Growth hormone (GH)-releasing hormone increases the expression of the dominant-negative GH isoform in cases of isolated GH deficiency due to GH splice-site mutations

An autosomal dominant form of isolated GH deficiency (IGHD II) can result from heterozygous splice site mutations that weaken recognition of exon 3 leading to aberrant splicing of GH-1 transcripts and production of a dominant-negative 17.5-kDa GH isoform. Previous studies suggested that the extent of missplicing varies with different mutations and the level of GH expression and/or secretion. To study this, wt-hGH and/or different hGH-splice site mutants (GH-IVS+2, GH-IVS+6, GH-ISE+28) were transfected in rat pituitary cells expressing human GHRH receptor (GC-GHRHR). Upon GHRH stimulation, GC-GHRHR cells coexpressing wt-hGH and each of the mutants displayed reduced hGH secretion and intracellular GH content when compared with cells expressing only wt-hGH, confirming the dominant-negative effect of 17.5-kDa isoform on the secretion of 22-kDa GH. Furthermore, increased amount of 17.5-kDa isoform produced after GHRH stimulation in cells expressing GH-splice site mutants reduced production of endogenous rat GH, which was not observed after GHRH-induced increase in wt-hGH. In conclusion, our results support the hypothesis that after GHRH stimulation, the severity of IGHD II depends on the position of splice site mutation leading to the production of increasing amounts of 17.5-kDa protein, which reduces the storage and secretion of wt-GH in the most severely affected cases. Due to the absence of GH and IGF-I-negative feedback in IGHD II, a chronic up-regulation of GHRH would lead to an increased stimulatory drive to somatotrophs to produce more 17.5-kDa GH from the severest mutant alleles, thereby accelerating autodestruction of somatotrophs in a vicious cycle.

Identification of a fibronectin interaction site in the extracellular matrix protein ameloblastin

Mammalian teeth are composed of hydroxyapatite crystals that are embedded in a rich extracellular matrix. This matrix is produced by only two cell types, the mesenchymal odontoblasts and the ectodermal ameloblasts. Ameloblasts secrete the enamel proteins amelogenin, ameloblastin, enamelin and amelotin. Odontoblasts secrete collagen type I and several calcium-binding phosphoproteins including dentin sialophosphoprotein, dentin matrix protein, bone sialoprotein and osteopontin. The latter four proteins have recently been grouped in the family of the SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) because they display similar gene structures and because they contain an RGD tripeptide sequence that binds to integrin receptors and thus mediates cell adhesion. We have prepared all the other tooth-specific proteins in recombinant form and examined whether they might also promote cell adhesion similar to the SIBLINGs. We found that only ameloblastin consistently mediated adhesion of osteoblastic and fibroblastic cells to plastic or titanium surfaces. The activity was dependent on the intact three-dimensional structure of ameloblastin and required de novo protein synthesis of the adhering cells. By deletion analysis and in vitro mutagenesis, the active site could be narrowed down to a sequence of 13 amino acid residues (VPIMDFADPQFPT) derived from exon 7 of the rat ameloblastin gene or exons 7-9 of the human gene. Kinetic studies and RNA interference experiments further demonstrated that this sequence does not directly bind to a cell surface receptor but that it interacts with cellular fibronectin, which in turn binds to integrin receptors. The identification of a fibronectin-binding domain in ameloblastin might permit interesting applications for dental implantology. Implants could be coated with peptides containing the active sequence, which in turn would recruit fibronectin from the patient's blood. The recruited fibronectin should then promote cell adhesion on the implant surface, thereby accelerating osseointegration of the implant.

Sleep and biomarkers of atherosclerosis in elderly Alzheimer caregivers and controls

Perturbed sleep might contribute to cardiovascular disease by accelerating atherosclerosis. Sleep is poor in Alzheimer caregivers who are also a group at increased cardiovascular risk.

