bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strong signal increase in STED fluorescence microscopy by imaging regions of subdiffraction extent
Authors: Göttfert Fabian , Pleiner Tino , Heine Jörn , Westphal Volker , Görlich Dirk , Sahl Steffen J. , Hell Stefan W. 
Published: February 2017

Significance
In stimulated emission depletion (STED) fluorescence microscopy, the diffraction resolution barrier is overcome by applying a doughnut-shaped light beam that transiently switches fluorescence off, confining molecular emission to subdiffraction-sized regions around the doughnut center. Unfortunately, the doughnut intensities required for high resolution exacerbate photobleaching. Our remedy, called MINFIELD, exploits the fact that fluorescence off-switching by STED does not require the high intensities of the doughnut crest. By recording subdiffraction-sized areas or volumes in the sample, molecular exposure to high intensities is avoided and photobleaching is reduced by more than 100-fold. Fluorescence analysis of cellular structures becomes possible in unprecedented detail. Providing larger signal and faster recording times, MINFIELD-STED microscopy should open a unique range of superresolution imaging applications in the life sciences.
Simulating the dynamics of the mechanochemical cycle of myosin-V
Authors: Mukherjee Shayantani , Alhadeff Raphael , Warshel Arieh 
Published: February 2017

Significance
The free-energy landscape of the complete mechanochemical cycle of myosin-V is used in simulating the real-time features of the directional motion. The combination of Langevin dynamics simulations and time-dependent Monte Carlo simulations reproduces the observed trend in terms of stall force and force/velocity profile. The present study also addresses the role of the powerstroke and finds it to be the result of the complete free-energy landscape rather than the driving force of the energy conversion by the system.
Borderline Tuberculoid Leprosy Masquerading as Granuloma Annulare: A Clinical and Histological Pitfall
Authors: Zhu Tian Hao , Kamangar Faranak , Silverstein Marc , Fung Maxwell A. 
Published: February 2017

Introduction:Leprosy is a chronic granulomatous disease caused byMycobacterium leprae, an intracellular acid-fast bacillus that tends to infect the skin and peripheral nerves. Because of the wide array of cutaneous manifestation, diagnosis is not always straightforward, especially in nonendemic regions of the world such as the United States.Case Report:The authors report an unusual case of borderline tuberculoid leprosy in an 80-year-old white woman from California. Clinical examination revealed multiple nonscaly annular plaques, with central clearing and absence of lesional anesthesia, distributed over the trunk and extremities initially clinically diagnosed as granuloma annulare (GA). After 2 years of unsuccessful treatment with topical corticosteroid, biopsy revealed a palisaded and interstitial granulomatous infiltrate with necrobiosis, without discrete granulomas, compatible with GA. However, the presence of perineural lymphocytes in the reticular dermis prompted a Fite stain, which revealed acid-fast bacilli within the Schwann cells of a small peripheral nerve, pathognomonic for leprosy.Conclusion:This is the first reported case of leprosy masquerading both clinically and histologically as GA. Dermatopathologists should be aware of the possibility of leprosy given the presence of perineural lymphocytes amidst any pattern of granulomatous infiltrate and obtain a Fite stain.
Microscopy of Common Nail Cosmetics
Authors: Zimmer Katelyn A. , Clay Tiffany , Vidal Claudia I. , Chaudhry Sofia , Hurley Maria Y. 
Published: February 2017

