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Evaluation capacity building (ECB) continues to attract attention. Over the past two decades, a broad literature has emerged-covering the dimensions, contexts, and practices of ECB. This article presents findings from a bibliometric analysis of ECB articles published in six evaluation journals from 2000 to 2019. The findings shed light on the communities of scholars that contribute to the ECB knowledge base, the connections between these communities, and the themes they cover. Informed by the findings, future directions for ECB scholarship and how bibliometric analysis can supplement more established approaches to literature reviews are discussed., Competing Interests: Declaration of Competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Metastatic breast-cancer is a major cause of death in women worldwide, yet the relationship between oncogenic drivers that promote metastatic versus primary cancer is still contentious. To elucidate this relationship in treatment-naive animals, we hereby describe mammary-specific transposon-mutagenesis screens in female mice together with loss-of-function Rb, which is frequently inactivated in breast-cancer. We report gene-centric common insertion-sites (gCIS) that are enriched in primary-tumors, in metastases or shared by both compartments. Shared-gCIS comprise a major MET-RAS network, whereas metastasis-gCIS form three additional hubs: Rho-signaling, Ubiquitination and RNA-processing. Pathway analysis of four clinical cohorts with paired primary-tumors and metastases reveals similar organization in human breast-cancer with subtype-specific shared-drivers (e.g. RB1-loss, TP53-loss, high MET, RAS, ER), primary-enriched (EGFR, TGFβ and STAT3) and metastasis-enriched (RHO, PI3K) oncogenic signaling. Inhibitors of RB1-deficiency or MET plus RHO-signaling cooperate to block cell migration and drive tumor cell-death. Thus, targeting shared- and metastasis- but not primary-enriched derivers offers a rational avenue to prevent metastatic breast-cancer., (© 2023. The Author(s).)

Background: Co-production is an umbrella term used to describe the process of generating knowledge through partnerships between researchers and those who will use or benefit from research. Multiple advantages of research co-production have been hypothesized, and in some cases documented, in both the academic and practice record. However, there are significant gaps in understanding how to evaluate the quality of co-production. This gap in rigorous evaluation undermines the potential of both co-production and co-producers., Methods: This research tests the relevance and utility of a novel evaluation framework: Research Quality Plus for Co-Production (RQ + 4 Co-Pro). Following a co-production approach ourselves, our team collaborated to develop study objectives, questions, analysis, and results sharing strategies. We used a dyadic field-test design to execute RQ + 4 Co-Pro evaluations amongst 18 independently recruited subject matter experts. We used standardized reporting templates and qualitative interviews to collect data from field-test participants, and thematic assessment and deliberative dialogue for analysis. Main limitations include that field-test participation included only health research projects and health researchers and this will limit perspective included in the study, and, that our own co-production team does not include all potential perspectives that may add value to this work., Results: The field test surfaced strong support for the relevance and utility of RQ + 4 Co-Pro as an evaluation approach and framework. Research participants shared opportunities for fine-tuning language and criteria within the prototype version, but also, for alternative uses and users of RQ + 4 Co-Pro. All research participants suggested RQ + 4 Co-Pro offered an opportunity for improving how co-production is evaluated and advanced. This facilitated our revision and publication herein of a field-tested RQ + 4 Co-Pro Framework and Assessment Instrument., Conclusion: Evaluation is necessary for understanding and improving co-production, and, for ensuring co-production delivers on its promise of better health.. RQ + 4 Co-Pro provides a practical evaluation approach and framework that we invite co-producers and stewards of co-production-including the funders, publishers, and universities who increasingly encourage socially relevant research-to study, adapt, and apply., (© 2023. The Author(s).)

Immune-checkpoint (IC) modulators like the poliovirus receptor (PVR) and programmed death ligand 1 (PD-L1) attenuate innate and adaptive immune responses and are potential therapeutic targets for diverse malignancies, including triple-negative breast cancer (TNBC). The retinoblastoma tumor suppressor, pRB, controls cell growth through E2F1-3 transcription factors, and its inactivation drives metastatic cancer, yet its effect on IC modulators is contentious. Here, we show that RB-loss and high E2F1/E2F2 signatures correlate with expression of PVR, CD274 (PD-L1 gene) and other IC modulators and that pRB represses whereas RB depletion and E2F1 induce PVR and CD274 in TNBC cells. Accordingly, the CDK4/6 inhibitor, palbociclib, suppresses both PVR and PD-L1 expression. Palbociclib also counteracts the effect of CDK4 on SPOP, leading to its depletion, but the overall effect of palbociclib is a net reduction in PD-L1 level. Hydrochloric acid, commonly used to solubilize palbociclib, counteracts its effect and induces PD-L1 expression. Remarkably, lactic acid, a by-product of glycolysis, also induces PD-L1 as well as PVR. Our results suggest a model in which CDK4/6 regulates PD-L1 turnover by promoting its transcription via pRB-E2F1 and degradation via SPOP and that the CDK4/6-pRB-E2F pathway couples cell proliferation with the induction of multiple innate and adaptive immunomodulators, with direct implications for cancer progression, anti-CDK4/6- and IC-therapies., (© 2023. The Author(s).)

