]; 34% [0.5% QD]; 24% [vehicle BID]; 28% [vehicle QD]. The rate (53%) of 1% BID was statistically significantly higher than (24%) vehicle BID. Treatment success was maintained for 4 weeks after end of tapinarof treatment. Treatment-emergent adverse events (TEAE) were higher with tapinarof (93/165; 56%) vs. vehicle (34/82; 41%) and mild-to-moderate in intensity.

Limitations

Large confirmation trials are needed.

Conclusions

Tapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.

Skin in the game: Existing and upcoming physician payment models in dermatology

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Oluwatobi A. Ogbechie-Godec, Arash Mostaghimi, Vinod E. Nambudiri

The art of being in 2 rooms at 1 time: Ethical issues with overlapping surgery

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Reid Waldman, Jane M. Grant-Kels

Low conversion rate of QuantiFERON-TB Gold screening tests in patients treated with tumor necrosis factor inhibitors: A retrospective cohort study identifying an important practice gap

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Jina Chung, Adam B. Aronson, Rithu Srikantha, Scott A. Vogelgesang, Karolyn A. Wanat

Dupilumab for hand eczema

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Matthew J. Zirwas

High neutrophil-to-lymphocyte ratio before starting anti-programmed cell death 1 immunotherapy predicts poor outcome in patients with metastatic melanoma

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Margaux Garnier, Julia Zaragoza, Nathalie Bénéton, Guido Bens, Victoire Meurisse, Mahtab Samimi, Hervé Maillard, Laurent Machet

Risk of thromboembolic events in patients treated with thalidomide for cutaneous lupus erythematosus: A multicenter retrospective study

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Elise Cesbron, Didier Bessis, Marie Jachiet, Dan Lipsker, Nadège Cordel, Jean-David Bouaziz, Martine Bagot, Laurent Arnaud, Annick Barbaud, Camille Francès, François Chasset, Study Group of Systemic Diseases in Dermatology (Étude des Maladies Systémiques en Dermatologie)

Atopic dermatitis is not a risk factor for keratoconus: A population-based cohort study

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Hyun Sun Jeon, Mira Choi, Seong Jun Byun, Leejee H. Suh, Joon Young Hyon, Kyu Hyung Park, Sang Jun Park

In-office compounding of lidocaine-epinephrine: An option for anesthesia preparation before skin biopsy

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Ross Pearlman, Steven R. Feldman, Leah Cardwell, Katarina R. Kesty

Dermatology faculty and residents' perspectives on the dermatology residency application process: A nationwide survey

Publication date: July 2018

Source: Journal of the American Academy of Dermatology, Volume 79, Issue 1

Author(s): Nathan W. Rojek, Kanade Shinkai, Nicole Fett

Rajeunir, c’est vieux comme le monde…

Publication date: Available online 4 July 2018
Source:Annales de Chirurgie Plastique Esthétique
Author(s): J. Glicenstein, T. Awada
Les légendes et les mythes sur l'éternelle jeunesse existent depuis l'Antiquité. Avant le XIX^e siècle, ceux qui souhaitaient rajeunir utilisaient des bains ou des injections de sang, recherchaient la Fontaine de Jouvence, ou faisaient appel à un alchimiste qui prétendait avoir trouvé l'élixir de longue vie. Au XIX^e siècle, Charles Edouard Brown Séquard, (1819–1894) après la découverte du rôle des glandes endocrines et des sécrétions testiculaires, s'injecta un extrait de testicule de cobaye et de chien et s'en trouva rajeuni ! Au début du XX^e siècle, plusieurs chirurgiens transplantèrent des testicules humains, provenant de condamnés à mort exécutés ou de donneurs volontaires. Les transplantations de testicules de singe par Serge Voronoff (1866–1951), dans les années 1920, eurent un grand retentissement et plus de 300 interventions de ce type furent réalisées. La simple ligature des canaux déférents (vasectomie) fut préconisée par Eugen Steinach (1866–1944). Sigmund Freud en fut l'un des « bénéficiaires ». Steinach proposa aussi l'irradiation des ovaires pour le rajeunissement féminin. Alexis Carrel (1873–1944) et Charles Lindbergh (1902–1974) réalisèrent en 1935 une pompe destinée à nourrir et à rajeunir des organes isolés. La découverte récente des cellules souches pluripotentes et celles de molécules sénolytiques suscitent de nouveaux espoirs.Legends and myths regarding eternal youth exist since Antiquity. Prior to the 19th century those wishing to rejuvenate used baths or blood injections, searching to the Fountain of Youth or calling for an alchemist claiming to have found the Elixir of Youth. In the 19th century, Charles Edouard Brown Séquard (1819–1894), after the discovery of the function of the endocrinal glands and testicular secretions, inject himself with an extract from guinea pigs and dogs. He found himself rejuvenated! In the beginning of the 20th century, several surgeons transplanted human testicles coming from death row prisoners inmates or voluntary donors. The transplantation of monkey testicles by Serge Voronoff (1866–1951) had a important aftermath and more than 300 similar interventions took place. The simple ligation of the vas deferens (vasectomy) was recommended by Eugen Steinach (1866–1944). Sigmund Freud was one of the "beneficiaries". Steinach also advised the irradiation of the ovaries for female rejuvenation. In 1935, Alexis Carrel (1873–1944) and Charles Lindbergh (1902–1974) built a pump to feed and regenerate targeted organs. The discovery of pluripotent stem cells and senolytic molecules are building up new hopes on the matter.

Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial

Abstract

Background

Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.

Methods

M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m²) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.

Results

There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.

Conclusions

Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Carboplatin and Pembrolizumab Chemoimmunotherapy Achieves Remission in Recurrent, Metastatic Sebaceous Carcinoma

A 72-year-old Caucasian woman who had recurrent sebaceous carcinoma of the right orbit with bilateral cervical lymph node involvement 24 months after orbital exenteration was treated with carboplatin (area under the curve of 5) and pembrolizumab (2 mg/kg) for 6 cycles, followed by maintenance pembrolizumab. She obtained a complete pathological remission and remains free of local, regional, and systemic disease at 15 months. Accepted for publication May 1, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Katherine A. Lane, M.D., Ophthalmic Consultants of Vermont, South Burlington, VT. kate.lane@ocvtdoctors.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Orbital Extension of Conjunctival Pseudoadenomatous Hyperplasia

A 41-year-old woman developed persistent unilateral conjunctivitis following an upper respiratory infection. A white cystic lesion of the inferior fornix was noted on computed tomography scan to extend behind the orbital septum into the anterior portion of the orbit. Following subtotal excision, histopathology showed benign pseudoadenomatous (pseudoglandular) hyperplasia. The case represents the 5th report of this lesion occurring in the conjunctiva and the only instance of its extension into the orbit. Accepted for publication May 18, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Norman C. Charles, M.D., NYU Langone Medical Center, 550 First Avenue, New York, NY 10016. E-mail: norman.charles@nyumc.org © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Lateral Canthotomy and Cantholysis in Operations Iraqi Freedom and Enduring Freedom: 2001–2011

