Dendrite intercalation between epidermal cells tunes nociceptor sensitivity to mechanical stimuli in Drosophila larvae.

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli. In wild-type larvae, dendrites of nociceptive class IV da neurons intercalate between epidermal cells at apodemes, which function as body wall muscle attachment sites, but not at other sites in the epidermis. From a genetic screen we identified miR-14 as a regulator of dendrite positioning in the epidermis: miR-14 is expressed broadly in the epidermis but not in apodemes, and miR-14 inactivation leads to excessive apical dendrite intercalation between epidermal cells. We found that miR-14 regulates expression and distribution of the epidermal Innexins ogre and Inx2 and that these epidermal gap junction proteins restrict epidermal dendrite intercalation. Finally, we found that altering the extent of epidermal dendrite intercalation had corresponding effects on nociception: increasing epidermal intercalation sensitized larvae to noxious mechanical inputs and increased mechanically evoked calcium responses in nociceptive neurons, whereas reducing epidermal dendrite intercalation had the opposite effects. Altogether, these studies identify epidermal dendrite intercalation as a mechanism for mechanical coupling of nociceptive neurons to the epidermis, with nociceptive sensitivity tuned by the extent of intercalation.

Dendrite intercalation between epidermal cells tunes nociceptor sensitivity to mechanical stimuli in Drosophila larvae.

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli. In wild-type larvae, dendrites of nociceptive class IV da neurons intercalate between epidermal cells at apodemes, which function as body wall muscle attachment sites, but not at other sites in the epidermis. From a genetic screen we identified miR-14 as a regulator of dendrite positioning in the epidermis: miR-14 is expressed broadly in the epidermis but not in apodemes, and miR-14 inactivation leads to excessive apical dendrite intercalation between epidermal cells. We found that miR-14 regulates expression and distribution of the epidermal Innexins ogre and Inx2 and that these epidermal gap junction proteins restrict epidermal dendrite intercalation. Finally, we found that altering the extent of epidermal dendrite intercalation had corresponding effects on nociception: increasing epidermal intercalation sensitized larvae to noxious mechanical inputs and increased mechanically evoked calcium responses in nociceptive neurons, whereas reducing epidermal dendrite intercalation had the opposite effects. Altogether, these studies identify epidermal dendrite intercalation as a mechanism for mechanical coupling of nociceptive neurons to the epidermis, with nociceptive sensitivity tuned by the extent of intercalation.

Pure and Mixed Desmoplastic Melanomas: A Retrospective Clinicopathologic Comparison of 33 Cases.

BACKGROUND: Pure and mixed desmoplastic melanomas (DMs) may have different natural histories and behaviors. METHODS: We conducted a retrospective review of patients diagnosed with DM at our institution between January 1997 and April 2019. A total of 33 unique DMs were identified and subsequently analyzed based on the histologic type (pure vs. mixed). RESULTS: The majority (57.6%) of our cases were classified as pure histology. Patients with pure DMs were more likely to be men (P = 0.035) and be older than 65 years (P = 0.019) compared with patients with mixed DMs. Patients with mixed DM were more likely to have mitoses present (P = 0.001) compared with patients with pure DM. There were no differences in ulceration, perineural invasion, vascular invasion, or survival between patients with pure and mixed histologic subtypes. In addition, no differences in sentinel lymph node biopsy, radiation, or chemotherapy were noted between the 2 histologic subtypes. Immunohistochemistry showed that 27.3% of the pure DMs stained with Melan-A and HMB45 were positive for these immunomarkers. CONCLUSIONS: Pure and mixed variants of DM were found to have similar clinicopathologic characteristics. Patients with the mixed histologic subtype were more likely to have mitoses, but no difference in the therapeutic management or patient survival was seen between the 2 subtypes.

The Immune System and Pathogenesis of Melanoma and Non-melanoma Skin Cancer.

Tumor development is the result of genetic derangement and the inability to prevent unfettered proliferation. Genetic derangements leading to tumorigenesis are variable, but the immune system plays a critical role in tumor development, prevention, and production. In this chapter, we will discuss the importance of the immune system as it relates to the development of skin cancer-both melanoma and non-melanoma skin cancers (NMSC).

