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The human population is ever increasing while the quality and quantity of natural resources used for livestock production decline. This calls for improved product efficiency and the development of improved and sustainable cattle production methods to produce higher quality products to satisfy the demands of both the modern and transient world. The goal of this review was to summarize the interactions, challenges, and opportunities in cattle production relating to their endocrine system, and how reproductive hormones and others impact economically important traits, animal welfare, and human health. A comprehensive literature search was conducted with a focus on analysis of natural hormones and the use of exogenous hormone administration for reproduction, growth, and development of beef and dairy cattle. Hormones regulate homeostasis and enhance important traits in cattle, including fertility, growth and development, health, and the production of both meat and milk products. Reproductive hormones such as testosterone, estradiol, progesterone, and related synthetics like trenbolone acetate and zeranol can be strategically utilized in both beef and dairy cattle production systems to enhance their most valuable traits, but the impact of these substances must account for the welfare of the animal as well as the health of the consumer. This scientific review provides a comprehensive analysis of the bovine endocrine system's impact on food animals and product quality which is vital for students, researchers, livestock producers, and consumers. Although important advances have been made in animal science and related technological fields, major gaps still exist in the knowledge base regarding the influence of hormones on the production and welfare of food animals as well as in the public perception of hormone use in food-producing animals. Filling these gaps through transformative and translational research will enhance both fundamental and applied animal science to feed a growing population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Adolescent and young adult (AYA) cancer survivors' families can face ongoing challenges into survivorship. Families' adjustment and functioning as a unit can subsequently impact AYAs' mental health and quality of life. This study examined AYA cancer survivors' perceived family functioning, compared with their peers, and investigated factors associated with family functioning. Methods: Eligible participants were aged between 15 and 40 years, fluent in English, and cancer survivors who had completed treatment. AYA cancer survivors were recruited from hospital clinics, and the comparison group from an affiliated university campus. Participants completed the McMaster Family Assessment Device, Kidcope, and the Depression, Anxiety and Stress Scale-Short Form. We analyzed between-group differences in family functioning using multivariate analysis of covariance and used partial correlations to investigate associations between demographic cancer-related psychological coping variables and family functioning. Results: Ninety-three AYA cancer survivors and 141 comparison peers participated (ages: 15-32 years). AYA cancer survivors reported significantly better family functioning ( p  = 0.029), lower depression ( p  = 0.016), and anxiety symptoms ( p  = 0.008) compared with the comparison group. Approximately one-third of AYA survivors (34.4%) reported clinically significant maladaptive family functioning; however, this was more prevalent in the comparison group (50.4%). After adjusting for covariates, poorer family functioning was associated with AYA survivors using more avoidant escape-oriented coping strategies ( p  = 0.010). Conclusions: Our cancer survivor cohort reported better family functioning and psychological outcomes compared with their peers. Interventions targeting avoidant coping behaviors may support improved family functioning in some survivors. Further research disentangling the relationship between coping mechanisms and family functioning among AYA cancer survivors is needed.

Preliminary research has shown the effectiveness of supervised exercise-based interventions in alleviating sequela resulting from metastatic prostate cancer. However, many individuals encounter barriers that limit the uptake of face-to-face exercise. Technology-enabled interventions offer a distance-based alternative. This pilot study aimed to explore the acceptability, safety and preliminary efficacy of a web-based exercise intervention ( ExerciseGuide ) in individuals with metastatic prostate cancer. Forty participants (70.2 ± 8.5 years) with metastatic prostate cancer were randomised into the 8-week intervention ( N = 20) or a wait-list control ( N = 20). The intervention arm had access to a computer-tailored website, personalised exercise prescription and remote supervision. ExerciseGuide was deemed acceptable with a score ≥20 on the client satisfaction questionnaire; however, the usability score was just below the pre-specified score of ≥68 on the software usability scale. There were no serious adverse events reported. Moderate-to-vigorous physical activity levels between baseline and follow-ups were significantly higher (10.0 min per day; 95% CI = (1.3-18.6); p = 0.01) in the intervention group compared to wait-list control. There were also greater improvements in step count (1332; 95% CI = (159-2505); p = 0.02) and identified motivation (0.4, 95% CI = (0.0, 0.7); p = 0.04). Our findings provide preliminary evidence that ExerciseGuide is acceptable, safe and efficacious among individuals with metastatic prostate cancer.