Abstract:
Nail clipping specimens are commonly submitted for the microscopic evaluation of nail disease; however, there may be missing clinical history regarding nail polish or other adornments present on the nail at the time of specimen retrieval. For this study, 6 types of nail cosmetics were chosen and applied to the nail plate of a volunteer. After a period of at least 24 hours, the nail plates with adornments and a control nail plate were clipped and placed in formalin. Specimens were processed using a standard nail protocol. All of the specimens, except the sticker appliqué, survived the fixation process. The glitter nail polish was the only specimen found to be polarizable. None of the specimens that survived fixation were found to be PAS-positive. Cosmetic nail enhancements are easily differentiated from the nail plate microscopically; nail cosmetics appear as a distinct layer of inorganic material lying atop the nail plate. There were 2 main microscopic patterns noted on the specimens: those with 2 layers and those with 3 layers.
Pathological Sampling of Basal Cell Carcinoma Re-excision Specimens: How Much is Enough?
Authors: Mesbah Ardakani Nima , Harvey Nathan Tobias , Mansford Vanessa , Wood Benjamin Andrew 
Published: February 2017

Abstract:
Basal cell carcinoma (BCC) is the most common cutaneous malignancy, comprising approximately 75%–80% of all skin cancers. Surgical excision is the most common first line treatment modality, with the intent of obtaining clear margins. If the initial excision is incomplete or inadequate, a re-excision will often be performed in an attempt to achieve histological clearance. The pathological examination of these specimens requires a balance between the need for adequate assessment and efficient use of laboratory resources. In this study, we sought to systematically compare different approaches to the pathological sampling of these specimens in the hope of providing an evidential basis for a rational approach. Seventy-four BCC re-excision specimens were entirely sampled and retrospectively examined to determine the rate of detection of residual BCC which would have been achieved using different sampling methodologies. Residual BCC was identified in 37 specimens (50%). Limited transverse sections through the centre of the ellipse resulted in a sensitivity for detection of residual BCC of 78% (or 85% if only “significant” residual tumor is considered). By including the entire scar or the remainder of the specimen except the polar pieces, the sensitivity improved to 95% and 97%, respectively. Only one case showed residual tumor in the apical sections alone, with tumor extending to the new surgical margin in that case. We hope that this data may help laboratories develop sampling protocols appropriate to their own cost–benefit analyses and patient populations.
Putative Intravascular Myofibroma Mimicking a Vascular Malformation With Phleboliths
Authors: Klufas Daniel M. , Que Syril Keena T. , Rothe Marti , Makkar Hanspaul S. , Murphy Michael J. 
Published: February 2017

Abstract:
Myofibroma is a rare, benign myofibroblastic tumor that commonly presents at birth or in early infancy, usually as a painless, slow-growing, solitary, nodular mass. We present a case of a 40-year-old woman with a painful, solitary, myofibroma on the right elbow. The unique features of this case include age and gender of the patient, site, pain on presentation, tumor morphology, and putative intravascular nature of the tumor.
Eccrine Syringofibroadenoma in Association With Acquired Epidermodysplasia Verruciformis
Authors: Tan Timothy , Guitart Joan , Liu Luzheng Lisa , Brieva Joaquin C. , Amin Sapna , Rani Monica , Gerami Pedram , Yazdan Pedram 
Published: February 2017

Abstract:
A 75-year-old man with human immunodeficiency virus infection and numerous biopsy-proven warts for 10 years, refractory to cryosurgery, cimetidine, and topical imiquimod, presented with numerous pink to hypopigmented verrucous papules and plaques involving the face, trunk, buttocks, and groin. Laboratory evaluation revealed a CD4 T-cell count of 62 cells per microliter and human immunodeficiency virus viral load of <117 copies per milliliter. Biopsy of a plaque groin lesion was performed. Histopathology revealed vertically oriented anastomosing strands of basaloid epithelium arising from multiple points along the epidermis in a background fibrovascular stroma. Ductal differentiation was identified. Areas of epidermis showed compact orthokeratosis, coarse hypergranulosis, and keratinocytes with abundant steel-blue–gray cytoplasm, indicative of viral cytopathic changes. Cytologic atypia was not identified. Human papillomavirus (HPV) genotyping of this lesion was positive for types 5 and 14. Overall, the findings were consistent with epidermodysplasia verruciformis in association with eccrine syringofibroadenoma (ESFA). The patient was subsequently treated with acitretin and showed clinical improvement. ESFA is an uncommon benign adnexal tumor with unknown pathogenesis. Although its association with HPV has rarely been reported, ESFA in the setting of acquired epidermodysplasia verruciformis has not been described. The development of ESFA in this case may be the result of HPV-induced cellular transformation.
Processing Adipose-Rich Mohs Samples: A Comparative Study of Effectiveness of Pretreatment With Liquid Nitrogen Versus Flash Freezing Spray
Authors: Reserva Jeave , Kozel Zachary , Krol Cindy , Speiser Jodi , Adams William , Tung Rebecca 
Published: February 2017

