Subepidermal calcified nodule presenting as a cutaneous horn: two cases and a review of the literature.

Subepidermal calcified nodules are an uncommon subtype of idiopathic calcinosis cutis. Morphologically, this entity typically present as a single, well-circumscribed, white-yellow nodule. Based on clinical appearance alone, subepidermal calcified nodules are frequently misdiagnosed and often requires histological confirmation. We describe two cases of subepidermal calcified nodules presenting atypically as cutaneous horns. Subepidermal calcified nodules presenting as a cutaneous horn has rarely been reported; on review, there are fewer than 10 such cases have been described within the past 30 years. The cases described here illustrate the clinical variety and should increase awareness of subepidermal calcified nodules presented.

Differences Between Female Singers With Phonotrauma and Vocally Healthy Matched Controls in Singing and Speaking Voice Use During 1 Week of Ambulatory Monitoring.

Purpose Previous ambulatory voice monitoring studies have included many singers and have combined speech and singing in the analyses. This study applied a singing classifier to the ambulatory recordings of singers with phonotrauma and healthy controls to determine if analyzing speech and singing separately would reveal voice use differences that could provide new insights into the etiology and pathophysiology of phonotrauma in this at-risk population. Method Forty-two female singers with phonotrauma (vocal fold nodules or polyps) and 42 healthy matched controls were monitored using an ambulatory voice monitor. Weeklong statistics (average, standard deviation, skewness, kurtosis) for sound pressure level (SPL), fundamental frequency, cepstral peak prominence, the magnitude ratio of the first two harmonics (H1-H2 ), and three vocal dose measures were computed from the neck surface acceleration signal and separated into singing and speech using a singing classifier. Results Mixed analysis of variance models found expected differences between singing and speech in each voice parameter, except SPL kurtosis. SPL skewness, SPL kurtosis, and all H1-H2 distributional parameters differentiated patients and controls when singing and speech were combined. Interaction effects were found in H1-H2 kurtosis and all vocal dose measures. Patients had significantly higher vocal doses in speech compared to controls. Conclusions Consistent with prior work, the pathophysiology of phonotrauma in singers is characterized by more abrupt/complete glottal closure (decreased mean and variation for H1-H2 ) and increased laryngeal forces (negatively skewed SPL distribution) during phonation. Application of a singing classifier to weeklong data revealed that singers with phonotrauma spent more time speaking on a weekly basis, but not more time singing, compared to controls. Results are used as a basis for hypothesizing about the role of speaking voice in the etiology of phonotraumatic vocal hyperfunction in singers.

Changes in a Daily Phonotrauma Index After Laryngeal Surgery and Voice Therapy: Implications for the Role of Daily Voice Use in the Etiology and Pathophysiology of Phonotraumatic Vocal Hyperfunction.

Purpose This study attempts to gain insights into the role of daily voice use in the etiology and pathophysiology of phonotraumatic vocal hyperfunction (PVH) by applying a logistic regression-based daily phonotrauma index (DPI) to predict group-based improvements in patients with PVH after laryngeal surgery and/or postsurgical voice therapy. Method A custom-designed ambulatory voice monitor was used to collect 1 week of pre- and postsurgery data from 27 female patients with PVH; 13 of these patients were also monitored after postsurgical voice therapy. Normative weeklong data were obtained from 27 matched controls. Each week was represented by the DPI, standard deviation of the difference between the first and second harmonic amplitudes (H1-H2). Results Compared to pretreatment, the DPI significantly decreased in the patient group after surgery (Cohen's d effect size = -0.86) and voice therapy (d = -1.06). The patient group DPI only normalized after voice therapy. Conclusions The DPI produced the expected pattern of improved ambulatory voice use across laryngeal surgery and postsurgical voice therapy in a group of patients with PVH. The results were interpreted as providing new objective information about the role of daily voice use in the etiology and pathophysiology of PVH. The DPI is viewed as an estimate of potential vocal fold trauma that relies on combining the long-term distributional characteristics of two parameters representing the magnitude of phonatory forces (neck-surface acceleration magnitude) and vocal fold closure dynamics (H1-H2). Further validation of the DPI is needed to better understand its potential clinical use.