Purpose: To describe outcomes and associated ocular injuries of lateral canthotomy and cantholysis (LCC) as performed in combat ocular trauma. Methods: Data from the Walter Reed Ocular Trauma Database of patients requiring LCC during Operations Iraqi Freedom and Enduring Freedom was reviewed as a retrospective cohort. Primary outcome measures included final visual acuity (VA) and Ocular Trauma Score. Secondary outcome measures were associated injuries and timing of surgery. Results: Thirty-six LCCs were recorded on a total of 890 eyes (4.04 %) in the Walter Reed Ocular Trauma Database. Eighteen out of 36 eyes (50.00%) had a final VA of the affected eye of 20/200 or worse vision. From the initial available VA measured either at the time of injury or at Walter Reed Army Medical Center, 13 eyes (40.63%) had no change in VA, 15 eyes (46.88%) had improvement, and 4 (12.5%) had a decrease in VA (n = 32, data unavailable for 4 eyes). Ocular Trauma score 0–65 was noted in 14 (38.9%) and 66–100 (61.1%). Retinal detachment (6, 16.67%), optic nerve injuries (7, 19.44%), orbital fractures (20, 55.56%), and retrobulbar hematoma (25, 69.44%) were commonly associated injuries. Of the 36 LCC, 18 (50.00%) were performed as the first surgery performed at the combat support hospital, 13 (36.11%) as the second, 4 (11.11%) as the third, and 1 (2.78%) as the fourth. Conclusions: The largest subgroup of patients had an improvement in VA associated with performance of LCC; however, half of patients remained with a final VA of equal to or worse than 20/200 due to severe ocular trauma. Accepted for publication May 11, 2018. Presentation at the Society of Military Ophthalmologist's Meeting on November 2017 in New Orleans, LA. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs under the Broad Agency Announcement for Extramural Medical Research, BAA-16-R-BAA1 under Award No. W81XWH-17-2-0007. The authors have no financial or conflicts of interest to disclose. The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Air Force, the Department of the Army, Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government. Address correspondence and reprint requests to Grant A. Justin, M.D., 3551 Roger Brooke Drive, Brooke Army Medical Center, San Antonio, TX 78219. E-mail: grant.a.justin@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Augmented and Virtual Reality Navigation for Interventions in the Musculoskeletal System

Abstract

Purpose of Review

Augmented reality (AR) and virtual reality (VR) are cutting-edge technologies that offer advanced navigational solutions. These systems are just starting to be used in interventional radiology and the literature has been limited to pre-clinical and translational experiments. In this paper, we present a review of AR and VR for musculoskeletal interventions.

Recent Findings

Mixed reality systems have evolved from costly research systems to fully commercialized clinical instruments designed to facilitate operators in navigating complex anatomy. Studies within interventional radiology have demonstrated safety, improved accuracy, and decreased exposure to ionizing radiation.

Summary

We review the progression of mixed reality systems from their early origins in computer science through their current day surgical applications, with a special focus on landmark studies within radiologic interventions for the musculoskeletal system. We highlight the instrumentation, clinical workflow, benefits and drawbacks, and suggested future directions for the two main AR systems: head-mounted display and image-overlay.

The wrongs of racist beliefs

Abstract

We care not only about how people treat us, but also what they believe of us. If I believe that you're a bad tipper given your race, I've wronged you. But, what if you are a bad tipper? It is commonly argued that the way racist beliefs wrong is that the racist believer either misrepresents reality, organizes facts in a misleading way that distorts the truth, or engages in fallacious reasoning. In this paper, I present a case that challenges this orthodoxy: the case of the supposedly rational racist. We live in a world that has been, and continues to be, structured by racist attitudes and institutions. As a result, the evidence might be stacked in favour of racist beliefs. But, if there are racist beliefs that reflect reality and are rationally justified, what could be wrong with them? Moreover, how do I wrong you by believing what I epistemically ought believe given the evidence? To address this challenge, we must recognize that there are not only epistemic norms governing belief, but moral ones as well. This view, however, is at odds with the assumption that moral obligation requires a kind of voluntary control that we lack with regard to our beliefs. This background assumption motivates many philosophers to try to explain away the appearance that beliefs can wrong by locating the wrong elsewhere, e.g., in an agent's actions. Further, even accounts that accept the thesis that racist beliefs can wrong restrict the class of beliefs that wrong to beliefs that are either false or the result of hot irrationality, e.g., the racist belief is a result of ill-will. In this paper I argue that although these accounts will capture many of the wrongs associated with racist beliefs, they will be only partial explanations because they cannot explain the wrong committed by the supposedly rational racist. The challenge posed by the supposedly rational racist concerns our epistemic practices in a non-ideal world. The world is an unjust place, and there may be many morally objectionable beliefs it justifies. To address this challenge, we must seriously consider the thesis that people wrong others in virtue of what they believe about them, and not just in virtue of what they do.

Occurrence and distribution of antibiotic resistance genes in the sediments of drinking water sources, urban rivers, and coastal areas in Zhuhai, China

Abstract

Antibiotic resistance genes (ARGs) are regarded as emerging contaminants related with human activities. Aquatic environments of an urban city are apt for the persistence and prevalence of ARGs. In this study, we investigated the occurrence and distribution of ARGs and integrase genes in the sediment samples collected from drinking water sources, urban rivers, and coastal areas of Zhuhai, China, in the dry and wet seasons of 2016. The results show that sulfonamide resistance gene of sulII was present at the highest detection frequency (85.71%); and its average concentrations were also the highest in both dry and wet seasons (3.78 × 10⁷ and 9.04 × 10⁷ copies/g sediment, respectively), followed by tetC, tetO, tetA, ermB, dfrA1, and bla_PSE-1. Temporally, the concentrations of total ARGs in the wet season were likely higher than those in the dry season; and spatially, the concentrations of total ARGs in the drinking water sources were substantially lower than those in the urban rivers and nearby coastal areas, indicating the different degrees of anthropogenic impact and consequent health risks. Positive correlations were found between intI1 and each quantitative ARG in all wet season samples rather than dry season samples, which suggested higher temperature and more rain in summer might have positive influences on ARG dissemination, especially that mediated by intI1 gene and class I integrons.

Tratamiento sistémico de la psoriasis moderada-grave en edad pediátrica en Galicia: estudio descriptivo