Abstract:
Processing of adipose-rich Mohs micrographic surgery (MMS) specimens poses challenges that may preclude complete margin evaluation. In this setting, the value of additional freezing methods using various cooling agents has not been previously investigated. The aim of this study is to compare the frozen section quality of high-adipose Mohs specimens processed without additional cooling treatments versus those pretreated with 1,1,1,2-tetrafluoroethane (TFE) or liquid nitrogen (LN2). A set of 3 sections were each taken from 24 adipose-rich Mohs micrographic surgery specimens. A section from each set was subjected to either no additional cooling treatment (control), two 10-second pulse sprays of 1,1,1,2-tetrafluoroethane, or three 2-second pulse sprays of LN2. After staining, 2 blinded raters evaluated slide quality based on the presence or absence of the following features: margin completeness, nuclear clearing, epidermal or adipose folding, holes, or venetian blind-like artifacts. Pretreatment of the sample with LN2 produced a significantly (P < 0.001) greater number of high-quality slides (19/24) compared to pretreatment with 1,1,1,2-tetrafluoroethane (1/24) and no additional treatment (0/24). The adjunctive use of LN2 spray before tissue embedding circumvents the challenges of processing “thick” (high-adipose) specimens and facilitates the production of high-quality frozen section slides during Mohs micrographic surgery.
Alpha–Melanocyte-stimulating Hormone Induces Vasodilation and Exerts Cardioprotection Through the Heme-Oxygenase Pathway in Rat Hearts
Authors: Vecsernyes Miklos , Szokol Miklos , Bombicz Mariann , Priksz Daniel , Gesztelyi Rudolf , Fulop Gabor Aron , Varga Balazs , Juhasz Bela , Haines David , Tosaki Arpad 
Published: February 2017

Abstract:
Alpha–melanocyte-stimulating hormone (α-MSH) is a protein with known capacity for protection against cardiovascular ischemia–reperfusion (I/R) injury. This investigation evaluates the capacity of α-MSH to mitigate I/R effects in an isolated working rat heart model and determine the dependency of these alterations on the activity of heme oxygenase-1 (HO-1, hsp-32), a heat shock protein that functions as a major antioxidant defense molecule. Healthy male Sprague Dawley rats were used for all experiments. After treatment with selected doses of α-MSH, echocardiographic examinations were performed on live, anesthetized animals. Hearts were harvested from anesthetized rats pretreated with α-MSH and/or the HO-1 inhibitor SnPP, followed by cardiac function assessment on isolated working hearts, which were prepared using the Langendorff protocol. Induction of global ischemia was performed, followed by during reperfusion assessment of cardiac functions. Determination of incidence of cardiac arrhythmias was made by electrocardiogram. Major outcomes include echocardiographic data, suggesting that α-MSH has mild effects on systolic parameters, along with potent antiarrhythmic effects. Of particular significance was the specificity of dilatative effects on coronary vasculature, and similar outcomes of aortic ring experiments, which potentially allow different doses of the compound to be used to selectively target various portions of the vasculature for dilation.
G Protein Coupled Receptor-mediated Transactivation of Extracellular Proteases
Authors: Schafer Allison E. , Blaxall Burns C. 
Published: February 2017