Differences in Weeklong Ambulatory Vocal Behavior Between Female Patients With Phonotraumatic Lesions and Matched Controls.

Purpose Previous work using ambulatory voice recordings has shown no differences in average vocal behavior between patients with phonotraumatic vocal hyperfunction and matched controls. This study used larger groups to replicate these results and expanded the analysis to include distributional characteristics of ambulatory voice use and measures indicative of glottal closure. Method Subjects included 180 adult women: 90 diagnosed with vocal fold nodules or polyps and 90 age-, sex-, and occupation-matched controls with no history of voice disorders. Weeklong summary statistics (average, variability, skewness, kurtosis) of voice use were computed from neck-surface acceleration recorded using an ambulatory voice monitor. Voice measures included estimates of sound pressure level (SPL), fundamental frequency (f o), cepstral peak prominence, and the difference between the first and second harmonic magnitudes (H1-H2). Results Statistical comparisons resulted in medium-large differences (Cohen's d ≥ 0.5) between groups for SPL skewness, f o variability, and H1-H2 variability. Two logistic regressions (theory-based and stepwise) found SPL skewness and H1-H2 variability to classify patients and controls based on their weekly voice data, with an area under the receiver operating characteristic curve of 0.85 and 0.82 on training and test sets, respectively. Conclusion Compared to controls, the weekly voice use of patients with phonotraumatic vocal hyperfunction reflected higher SPL tendencies (negatively skewed SPL) with more abrupt glottal closure (reduced H1-H2 variability, especially toward higher values). Further work could examine posttreatment data (e.g., after surgery and/or therapy) to determine the extent to which these differences are associated with the etiology and pathophysiology of phonotraumatic vocal fold lesions.

Geographic differences in substance use screening for justice-involved youth.

Justice-involved youth report high rates of substance use. Community Supervision (CS) agencies are uniquely positioned to impact public health through substance use identification and early intervention. Geographic location (i.e., living in an urban versus rural area) is an understudied factor that can be associated with differences in service and resource availability. A secondary analysis of a nationally representative sample of CS agencies assessed agency and youth characteristics, as well as substance use screening in urban and rural CS agencies. Respondents representing rural agencies reported higher rates of substance use, yet were less likely to report using screeners focused on substance use. Respondents representing urban CS agencies reported a wider variety of screening instruments and were more likely to test for drug use during screening. Differences in the screening process can reflect adaptive and culturally responsive approaches to addressing substance use as well as unique barriers to service provision. System-wide improvement is contingent upon implementation strategies that identify and acknowledge geographic differences to more adequately address the common and unique needs of the justice-involved youth they serve.

Comparison of Pitch Strength With Perceptual and Other Acoustic Metric Outcome Measures Following Medialization Laryngoplasty.

INTRODUCTION: The diagnoses of voice disorders, as well as treatment outcomes, are often tracked using visual (eg, stroboscopic images), auditory (eg, perceptual ratings), objective (eg, from acoustic or aerodynamic signals), and patient report (eg, Voice Handicap Index and Voice-Related Quality of Life) measures. However, many of these measures are known to have low to moderate sensitivity and specificity for detecting changes in vocal characteristics, including vocal quality. OBJECTIVE: The objective of this study was to compare changes in estimated pitch strength (PS) with other conventionally used acoustic measures based on the cepstral peak prominence (smoothed cepstral peak prominence, cepstral spectral index of dysphonia, and acoustic voice quality index), and clinical judgments of voice quality (GRBAS [grade, roughness, breathiness, asthenia, strain] scale) following laryngeal framework surgery. METHODS: This study involved post hoc analysis of recordings from 22 patients pretreatment and post treatment (thyroplasty and behavioral therapy). Sustained vowels and connected speech were analyzed using objective measures (PS, smoothed cepstral peak prominence, cepstral spectral index of dysphonia, and acoustic voice quality index), and these results were compared with mean auditory-perceptual ratings by expert clinicians using the GRBAS scale. RESULTS: All four acoustic measures changed significantly in the direction that usually indicates improved voice quality following treatment (P < 0.005). Grade and breathiness correlated the strongest with the acoustic measures (|r| ~ 0.7) with strain being the least correlated. CONCLUSIONS: Acoustic analysis on running speech highly correlates with judged ratings. PS is a robust, easily obtained acoustic measure of voice quality that could be useful in the clinical environment to follow treatment of voice disorders.