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): A. Batalla, R. Fernández-Torres, L. Rodríguez-Pazos, B. Monteagudo, R. Pardavila-Riveiro, R. Rodríguez-Lojo, Á. Zulaica, M. Cabanillas, E. Fonseca, Á. León, L. Fernández-Díaz, T. Abalde, L. Salgado-Boquete, F. Valdés, M.J. Seoane-Pose, H. Vázquez-Veiga, I. Suárez-Conde, J. Álvarez-López, Á. Flórez
Antecedentes y objetivoLos trabajos sobre el tratamiento sistémico de la psoriasis en edad pediátrica son escasos. El objetivo principal de este trabajo consistió en describir qué tratamientos sistémicos se emplean en práctica clínica en psoriasis moderada-grave en edad pediátrica. Secundariamente se describió la efectividad y perfil de seguridad de dichos tratamientos.Materiales y métodosEstudio descriptivo transversal multicéntrico, de los pacientes con psoriasis moderada-grave, que siendo menores de 18 años estuviesen recibiendo o hubieran recibido tratamiento sistémico (clásico o biológico) o fototerapia. Se recogieron datos clínico-demográficos, tipo de tratamiento recibido, y tolerancia, efectos indeseables y respuesta al mismo.ResultadosSe obtuvieron datos de 40 pacientes (60% sexo femenino, edad media 13 años), que realizaron 63 ciclos de tratamiento. Teniendo en cuenta el primer tratamiento (n=40), la fototerapia fue la opción más frecuente (68%), seguida de acitretino (15%). Considerando el total de ciclos de tratamiento (n=63), el tratamiento más frecuentemente empleado fue la fototerapia (57%), seguida de metotrexato (16%). En la semana 12 (incluye evaluación de fototerapia), el 66% y el 22% fueron buenos respondedores o respondedores parciales, respectivamente. En la semana 24 (datos exclusivos sobre fármacos sistémicos), el 36% y el 32% continuaron con respuestas buenas y parciales. Los tratamientos fueron bien tolerados (97%) y los efectos indeseables escasos (11%), sin que en ningún caso motivasen la suspensión del fármaco.ConclusionesEn la población menor de 18 años con psoriasis moderada-grave evaluada la fototerapia fue el tratamiento más utilizado, seguida de metotrexato. Los tratamientos consiguieron porcentajes de buenos respondedores del 66% en la semana 12 (incluida fototerapia), y del 36% en la semana 24 (fármacos sistémicos sin fototerapia), presentando un buen perfil de seguridad.Background and objectiveStudies on the use of systemic therapy for psoriasis in pediatric patients are scarce. The main aim of this study was to describe the systemic treatments used for moderate to severe psoriasis in pediatric clinical settings. The second aim was to describe the effectiveness and safety of these treatments.Material and methodsDescriptive, cross-sectional, multicenter study of patients under 18 years of age with moderate to severe psoriasis who were being treated or had been treated with a systemic drug (conventional or biologic) or phototherapy. We recorded demographic and clinical information, treatments received, tolerance, adverse effects, and response to treatment.ResultsData were collected for 40 patients (60% female; mean age, 13 years) who had received 63 treatments in total. The most common first treatment (n=40) was phototherapy (administered to 68% of patients), followed by acitretin (15%). The most common treatments overall (n=63) were phototherapy (57%) and methotrexate (16%). At week 12 (evaluation of systemic treatment and phototherapy), 66% of the patients were classified as good responders and 22% as partial responders. The respective rates for week 24 (evaluation of systemic treatment only) were 36% and 32%. The treatments were well tolerated (97%) and adverse effects were reported in just 11% of cases. There were no treatment discontinuations because of adverse effects.ConclusionsPhototherapy, followed by methotrexate, was the most common treatment for moderate to severe psoriasis in this series of patients under 18 years. The treatments showed a favorable safety profile and were associated with a good response rate of 66% at week 12 (systemic treatment and phototherapy) and 36% at week 24 (systemic treatment only).

Graphical abstract

Sarcomas cutáneos: directrices para el diagnóstico y tratamiento. Dermatofibrosarcoma protuberans

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): B. Llombart, C. Serra, C. Requena, M. Alsina, D. Morgado-Carrasco, V. Través, O. Sanmartín
Los sarcomas constituyen un grupo amplio de tumores, muchos de ellos con comportamiento biológico y agresividad diferentes entre sí, que habitualmente requieren un tratamiento multidisciplinario, frecuentemente complejo. El desarrollo en las últimas décadas de la dermatología quirúrgica y oncológica ha permitido que los dermatólogos se conviertan en los especialistas responsables del diagnóstico y tratamiento del cáncer cutáneo. El propósito de este artículo es revisar los principales sarcomas de partes blandas de localización típicamente cutánea.El dermatofibrosarcoma protuberans es un sarcoma de bajo grado de malignidad, con un crecimiento lento e infiltrativo localmente y escasa capacidad metastásica (<3%). El tratamiento de elección es la cirugía micrográfica de Mohs. Es recomendable solicitar el estudio de la translocación COL1A1-PDGFB cuando existen dudas diagnósticas, y para determinar qué pacientes pueden responder a los fármacos inhibidores de la tirosina quinasa. El imatinib está indicado en el dermatofibrosarcoma protuberans localmente avanzado y metastásico.Sarcomas comprise a broad group of tumors, many of whose biological behavior and aggressiveness differ from one type to another. The therapeutic approach is generally multidisciplinary and often complex. Developments in surgical and oncological dermatology during the last few decades have positioned dermatologists as specialists in the diagnosis and treatment of skin cancer. The aim of this article is to review the main soft tissue sarcomas that typically affect the skin. Dermatofibrosarcoma protuberans is a low-grade malignant sarcoma. It exhibits slow-growth, is locally invasive, and has low metastatic potential (<3%). Mohs micrographic surgery is the treatment of choice. The COL1A1-PDGFB translocation should be analyzed in cases of unclear diagnosis and when it is necessary to identify candidates for tyrosine kinase inhibitors. Imatinib is indicated for the treatment of locally advanced and metastatic dermatofibrosarcoma protuberans.

Graphical abstract

Experiencia de un investigador y un dermatólogo sobre el conocimiento del curso clínico del vitiligo no segmentario

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): M.L. Peralta-Pedrero, F. Jurado Santa-Cruz

Estudio ecográfico de metástasis cutáneas de origen visceral

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): C. Cuenca-Barrales, P. Aguayo-Carreras, A. Bueno-Rodriguez, R. Ruiz-Villaverde

Cirugía funcional en tumores malignos subungueales. Serie de casos y revisión de la literatura

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): M. Flores-Terry, G. Romero-Aguilera, C. Mendoza, M. Franco, P. Cortina, M. Garcia-Arpa, L. Gonzalez-Ruiz, J.A. Garrido
Antecedentes y objetivosEl tratamiento clásico de los tumores malignos subungueales (TMSU), carcinoma epidermoide (CESU) y melanoma (MSU), es la amputación. La cirugía funcional del aparato ungueal (CFAU) puede preservar la función sin modificar el pronóstico. Presentamos nuestra serie de TMSU manejados con CFAU, describimos la técnica y revisamos sus indicaciones.Material y métodosEstudio observacional retrospectivo de TMSU tratados con CFAU entre 2008 y 2017, con exéresis supraperióstica en bloque del aparato ungueal, margen a 5mm, y cierre con injerto de piel total.ResultadosSe trataron 11 TMSU, de los cuales 7 fueron MSU (4 in situ, espesor medio: 1,17mm; rango: 0-4mm) y 4 CESU (espesor medio: 3,4mm; rango: 1,6-6mm). Se realizó CFAU en 9 casos y 2 amputaciones en sendos MSU invasivos. El seguimiento medio fue 39 meses, con un rango de 12-96 meses. No hubo recidivas locales ni regionales. Solo un caso —una de las 2 amputaciones— tuvo metástasis (cerebrales) y muerte.La revisión de la literatura de CFAU en TMSU mostró 5 series (103 pacientes en total) con CESU y 14 series (243 pacientes en total) con MSU. El análisis de nuestros casos y de los casos publicados muestra muy escasas recurrencias locales (<7%), y mejores resultados funcionales y estéticos frente a la amputación.ConclusionesLa CFAU es de elección en CESU sin afectación ósea y MSU no invasivo o delgado (Breslow <1mm). Es factible en MSU de grosores intermedios siempre con detallado estudio histológico de márgenes que asegure una resección completa. Por el contrario, en CESU con afectación ósea, MSU muy grueso (>4mm) o recurrencias, la amputación debe ser habitualmente de elección.Background and objectivesAmputation is the conventional treatment for malignant subungual tumors (MSUTs), namely, subungual squamous cell carcinoma (SUSCC) and subungual melanoma (SUM). Functional surgery consisting of wide local excision (WLE) of the nail unit can preserve function without modifying prognosis in such cases. We present a series of MSUTs treated with WLE of the nail unit, describe the technique, and review its indications.Material and methodsRetrospective observational study of MSUTs treated with WLE of the nail unit between 2008 and 2017. The technique consisted of en bloc supraperiosteal excision of the nail unit with a margin of 5mm followed by repair with a full-thickness graft.ResultsEleven MSUTs were treated in the study period: 7 SUMs (4 in situ; mean thickness, 1.17mm; range, 0-4mm) and 4 SUSCCs (mean thickness, 3.4mm; range, 1.6-6mm). WLE of the nail unit was performed in 9 patients and amputation in 2 patients with invasive SUM. Mean follow-up was 39 months (range, 12-96 months) and no local or regional recurrences were detected. One of the 2 patients who underwent amputation developed metastasis to the brain and died. In our review of the literature, we identified 5 series of patients with SUSCC treated with WLE of the nail unit (105 patients) and 14 series of patients with SUM (243 patients). Based on an analysis of these cases and ours, it would appear that WLE of the nail unit is associated with a very low rate of local recurrence (<7%) and offers better functional and cosmetic outcomes than amputation.ConclusionsWLE of the nail unit is the treatment of choice for SUSCC without bone involvement and for thin noninvasive SUM (Breslow depth <1mm). It is also feasible in intermediate-thickness SUMs when detailed histologic examination of the margins confirms complete resection. Amputation, by contrast, is the treatment of choice for SUSCCs with bone involvement, very thick SUMs (>4mm), and recurrent tumors.