Doubly charged ion mass spectra of alkyl-substituted furans and pyrroles

Doubly charged ion mass spectra of alkyl-substituted furans and pyrroles were obtained using a double-focusing magnetic mass spectrometer operated at 3.2 kV accelerating voltage. Molecular ions were the dominant species found in doubly charged spectra of lower molecular weight heterocydic compounds, whereas the spectra of the higher weight homologues were typified by abundant fragment ions from extensive decomposition. Measured doubly charged ionization and appearance energies ranged from 22.8 to 47.9 eV. Ionization energies were correlated with values calculated using self-consistent field–molecular orbital techniques. A multichannel diabatic curve-crossing model was developed to investigate the fundamental organic ion reactions responsible for development of doubly charged ion mass spectra. Probabilities for Landau–Zener type transitions between reactant and product curves were determined and used in the collision model to predict charge-transfer cross-sections, which compared favorably with experimental cross-sections obtained using time-of-flight techniques.

Oxotremorine Delays and Scopolamine Accelerates Sexual Exhaustion When Applied to the Preoptic Area in Male Hamsters

Acetylcholine (ACh) has not been tested for a role in the development of sexual exhaustion in males. However, male hamsters receiving infusions into the medial preoptic area (MPOA) of the muscarinic agonist oxotremorine (OXO) or antagonist scopolamine (SCO) show changes in the postejaculatory interval, one of the measures that changes most consistently as exhaustion approaches. In addition, central SCO treatments cause changes in the patterning of intromissions that resemble those signaling exhaustion. To extend these observations and more thoroughly test the dependence of sexual exhaustion on ACh, male hamsters received MPOA treatments of OXO, SCO or the combination of the two before mating to exhaustion. Relative to placebo, OXO infusions caused small but consistent increases in ejaculation frequency and long intromission latency, delaying the appearance of exhaustion. Scopolamine treatments did the reverse, dramatically accelerating the development of exhaustion. Consistent with and possibly responsible for these changes were effects on the quality of performance prior to exhaustion. These included differences in overall copulatory efficiency (e.g., ejaculations/intromission), which was increased by OXO and decreased by SCO. They also extended to several standard measures of copulatory behavior, including intromission frequency, ejaculation latency and the postejaculatory interval: Most of these were increased by SCO and decreased by OXO. Finally, whereas most or all effects of OXO were counteracted by SCO, most or all of the responses to SCO resisted change by added OXO. This asymmetry in the responses to combined treatment raises the possibility that the effects of these drugs on sexual exhaustion and other elements of male behavior are mediated by distinct muscarinic receptors. Copyright 2013 Elsevier Inc. All rights reserved.

The role of warning behaviors in threat assessment: an exploration and suggested typology

The concept of warning behaviors offers an additional perspective in threat assessment. Warning behaviors are acts which constitute evidence of increasing or accelerating risk. They are acute, dynamic, and particularly toxic changes in patterns of behavior which may aid in structuring a professional's judgment that an individual of concern now poses a threat - whether the actual target has been identified or not. They require an operational response. A typology of eight warning behaviors for assessing the threat of intended violence is proposed: pathway, fixation, identification, novel aggression, energy burst, leakage, directly communicated threat, and last resort warning behaviors. Previous research on risk factors associated with such warning behaviors is reviewed, and examples of each warning behavior from various intended violence cases are presented, including public figure assassination, adolescent and adult mass murder, corporate celebrity stalking, and both domestic and foreign acts of terrorism. Practical applications and future research into warning behaviors are suggested. Copyright © 2011 John Wiley & Sons, Ltd.

Writing center handbooks and travel guidebooks : redesigning instructional texts for multicultural, multilingual, and multinational contexts