Impact of Allogeneic Hematopoietic Stem Cell Transplantation on the HIV Reservoir and Immune Response in 3 HIV-Infected Individuals.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to significant changes to the HIV reservoir and HIV immune responses, indicating that further characterization of HIV-infected patients undergoing HSCT is warranted. METHODS: We studied 3 patients who underwent HSCT after either reduced intensity conditioning or myeloablative conditioning regimen. We measured HIV antigens and antibodies (Ag/Ab), HIV-specific CD4 T-cell responses, HIV RNA, and DNA in plasma, peripheral blood mononuclear cells, isolated CD4 T cells from peripheral blood, and lymph node cells. The patients remained on antiretroviral therapy throughout the follow-up period. RESULTS: All patients have been in continued remission for 4-6 years post-HSCT. Analyses of HIV RNA and DNA levels showed substantial reductions in HIV reservoir-related measurements in all 3 patients, changes in immune response varied with pronounced reductions in 2 patients and a less dramatic reduction in 1 patient. One patient experienced unexpected viral rebound 4 years after HSCT. CONCLUSIONS: These 3 cases highlight the substantial changes to the HIV reservoir and the HIV immune response in patients undergoing allogeneic HSCT. The viral rebound observed in 1 patient indicates that replication competent HIV can re-emerge several years after HSCT despite these marked changes.

CD4+ T Follicular Helper and IgA+ B Cell Numbers in Gut Biopsies from HIV-Infected Subjects on Antiretroviral Therapy Are Similar to HIV-Uninfected Individuals.

BACKGROUND: Disruption of gastrointestinal tract epithelial and immune barriers contribute to microbial translocation, systemic inflammation, and progression of HIV-1 infection. Antiretroviral therapy (ART) may lead to reconstitution of CD4+ T cells in gut-associated lymphoid tissue (GALT), but its impact on humoral immunity within GALT is unclear. Therefore, we studied CD4+ subsets, including T follicular helper cells (Tfh), as well as resident B cells that have switched to IgA production, in gut biopsies, from HIV+ subjects on suppressive ART compared to HIV-negative controls (HNC). METHODS: Twenty-three HIV+ subjects on ART and 22 HNC undergoing colonoscopy were recruited to the study. Single-cell suspensions were prepared from biopsies from left colon (LC), right colon (RC), and terminal ileum (TI). T and B lymphocyte subsets, as well as EpCAM+ epithelial cells, were accurately enumerated by flow cytometry, using counting beads. RESULTS: No significant differences in the number of recovered epithelial cells were observed between the two subject groups. However, the median TI CD4+ T cell count/106 epithelial cells was 2.4-fold lower in HIV+ subjects versus HNC (19,679 versus 47,504 cells; p = 0.02). Similarly, median LC CD4+ T cell counts were reduced in HIV+ subjects (8,358 versus 18,577; p = 0.03) but were not reduced in RC. Importantly, we found no significant differences in Tfh or IgA+ B cell counts at either site between HIV+ subjects and HNC. Further analysis showed no difference in CD4+, Tfh, or IgA+ B cell counts between subjects who commenced ART in primary compared to chronic HIV-1 infection. Despite the decrease in total CD4 T cells, we could not identify a selective decrease of other key subsets of CD4+ T cells, including CCR5+ cells, CD127+ long-term memory cells, CD103+ tissue-resident cells, or CD161+ cells (surrogate marker for Th17), but there was a slight increase in the proportion of T regulatory cells. CONCLUSION: While there were lower absolute CD4+ counts in the TI and LC in HIV+ subjects on ART, they were not associated with significantly reduced Tfh cell counts or IgA+ B cells, suggesting that this important vanguard of adaptive immune defense against luminal microbial products is normalized following ART.