Graphical abstract

A new decentralized biological treatment process based on activated carbon targeting organic micropollutant removal from hospital wastewaters

Abstract

Although hospital wastewaters (HWWs) are usually discharged in urban sewage systems, their separate treatment has several benefits, such as the specific treatment of potential toxics as well as avoidance of further dilutions. In this work, an integrated industrial pilot plant (2200 L) corresponding to the technology SeMPAC^® is proposed and validated for such purpose. The process consists of a sequential batch reactor (SBR) connected to an external submerged microfiltration membrane, in which powdered activated carbon (PAC) is directly added into the biological reactor to enhance the removal of the organic micropollutants (OMPs). The combination of different redox conditions in the SBR, as well as the operation at long sludge retention times (SRTs) and high biomass concentrations favored OMP biotransformation in the SBR, being their final removal efficiencies enhanced clearly after PAC addition, especially for the recalcitrant compounds. A periodical renewal of the adsorbent is necessary to overcome its gradual saturation. The main operational conditions were influenced by (i) the recalcitrant OMP carbamazepine, which defines the PAC dosage; (ii) the easily degradable OMP ibuprofen, which can be used to optimize the duration of the aerobic cycle; and (iii) the denitrification efficiency, which defines the correct time length of the anoxic period.

A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening

Clinical Pearls: Fluorescent tattoos as anatomic markers to track trichologic responses

Drug Utilization Patterns and Adherence in Patients on Systemic Medications for the Treatment of Psoriasis: A Retrospective Comparative Cohort Study

There is limited data on adherence to systemic medications for psoriasis in real-world practice. Using a large US health insurance claims database, we found significantly increased odds of adherence to biologics compared to methotrexate. Dermatologists should consider adherence when choosing systemic treatments for psoriasis patients.

Apremilast for moderate hidradenitis suppurativa: results of a randomized controlled trial

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Allard R.J.V. Vossen, M.B.A. van Doorn, Hessel H. van der Zee, Errol P. Prens
BackgroundEffective anti-inflammatory treatments for hidradenitis suppurativa (HS) are limited.ObjectiveTo evaluate the efficacy and short-term safety of apremilast in patients with moderate HS.MethodsTwenty patients with moderate HS were randomised in a 3 : 1 ratio, to receive blinded treatment with apremilast 30 mg twice daily or placebo for 16 weeks. The primary outcome was the Hidradenitis Suppurativa Clinical Response (HiSCR) at week 16. Linear mixed effects modeling (ANCOVA) was used to assess secondary clinical outcomes between treatment groups.ResultsThe HiSCR was met in 8 of 15 (53.3%) patients in the apremilast group and none of 5 patients (0%) in the placebo group (P=0.055) at week 16. Moreover, apremilast-treated patients showed a significantly lower abscess and nodule count (mean difference -2.6; 95% confidence interval -6.0, -0.9; P=0.011), NRS for pain (-2.7; -4.5, -0.9; P=0.009) and itch (-2.8; -5.0, -0.6; P=0.015) over 16 weeks compared with placebo-treated patients. There was no significant difference in the DLQI over time between the two treatment groups (-3.4; -9.0, 2.3; P=0.230). The most frequently reported adverse events in the apremilast-treated patients were mild to moderate headache and gastro-intestinal symptoms, which have not resulted in drop-outs.LimitationsSmall number of patients, relatively short study duration.ConclusionApremilast at a dose of 30 mg twice daily demonstrated clinically meaningful efficacy and was generally well tolerated in patients with moderate HS.

A Phase 2, Randomized Dose-Finding Study of Tapinarof (GSK2894512 Cream) for the Treatment of Atopic Dermatitis

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Johnny Peppers, Amy S. Paller, Tomoko Maeda-Chubachi, Sterling Wu, Kevin Robbins, Kelly Gallagher, John E. Kraus
BackgroundSafe and efficacious topical treatments are needed for atopic dermatitis (AD).ObjectiveWe assessed the safety and efficacy of tapinarof cream (2 concentrations; 2 application frequencies) in patients with AD.MethodsDouble-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients aged 12-65 years, with body surface area (BSA) involvement ≥5% and ≤35% and Investigator Global Assessment (IGA) ≥3 (moderate-severe) at Baseline. Primary endpoint included IGA score of clear or almost clear (0 or 1), and minimum 2-grade improvement ("treatment success") at Week 12. Secondary analyses: ≥ 75% improvement in Eczema Area Severity Index (EASI 75), reduction of numeric rating scale (NRS) Itch from Baseline, and other prespecified endpoints.ResultsTreatment success rates at Week 12 were: 53% [1% BID]; 46% [1% QD]; 37% [0.5% BID]; 34% [0.5% QD]; 24% [vehicle BID]; 28% [vehicle QD]. The rate (53%) of 1% BID was statistically significantly higher than (24%) vehicle BID. Treatment success was maintained for 4 weeks after end of tapinarof treatment. Treatment-emergent adverse events (TEAE) were higher with tapinarof (93/165; 56%) vs. vehicle (34/82; 41%) and mild-to-moderate in intensity.LimitationsLarge confirmation trials are needed.ConclusionsTapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.