Evaluation capacity building (ECB) continues to attract the attention and interest of scholars and practitioners. Over the years, models, frameworks, strategies, and practices related to ECB have been developed and implemented. Although ECB is highly contextual, the evolution of knowledge in this area depends on learning from past efforts in a structured approach. The purpose of the present article is to integrate the ECB literature in evaluation journals. More specifically, the article aims to answer three questions: What types of articles and themes comprise the current literature on ECB? How are current practices of ECB described in the literature? And what is the current status of research on ECB? Informed by the findings of the review, the article concludes with suggestions for future ECB practice and scholarship., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Research co-production is an umbrella term used to describe research users and researchers working together to generate knowledge. Research co-production is used to create knowledge that is relevant to current challenges and to increase uptake of that knowledge into practice, programs, products, and/or policy. Yet, rigorous theories and methods to assess the quality of co-production are limited. Here we describe a framework for assessing the quality of research co-production-Research Quality Plus for Co-Production (RQ+ 4 Co-Pro)-and outline our field test of this approach., Methods: Using a co-production approach, we aim to field test the relevance and utility of the RQ+ 4 Co-Pro framework. To do so, we will recruit participants who have led research co-production projects from the international Integrated Knowledge Translation Research Network. We aim to sample 16 to 20 co-production project leads, assign these participants to dyadic groups (8 to 10 dyads), train each participant in the RQ+ 4 Co-Pro framework using deliberative workshops and oversee a simulation assessment exercise using RQ+ 4 Co-Pro within dyadic groups. To study this experience, we use a qualitative design to collect participant demographic information and project demographic information and will use in-depth semi-structured interviews to collect data related to the experience each participant has using the RQ+ 4 Co-Pro framework., Discussion: This study will yield knowledge about a new way to assess research co-production. Specifically, it will address the relevance and utility of using RQ+ 4 Co-Pro, a framework that includes context as an inseparable component of research, identifies dimensions of quality matched to the aims of co-production, and applies a systematic and transferable evaluative method for reaching conclusions. This is a needed area of innovation for research co-production to reach its full potential. The findings may benefit co-producers interested in understanding the quality of their work, but also other stewards of research co-production. Accordingly, we undertake this study as a co-production team representing multiple perspectives from across the research enterprise, such as funders, journal editors, university administrators, and government and health organization leaders., (© 2022. The Author(s).)

