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Objectives: Transgender women often seek to feminize their voice so that it becomes congruent with their gender identity. Many receive voice therapy (VT) with good results. Some also need pitch-raising surgery. The purpose of this study was to investigate long-term effects and to compare outcomes between cricothyroid approximation (CTA) and glottoplasty (GP)., Methods: This study included retrospective data from 24 patients (35-67 years). Eleven patients had undergone CTA and 13 had undergone GP. Audio recordings were performed in a sound-treated booth and patients answered questionnaires before and after VT, post surgery, and at 1-year follow-up. Fundamental frequency (f o ) measures were extracted from voice range profiles (VRPs) and speech range profiles (SRPs) and were compared with cisgender data., Results: Minimum f o in VRP increased significantly only after CTA (95 to 123 Hz). Maximum f o in VRP was significantly lowered after GP (765 to 652 Hz), even more after CTA (677 to 475 Hz). Speaking mean f o increased significantly after VT and post surgery, and was thereafter stable (CTA 167 Hz, GP 169 Hz). The maximum f o in the SRP increased only after VT. The frequency ranges were strongly reduced after CTA. Patients were in general satisfied at follow-up and rated the GP outcomes more favorably than CTA., Conclusions: Both surgical methods have advantages and disadvantages. The very restricted speaking and physiological frequency ranges, which do not favor an optimal female voice, were mainly found after the irreversible CTA. Thus, CTA is no longer performed at our hospital, whereas surgical techniques based on GP are being developed further. We strongly recommend the use of VRPs to evaluate treatment effects., (Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

We assessed the ability of preschool children to assign the most difficult tasks to a symbolic helper. First, children were taught that a toy "helper" could aid them in remembering the location of a hidden item. Children preferentially assigned the helper to the objectively most difficult locations to remember. Each child then completed eight more tests, assessing a range of different skills such as counting, object identification, and word reading. Children again could assign some stimuli in each task to the helper, leaving the remaining stimuli for themselves to respond to in the given tasks. They were not explicitly told to assign the hardest stimulus to the helper. However, children consistently still did so in most tasks, although some tasks showed an effect of age where older children were more proficient in assigning the objectively more difficult stimuli to the helper. These results highlight a potential form of metacognition in young children in which they can monitor difficulty across varied kinds of assessments and use a generalized tool for asking for help that does not require verbal responding.

We used a GIS analysis of sodium and chloride concentrations in private water wells in a southeastern New York township to describe the pattern of distribution of road salt in aquifers tapped for drinking water. The primary source of road salt was sodium chloride, and sodium and chloride concentrations were significantly correlated ( = 0.80, < 0.01). Chloride concentrations in wells increased as the percentage of impervious surface cover (ISC) within a 250-m radius around wells increased ( = 0.87, < 0.01) and declined with increasing distance to the nearest road ( = 0.76, < 0.01). Wells that were located lower in elevation than the nearest road had higher concentrations of chloride than wells that were higher than the nearest road, but this occurred only when the nearest road was >30 m from the wells ( < 0.01). Chloride concentrations were not affected by well depth or adjacent road type (major or minor roads). Surface geology and hydrologic soil class had significant effects ( < 0.01) on chloride concentrations in wells, with porous surface geology types and well-drained soils having higher concentrations; these effects may be confounded by the fact that ISC was more likely to occur on these permeable surface geology and soil types. Hot and cold spot analysis revealed substantial unevenness in chloride concentrations. Results for sodium were similar to those for chloride. Overall, these results indicate that road salt contamination of groundwater is unevenly distributed and is affected by landscape factors that can be used to guide well testing and best management practices of deicing salt distribution., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Objective: This investigation comprehensively assessed the technology use, preferences, and capacity of diverse injured trauma survivors with posttraumatic stress disorder (PTSD) symptoms., Method: A total of 121 patients participating in a randomized clinical trial (RCT) of stepped collaborative care targeting PTSD symptoms were administered baseline one-, three-, and six-month interviews that assessed technology use. Longitudinal data about the instability of patient cell phone ownership and phone numbers were collected from follow-up interviews. PTSD symptoms were also assessed over the course of the six months after injury. Regression analyses explored the associations between cell phone instability and PTSD symptoms., Results: At baseline, 71.9% (n = 87) of patients reported current cell phone ownership, and over half (58.2%, n = 46) of these patients possessed basic cell phones. Only 19.0% (n = 23) of patients had no change in cell phone number or physical phone over the course of the six months postinjury. In regression models that adjusted for relevant clinical and demographic characteristics, cell phone instability was associated with higher six-month postinjury PTSD symptom levels (p < 0.001)., Conclusions: Diverse injured patients at risk for the development of PTSD have unique technology use patterns, including high rates of cell phone instability. These observations should be strongly considered when developing technology-supported interventions for injured patients with PTSD.