A Comparison of Skin Cancer Screening and Treatment Costs at a Massachusetts Cancer Center, 2008 versus 2013

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Frederick C. Morgan, Juanita Duran, Belen Fraile, Pritesh S. Karia, Jennifer Y. Lin, Patrick A. Ott, Emily Stamell Ruiz, David M. Wang, Yichen Zhang, Chrysalyne D. Schmults
BackgroundTemporal analyses of skin cancer costs are needed to examine how expenditure differences between diagnoses are changing.ObjectiveTo tabulate the costs of skin cancer-related care (SCRC), including both screening and treatment, at an academic cancer center at two time points.MethodsCost data (insurance and patient payments) at an academic cancer center from 2008 and 2013 were queried for International Classification of Diseases, Ninth Revision (ICD-9) codes pertaining to skin cancer. Screening costs were separated from treatment costs through associated Current Procedure Terminology (CPT) codes.ResultsThe total annual cost of SCRC increased by 64%, the number of patients receiving SCRC increased by 45%, and the mean cost per patient treated increased by 13%. Screening accounted for 17% and 16% of total annual costs in 2008 and 2013, respectively. The mean cost per melanoma patient increased by 84%, which was the largest increase among skin cancer diagnoses. In 2013, the few melanoma patients treated with ipilimumab (n=48, 4% of melanoma patients) accounted for 42% of melanoma treatment costs and 20% of SCRC costs.LimitationsPrescription costs were unavailableConclusionMelanoma costs increased due to the introduction of ipilimumab. Ongoing studies are needed to monitor SCRC cost-effectiveness at a national level.

Chronic Non-Melanoma Skin Cancers and Health Related Impairment: A Case-Control Study

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Adam Sutton, Ashley Crew, Shauna Higgins, Andrew Kwong, Ashley Wysong

Comparative health risk of inhaled exposure to organic solvents, toxic metals, and hexavalent chromium from the use of spray paints in Taiwan

Abstract

The study investigated the exposure of spray painters to organic solvents, toxic metals, and hexavalent chromium over 21 working days in 2017. The results found these concentrations of 12 VOCs to be below the short-term exposure limit (STEL) established by the US Occupational Safety and Health Administration (OSHA). The mass concentration of total particulate matter (PM) exposure to workers was 20.01 ± 10.78 mg/m³, which exceeds OSHA's permissible exposure level of 15 mg/m³. The mean concentration of the total metals for all particle sizes was 109.1 ± 12.0 μg/m³, and those for lead (496,017.0 ng/m³) and iron (252,123.8 ng/m³) were the highest of metal elements. Significantly, the mean concentrations of Pb and As exceeded OSHA's permissible exposure limits (PELs) of 0.05 and 0.01 mg/m³, respectively. The total hexavalent chromium concentration was 1163.01 ng/m³, and the individual particle sizes (PM_1−2.5, PM₁, and PM_0.25) were strongly and positively correlated with the Cr(VI) concentrations for PM_2.5. The study determined that approximately 56.14% of the hexavalent chromium inhaled during the spray-painting process was deposited in the upper respiratory system of the head airway region, followed by the alveolar and tracheobronchial regions, with fractions of 11.93 and 0.05%, respectively. Although the mean ratio of hexavalent chromium to total chromium was only 3.6% for all particle sizes, the cancer risk of the total particles in Cr(VI) (1.6 × 10⁻³) exceeded the acceptable risk value (10⁻⁶). The cancer risks of As and Cr(VI) associated with quasi-ultrafine particles, PM_0.5–1, PM_1–2.5, and PM_> 2.5, also exceeded 10⁻⁶. Comparison of the carcinogenicity risk of VOCs and metals suggests that the adverse health effect of inhaled particles on spray-painting workers is more serious than that from VOC exposure.

Industry mimetic isomorphism and sustainable development based on the X-STATIS and HJ-biplot methods

Abstract

Based on both neo-institutional theory and comparative institutional analysis, this paper studies the role that mimetic forces play in the patterns and evolution of behavior concerning company sustainability. The panel data is composed of 6600 observations of 600 international large listed companies belonging to 39 different activity sectors for the period 2004–2014. Through employing the multivariate statistical methods HJ-biplot and X-STATIS, which provide a useful visualization of a complex data structure in a low-dimensional space, it can be observed that mimetic forces indicate that firms operating in high-impact sectors—sectors that operate under greater pressure from interest groups—face greater social and environmental risks and have higher corporate social responsibility (CSR) scores than companies from other sectors. The adoption or development of CSR practices depends largely on the type of industry in which the company operates, as stakeholder engagement in different industry sectors has different areas of concern. Therefore, companies operating in more polluting sectors, such as mining, paper, chemicals, or oil, give higher priority to environmental protection and defense of human rights, while other, less polluting companies involved in the communication sector are concerned to a greater extent by social issues, such as business ethics or the rights of their employees. Finally, this paper evidences that firms operating in similar contexts, in industries that face analogous risks and challenges, probably develop common policies and regulations with the aim of mitigating the pressures applied by their major stakeholder groups.

Alcohol Consumption during Adolescence in a Mouse Model of Binge Drinking Alters the Intrinsic Excitability and Function of the Prefrontal Cortex through a Reduction in the Hyperpolarization-Activated Cation Current

Periodic episodes of excessive alcohol consumption ("binge drinking") occur frequently among adolescents, and early binge drinking is associated with an increased risk of alcohol use disorders later in life. The PFC undergoes significant development during adolescence and hence may be especially susceptible to the effects of binge drinking. In humans and in animal models, adolescent alcohol exposure is known to alter PFC neuronal activity and produce deficits in PFC-dependent behaviors, such as decision making, response inhibition, and working memory. Using a voluntary intermittent access to alcohol (IA EtOH) procedure in male mice, we demonstrate that binge-level alcohol consumption during adolescence leads to altered drinking patterns and working memory deficits in young adulthood, two outcomes that suggest medial PFC dysfunction. We recorded from pyramidal neurons (PNs) in the prelimbic subregion of the medial PFC in slices obtained from mice that had IA EtOH and found that they display altered excitability, including a hyperpolarization of the resting membrane potential and reductions in the hyperpolarization-activated cation current (I_h) and in intrinsic persistent activity (a mode of neuronal firing that is dependent on I_h). Many of these effects on intrinsic excitability were sustained following abstinence and observed in mice that showed working memory deficits. In addition, we found that resting membrane potential and the I_h-dependent voltage "sag" in prelimbic PFC PNs are developmentally regulated during adolescence, suggesting that adolescent alcohol exposure may compromise PFC function by arresting the normal developmental trajectory of PN intrinsic excitability.

SIGNIFICANCE STATEMENT Binge alcohol drinking during adolescence has negative consequences for the function of the developing PFC. Using a mouse model of voluntary binge drinking during adolescence, we found that this behavior leads to working memory deficits and altered drinking behavior in adulthood. In addition, we found that adolescent drinking is associated with specific changes to the intrinsic excitability of pyramidal neurons in the PFC, reducing the ability of these neurons to generate intrinsic persistent activity, a phenomenon thought to be important for working memory. These findings may help explain why human adolescent binge drinkers show performance deficits on tasks mediated by the PFC.

{alpha}2{delta}-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses

α₂-4 is an auxiliary subunit of voltage-gated Ca_v1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α₂-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α₂-4, we used genome editing to generate an α₂-4 knock-out (α₂-4 KO) mouse. In male and female α₂-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α₂-4 KO retina. In reconstructions of α₂-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α₂-4 KO mice correlates with a progressive loss of Ca_v1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α₂-4 KO mice and better under photopic than scotopic conditions. We conclude that α₂-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.

SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α₂-4, a subunit of voltage-gated Ca²⁺ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca²⁺ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α₂-4. Our results suggest that alterations in presynaptic Ca²⁺ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α₂-4.