Clinical Psoriasiform Dermatitis Following Dupilumab Use for Autoeczematization Secondary to Chronic Stasis Dermatitis.

T helper 2 (Th2) and T helper 1 (Th1) mediated immune processes lie on a spectrum. Autoeczematization secondary to chronic stasis dermatitis may fall on the Th2 side of the spectrum due to skin stretch and chronic barrier dysfunction, supporting a primary Th2 response to self-antigen. In our patient, we posited that dupilumab would benefit autoeczematization secondary to chronic stasis dermatitis given its efficacy in atopic dermatitis, a Th2-mediated immune process. We report a case of clinical psoriasiform dermatitis, suggesting a shift toward a Th1-mediated immune process developing during dupilumab treatment for autoeczematization secondary to chronic stasis dermatitis.

Psoriasis and Psoriatic Arthritis Cardiovascular Disease Endotypes Identified by Red Blood Cell Distribution Width and Mean Platelet Volume.

In a subset of psoriasis (PsO) and psoriatic arthritis (PsA) patients, the skin and/or joint lesions appear to generate biologically significant systemic inflammation. Red cell distribution width (RDW) and mean platelet volume (MPV) are readily available clinical tests that reflect responses of the bone marrow and/or plasma thrombogenicity (e.g., inflammation), and can be markers for major adverse cardiac events (MACE). We aimed to evaluate if RDW and MPV may be employed as inexpensive, routinely obtained biomarkers in predicting myocardial infarction (MI), atrial fibrillation (AF), and chronic heart failure (CHF) in psoriatic and psoriatic arthritis patients. The study was divided into two parts: (a) case control study employing big data (Explorys) to assess MPV and RDW in psoriasis, psoriatic arthritis and control cohorts; (b) a clinical observational study to validate the predictive value of RDW and to evaluate RDW response to anti-psoriatic therapies. We used Explorys, an aggregate electronic database, to identify psoriatic patients with available MPV and RDW data and compared them to gender and age matched controls. The incidence of myocardial infarction (MI), atrial fibrillation (AF), and chronic heart failure (CHF) was highest among patients with both elevated RDW and MPV, followed by patients with high RDW and normal MPV. RDW elevation among PsA patients was associated with an increased risk of MI, AF, and CHF. In a local clinical cohort, high RDWs were concentrated in a subset of patients who also had elevated circulating resistin levels. Among a small subset of participants who were treated with various systemic and biologic therapies, and observed over a year, and in whom RDW was elevated at baseline, a sustained response to therapy was associated with a decrease in RDW. RDW and MPV, tests commonly contained within routine complete blood count (CBC), may be a cost-effective manner to identify PsO and PsA patients at increased risk of MACE.

Low-dose naltrexone: a unique treatment for amyopathic dermatomyositis.

Gottron papules, a heliotrope rash, scalp and extremity erythema, pruritus, and fatigue are the characteristic signs and symptoms of amyopathic dermatomyositis (ADM). Amyopathic dermatomyositis is considered a distinct entity from dermatomyositis (DM) because the characteristic muscle weakness and muscle enzyme elevations of DM are absent in ADM. With respects to treatment, ADM treatments have traditionally included topical corticosteroids and/or systemic immunosuppressants and immunomodulators. Herein we present a patient with refractory ADM that was responsive to low-dose naltrexone therapy.

Utilization and Cost of Inpatient Dermatologic Procedures: A Cross-sectional Analysis.

Knowledge surrounding inpatient dermatologic procedure costs is limited; therefore to learn more, we performed a cross-sectional analysis of dermatologic procedures contained in a publicly available Washington State Comprehensive Hospital Abstract Reporting System database from 2014. Dermatologic procedure utilization and cost were evaluated based on several parameters including demographics, length of hospital stay, payments, and payers. SAS 9.4 was used for the analysis. A total of 14,768 patients underwent dermatologic procedures in 2014 and 81.0% were white. The average age was 53 years (SD = 0.17), and the average payment for all patients who underwent dermatologic procedures was $85,059.48 (SD = $1,284.34). The average hospital length of stay was 8.91 days (SD = 0.07). The most common admission type was elective (66.2%), the most common admit source was a non-healthcare facility point of origin (78.2%), the most common primary payer was Medicare (36.2%), and the most common procedure was incision and drainage of skin and subcutaneous tissue (26.5%), followed by closure of skin and subcutaneous tissue of other sites (20%). This analysis demonstrated that inpatient dermatologic procedures are a significant driver of inpatient health care costs, and it is critical to determine factors that increase inpatient costs related to dermatologic procedures in order to develop strategies for reducing healthcare costs.