Fli-1, a member of the ETS family of transcription factors, was discovered in 1991 through retroviral insertional mutagenesis as a driver of mouse erythroleukemias. In the past 30 years, nearly 2000 papers have defined its biology and impact on normal development and cancer. In the hematopoietic system, Fli-1 controls self-renewal of stem cells and their differentiation into diverse mature blood cells. Fli-1 also controls endothelial survival and vasculogenesis, and high and low levels of Fli-1 are implicated in the auto-immune diseases systemic lupus erythematosus and systemic sclerosis, respectively. In addition, aberrant Fli-1 expression is observed in, and is essential for, the growth of multiple hematological malignancies and solid cancers. Here, we review the historical context and latest research on Fli-1, focusing on its role in hematopoiesis, immune response, and malignant transformation. The importance of identifying Fli-1 modulators (both agonists and antagonists) and their potential clinical applications is discussed., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Despite extensive analysis of pRB phosphorylation in vitro, how this modification influences development and homeostasis in vivo is unclear. Here, we show that homozygous Rb ∆K4 and Rb ∆K7 knock-in mice, in which either four or all seven phosphorylation sites in the C-terminal region of pRb, respectively, have been abolished by Ser/Thr-to-Ala substitutions, undergo normal embryogenesis and early development, notwithstanding suppressed phosphorylation of additional upstream sites. Whereas Rb ∆K4 mice exhibit telomere attrition but no other abnormalities, Rb ∆K7 mice are smaller and display additional hallmarks of premature aging including infertility, kyphosis, and diabetes, indicating an accumulative effect of blocking pRb phosphorylation. Diabetes in Rb ∆K7 mice is insulin-sensitive and associated with failure of quiescent pancreatic β-cells to re-enter the cell cycle in response to mitogens, resulting in induction of DNA damage response (DDR), senescence-associated secretory phenotype (SASP), and reduced pancreatic islet mass and circulating insulin level. Pre-treatment with the epigenetic regulator vitamin C reduces DDR, increases cell cycle re-entry, improves islet morphology, and attenuates diabetes. These results have direct implications for cell cycle regulation, CDK-inhibitor therapeutics, diabetes, and longevity., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: The COVID-19 pandemic has prompted the increasing popularity of several emerging therapies or preventives that lack scientific evidence or go against medical directives. One such therapy involves the consumption of chlorine dioxide, which is commonly used in the cleaning industry and is available commercially as a mineral solution. This substance has been promoted as a preventive or treatment agent for several diseases, including SARS-CoV-2 infection. As interest in chlorine dioxide has grown since the start of the pandemic, health agencies, institutions, and organizations worldwide have tried to discourage and restrict the consumption of this substance., Objective: The aim of this study is to analyze search engine trends in Mexico to evaluate changes in public interest in chlorine dioxide since the beginning of the COVID-19 pandemic., Methods: We retrieved public query data for the Spanish equivalent of the term "chlorine dioxide" from the Google Trends platform. The location was set to Mexico, and the time frame was from March 3, 2019, to February 21, 2021. A descriptive analysis was performed. The Kruskal-Wallis and Dunn tests were used to identify significant changes in search volumes for this term between four consecutive time periods, each of 13 weeks, from March 1, 2020, to February 27, 2021., Results: From the start of the pandemic in Mexico (February 2020), an upward trend was observed in the number of searches compared with that in 2019. Maximum volume trends were recorded during the week of July 19-25, 2020. The search volumes declined between September and November 2020, but another peak was registered in December 2020 through February 2021, which reached a maximum value on January 10. Percentage change from the first to the fourth time periods was +312.85, -71.35, and +228.18, respectively. Pairwise comparisons using the Kruskal-Wallis and Dunn tests showed significant differences between the four periods ( P <.001)., Conclusions: Misinformation is a public health risk because it can lower compliance with the recommended measures and encourage the use of therapies that have not been proven safe. The ingestion of chlorine dioxide presents a danger to the population, and several adverse reactions have been reported. Programs should be implemented to direct those interested in this substance to accurate medical information., Competing Interests: Conflicts of Interest: None declared., (©Jonathan Matias Chejfec-Ciociano, Juan Pablo Martínez-Herrera, Alexa Darianna Parra-Guerra, Ricardo Chejfec, Francisco José Barbosa-Camacho, Juan Carlos Ibarrola-Peña, Gabino Cervantes-Guevara, Guillermo Alonso Cervantes-Cardona, Clotilde Fuentes-Orozco, Enrique Cervantes-Pérez, Benjamín García-Reyna, Alejandro González-Ojeda. Originally published in JMIR Infodemiology (https://infodemiology.jmir.org), 27.01.2022.)

Human immunodeficiency virus (HIV) is a viral infection that, when transmitted through the exchange of certain bodily fluids, destroys various immune cells and contributes to an overall weakened immune system. If left untreated, HIV progresses to acquired immunodeficiency syndrome (AIDS) - a chronic, life-threatening condition that puts patients at risk for opportunistic infections. Since the emergence of HIV nearly a century ago, the world has seen tremendous advances in elucidating its pathology and progression. These advances have been accompanied by an increased understanding of how subsequent effects and symptoms manifest in afflicted individuals. These discoveries, coupled with the ever-improving technologies and methodologies used for detection and treatment, provide the scientific and medical community with a solid grasp of HIV. Despite this significant headway, there is still much progress to be made; medical advances have allowed people with HIV to manage their disease and live a longer, healthier life, but a definite cure is yet to be found. Thus, the following literature review serves as both an extensive compendium of our current understanding of HIV - its pathology, testing/detection, repercussions, and treatment - and an acknowledgement of the areas that still require further research., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Patel et al.)

The eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the 'Collagen containing extracellular matrix' pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.

Aim: Fabry disease is a lysosomal storage disorder leading to glycosphingolipid accumulation in different organs, tissues and biological fluids. The development of a Fabry disease gene therapy trial is underway in Canada. A tool to determine the distribution of Gb3 biomarkers in tissues of Fabry mice might be applicable to monitor the effect of gene therapy. Results & methodology: An ultra-performance LC-MS/MS (UPLC-MS/MS) method for the analysis of 22 Gb3 isoform/analogs in various Fabry mice tissues was developed and validated. Marked variation in biomarker organ distribution was found with higher levels in the spleen, followed by the small intestine, kidneys, lungs, heart, liver and brain., Conclusion: The devised method is sensitive and useful for the evaluation of biomarker profiles in Fabry mice., Competing Interests: Financial & competing interests disclosure This research was funded by a Grant-in-Aid of research from the Canadian Institutes of Health Research (CIHR, 129737). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Presenting target and non-target information in different modalities influences target localization if the non-target is within the spatiotemporal limits of perceptual integration. When using auditory and visual stimuli, the influence of a visual non-target on auditory target localization is greater than the reverse. It is not known, however, whether or how such perceptual effects extend to goal-directed behaviours. To gain insight into how audio-visual stimuli are integrated for motor tasks, the kinematics of reaching movements towards visual or auditory targets with or without a non-target in the other modality were examined. When present, the simultaneously presented non-target could be spatially coincident, to the left, or to the right of the target. Results revealed that auditory non-targets did not influence reaching trajectories towards a visual target, whereas visual non-targets influenced trajectories towards an auditory target. Interestingly, the biases induced by visual non-targets were present early in the trajectory and persisted until movement end. Subsequent experimentation indicated that the magnitude of the biases was equivalent whether participants performed a perceptual or motor task, whereas variability was greater for the motor versus the perceptual tasks. We propose that visually induced trajectory biases were driven by the perceived mislocation of the auditory target, which in turn affected both the movement plan and subsequent control of the movement. Such findings provide further evidence of the dominant role visual information processing plays in encoding spatial locations as well as planning and executing reaching action, even when reaching towards auditory targets.