Insights into the Contribution of Voltage-Gated Sodium Channel 1.7 to Paclitaxel-Induced Neuropathy

Loss of CaMKI Function Disrupts Salt Aversive Learning in C. elegans

The ability to adapt behavior to environmental fluctuations is critical for survival of organisms ranging from invertebrates to mammals. Caenorhabditis elegans can learn to avoid sodium chloride when it is paired with starvation. This behavior may help animals avoid areas without food. Although some genes have been implicated in this salt-aversive learning behavior, critical genetic components, and the neural circuit in which they act, remain elusive. Here, we show that the sole worm ortholog of mammalian CaMKI/IV, CMK-1, is essential for salt-aversive learning behavior in C. elegans hermaphrodites. We find that CMK-1 acts in the primary salt-sensing ASE neurons to regulate this behavior. By characterizing the intracellular calcium dynamics in ASE neurons using microfluidics, we find that loss of cmk-1 has subtle effects on sensory-evoked calcium responses in ASE axons and their modulation by salt conditioning. Our study implicates the expression of the conserved CaMKI/CMK-1 in chemosensory neurons as a regulator of behavioral plasticity to environmental salt in C. elegans.

SIGNIFICANCE STATEMENT Like other animals, the nematode Caenorhabditis elegans depends on salt for survival and navigates toward high concentrations of this essential mineral. In addition to its role as an essential nutrient, salt also causes osmotic stress at high concentrations. A growing body of evidence indicates that C. elegans balances the requirement for salt with the danger it presents through a process called salt-aversive learning. We show that this behavior depends on expression of a calcium/calmodulin-dependent kinase, CMK-1, in the ASE salt-sensing neurons. Our study identifies CMK-1 and salt-sensitive chemosensory neurons as key factors in this form of behavioral plasticity.

Deep Neural Networks for Modeling Visual Perceptual Learning

Understanding visual perceptual learning (VPL) has become increasingly more challenging as new phenomena are discovered with novel stimuli and training paradigms. Although existing models aid our knowledge of critical aspects of VPL, the connections shown by these models between behavioral learning and plasticity across different brain areas are typically superficial. Most models explain VPL as readout from simple perceptual representations to decision areas and are not easily adaptable to explain new findings. Here, we show that a well -known instance of deep neural network (DNN), whereas not designed specifically for VPL, provides a computational model of VPL with enough complexity to be studied at many levels of analyses. After learning a Gabor orientation discrimination task, the DNN model reproduced key behavioral results, including increasing specificity with higher task precision, and also suggested that learning precise discriminations could transfer asymmetrically to coarse discriminations when the stimulus conditions varied. Consistent with the behavioral findings, the distribution of plasticity moved toward lower layers when task precision increased and this distribution was also modulated by tasks with different stimulus types. Furthermore, learning in the network units demonstrated close resemblance to extant electrophysiological recordings in monkey visual areas. Altogether, the DNN fulfilled predictions of existing theories regarding specificity and plasticity and reproduced findings of tuning changes in neurons of the primate visual areas. Although the comparisons were mostly qualitative, the DNN provides a new method of studying VPL, can serve as a test bed for theories, and assists in generating predictions for physiological investigations.

SIGNIFICANCE STATEMENT Visual perceptual learning (VPL) has been found to cause changes at multiple stages of the visual hierarchy. We found that training a deep neural network (DNN) on an orientation discrimination task produced behavioral and physiological patterns similar to those found in human and monkey experiments. Unlike existing VPL models, the DNN was pre-trained on natural images to reach high performance in object recognition, but was not designed specifically for VPL; however, it fulfilled predictions of existing theories regarding specificity and plasticity and reproduced findings of tuning changes in neurons of the primate visual areas. When used with care, this unbiased and deep-hierarchical model can provide new ways of studying VPL from behavior to physiology.

Neural Coding of Whisker-Mediated Touch in Primary Somatosensory Cortex Is Altered Following Early Blindness

Sensory systems do not develop and function independently of one another, yet they are typically studied in isolation. Effects of multisensory interactions on the developing neocortex can be revealed by altering the ratios of incoming sensory inputs associated with different modalities. We investigated neural responses in primary somatosensory cortex (S1) of short-tailed opossums (Monodelphis domestica; either sex) after the elimination of visual input through bilateral enucleation very early in development. To assess the influence of tactile experience after vision loss, we also examined naturally occurring patterns of exploratory behavior. In early blind (EB) animals, overall levels of tactile experience were similar to those of sighted controls (SC); locomotor activity was unimpaired and accompanied by whisking. Using extracellular single-unit recording techniques under anesthesia, we found that EB animals exhibited a reduction in the magnitude of neural responses to whisker stimuli in S1, coupled with spatial sharpening of receptive fields, in comparison to SC animals. These alterations manifested as two different effects on sensory processing in S1 of EB animals: the ability of neurons to detect single whisker stimulation was decreased, whereas their ability to discriminate between stimulation of neighboring whiskers was enhanced. The increased selectivity of S1 neurons in EB animals was reflected in improved population decoding performance for whisker stimulus position, particularly along the rostrocaudal axis of the snout, which aligns with the primary axis of natural whisker motion. These findings suggest that a functionally distinct form of somatosensory plasticity occurs when vision is lost early in development.

SIGNIFICANCE STATEMENT After sensory loss, compensatory behavior mediated through the spared senses could be generated entirely through the recruitment of brain areas associated with the deprived sense. Alternatively, functional compensation in spared modalities may be achieved through a combination of plasticity in brain areas corresponding to both spared and deprived sensory modalities. Although activation of neurons in cortex associated with a deprived sense has been described frequently, it is unclear whether this is the only substrate available for compensation or if plasticity within cortical fields corresponding to spared modalities, particularly primary sensory cortices, may also contribute. Here, we demonstrate empirically that early loss of vision alters coding of sensory inputs in primary somatosensory cortex in a manner that supports enhanced tactile discrimination.

Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.

SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, because FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease.

This Week in The Journal

Glial {beta}II Spectrin Contributes to Paranode Formation and Maintenance

Action potential conduction along myelinated axons depends on high densities of voltage-gated Na⁺ channels at the nodes of Ranvier. Flanking each node, paranodal junctions (paranodes) are formed between axons and Schwann cells in the peripheral nervous system (PNS) or oligodendrocytes in the CNS. Paranodal junctions contribute to both node assembly and maintenance. Despite their importance, the molecular mechanisms responsible for paranode assembly and maintenance remain poorly understood. βII spectrin is expressed in diverse cells and is an essential part of the submembranous cytoskeleton. Here, we show that Schwann cell βII spectrin is highly enriched at paranodes. To elucidate the roles of glial βII spectrin, we generated mutant mice lacking βII spectrin in myelinating glial cells by crossing mice with a floxed allele of Sptbn1 with Cnp-Cre mice, and analyzed both male and female mice. Juvenile (4 weeks) and middle-aged (60 weeks) mutant mice showed reduced grip strength and sciatic nerve conduction slowing, whereas no phenotype was observed between 8 and 24 weeks of age. Consistent with these findings, immunofluorescence microscopy revealed disorganized paranodes in the PNS and CNS of both postnatal day 13 and middle-aged mutant mice, but not in young adult mutant mice. Electron microscopy confirmed partial loss of transverse bands at the paranodal axoglial junction in the middle-aged mutant mice in both the PNS and CNS. These findings demonstrate that a spectrin-based cytoskeleton in myelinating glia contributes to formation and maintenance of paranodal junctions.