Distributive Processing by the Iron(II)/α-Ketoglutarate-Dependent Catalytic Domains of the TET Enzymes Is Consistent with Epigenetic Roles for Oxidized 5-Methylcytosine Bases.

The ten-eleven translocation (TET) proteins catalyze oxidation of 5-methylcytosine ((5m)C) residues in nucleic acids to 5-hydroxymethylcytosine ((5hm)C), 5-formylcytosine ((5f)C), and 5-carboxycytosine ((5ca)C). These nucleotide bases have been implicated as intermediates on the path to active demethylation, but recent reports have suggested that they might have specific regulatory roles in their own right. In this study, we present kinetic evidence showing that the catalytic domains (CDs) of TET2 and TET1 from mouse and their homologue from Naegleria gruberi, the full-length protein NgTET1, are distributive in both chemical and physical senses, as they carry out successive oxidations of a single (5m)C and multiple (5m)C residues along a polymethylated DNA substrate. We present data showing that the enzyme neither retains (5hm)C/(5f)C intermediates of preceding oxidations nor slides along a DNA substrate (without releasing it) to process an adjacent (5m)C residue. These findings contradict a recent report by Crawford et al. ( J. Am. Chem. Soc. 2016 , 138 , 730 ) claiming that oxidation of (5m)C by CD of mouse TET2 is chemically processive (iterative). We further elaborate that this distributive mechanism is maintained for TETs in two evolutionarily distant homologues and posit that this mode of function allows the introduction of (5m)C forms as epigenetic markers along the DNA.

Cigarette Cue Attentional Bias in Cocaine-Smoking and Non-Cocaine-Using Cigarette Smokers.

INTRODUCTION: Cigarette smoking in cocaine users is nearly four times higher than the national prevalence and cocaine use increases cigarette smoking. The mechanisms underlying cigarette smoking in cocaine-using individuals need to be identified to promote cigarette and cocaine abstinence. Previous studies have examined the salience of cigarette and cocaine cues separately. The present aim was to determine whether cigarette attentional bias (AB) is higher in cigarettes smokers who smoke cocaine relative to individuals who only smoke cigarettes. METHODS: Twenty cigarette smokers who smoke cocaine and 20 non-cocaine-using cigarette smokers completed a visual probe task with eye-tracking technology. During this task, the magnitude of cigarette and cocaine AB was assessed through orienting bias, fixation time, and response time. RESULTS: Cocaine users displayed an orienting bias towards cigarette cues. Cocaine users also endorsed a more urgent desire to smoke to relieve negative affect associated with cigarette craving than non-cocaine users (g = 0.6). Neither group displayed a cigarette AB, as measured by fixation time. Cocaine users, but not non-cocaine users, displayed a cocaine AB as measured by orienting bias (g = 2.0) and fixation time (g = 1.2). There were no significant effects for response time data. CONCLUSIONS: Cocaine-smoking cigarettes smokers display an initial orienting bias toward cigarette cues, but not sustained cigarette AB. The incentive motivation underlying cigarette smoking also differs. Cocaine smokers report more urgent desire to smoke to relieve negative affect. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for cigarette and cocaine use disorders. IMPLICATIONS: These results suggest that cocaine-smoking cigarette smokers display an initial orienting bias towards cigarette cues, but not sustained attention towards cigarette cues, relative to non-cocaine-using smokers. Smoked cocaine users also report a more urgent desire to smoke to relieve negative affect than non-cocaine users. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for both cigarette and cocaine use disorders.