Background: High quality acute flaccid paralysis (AFP) surveillance is required to maintain polio-free status of a country. Papua New Guinea (PNG) is considered as one of the highest risk countries for polio re-importation and circulation in the Western Pacific Region (WPRO) of the World Health Organization due to poor healthcare infrastructure and inadequate performance in AFP surveillance. The Government of PNG, in collaboration with WHO, piloted the introduction of short-message-service (SMS) to sensitize pediatricians and provincial disease control officers on AFP and to receive notification of possible AFP cases to improve surveillance quality in PNG., Methods: Ninety six health care professionals were registered to receive SMS reminders to report any case of acute flaccid paralysis. Fourteen SMS messages were sent to each participant from September 2012 to November 2013. The number of reported AFP cases were compared before and after the introduction of SMS., Results: Two hundred fifty three unique responses were received with an overall response rate of 21 %. More than 80 % of responses were reported within 3 days of sending the SMS. The number of reported AFP cases increased from 10 cases per year in 2009-2012 to 25 cases per year during the study period and correlated with provincial participation of the health care professionals., Conclusions: Combined with improved sensitization of health care professionals on AFP reporting criteria and sample collection, SMS messaging provides an effective means to increase timely reporting and improve the availability of epidemiologic information on polio surveillance in PNG.

Age-related mediolateral instability during forward stepping reactions evoked by whole-body perturbation is believed to occur independent of the initial temporospatial parameters prior to step-contact. Recent research is beginning to explore the restabilisation phase, following step-contact, as the origin of such instability. This work sought to uncover potential mechanisms underlying age-related mediolateral instability during restabilisation by examining whole-body centre of mass (COM) kinematics and the orientation of the net ground reaction force relative to the COM. Healthy younger (n=20) and older adults (n=20) were anchored to a rigid frame, via adjustable cable. After establishing a standardised initial forward lean, cable release occurred with pseudorandom timing. Participants regained their balance using a single self-selected step. The potential for lateral instability was quantified by COM kinematics. The angle of divergence of the line of action of the net ground reaction force relative to the COM was quantified and examined at three discrete points during restabilisation, as indices of COM control. Age-related differences in magnitude and trial-to-trial variability were analysed. Older adults exhibited increased ML COM incongruity and trial-to-trial variability, which were reduced with trial repetition. Older adults required an increased time to reorient the net ground reaction force, which was correlated with the increased lateral COM displacement during restabilisation. The present results support the idea that age-related mediolateral instability occurs during restabilisation and may be linked to the reactive control of the orientation of the net ground reaction force with respect to the centre of mass., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Previous studies showed that core cooling rates are similar when only the head or only the body is cooled. Structural equation modeling was used on data from two cold water studies involving body-only, or whole body (including head) cooling. Exposure of both the body and head increased core cooling, while only body cooling elicited shivering. Body fat attenuates shivering and core cooling. It is postulated that this protection occurs mainly during body cooling where fat acts as insulation against cold. This explains why head cooling increases surface heat loss with only 11% while increasing core cooling by 39%., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This study isolated the effects of dorsal, facial, and whole-head immersion in 17 degrees C water on peripheral vasoconstriction and the rate of body core cooling. Seven male subjects were studied in thermoneutral air (approximately 28 degrees C). On 3 separate days, they lay prone or supine on a bed with their heads inserted through the side of an adjustable immersion tank. Following 10 min of baseline measurements, the water level was raised such that the water immersed the dorsum, face, or whole head, with the immersion period lasting 60 min. During the first 30 min, the core (esophageal) cooling rate increased from dorsum (0.29 ± 0.2 degrees C h-1) to face (0.47 ± 0.1 degrees C h-1) to whole head (0.69 ± 0.2 degrees C h(-1)) (p < 0.001); cooling rates were similar during the final 30 min (mean, 0.16 ± 0.1 degrees C h(-1)). During the first 30 min, fingertip blood flow (laser Doppler flux as percent of baseline) decreased faster in whole-head immersion (114 ± 52% h(-1)) than in either facial (51 ± 47% h-1) or dorsal (41 ± 55% h(-1)) immersion (p < 0.03); rates of flow decrease were similar during minutes 30 to 60 (mean, 22.5 ± 19% h(-1)). Total head heat loss over 60 min was significantly different between whole-head (120.5 ± 13 kJ), facial (86.8 ± 17 kJ), and dorsal (46.0 ± 11 kJ) immersion (p < 0.001). The rate of core cooling, relative to head heat loss, was similar in all conditions (mean, 0.0037 ± 0.001 degree C kJ(-1)). Although the whole head elicited a higher rate of vasoconstriction, the face did not elicit more vasoconstriction than the dorsum. Rather, the progressive increase in core cooling from dorsal to facial to whole-head immersion simply correlates with increased heat loss.