Effects of a Novel Probiotic Combination on Pathogenic Bacterial-Fungal Polymicrobial Biofilms.

Dysbiosis of the gut microbiome has been implicated in inflammatory bowel diseases. We have shown that levels of Candida tropicalis, along with those of Escherichia coli and Serratia marcescens, are significantly elevated in Crohn's disease (CD) patients. Here, we evaluated the ability of a novel probiotic to prevent and treat polymicrobial biofilms (PMB) formed by C. tropicalis with E. coli and S. marcescens Since Candida albicans has been reported to be elevated in CD patients, we investigated the interactions of C. albicans with these bacterial species in biofilm formation. We determined whether the interaction between Candida spp. and bacteria is specific by using Trichosporon inkin and Saccharomyces fibuligera as comparators. Additionally, the effects of probiotics on C. albicans germination and biofilm formation were determined. To determine the ability of the probiotic to prevent or treat mature biofilms, probiotic filtrate was added to the PMB at early (prevention) and mature (treatment) phases. Biofilm thickness and architecture were assessed by confocal scanning laser microscopy. The effects of the probiotic on germination were evaluated in the presence of serum. Exposure of C. tropicalis PMB to probiotic filtrate reduced biofilm matrix, decreased thickness, and inhibited hyphal formation. We showed that C. albicans or C. tropicalis formed significantly thicker PMB than control biofilms, indicating that this interaction is Candida specific. Treatment with probiotic filtrate inhibited C. albicans germination and prevented/treated C. albicans PMB. The designed probiotic may have utility in the management of biofilm-associated gastrointestinal diseases such as Crohn's and colorectal cancer.IMPORTANCE The effects of diversity of the gut microbiome on inflammation have centered mainly on bacterial flora. Recent research has implicated fungal species and their interactions with other organisms in the inflammatory process. New ways to restore microbial balance in the gut are being explored. Our goal was to identify beneficial probiotic strains that would antagonize these fungal and bacterial pathogens that are elevated in the inflamed gut, and which also have antibiofilm activity. Fungus-bacterium correlation analysis allowed us to identify candidate probiotic species that can antagonize microbial pathogens, which we subsequently incorporated into a novel probiotic formulation. Amylase, which is known to have some antibiofilm activity, was also added to the probiotic mixture. This novel probiotic may have utility for the management of inflammatory bowel diseases by disrupting polymicrobial biofilm formation.

A conserved morphogenetic mechanism for epidermal ensheathment of nociceptive sensory neurites.

Interactions between epithelial cells and neurons influence a range of sensory modalities including taste, touch, and smell. Vertebrate and invertebrate epidermal cells ensheath peripheral arbors of somatosensory neurons, including nociceptors, yet the developmental origins and functional roles of this ensheathment are largely unknown. Here, we describe an evolutionarily conserved morphogenetic mechanism for epidermal ensheathment of somatosensory neurites. We found that somatosensory neurons in Drosophila and zebrafish induce formation of epidermal sheaths, which wrap neurites of different types of neurons to different extents. Neurites induce formation of plasma membrane phosphatidylinositol 4,5-bisphosphate microdomains at nascent sheaths, followed by a filamentous actin network, and recruitment of junctional proteins that likely form autotypic junctions to seal sheaths. Finally, blocking epidermal sheath formation destabilized dendrite branches and reduced nociceptive sensitivity in Drosophila. Epidermal somatosensory neurite ensheathment is thus a deeply conserved cellular process that contributes to the morphogenesis and function of nociceptive sensory neurons.

Acne Severity and Sleep Quality in Adults.