In an increasingly interconnected world characterized by the accelerating interplay of cultural, linguistic, and national difference, the ability to negotiate that difference in an equitable and ethical manner is a crucial skill for both individuals and larger social groups. This dissertation, Writing Center Handbooks and Travel Guidebooks: Redesigning Instructional Texts for Multicultural, Multilingual, and Multinational Contexts, considers how instructional texts that ostensibly support the negotiation of difference (i.e., accepting and learning from difference) actually promote the management of difference (i.e., rejecting, assimilating, and erasing difference). As a corrective to this focus on managing difference, chapter two constructs a theoretical framework that facilitates the redesign of handbooks, guidebooks, and similar instructional texts. This framework centers on reflexive design practices and is informed by literacy theory (Gee; New London Group; Street), social learning theory (Wenger), globalization theory (Nederveen Pieterse), and composition theory (Canagarajah; Horner and Trimbur; Lu; Matsuda; Pratt). By implementing reflexive design practices in the redesign of instructional texts, this dissertation argues that instructional texts can promote the negotiation of difference and a multicultural/multilingual sensibility that accounts for twenty-first century linguistic and cultural realities. Informed by the theoretical framework of chapter two, chapters three and four conduct a rhetorical analysis of two forms of instructional text that are representative of the larger genre: writing center coach handbooks and travel guidebooks to Hong Kong. This rhetorical analysis reveals how both forms of text employ rhetorical strategies that uphold dominant monolingual and monocultural assumptions. Alternative rhetorical strategies are then proposed that can be used to redesign these two forms of instructional texts in a manner that aligns with multicultural and multilingual assumptions. These chapters draw on the work of scholars in Writing Center Studies (Boquet and Lerner; Carino; DiPardo; Grimm; North; Severino) and Technical Communication (Barton and Barton; Dilger; Johnson; Kimball; Slack), respectively. Chapter five explores how the redesign of coach handbooks and travel guidebooks proposed in this dissertation can be conceptualized as a political act. Ultimately, this dissertation argues that instructional texts are powerful heuristic tools that can enact social change if they are redesigned to foster the negotiation of difference and to promote multicultural/multilingual world views.

ISO 14001 in India: More than a certificate on the wall?

The growth of ISO 14001 certificates worldwide has led to much research on the role of voluntary standards in improving the environmental impacts of industry. Most of this research, however, has focused on industrialized countries, with very little research examining the effects of ISO 14001 and other voluntary initiatives in the developing world. This is especially unfortunate because it is in these very countries that proponents of ISO 14001 claim the largest benefits of the standard will occur, by helping polluting industries improve performance and by assisting environmental regulators in enforcing laws more effectively. Indian industries have begun adopting ISO 14001 at an accelerating pace, but there is little available information on what this means for the environmental performance of Indian firms. The research described here closes this gap by exploring the reasons for the increasing popularity of ISO 14001 in India, the ways in which firms use the standard and the benefits they obtain from it. Findings suggest that while the processoriented approach of ISO 14001 does offer important benefits, changing market demands towards cheaper certification and away from rigorous EMS implementation have devalued the standard for those interested in using it as an indicator of a firm’s environmental performance.

A new surgical approach for exclusion of renal artery aneurysms avoiding organ ischemia

INTRODUCTION: Surgical treatment of renal artery aneurysms is inevitably associated with temporary renal artery occlusion and risk of ischemic injury. We present a technique for renal artery grafting and aneurysm exclusion without interrupting renal blood flow. REPORT: A symptomatic renal artery aneurysm was bypassed with a venous graft between the abdominal aorta and the very distal renal artery utilizing a distal anastomotic device without interruption of renal blood flow. The aneurysm was then excluded by means of hemostatic clips. CONCLUSION: The presented surgical technique offers the major advantage of avoiding organ ischemia and accelerating the surgical procedure.

The free escape continuum of diffuse ions upstream of the Earth's quasi-parallel bow shock

The Earth's bow shock is very efficient in accelerating ions out of the incident solar wind distribution to high energies (≈ 200 keV/e). Fluxes of energetic ions accelerated at the quasi-parallel bow shock, also known as diffuse ions, are best represented by exponential spectra in energy/charge, which require additional assumptions to be incorporated into these model spectra. One of these assumptions is a so-called "free escape boundary" along the interplanetary magnetic field into the upstream direction. Locations along the IBEX orbit are ideally suited for in situ measurements to investigate the existence of an upstream free escape boundary for bow shock accelerated ions. In this study we use 2 years of ion measurements from the background monitor on the IBEX spacecraft, supported by ACE solar wind observations. The IBEX Background Monitor is sensitive to protons > 14 keV, which includes the energy of the maximum flux for diffuse ions. With increasing distance from the bow shock along the interplanetary magnetic field, the count rates for diffuse ions stay constant for ions streaming away from the bow shock, while count rates for diffuse ions streaming toward the shock gradually decrease from a maximum value to ~1/e at distances of about 10 RE to 14 RE. These observations of a gradual decrease support the transition to a free escape continuum for ions of energy >14 keV at distances from 10 RE to 14 RE from the bow shock.