Originally characterized as regulators of cytokinesis, septins were later implicated in other cellular processes. Recent studies show that septins have a broader role in microtubule-dependent processes, such as karyokinesis, exocytosis, and maintenance of cell shape. Many members of the septin family have been shown to colocalize or interact with the microtubule cytoskeleton, suggesting that these might be general properties of septins. Septins could play an important role in regulating microtubule dynamics by interacting with microtubule-associated proteins (MAPs) that modulate microtubule stability. Being able to associate with both microtubules and actin, septins can play an important role as adaptors between the two cytoskeletons and as regulators of processes in which both actin and microtubules are involved. As septins are associated with various neurodegenerative diseases and cancer, a better understanding of the biology of septins and their interactions with microtubules is important in order to develop possible therapeutic strategies for these diseases.

Global self-evaluations of health have proven to be sensitive predictors of morbidity and mortality. Yet researchers have only a limited understanding of how these self-evaluations are reached. This research compares two interpretations of self-rated health, as reflecting either a spontaneous assessment of one's health status and related practices, or an aspect of one's enduring self-concept. Using longitudinal data from successive waves of the National Population Health Survey in Canada (Statistics Canada, 1994-95, 1996-97, NPHS public use microdata documentation. Ottawa, Ontario: Statistics Canada; n = 7505), our analysis tests a model of change in self-rated health as predicted by respondents' baseline physical and mental health symptoms, social support, leisure physical activity, smoking, body mass index, and 2-yr changes in these characteristics. As in past research, self-rated health was sensitive to improvement or decline in these predictors. Much of the explained variance, however, was unique to respondents' self-rated health 2 yr earlier. Moreover, the effect of several predictors on respondents' self-rated health varied according to whether respondents intended to improve specific health-related behaviours in the future. These findings suggest that self-rated health is not only a spontaneous assessment of one's health status and related practices; like a self-concept, self-rated health may be regulated by efforts to achieve one's relatively important health-related goals., (Copyright 2002 Elsevier Science Ltd.)

The aim of this study was to determine the number of tibialis anterior biopsy samples and muscle fibers required to estimate the capillary supply of individual muscle fibers (C:F(i)). C:F(i) was calculated for 25 type 1 fibers in each of 8 images from 3 biopsies of 5 young healthy individuals. Sequential estimation analysis indicated that 50 fibers from one biopsy are sufficient to characterize the C:F(i) of the tibialis anterior for a group of subjects. Thus, when analyzing the capillarization of the tibialis anterior, the requirements of only one biopsy sample and 50 fibers means a great reduction in time for analysis and in the invasiveness of the procedure., (Copyright 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 546-548, 2002)

The bacterial tripeptide formyl-Met-Leu-Phe (fMLP) induces the secretion of enzyme(s) with phospholipase A(2) (PLA(2)) activity from human neutrophils. We show that circulating human neutrophils express groups V and X sPLA(2) (GV and GX sPLA(2)) mRNA and contain GV and GX sPLA(2) proteins, whereas GIB, GIIA, GIID, GIIE, GIIF, GIII, and GXII sPLA(2)s are undetectable. GV sPLA(2) is a component of both azurophilic and specific granules, whereas GX sPLA(2) is confined to azurophilic granules. Exposure to fMLP or opsonized zymosan results in the release of GV but not GX sPLA(2) and most, if not all, of the PLA(2) activity in the extracellular fluid of fMLP-stimulated neutrophils is due to GV sPLA(2). GV sPLA(2) does not contribute to fMLP-stimulated leukotriene B(4) production but may support the anti-bacterial properties of the neutrophil, because 10-100 ng per ml concentrations of this enzyme lead to Gram-negative bacterial membrane phospholipid hydrolysis in the presence of human serum. By use of a recently described and specific inhibitor of cytosolic PLA(2)-alpha (group IV PLA(2)alpha), we show that this enzyme produces virtually all of the arachidonic acid used for the biosynthesis of leukotriene B(4) in fMLP- and opsonized zymosan-stimulated neutrophils, the major eicosanoid produced by these pro-inflammatory cells.