Analysis of two candidate genes for Basan syndrome.

Basan syndrome is an extremely rare ectodermal dysplasia with autosomal dominant inheritance and variable expressivity. The etiology of Basan syndrome remains unknown. To identify the Basan syndrome gene, we sequenced keratin 14 (KRT14) and SMARCAD1 in a previously unreported kindred with the disease. Sequencing of the coding regions and splice junctions of KRT14 and SMARCAD1 was performed using PCR-amplified genomic DNA isolated from blood or saliva and standard PCR protocols. In vitro functional studies were performed for a variant identified in SMARCAD1. While direct sequencing of KRT14 failed to reveal any likely pathogenic sequence alterations or splice site variants, a heterozygous splicing variant (c.378+3A>T) that segregated with the disease was identified in the skin-specific isoform of SMARCAD1. In vitro studies failed to demonstrate a splicing defect in SMARCAD1. We screened two candidate genes for Basan syndrome in a 3-generation pedigree. The skin-specific isoform of SMARCAD1 remains a good candidate for this disease.

Geographic location of antineoplastic agent clinical trials conducted in developed and developing countries.

BACKGROUND: For the past 30 years, clinical trials have been increasingly conducted in developing countries. These trials allow results to be generalizable to similar populations, offer access to treatment for patients in need, and examine diseases with differing patterns than developed countries. However, the characteristics of antineoplastic clinical trials and recent trends in study location in developing countries are unknown. OBJECTIVE: The primary objective was to evaluate the location, study phase, results, funding source, and ethics board approval of randomized double-blind controlled clinical trials evaluating antineoplastic agents by geographic location. SETTING: This is a retrospective evaluation of studies indexed in the PubMed/Medline database published in 2007-2011. METHODS: Clinical trials were identified with the search terms "drug therapy", "antineoplastic agents" and "double blind method" and limited to English language, human, and randomized controlled trial. MAIN OUTCOME MEASURE: We assessed frequencies of characteristics of antineoplastic clinical trials. RESULTS: A total of 116 trials evaluating antineoplastic drug therapy were identified. The highest frequency of clinical trials were published in 2009 (27.6 %), followed by 2011 (23.3 %), 2010 (20.7 %), 2007 (14.6 %), and 2008 (13.8 %). According to geographic region, 33.8 % were conducted in North America, followed by Europe (31.5 %) and Asia (16.2 %). Based on economic status, the majority (77.8 %) of clinical trial locations were in developed countries and 22.2 % were in developing countries. No significant difference was found between study locations in developed countries and developing countries from 2007 to 2011. When comparing studies conducted in developing and developed countries, there was no difference in the year published, study phase, results, funding source, or investigational review board approval and informed consent. Studies conducted in developed countries were significantly more likely to be single country studies (p = 0.02) and published in a journal with an impact factor greater than 10 (p = 0.013) when compared to studies conducted in developing countries. CONCLUSIONS: Based on economic status, there was no significant location change of antineoplastic clinical trials from 2007 to 2011. Clinical trials conducted in developing countries were more often multi-country studies and published in journals with lower impact factors.

Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated ß-cell death.

OBJECTIVE: CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to ß-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for ß-cells. RESEARCH DESIGN AND METHODS: Peripheral blood CD4 T-cell responses to ß-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat ß-cells, and the rat insulinoma cell line INS-1E were examined. RESULTS: A total of 27 patients (54%) showed IL-17 reactivity to one or more ß-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1ß/interferon (IFN)-γ-induced and tumor necrosis factor (TNF)-α/IFN-γ-induced apoptosis in human islets, rat ß-cells, and INS-1E cells, in association with significant upregulation of ß-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-κB. CONCLUSIONS: Circulating IL-17(+) ß-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to ß-cell death involving IL-17 and STAT1 and NF-κB, rendering this cytokine a novel disease biomarker and potential therapeutic target.