SIGNIFICANCE STATEMENT Myelinating glia form paranodal axoglial junctions that flank both sides of the nodes of Ranvier. These junctions contribute to node formation and maintenance and are essential for proper nervous system function. We found that a submembranous spectrin cytoskeleton is highly enriched at paranodes in Schwann cells. Ablation of βII spectrin in myelinating glial cells disrupted the paranodal cell adhesion complex in both peripheral and CNSs, resulting in muscle weakness and sciatic nerve conduction slowing in juvenile and middle-aged mice. Our data show that a spectrin-based submembranous cytoskeleton in myelinating glia plays important roles in paranode formation and maintenance.

Perineuronal Nets in the Deep Cerebellar Nuclei Regulate GABAergic Transmission and Delay Eyeblink Conditioning

Perineuronal nets (PNNs), composed mainly of chondroitin sulfate proteoglycans, are the extracellular matrix that surrounds cell bodies, proximal dendrites, and axon initial segments of adult CNS neurons. PNNs are known to regulate neuronal plasticity, although their physiological roles in cerebellar functions have yet to be elucidated. Here, we investigated the contribution of PNNs to GABAergic transmission from cerebellar Purkinje cells (PCs) to large glutamatergic neurons in the deep cerebellar nuclei (DCN) in male mice by recording IPSCs from cerebellar slices, in which PNNs were depleted with chondroitinase ABC (ChABC). We found that PNN depletion increased the amplitude of evoked IPSCs and enhanced the paired-pulse depression. ChABC treatment also facilitated spontaneous IPSCs and increased the miniature IPSC frequency without changing not only the amplitude but also the density of PC terminals, suggesting that PNN depletion enhances presynaptic GABA release. We also demonstrated that the enhanced GABAergic transmission facilitated rebound firing in large glutamatergic DCN neurons, which is expected to result in the efficient induction of synaptic plasticity at synapses onto DCN neurons. Furthermore, we tested whether PNN depletion affects cerebellar motor learning. Mice having received the enzyme into the interpositus nuclei, which are responsible for delay eyeblink conditioning, exhibited the conditioned response at a significantly higher rate than control mice. Therefore, our results suggest that PNNs of the DCN suppress GABAergic transmission between PCs and large glutamatergic DCN neurons and restrict synaptic plasticity associated with motor learning in the adult cerebellum.

SIGNIFICANCE STATEMENT Perineuronal nets (PNNs) are one of the extracellular matrices of adult CNS neurons and implicated in regulating various brain functions. Here we found that enzymatic PNN depletion in the mouse deep cerebellar nuclei (DCN) reduced the paired-pulse ratio of IPSCs and increased the miniature IPSC frequency without changing the amplitude, suggesting that PNN depletion enhances GABA release from the presynaptic Purkinje cell (PC) terminals. Mice having received the enzyme in the interpositus nuclei exhibited a higher conditioned response rate in delay eyeblink conditioning than control mice. These results suggest that PNNs regulate presynaptic functions of PC terminals in the DCN and functional plasticity of synapses on DCN neurons, which influences the flexibility of adult cerebellar functions.

Neural Prediction Errors Distinguish Perception and Misperception of Speech

Humans use prior expectations to improve perception, especially of sensory signals that are degraded or ambiguous. However, if sensory input deviates from prior expectations, then correct perception depends on adjusting or rejecting prior expectations. Failure to adjust or reject the prior leads to perceptual illusions, especially if there is partial overlap (and thus partial mismatch) between expectations and input. With speech, "slips of the ear" occur when expectations lead to misperception. For instance, an entomologist might be more susceptible to hear "The ants are my friends" for "The answer, my friend" (in the Bob Dylan song Blowing in the Wind). Here, we contrast two mechanisms by which prior expectations may lead to misperception of degraded speech. First, clear representations of the common sounds in the prior and input (i.e., expected sounds) may lead to incorrect confirmation of the prior. Second, insufficient representations of sounds that deviate between prior and input (i.e., prediction errors) could lead to deception. We used crossmodal predictions from written words that partially match degraded speech to compare neural responses when male and female human listeners were deceived into accepting the prior or correctly reject it. Combined behavioral and multivariate representational similarity analysis of fMRI data show that veridical perception of degraded speech is signaled by representations of prediction error in the left superior temporal sulcus. Instead of using top-down processes to support perception of expected sensory input, our findings suggest that the strength of neural prediction error representations distinguishes correct perception and misperception.

SIGNIFICANCE STATEMENT Misperceiving spoken words is an everyday experience, with outcomes that range from shared amusement to serious miscommunication. For hearing-impaired individuals, frequent misperception can lead to social withdrawal and isolation, with severe consequences for wellbeing. In this work, we specify the neural mechanisms by which prior expectations, which are so often helpful for perception, can lead to misperception of degraded sensory signals. Most descriptive theories of illusory perception explain misperception as arising from a clear sensory representation of features or sounds that are in common between prior expectations and sensory input. Our work instead provides support for a complementary proposal: that misperception occurs when there is an insufficient sensory representations of the deviation between expectations and sensory signals.

Neural Network Interactions Modulate CRY-Dependent Photoresponses in Drosophila

Light is one of the chief environmental cues that reset circadian clocks. In Drosophila, CRYPTOCHROME (CRY) mediates acute photic resetting of circadian clocks by promoting the degradation of TIMELESS in a cell-autonomous manner. Thus, even circadian oscillators in peripheral organs can independently perceive light in Drosophila. However, there is substantial evidence for nonautonomous mechanisms of circadian photoreception in the brain. We have previously shown that the morning (M) and evening (E) oscillators are critical light-sensing neurons that cooperate to shift the phase of circadian behavior in response to light input. We show here that light can efficiently phase delay or phase advance circadian locomotor behavior in male Drosophila even when either the M- or the E-oscillators are ablated, suggesting that behavioral phase shifts and their directionality are largely a consequence of the cell-autonomous nature of CRY-dependent photoreception. Our observation that the phase response curves of brain and peripheral oscillators are remarkably similar further supports this idea. Nevertheless, the neural network modulates circadian photoresponses. We show that the M-oscillator neurotransmitter pigment dispersing factor plays a critical role in the coordination between M- and E-oscillators after light exposure, and we uncover a potential role for a subset of dorsal neurons in the control of phase advances. Thus, neural modulation of autonomous light detection might play an important role in the plasticity of circadian behavior.

SIGNIFICANCE STATEMENT Input pathways provide circadian rhythms with the flexibility needed to harmonize their phase with environmental cycles. Light is the chief environmental cue that synchronizes circadian clocks. In Drosophila, the photoreceptor CRYPTOCHROME resets circadian clocks cell-autonomously. However, recent studies indicate that, in the brain, interactions between clock neurons are critical to reset circadian locomotor behavior. We present evidence supporting the idea that the ability of flies to advance or delay their rhythmic behavior in response to light input essentially results from cell-autonomous photoreception. However, because of their networked organization, we find that circadian neurons have to cooperate to reset the phase of circadian behavior in response to photic cues. Our work thus helps to reconcile cell-autonomous and non-cell-autonomous models of circadian entrainment.