Poor sleep quality is extremely prevalent, with about one third of adults in the USA obtaining less than the recommended amount of sleep. In addition, poor sleep quality has been linked to an increased risk of many conditions, including diabetes, hypertension, psychiatric conditions, and overall all-cause mortality. Research has shown that sleep disturbance does impact skin disease, although many details of this relationship are still unclear. The goal of this study is to determine if there is a relationship between acne severity and sleep quality in adults. Forty subjects with acne were recruited from dermatology clinics in Cleveland, OH, to participate in this study. Acne severity was assessed using the Global Acne Grading Scale (GAGS). To assess sleep quality, subjects completed the Pittsburgh Sleep Quality Index (PSQI) and completed a seven-day sleep journal. Subjects also completed the Dermatology Life Quality Index (DLQI), the Patient Health Questionnaire-2 (PHQ-2), and provided information about current and past acne treatments as well as their opinion regarding their own acne severity and exacerbating factors. Our findings support the hypothesis that there is a potential relationship between sleep quality and acne.

The ICM research agenda on critical care ultrasonography.

PURPOSE: Critical care ultrasonography has utility for the diagnosis and management of critical illness and is in widespread use by frontline intensivists. As there is a need for research to validate and extend its utility, the Editor of Intensive Care Medicine included critical care ultrasonography as a topic in the ICM Research Agenda issue. METHODS: Eleven international experts in the field of critical care ultrasonography contributed to the writing project. With the intention of developing a research agenda for the field, they reviewed best standards of care, new advances in the field, common beliefs that have been contradicted by recent trials, and unanswered questions related to critical care ultrasonography. RESULTS: The writing group focused on the provision of training in critical care ultrasonography, technological advances, and some specific clinical applications. CONCLUSIONS: The writing group identified several fields of interest for research and proposed ten research studies that would address important aspects of critical care ultrasonography.

In vitro quantification of time dependent thrombus size using magnetic resonance imaging and computational simulations of thrombus surface shear stresses.

Thrombosis and thromboembolization remain large obstacles in the design of cardiovascular devices. In this study, the temporal behavior of thrombus size within a backward-facing step (BFS) model is investigated, as this geometry can mimic the flow separation which has been found to contribute to thrombosis in cardiac devices. Magnetic resonance imaging (MRI) is used to quantify thrombus size and collect topographic data of thrombi formed by circulating bovine blood through a BFS model for times ranging between 10 and 90 min at a constant upstream Reynolds number of 490. Thrombus height, length, exposed surface area, and volume are measured, and asymptotic behavior is observed for each as the blood circulation time is increased. Velocity patterns near, and wall shear stress (WSS) distributions on, the exposed thrombus surfaces are calculated using computational fluid dynamics (CFD). Both the mean and maximum WSS on the exposed thrombus surfaces are much more dependent on thrombus topography than thrombus size, and the best predictors for asymptotic thrombus length and volume are the reattachment length and volume of reversed flow, respectively, from the region of separated flow downstream of the BFS.

Impact of financial incentives on documented immunization rates in the inner city: results of a randomized controlled trial.

OBJECTIVE: This study determined the effect of 2 financial incentives---bonus and enhanced fee-for-service---on documented immunization rates during a second period of observation. METHODS: Incentives were given to 57 randomly selected inner-city physicians 4 times at 4-month intervals based on the performance of 50 randomly selected children. Coverage from linked records from all sources was determined for a subsample of children within physician offices. RESULTS: Up-to-date coverage rates documented in the charts increased significantly for children in the bonus group (49.7% to 55.6%; P <.05) and the enhanced fee-for-service group (50.8% to 58.2%; P <.01) compared with the control group. The number of immunizations given by these physicians did not change significantly, although the number of immunizations given by others and documented by physicians in the bonus group did increase (P <.05). Up-to-date coverage for all groups increased from 20 to 40 percentage points when immunizations from physician charts were combined with other sources. CONCLUSIONS: Both financial incentives produced a significant increase in coverage levels. Increases were primarily due to better documentation not to better immunizing practices. The financial incentives appeared to provide motivation to physicians but were not sufficient to overcome entrenched behavior patterns. However, true immunization coverage was substantially higher than that documented in the charts.