Integrin signaling relies on multiple, distinct pathways to impact a diverse set of cell behaviors. The Rho family of GTPases are well-established downstream signaling partners of integrins that regulate cell shape, polarity, and migration. The nematode C. elegans provides a simple in vivo system for studying both integrins and the Rho family. Our previous work showed that the C. elegans α integrin cytoplasmic tails have tissue-specific functions during development. Here, we use chimeric α integrins to show that the cytoplasmic tails can rescue the loss of the Rho family of GTPases in three cell types in the somatic gonad. Knockdown of rho-1 by RNAi causes defects in sheath cell actin organization, ovulation, and vulva morphology. Chimeric α integrin ina-1 with the pat-2 cytoplasmic tail can rescue both actin organization and ovulation after rho-1 RNAi, yet cannot restore vulva morphology. Knockdown of cdc-42 by RNAi causes defects in sheath cell actin organization, ovulation, vulva morphology, and distal tip cell migration. Chimeric α integrin pat-2 with the ina-1 cytoplasmic tail can rescue vulva morphology defects and distal tip cell migration after cdc-42 RNAi, yet cannot restore sheath cell actin organization or ovulation. Disruption of Rac yields the same phenotype in distal tip cells regardless of α integrin cytoplasmic tail composition. Taken together, the cytoplasmic tails of α integrins can bypass signaling from members of the Rho family of GTPases during development., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A new wave of emerging therapies for the treatment of autoimmune and inflammatory diseases is under development. These therapies interrupt intracellular signalling through kinase inhibition. By interrupting one or more kinases it is possible to modulate the function of cellular structures such as surface receptors, signalling proteins and transcription of nuclear proteins and thus influence the behaviour of the cell types targeted. With these advances comes the significant potential to develop highly effective orally bioavailable therapeutics. The targets generating the greatest enthusiasm at this time for the treatment of autoimmune and inflammatory diseases include Janus-associated kinase, spleen tyrosine kinase, phosphodiesterase-4, Bruton's tyrosine kinase and phosphatidylinositol-3 kinase. Ultimately human trials will help us understand the potential risks and benefits of these novel approaches across a number of diseases.

Objective: We sought to develop a list of 5 tests, treatments, or services commonly used in rheumatology practice whose necessity or value should be questioned and discussed by physicians and patients., Methods: We used a multistage process combining consensus methodology and literature reviews to arrive at the American College of Rheumatology's (ACR) Top 5 list. Rheumatologists from diverse practice settings generated items using the Delphi method. Items with high content agreement and perceived high prevalence advanced to a survey of ACR members, who comprise >90% of the US rheumatology workforce. To increase the response rate, a nested random sample of 390 rheumatologists received more intensive survey followup. The samples were combined and weighting procedures were applied to ensure generalizability. Items with high ratings underwent literature review. Final items were then selected and formulated by the task force., Results: One hundred five unique items were proposed and narrowed down to 22 items during the Delphi rounds. A total of 1,052 rheumatologists (17% of those contacted) participated in the member-wide survey, whereas 33% of those in the nested random sample participated; respondent characteristics were similar in both samples. Based on survey results and available scientific evidence, 5 items (relating to antinuclear antibodies, Lyme disease, magnetic resonance imaging, bone absorptiometry, and biologic therapy for rheumatoid arthritis) were selected for inclusion., Conclusion: The ACR Top 5 list is intended to promote discussions between physicians and patients about health care practices in rheumatology whose use should be questioned and to assist rheumatologists in providing high-value care., (Copyright © 2013 by the American College of Rheumatology.)