Abstract:
G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor, activation of heterotrimeric G proteins and induction of subsequent signaling molecules. It is now known that GPCR signaling occurs through G protein-independent pathways including signaling through β-arrestin and transactivation of other receptor types. Generally, transactivation occurs when activation of one receptor leads to the activation of another receptor(s). GPCR-mediated transactivation is an essential component of GPCR signaling, as activation of other receptor types, such as receptor tyrosine kinases, allows GPCRs to expand their signal transduction and affect various cellular responses. Several mechanisms have been identified for receptor transactivation downstream of GPCRs, one of which involves activation of extracellular proteases, such as a disintegrin and metalloprotease, and matrix metalloproteases . These proteases cleave and release ligands that are then able to activate their respective receptors. A disintegrin and metalloprotease, and matrix metalloproteases can be activated via various mechanisms downstream of GPCR activation, including activation via second messenger, direct phosphorylation, or direct G protein interaction. Additional understanding of the mechanisms involved in GPCR-mediated protease activation and subsequent receptor transactivation could lead to identification of new therapeutic targets.
Bioequivalence of a New Oral Levosulpiride Formulation Compared With a Standard One in Healthy Volunteers
Authors: De Gregori Simona , Cipollina Laura , De Silvestri Annalisa , Ventura Marianna , Michelini Roberta , Morosini Monica , Montagna Michela , Tinelli Carmine , Regazzi Mario , Molinaro Mariadelfina , Imberti Roberto 
Published: February 2017

Background:
A monocentric, single-dose, open-label, 2-way, crossover randomized study was conducted by the San Matteo Phase I Clinical Trial Unit and Experimental Therapy (Pavia, Italy) to assess the bioequivalence and the systemic tolerability of a new oral formulation of levosulpiride (tablet 25 mg: test) versus a commercially available formulation on the Italian market (tablet 25 mg: reference).

Methods:
Thirty-five healthy adult volunteers, men (n = 19) and women (n = 16), aged between 18 and 55 years were screened and 32 of them were enrolled in the study. After having signed the written informed consent, each subject received a single oral dose of Test or Reference product with 250 mL of natural mineral water, in fasting conditions, interspersed with a 6-day washout period Blood samples were collected up to 36 hours after drug administration: the drug plasma levels were determined by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The pharmacokinetic parameters included peak plasma concentration (Cmax), time corresponding to Cmax (tmax), area under the plasma concentration–time curve from zero to infinity (AUC0
–∞) or to the last sampling time assessment (AUC0–36), the elimination rate constant (ke), and the terminal half-life (t1/2). Safety was measured by pre- and post-treatment specific biochemical investigations, physical examination, electrocardiogram, occurrence of adverse events, and any information on patients' withdrawal.

Results:
The geometric mean ratio Test/Reference (90% confidence interval) for levosulpiride was 103.0% (95.8–110.8) for AUC0–36, 103.6% (95.9–111.9) for AUC0–∞, and 104.3% (94.9–114.6) for Cmax. ke and t1/2 were 0.07 (SD: 0.02) and 9 hours (8–12) for both the formulations. Clearance (L/h) was 29.6 (±13.5) and 30.7 (±14.2) for the test and the reference product, respectively.

Conclusions:
Because the acceptance criteria required by the drug regulatory agency (European Medicines Agency, EMA) for bioequivalence prescribe limits of 80%–120% for untransformed data and 80%–125% for “ln” transformed data, we can confirm that the 2 formulations are bioequivalent, in terms of the rate and extent of absorption.
Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study
Authors: Coelingh Bennink Herjan J.T. , Verhoeven Carole , Zimmerman Yvette , Visser Monique , Foidart Jean-Michel , Gemzell-Danielsson Kristina 
Published: February 2017

Abstract

Objective:
Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated.

Methods:
This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers.

Results:
Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent.