Background: Few individuals with metastatic prostate cancer have access to prostate cancer-specific exercise support, despite demonstrated benefits. eHealth tools, such as websites, may be viable options for increasing access. To be effective and acceptable, future eHealth websites need to consider end-users' perspectives, capacity and needs. We aim to provide insight into these factors by exploring daily priorities, activities and health literacy of individuals with metastatic prostate cancer and their perspectives towards exercise and exercise-based web-based eHealth interventions., Methods: Semi-structured interviews explored participant's experiences and understanding of their disease, exercise levels, advice received from health care providers, as well as acceptability of and suggested content for an eHealth tool. A thematic analysis was undertaken., Results: Interviews were conducted with eighteen Australians (55-83 years; M = 71.5, SD = 8.9) living with metastatic prostate cancer. Needing to perform daily responsibilities was a key priority. Participants had limited understanding of the benefits of prostate cancer-specific exercise, and less than half discussed exercise with their health team. Fourteen men felt they could report metastases location, but only four could provide detailed information, which has clinical implications for exercise prescription. A potential web-based intervention was considered acceptable by seventeen men for reasons such as affordability, accessibility and convenience. User-friendly design and practitioner support were important., Conclusions: Results identified key aspects useful for person-centred design of exercise programs. Participants were positive towards the proposed web-based tool and expressed the need for individualised, user-friendly and reliable information with support from a professional embedded. Lastly, not all participants could accurately report metastasis locations.

Background: Digital health interventions such as tailored websites are emerging as valuable tools to provide individualized exercise and behavioral change information for individuals diagnosed with cancer., Objective: The aim of this study is to investigate and iteratively refine the acceptability and usability of a web-based exercise intervention (ExerciseGuide) for men with metastatic prostate cancer and determine how well individuals can replicate the video-based exercise prescription., Methods: A laboratory-based multi-methods design was used, incorporating questionnaires, think-aloud tests, interviews, and movement screening among 11 men aged 63 to 82 years with metastatic prostate cancer. Overall, 9 participants were undergoing androgen deprivation therapy, and 2 were completing chemotherapy. Data were collected in two waves, with changes made for quality improvement after participant 5., Results: The intervention's usability score was deemed moderate overall but improved after modifications (from 60, SD 2.9 to 69.6, SD 2.2 out of 100). Overall, the participants found the intervention acceptable, with scores improving from wave 1 (24.2, SD 1.1 out of 30) to wave 2 (26.3, SD 2.1 out of 30). The personalized multimodal exercise prescription and computer-tailored education were seen as valuable. After wave 1, website navigation videos were added, medical terminology was simplified, and a telehealth component was included after expert real-time telehealth support was requested. Wave 2 changes included the added variety for aerobic exercise modes, reduced computer-tailoring question loads, and improved consistency of style and grammar. Finally, the participants could replicate the resistance exercise videos to a satisfactory level as judged by the movement screen; however, additional technique cueing within the videos is recommended to address safety concerns., Conclusions: The acceptability and usability of ExerciseGuide were deemed satisfactory. Various problems were identified and resolved. Notably, the participants requested the inclusion of personalized expert support through telehealth. The resistance training algorithms were shown to provide appropriate content safely, and the users could replicate the exercise technique unaided to a satisfactory level. This study has optimized the ExerciseGuide intervention for further investigation in this population., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001978257; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618001978257., (©Holly EL Evans, Cynthia C Forbes, Daniel A Galvão, Corneel Vandelanotte, Robert U Newton, Gary Wittert, Suzanne Chambers, Andrew D Vincent, Ganessan Kichenadasse, Danielle Girard, Nicholas Brook, Camille E Short. Originally published in JMIR Cancer (https://cancer.jmir.org), 28.07.2021.)