Gout is an inflammatory arthritis characterized by sudden, painful inflammation. Gout can affect any joint in an asymmetric distribution. Gouty attacks may be isolated or can be followed by years of recurrent flares. Over time, elevated serum urate levels and tophaceous deposits can lead to deformity and disability from underlying bony erosion. The concept of 'treatment-failure gout' describes a unique population that has been either unable to tolerate allopurinol or who have not experienced normalization of serum urate levels on allopurinol. It is estimated that approximately 1-1.5% of the estimated 3-8 million people with gout in the USA have treatment-failure gout. Pegloticase is an US FDA-approved intravenous medication that is a mammalian recombinant uricase conjugated to monomethoxy polyethylene glycol. Two recent Phase III trials have found pegloticase to be effective in the management of treatment-failure gout. These studies also highlight safety concerns regarding the drug's immunogenicity.

Widespread use of salts as deicing agents on roads has been perceived as a significant source of environmental and economic damage. Early studies focused on near-road and short-term effects where concentrations can exceed several grams per liter. Evidence is accumulating that the use of salts has significant effects over broader areas, longer time frames, and is affecting a range of ecological processes. Concentrations of NaCl can be elevated throughout an ecosystem to >100 mg Cl(-) /L, which may have nonlethal and possibly subtle effects on sensitive life stages of several organisms. NaCl seems subject to retention within terrestrial and aquatic ecosystems, thus prolonging the actual duration of exposure and leading to elevated warm-season concentrations when reproduction may be occurring or other sensitive life stages are present. Many of the alternatives to NaCl reduce some of these negative effects, although are currently cost prohibitive for large-scale use. Some techniques for managing application rates are improvements in technology, while others involve novel mixtures of organic compounds that may have new environmental consequences. The increasing evidence of these widespread and persistent environmental consequences must be brought into decisions on deicing procedures., (© 2011 New York Academy of Sciences.)

Dax1, an atypical orphan nuclear receptor expressed in steroidogenic tissues, has recently been shown to be expressed in mouse embryonic stem (mES) cells and is required for pluripotency. While the mechanisms of transcriptional regulation of Dax1 in steroidogenic organs have been well characterized, those in mES cells have not. Here we report that 500 bp of the Dax1 gene promoter sequence are sufficient to drive expression in mES cells. In steroidogenic tissues, NR5A1 (Sf1) binds to nuclear receptor binding sites within this sequence to regulate Dax1 expression. In mES cells, while NR5A1 (Sf1) is not expressed, NR5A2 (LRH-1) expression is robust. Luciferase assays, EMSA and overexpression/knockdown studies demonstrate that LRH-1 binds the -128 site and regulates Dax1 in mES cells. Predicated on recent work indicating that Nanog binds to the Dax1 intron, we have used chromatin immunoprecipitation experiments (ChIP) to define an intronic site that is bound by Nanog. Overexpression and knockdown of Nanog in mES cells result in alteration of Dax1 expression, and luciferase assays reveal that this sequence can enhance transcription of a Dax1 reporter construct. These data indicate that LRH-1 and Nanog cooperate to regulate Dax1 expression in mES cells., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Dax1 (Nr0b1) is an atypical orphan nuclear receptor that has recently been shown to play a role in mouse embryonic stem (mES) cell pluripotency. Here we describe a mechanism by which Dax1 maintains pluripotency. In steroidogenic cells, Dax1 protein interacts with the NR5A nuclear receptor steroidogenic factor 1 (Nr5a1) to inhibit transcription of target genes. In mES cells, liver receptor homolog 1 (LRH-1, Nr5a2), the other NR5A family member, is expressed, and LRH-1 has been shown to interact with Dax1. We demonstrate by coimmunoprecipitation that Dax1 is, indeed, able to form a complex with LRH-1 in mES cells. Because Dax1 was historically characterized as an inhibitor of steroidogenic factor 1-mediated transcriptional activation, we hypothesized that Dax1 would inhibit LRH-1 action in mES cells. Therefore, we examined the effect of Dax1 on the LRH-1-mediated activation of the critical ES cell factor Oct4 (Pou5f1). Chromatin immunoprecipitation localized Dax1 to the Oct4 promoter at the LRH-1 binding site, and luciferase assays together with Dax1 overexpression and knockdown experiments revealed that, rather than repress, Dax1 accentuated LRH-1-mediated activation of the Oct4 gene. Similar to our previously published studies that defined the RNA coactivator steroid receptor RNA activator as the critical mediator of Dax1 coactivation function, Dax1 augmentation of LRH-1-mediated Oct4 activation is dependent upon steroid receptor RNA activator. Finally, utilizing published chromatin immunoprecipitation data of whole-genome binding sites of LRH-1 and Dax1, we show that LRH-1 and Dax1 commonly colocalize at 288 genes (43% of LRH-1 target genes), many of which are involved in mES cell pluripotency. Thus, our results indicate that Dax1 plays an important role in the maintenance of pluripotency in mES cells through interaction with LRH-1 and transcriptional activation of Oct4 and other genes.