Conclusions:
In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.
Association of sleep disturbance and sexual function in postmenopausal women
Authors: Kling Juliana M. , Manson JoAnn E. , Naughton Michelle J. , Temkit M’hamed , Sullivan Shannon D. , Gower Emily W. , Hale Lauren , Weitlauf Julie C. , Nowakowski Sara , Crandall Carolyn J. 
Published: February 2017

Abstract

Objective:
Sleep disturbance and sexual dysfunction are common in menopause; however, the nature of their association is unclear. The present study aimed to determine whether sleep characteristics were associated with sexual activity and sexual satisfaction.

Methods:
Sexual function in the last year and sleep characteristics (past 4 wk) were assessed by self-report at baseline for 93,668 women age 50 to 79 years enrolled in the Women's Health Initiative (WHI) Observational Study (OS). Insomnia was measured using the validated WHI Insomnia Rating Scale. Sleep-disordered breathing (SDB) risk was assessed using questions adapted from the Berlin Questionnaire. Using multivariate logistic regression, we examined cross-sectional associations between sleep measures and two indicators of sexual function: partnered sexual activity and sexual satisfaction within the last year.

Results:
Fifty-six percent overall reported being somewhat or very satisfied with their current sexual activity, and 52% reported partnered sexual activity within the last year. Insomnia prevalence was 31%. After multivariable adjustment, higher insomnia scores were associated with lower odds of sexual satisfaction (yes/no) (odds ratio [OR] 0.92, 95% CI, 0.87-0.96). Short sleep duration (<7-8 h) was associated with lower odds of partnered sexual activity (yes/no) (≤5 h, OR 0.88, 95% CI, 0.80-0.96) and less sexual satisfaction (≤5 h, OR 0.88, 95% CI, 0.81-0.95).

Conclusions:
Shorter sleep durations and higher insomnia scores were associated with decreased sexual function, even after adjustment for potential confounders, suggesting the importance of sufficient, high-quality sleep for sexual function. Longitudinal investigation of sleep and its impact on sexual function postmenopause will clarify this relationship.
Use of a novel fractional CO2 laser for the treatment of genitourinary syndrome of menopause: 1-year outcomes
Authors: Sokol Eric R. , Karram Mickey M. 
Published: February 2017

Abstract

Objectives:
To assess safety and efficacy of a fractional CO2 laser therapy for the treatment of genitourinary syndrome of menopause (GSM) with follow-up to 1 year posttreatment.

Methods:
Women presenting with GSM and meeting inclusion criterion were enrolled. Visual Analog Scales were used to grade vaginal pain, burning, itching, dryness, dyspareunia, and dysuria. Dilators were used to rate vaginal elasticity at baseline and at each follow-up visit. Before each treatment and at follow-up, Vaginal Health Index scoring and Female Sexual Function Index questionnaires were completed. Women received three vaginal laser treatments spaced 6 weeks apart. Participant satisfaction was measured on 5-point Likert scales (1 = very dissatisfied, 5 = very satisfied).

Results:
Of 30 women (mean age 58.6 ± 8.8 years), three were lost to follow-up at 3 months and six at 1 year. None were discontinued or withdrew due to an adverse event. Average improvement in Visual Analog Scale scores for all symptom categories was statistically significant at 3 months and remained so through 1 year, except dysuria. Differences between data at 3 months and 1 year were not statistically significant, indicating persistence of positive outcomes. Average overall improvement in pain was 1.9 (±3.4), burning 1.9 (±3.1), itching 1.4 (±1.9), dryness 5.9 (±2.8), dyspareunia 4.9 (±3.3), and dysuria 0.9 (±3.1). Improvement in average Vaginal Health Index and Female Sexual Function Index scores was also statistically significant (P < 0.0001). Of 19 women undergoing dilator examination at 1 year, 18 (94.8%) were comfortable with the same or larger dilator size. Twenty-two of 24 women (92%) were satisfied or extremely satisfied with the treatment at 1 year.

Conclusions:
Based on study data up to 1 year, the fractional CO2 laser may be an effective and safe treatment for women suffering from symptoms of GSM, although additional studies with larger populations and placebo control is needed to confirm these results.