Nerve Injury-Induced Chronic Pain Is Associated with Persistent DNA Methylation Reprogramming in Dorsal Root Ganglion

Nerve injury-induced hyperactivity of primary sensory neurons in the dorsal root ganglion (DRG) contributes to chronic pain development, but the underlying epigenetic mechanisms remain poorly understood. Here we determined genome-wide changes in DNA methylation in the nervous system in neuropathic pain. Spinal nerve ligation (SNL), but not paclitaxel treatment, in male Sprague Dawley rats induced a consistent low-level hypomethylation in the CpG sites in the DRG during the acute and chronic phases of neuropathic pain. DNA methylation remodeling in the DRG occurred early after SNL and persisted for at least 3 weeks. SNL caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands, in introns, intergenic regions, and repetitive sequences. In contrast, SNL caused more gains of methylation in the spinal cord and prefrontal cortex. The DNA methylation changes in the injured DRGs recapitulated developmental reprogramming at the neonatal stage. Methylation reprogramming was correlated with increased gene expression variability. A diet deficient in methyl donors induced hypomethylation and pain hypersensitivity. Intrathecal administration of the DNA methyltransferase inhibitor RG108 caused long-lasting pain hypersensitivity. DNA methylation reprogramming in the DRG thus contributes to nerve injury-induced chronic pain. Restoring DNA methylation may represent a new therapeutic approach to treat neuropathic pain.

SIGNIFICANCE STATEMENT Epigenetic mechanisms are critically involved in the transition from acute to chronic pain after nerve injury. However, genome-wide changes in DNA methylation in the nervous system and their roles in neuropathic pain development remain unclear. Here we used digital restriction enzyme analysis of methylation to quantitatively determine genome-wide DNA methylation changes caused by nerve injury. We showed that nerve injury caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands in the dorsal root ganglion. Reducing DNA methylation induced pain hypersensitivity, whereas increasing DNA methylation attenuated neuropathic pain. These findings extend our understanding of the epigenetic mechanism of chronic neuropathic pain and suggest new strategies to treat nerve injury-induced chronic pain.

Classification of Neurons in the Primate Reticular Formation and Changes after Recovery from Pyramidal Tract Lesion

The reticular formation is important in primate motor control, both in health and during recovery after brain damage. Little is known about the different neurons present in the reticular nuclei. Here we recorded extracellular spikes from the reticular formation in five healthy female awake behaving monkeys (193 cells), and in two female monkeys 1 year after recovery from a unilateral pyramidal tract lesion (125 cells). Analysis of spike shape and four measures derived from the interspike interval distribution identified four clusters of neurons in control animals. Cluster 1 cells had a slow firing rate. Cluster 2 cells had narrow spikes and irregular firing, which often included high-frequency bursts. Cluster 3 cells were highly rhythmic and fast firing. Cluster 4 cells showed negative spikes. A separate population of 42 cells was antidromically identified as reticulospinal neurons in five anesthetized female monkeys. The distribution of spike width in these cells closely overlaid the distribution for cluster 2, leading us tentatively to suggest that cluster 2 included neurons with reticulospinal projections. In animals after corticospinal lesion, cells could be identified in all four clusters. The firing rate of cells in clusters 1 and 2 was increased in lesioned animals relative to control animals (by 52% and 60%, respectively); cells in cluster 2 were also more regular and more bursting in the lesioned animals. We suggest that changes in both membrane properties and local circuits within the reticular formation occur following lesioning, potentially increasing reticulospinal output to help compensate for lost corticospinal descending drive.

SIGNIFICANCE STATEMENT This work is the first to subclassify neurons in the reticular formation, providing insights into the local circuitry of this important but little understood structure. The approach developed can be applied to any extracellular recording from this region, allowing future studies to place their data within our current framework of four neural types. Changes in reticular neurons may be important to subserve functional recovery after damage in human patients, such as after stroke or spinal cord injury.

Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

Activating Transcription Factor 4 (ATF4) has been postulated as a key regulator of learning and memory. We previously reported that specific hippocampal ATF4 downregulation causes deficits in synaptic plasticity and memory and reduction of glutamatergic functionality. Here we extend our studies to address ATF4's role in neuronal excitability. We find that long-term ATF4 knockdown in cultured rat hippocampal neurons significantly increases the frequency of spontaneous action potentials. This effect is associated with decreased functionality of metabotropic GABA_B receptors (GABA_BRs). Knocking down ATF4 results in significant reduction of GABA_BR-induced GIRK currents and increased mIPSC frequency. Furthermore, reducing ATF4 significantly decreases expression of membrane-exposed, but not total, GABA_BR 1a and 1b subunits, indicating that ATF4 regulates GABA_BR trafficking. In contrast, ATF4 knockdown has no effect on surface expression of GABA_BR2s, several GABA_BR-coupled ion channels or β2 and 2 GABA_ARs. Pharmacologic manipulations confirmed the relationship between GABA_BR functionality and action potential frequency in our cultures. Specifically, the effects of ATF4 downregulation cited above are fully rescued by transcriptionally active, but not by transcriptionally inactive, shRNA-resistant, ATF4. We previously reported that ATF4 promotes stabilization of the actin-regulatory protein Cdc42 by a transcription-dependent mechanism. To test the hypothesis that this action underlies the mechanism by which ATF4 loss affects neuronal firing rates and GABA_BR trafficking, we downregulated Cdc42 and found that this phenocopies the effects of ATF4 knockdown on these properties. In conclusion, our data favor a model in which ATF4, by regulating Cdc42 expression, affects trafficking of GABA_BRs, which in turn modulates the excitability properties of neurons.

SIGNIFICANCE STATEMENT GABA_B receptors (GABA_BRs), the metabotropic receptors for the inhibitory neurotransmitter GABA, have crucial roles in controlling the firing rate of neurons. Deficits in trafficking/functionality of GABA_BRs have been linked to a variety of neurological and psychiatric conditions, including epilepsy, anxiety, depression, schizophrenia, addiction, and pain. Here we show that GABA_BRs trafficking is influenced by Activating Transcription Factor 4 (ATF4), a protein that has a pivotal role in hippocampal memory processes. We found that ATF4 downregulation in hippocampal neurons reduces membrane-bound GABA_BR levels and thereby increases intrinsic excitability. These effects are mediated by loss of the small GTPase Cdc42 following ATF4 downregulation. These findings reveal a critical role for ATF4 in regulating the modulation of neuronal excitability by GABA_BRs.

Oscillatory Encoding of Visual Stimulus Familiarity

Familiarity of the environment changes the way we perceive and encode incoming information. However, the neural substrates underlying this phenomenon are poorly understood. Here we describe a new form of experience-dependent low-frequency oscillations in the primary visual cortex (V1) of awake adult male mice. The oscillations emerged in visually evoked potentials and single-unit activity following repeated visual stimulation. The oscillations were sensitive to the spatial frequency content of a visual stimulus and required the mAChRs for their induction and expression. Finally, ongoing visually evoked (4–8 Hz) oscillations boost the visually evoked potential amplitude of incoming visual stimuli if the stimuli are presented at the high excitability phase of the oscillations. Our results demonstrate that an oscillatory code can be used to encode familiarity and serves as a gate for oncoming sensory inputs.

SIGNIFICANCE STATEMENT Previous experience can influence the processing of incoming sensory information by the brain and alter perception. However, the mechanistic understanding of how this process takes place is lacking. We have discovered that persistent low-frequency oscillations in the primary visual cortex encode information about familiarity and the spatial frequency of the stimulus. These familiarity evoked oscillations influence neuronal responses to the oncoming stimuli in a way that depends on the oscillation phase. Our work demonstrates a new mechanism of visual stimulus feature detection and learning.