Scientists have long hypothesized the existence of tissue-specific (somatic) stem cells and have searched for their location in different organs. The theory that adrenocortical organ homeostasis is maintained by undifferentiated stem or progenitor cells can be traced back nearly a century. Similar to other organ systems, it is widely believed that these rare cells of the adrenal cortex remain relatively undifferentiated and quiescent until needed to replenish the organ, at which time they undergo proliferation and terminal differentiation. Historical studies examining cell cycle activation by label retention assays and regenerative potential by organ transplantation experiments suggested that the adrenocortical progenitors reside in the outer periphery of the adrenal gland. Over the past decade, the Hammer laboratory, building on this hypothesis and these observations, has endeavored to understand the mechanisms of adrenocortical development and organ maintenance. In this review, we summarize the current knowledge of adrenal organogenesis. We present evidence for the existence and location of adrenocortical stem/progenitor cells and their potential contribution to adrenocortical carcinomas. Data described herein come primarily from studies conducted in the Hammer laboratory with incorporation of important related studies from other investigators. Together, the work provides a framework for the emerging somatic stem cell field as it relates to the adrenal gland.

Chloride concentrations are increasing at a rate that threatens the availability of fresh water in the northeastern United States. Increases in roadways and deicer use are now salinizing fresh waters, degrading habitat for aquatic organisms, and impacting large supplies of drinking water for humans throughout the region. We observed chloride concentrations of up to 25% of the concentration of seawater in streams of Maryland, New York, and New Hampshire during winters, and chloride concentrations remaining up to 100 times greater than unimpacted forest streams during summers. Mean annual chloride concentration increased as a function of impervious surface and exceeded tolerance for freshwater life in suburban and urban watersheds. Our analysis shows that if salinity were to continue to increase at its present rate due to changes in impervious surface coverage and current management practices, many surface waters in the northeastern United States would not be potable for human consumption and would become toxic to freshwater life within the next century.

Ammonium (NH(4)(+)) concentrations in air and precipitation at the Institute of Ecosystem Studies (IES) in southeastern New York, USA declined over an 11-year period from 1988 to 1999, but increased from 1999 to 2001. These trends in particulate NH(4)(+) correlated well with trends in particulate SO(4)(2-) over the 1988-2001 period. The NH(4)(+) trends were not as well correlated with local cattle and milk production, which declined continuously throughout the period. This suggests that regional transport of SO(4)(2-) may have a greater impact on concentrations of NH(4)(+) and subsequent deposition than local agricultural emissions of NH(3). Ammonium concentrations in precipitation correlated significantly with precipitation SO(4)(2-) concentrations for the 1984-2001 period although NH(4)(+) in precipitation increased after 1999 and SO(4)(2-) in precipitation continued to decline after 1999. The correlation between NH(4)(+) and SO(4)(2-) was stronger for particulates than for precipitation. Particulate NH(4)(+) concentrations were also correlated with particulate SO(4)(2-) concentrations at 31 of 35 eastern U.S. CASTNet sites that had at least 10 years of data. Air concentrations of NH(4)(+) and SO(4)(2-) were more strongly correlated at the sites that were located within an agricultural landscape than in forested sites. At most of the sites there was either no trend or a decrease in NH(4)(+) dry deposition during the 1988-2001 period. The sites that showed an increasing trend in NH(4)(+) dry deposition were generally located in the southeastern U.S. The results of this study suggest that, in the northeastern U.S., air concentrations of NH(4)(+) and subsequent deposition may be more closely linked to SO(4)(2-) and thus SO(2) emissions than with NH(3) emissions. These results also suggest that reductions in S emissions have reduced NH(4)(+) transport to and NH(4)(+)-N deposition in the Northeast.