Group IIa phospholipase A(2) (GIIa PLA(2)) is released by some cells in response to interleukin-1beta. The purpose of this study was to determine whether interleukin-1beta would stimulate the synthesis and release of GIIa PLA(2) from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA(2) in the regulation of this process. Whereas GIIa PLA(2) mRNA was not identified in untreated cells, exposure to interleukin-1beta resulted in the sustained expression of GIIa PLA(2) mRNA. Interleukin-1beta also stimulated a progressive increase in cellular and extracellular GIIa PLA(2) protein levels and increased extracellular PLA(2) activity 70-fold. In addition, interleukin-1beta stimulated the p38 MAPK-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 MAPK inhibitor, SB202190, decreased interleukin-1beta stimulated MAPKAP-K2 activity, GIIa PLA(2) mRNA expression, GIIa PLA(2) protein synthesis, and the release of extracellular PLA(2) activity. Infection with an adenovirus encoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA(2) protein synthesis and the release of GIIa PLA(2) and increased extracellular PLA(2) activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA(2) protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA(2) protein synthesis and release by interleukin-1beta-stimulated cells. These results provide direct evidence that p38 MAPK activation was necessary for interleukin-1beta-induced synthesis and release of GIIa PLA(2) by cardiomyocytes.

Prediction equations of shivering metabolism are critical to the development of models of thermoregulation during cold exposure. Although the intensity of maximal shivering has not yet been predicted, a peak shivering metabolic rate (Shivpeak) of five times the resting metabolic rate has been reported. A group of 15 subjects (including 4 women) [mean age 24.7 (SD 6) years, mean body mass 72.1 (SD 12) kg, mean height 1.76 (SD 0.1) m, mean body fat 22.3 (SD 7)% and mean maximal oxygen uptake (VO2max) 53.2 (SD 9) ml O2.kg-1.min-1] participated in the present study to measure and predict Shivpeak. The subjects were initially immersed in water at 8 degrees C for up to 70 min. Water temperature was then gradually increased at 0.8 degree C.min-1 to a value of 20 degrees C, which it was expected would increase shivering heat production based on the knowledge that peripheral cold receptors fire maximally at approximately this temperature. This, in combination with the relatively low core temperature at the time this water temperature was reached, was hypothesized would stimulate Shivpeak. Prior to warming the water from 8 to 20 degrees C, the oxygen consumption was 15.1 (SD 5.5) ml.kg-1.min-1 at core temperatures of approximately 35 degrees C. After the water temperature had risen to 20 degrees C, the observed Shivpeak was 22.1 (SD 4.2) ml O2.kg-1.min-1 at core and mean skin temperatures of 35.2 (SD 0.9) and 22.1 (SD 2.2) degrees C, respectively. The Shivpeak corresponded to 4.9 (SD 0.8) times the resting metabolism and 41.7 (SD 5.1)% of VO2max. The best fit equation predicting Shivpeak was Shivpeak (ml O2.kg-1.min-1) = 30.5 + 0.348 x VO2max (ml O2.kg-1.min-1) - 0.909 x body mass index (kg.m-2) - 0.233 x age (years); (P = 0.0001; r2 = 0.872).

The purpose of this study was to define the role of secretory phospholipase A2 (sPLA2), calcium-independent PLA2, and cytosolic PLA2 (cPLA2) in arachidonic acid (AA) release from fMLP-stimulated human neutrophils. While fMLP induced the release of extracellular sPLA2 activity and AA, 70% of sPLA2 activity remained associated with the cell. Treatment with the cell-impermeable sPLA2 inhibitors DTT or LY311-727, or the anti-sPLA2 Ab 3F10 all inactivated extracellular sPLA2 activity, but had minimal effect on neutrophil AA mass release. In contrast, coincubation of streptolysin-O toxin-permeabilized neutrophils with DTT, LY311-727, or 3F10 all decreased [3H8]AA release from [3H8]AA-labeled, fMLP-stimulated cells. Exposure to fMLP resulted in a decrease in the electrophoretic mobility of cPLA2, a finding consistent with cPLA2 phosphorylation, and stimulated the translocation of cPLA2 from cytosolic to microsomal and nuclear compartments. The role of cPLA2 was further evaluated with the cPLA2 inhibitor methyl arachidonyl fluorophosphonate, which attenuated cPLA2 activity in vitro and decreased fMLP-stimulated AA mass release by intact neutrophils, but had no effect on neutrophil sPLA2 activity. Inhibition of calcium-independent PLA2 with haloenol lactone suicide substrate had no effect on neutrophil cPLA2 activity or AA mass release. These results indicate a role for cPLA2 and an intracellular or cell-associated sPLA2 in the release of AA from fMLP-stimulated human neutrophils.