Dose–effect relationship in routine outpatient psychotherapy: Does treatment duration matter?

Objective: There is an ongoing debate concerning how outcome variables change during the course of psychotherapy. We compared the dose–effect model, which posits diminishing effects of additional sessions in later treatment phases, against a model that assumes a linear and steady treatment progress through termination. Method: Session-by-session outcome data of 6,375 outpatients were analyzed, and participants were categorized according to treatment length. Linear and log-linear (i.e., negatively accelerating) latent growth curve models (LGCMs) were estimated and compared for different treatment length categories. Results: When comparing the fit of the various models, the log-linear LGCMs assuming negatively accelerating treatment progress consistently outperformed the linear models irre- spective of treatment duration. The rate of change was found to be inversely related to the length of treatment. Conclusion: As proposed by the dose–effect model, the expected course of improvement in psychotherapy appears to follow a negatively accelerated pattern of change, irrespective of the duration of the treatment. However, our results also suggest that the rate of change is not constant across various treatment lengths. As proposed by the “good enough level” model, longer treatments are associated with less rapid rates of change.

The development of self-esteem

In this article, we review new insights gained from recent longitudinal studies examining the development of self-esteem and its influence on important life outcomes. The evidence supports the following three conclusions. First, self-esteem increases from adolescence to middle adulthood, peaks at about age 50 to 60 years, and then decreases at an accelerating pace into old age; moreover, there are no cohort differences in the self-esteem trajectory from adolescence to old age. Second, self-esteem is a relatively stable, but by no means immutable, trait; individuals with relatively high (or low) self-esteem at one stage of life are likely to have relatively high (or low) self-esteem decades later. Third, high self-esteem prospectively predicts success and well-being in life domains such as relationships, work, and health. Given the increasing evidence that self-esteem has important real-world consequences, the topic of self-esteem development is of considerable societal significance.

The Road Not Taken: Enabling and Limiting Mobility in the Eastern Pamirs

Based on fieldwork conducted between 2008 and 2011, this article explores the role of roads in enabling and limiting the movement of people and goods in Tajikistan’s Eastern Pamirs. The article focuses on the Pamir Highway and a newly established trade route linking Tajikistan with China. Besides materially facilitating mobility, both roads serve as trajectories for opportunities, but often also signify the lack of such to those who live along them. This article thus seeks to analyse the shifting roles of roads against the backdrop of past and present state dispensations, shifting ideologies and newly emerging economic practices. By emphasising roads as both enabling and limiting spatial entities shaped by materiality, politics and economics, this article argues, on the one hand, that roads are important factors in directing and accelerating the mobility of people and goods and, on the other, that roads are also symbols of immobility inasmuch as they set limitations on the movement of people.

The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs.

Acquired thrombotic thrombocytopenic purpura (TTP) is the consequence of a severe ADAMTS13 deficiency resulting from autoantibodies inhibiting ADAMTS13 or accelerating its clearance. Despite the success of plasma exchange the risk of relapse is high. From 2 patients (A and B), splenectomized for recurrent episodes of acquired TTP, the splenic B-cell response against ADAMTS13 was characterized through generation of human monoclonal anti-ADAMTS13 autoantibodies (mAbs) by cloning an immunoglobulin G (IgG)4κ- and IgG4λ-Fab library using phage display technology and by Epstein-Barr virus transformation of switched memory B cells (CD19+/CD27+/IgG+). Sequence analysis of the anti-ADAMTS13 IgGs of both patients revealed that the VH gene use was limited in our patients to VH1-3 (55%), VH1-69 (17%), VH3-30 (7%), and VH4-28 (21%) and contained 8 unique and thus far not reported heavy-chain complementarity determining region 3 motifs, of which 4 were shared by the 2 patients. The discovery of several highly similar anti-ADAMTS13 autoantibodies in 2 unrelated TTP patients suggests that the autoimmune response is antigen driven, because the probability that such similar immunoglobulin rearrangements happen by chance is very low (< 10(-9)).

Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥20 g/day for ≥5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.