A quasi-experimental design was used to assess the efficacy of a leisure education-based later-life planning model for 10 older adults with mental retardation. Prior to the initiation of the planning process, they were interviewed and completed three standardized scales designed to assess life and leisure satisfaction and leisure constraints. A comparison group completed these scales but did not participate in the planning process. At the completion of the study, both groups completed the same scales. Results demonstrated that the planning-process group had significantly higher life and leisure satisfaction at the end of the study. Many participants also made changes to their lifestyles consistent with plans made during the study. Results suggest that a later-life planning process may contribute to the quality of life of older adults with mental retardation.

Local shear stresses generated by blood flow exert direct mechanical effects on adhesion of circulating leukocytes to vascular endothelium, but their effects on expression of endothelial-leukocyte adhesion molecules have not been determined. Shear stress in rabbit carotid arteries was increased by 170% or decreased by 73% in 5 days by surgical manipulations. En face immunofluorescence staining with the monoclonal antibody Rb1/9 revealed that vascular cell adhesion molecule-1 (VCAM-1) expression was greatly increased under low shear stress, but the distribution of staining was patchy. Thus, 71.4 +/- 7.8% of fields were VCAM-1 positive versus 2.4 +/- 0.47% of fields in control arteries. Frequently, large regions showed consistent but heterogeneous staining. Occasionally, small islands of cells were labeled intensely. Monocytes, detected by use of the monocyte-specific antibody HAM 56, adhered to endothelium under low shear stress; 64.5 +/- 8.2% of the monocytes colocalized with detectable VCAM-1, although many (83.2 +/- 2.8%) VCAM-1-positive regions were devoid of monocytes. VCAM-1 expression also increased significantly but to a lesser extent when shear stress was approximately doubled. Thus, 8.7 +/- 1.5% of fields were VCAM-1 positive under high shear versus 2.5 +/- 0.87% under normal shear stress. No monocytes were detected at high shear stress. At normal shear stresses, intercellular adhesion molecule-1 (ICAM-1), detected by use of the monoclonal antibody Rb2/3, was extensively distributed; thus, 53.5 +/- 5.5% of fields contained ICAM-1-positive cells. The junctional regions of the cells were heavily stained.(ABSTRACT TRUNCATED AT 250 WORDS)

Background and Purpose: Although the success of conservative management of congenital muscular torticollis has been well documented, relatively little is known about the determinants of response to treatment, such as treatment duration. The purpose of this study was to determine how factors such as severity of restriction of range of motion, age at initiation of treatment, and presence of a palpable intramuscular fibrotic sternocleidomastoid muscle mass affect treatment duration., Subjects: One hundred one children (mean age = 4 months, SD = 2.87, range = 0.5-15.5) who were diagnosed with congenital muscular torticollis and referred to physical therapy at British Columbia's Children's Hospital (Vancouver, British Columbia, Canada) prior to 2 years of age were included in the study., Methods: Following a standardized initial assessment, parents were taught the home treatment program, which included passive stretches of the affected sternocleidomastoid muscle and strengthening exercises for the contralateral side, and positioning and handling skills. Evaluation at 2-week intervals included measurement of passive neck rotation and lateral flexion using an adapted standard goniometer. Treatment duration was defined as the time between initiation of treatment and achievement of full passive neck range of motion., Results: Complete recovery (full passive range of motion) was achieved in all but one of the children in this sample. The mean treatment duration was 4.7 months (SD = 5.06, range = 1-36). Correlations were noted between severity of restriction and treatment duration (r = .31) as well as between presence of a mass and treatment duration (r = .26). Multiple regression analysis revealed that severity of restriction was the strongest predictor of treatment duration., Conclusion and Discussion: The results of this study will make it possible for therapists to better predict treatment duration at the time of the initial assessment. By providing parents with more precise information about the length of treatment, parents may be more willing to adhere to the exercise program. [Emery C. The determinants of treatment duration for congenital muscular torticollis.

Vascular structures readily remodel in response to hemodynamic cues associated with changes in blood flows. These remodeling processes are invoked by a wealth of developmental, physiological, and pathological phenomena. Current work is providing novel clues concerning flow sensing by endothelial cells, the signal transduction pathways that translate flow detection into endothelial responses, and some of the signals that are transmitted to the effector cells, the vascular smooth muscle cells in the media. However, most of these mechanisms relate to acute responses to altered flow, and how important they are in eliciting tissue remodeling is unknown. Also, there is very little information on the processes that accomplish "modeling," beyond evidence that modulation of new tissue synthesis occurs. There is a potential for experiments in the near future to provide fundamental information on the genesis of the vascular structure-function relations, which now clearly spans much of the pre- and postnatal life., (Copyright © 1992. Published by Elsevier Inc.)

Three modified procedures for the separation of cardiac myosin light chains are carefully compared. Ion-exchange chromatography gives a purified cardiac myosin light chain 1, whereas light chain 2 is always contaminated by light chain 1. Reversed-phase high-performance liquid chromatography gives the best resolution of these light chains and needs only 20 min for each run. However, it requires pure preparation of myosin light chains before separation. Isoelectric precipitation is the simplest procedure and suitable for large quantities of material. Although it gives the highest yield the separation is not adequate. A modified and rapid procedure for the isolation of cardiac and skeletal total myosin light chains is also presented.

The presence of ventricular myosin light chains in the atria of children with congenital heart disease was demonstrated by two-dimensional polyacrylamide gel electrophoresis, peptide mapping, and Western blot analysis. Ventricular myosin light chains were present in 27% of biopsies from 91 children with different forms of congenital heart disease. Perimembranous ventricular septal defects and tetralogy of Fallot were associated with the presence of ventricular myosin light chains in 50% of patients. The presence of ventricular myosin light chains in these atria did not correlate with pressure or volume overload. Analysis of myosin heavy chain isotype in the same biopsies by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, peptide mapping, and Western blot analysis indicated that there was no detectable expression of ventricular myosin heavy chain (beta-subunit), suggesting that the genes for the myosin heavy chains and light chains are not expressed coordinately.

The exact nature of the mechanisms at work during movement of the human spine are not well understood, nor well defined. The spine supports the torso against loads and allows freedom of motion, within physiologic limits, at the same time. A great deal of information characterizing various attributes of the spine is available. Research has provided values for flexural stiffness, axial compliance, range of motion under various loading modalities, and considerably more. This study will focus not on isolated topics, but rather serve as a broad introduction to the behavior of the spine as a whole.

Adaptive responses of rabbit common carotid arteries were examined after 70-80% reductions in blood flow produced by ipsilateral external carotid artery ligation. These flow reductions elicited growth inhibition of arterial wall tissue in immature rabbits. Specifically, experimental carotid arteries exhibited DNA levels significantly lower, by 35%, than contralateral control arteries 1 mo after external carotid ligation. Lower elastin contents (38%) were also observed, although collagen contents were not affected. These changes were accompanied by a relative reduction in wall mass of 30% and a 31% reduction in internal diameter. Adult rabbits exhibited decreased internal diameter (21%) after flow reduction, but no significant change in vessel mass or wall constituents was observed. Early diameter reductions were vasoconstrictor in origin, but the vessel functioned as a smaller artery rather than as a partially constricted normal vessel after 1 mo, i.e., both maximally dilated and maximally constricted diameters were reduced. A reduction in endothelial cell number was detected for the narrowed vessels. Manipulation of local flow conditions indicated that the vessels responded to changes in mean blood flow rather than the pulsatile component of flow.

We have isolated and analyzed the structure of the genes coding for the alpha and beta forms of the human cardiac myosin heavy chain (MYHC). Detailed analysis of four overlapping MYHC genomic clones shows that the alpha-MYHC and beta-MYHC genes constitute a total length of 51 kilobases and are tandemly linked. The beta-MYHC-encoding gene, predominantly expressed in the normal human ventricle and also in slow-twitch skeletal muscle, is located 4.5 kilobases upstream of the alpha-MYHC-encoding gene, which is predominantly expressed in normal human atrium. We have determined the nucleotide sequences of the beta form of the MYHC gene, which is 100% homologous to the cardiac MYHC cDNA clone (pHMC3). It is unlikely that the divergence of a few nucleotide sequences from the cardiac beta-MYHC cDNA clone (pHMC3) reported in a MYHC cDNA clone (pSMHCZ) from skeletal muscle is due to a splicing mechanism. This finding suggests that the same beta form of the cardiac MYHC gene is expressed in both ventricular and slow-twitch skeletal muscle. The promoter regions of both alpha- and beta-MYHC genes, as well as the first four coding regions in the respective genes, have also been sequenced. The sequences in the 5'-flanking region of the alpha- and beta-MYHC-encoding genes diverge extensively from one another, suggesting that expression of the alpha- and beta-MYHC genes is independently regulated.

We examined the cardiovascular responses to bottle feeding in newborn lambs. Feeding induced a persistent rise in blood pressure, from 76.3 +/- 1.9 mmHg to 114 +/- 3.8 mmHg, that lasted for the duration of the feeding episode. This was accompanied by a transient tachycardia that lasted for approximately 10 s at the beginning of each feeding episode. Vasoconstriction of the hindlimb circulation, the gastrointestinal tract, kidneys, and adrenal and thyroid glands contributed to the pressor response, whereas changes in skeletal muscle resistance were not statistically significant. Of tissues assessed, only those actively involved in feeding (tongue and esophagus) vasodilated. Feeding tachycardia was greatly inhibited or abolished by the beta-blocker propranolol but the alpha-blocker phentolamine caused only moderate inhibition of the pressor response. Furthermore, chemical sympathectomy with 6-hydroxydopamine delayed the onset of the pressor response but did not abolish the ultimate rise in pressure. These findings indicate that feeding causes a significant pressor response in newborn lambs that is only partially mediated by sympathetic innervation.