Developing a deeper understanding of biological components of sperm is essential to improving cryopreservation techniques and reproductive technologies. To fully ascertain the functional determinants of fertility, lipidomic methods have come to the forefront. Lipidomics is the study of the lipid profile (lipidome) within a cell, tissue, or organism and provides a quantitative analysis of the lipid content in that sample. Sperm cells are composed of various lipids, each with their unique contribution to the overall function of the cell. Lipidomics has already been used to find new and exciting information regarding the fatty acid content of sperm cells from different species. While the applications of lipidomics are rapidly evolving, gaps in the knowledge base remain unresolved. Current limitations of lipidomics studies include the number of available samples to analyze and the total amount of cells within those samples needed to detect changes in the lipid profiles across different subjects. The information obtained through lipidomics research is essential to systems and cellular biology. This review provides a concise analysis of the most recent developments in lipidomic research. This scientific resource is important because these developments can be used to not only combat the reproductive challenges faced when using cryopreserved semen and artificial reproductive technologies in livestock such as cattle, but also other mammals, such as humans or endangered species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Evans, Dinh, Hardcastle, Gilmore, Ugur, Hitit, Jousan, Nicodemus and Memili.)

Introduction: Preliminary research has shown the effectiveness of supervised exercise-based interventions in alleviating sequela resulting from metastatic prostate cancer. Despite this, many individuals do not engage in sufficient exercise to gain the benefits. There are many barriers, which limit the uptake of face-to-face exercise in this population including lack of suitable facilities, remoteness, and access to experts, significant fatigue, urinary incontinence and motivation. Technology-enabled interventions offer a distance-based alternative. This protocol describes a pilot two-armed randomised controlled study that will investigate the feasibility and preliminary efficacy of an online exercise and behavioural change tool (ExerciseGuide) amongst individuals with metastatic prostate cancer., Methods: Sixty-six participants with histologically diagnosed metastatic prostate cancer will be randomised into either the 8-week intervention or a wait-list control. The intervention arm will have access to a tailored website, remote supervision, and tele-coaching sessions to enhance support and adherence. Algorithms will individually prescribe resistance and aerobic exercise based upon factors such as metastasis location, pain, fatigue, confidence and current exercise levels. Behavioural change strategies and education on exercise benefits, safety and lifestyle are also tailored through the website. The primary outcome will be intervention feasibility (safety, usability, acceptability, and adherence). Secondary exploratory outcomes include changes in physical activity, quality of life, sleep, and physical function. Outcomes will be measured at baseline and week 9., Discussion: The study aims to determine the potential feasibility of an online remotely monitored exercise intervention developed for individuals with metastatic prostate cancer. If feasible, this pilot intervention will inform the design and implementation of further distance-based interventions., Trial Registration: ANZCTR, ACTRN12614001268639 . Registered 10 December 2018, https://anzctr.org.au/ACTRN12618001979246.aspx.

Background: Bone destruction is a hallmark of multiple myeloma (MM). It has been reported that proteasome inhibitors (PIs) can reduce bone resorption and increase bone formation in MM patients, but the underlying mechanisms remain unclear., Methods: Mesenchymal stem cells (MSCs) were treated with various doses of PIs, and the effects of bortezomib or carfilzomib on endoplasmic reticulum (ER) stress signaling pathways were analyzed by western blotting and real-time PCR. Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were used to determine the osteogenic differentiation in vitro. Specific inhibitors targeting different ER stress signaling and a Tet-on inducible overexpressing system were used to validate the roles of key ER stress components in regulating osteogenic differentiation of MSCs. Chromatin immunoprecipitation (ChIP) assay was used to evaluate transcription factor-promoter interaction. MicroCT was applied to measure the microarchitecture of bone in model mice in vivo., Results: We found that both PERK-ATF4 and IRE1α-XBP1s ER stress branches are activated during PI-induced osteogenic differentiation. Inhibition of ATF4 or XBP1s signaling can significantly impair PI-induced osteogenic differentiation. Furthermore, we demonstrated that XBP1s can transcriptionally upregulate ATF4 expression and overexpressing XBP1s can induce the expression of ATF4 and other osteogenic differentiation-related genes and therefore drive osteoblast differentiation. MicroCT analysis further demonstrated that inhibition of XBP1s can strikingly abolish bortezomib-induced bone formation in mouse., Conclusions: These results demonstrated that XBP1s is a master regulator of PI-induced osteoblast differentiation. Activation of IRE1α-XBP1s ER stress signaling can promote osteogenesis, thus providing a novel strategy for the treatment of myeloma bone disease.

The objective of the current study was to determine the fatty acid composition of sperm from Holstein bulls with different freezability (Good and Poor; n = 12). Fatty acids were extracted from frozen sperm in 1:2 (v/v) chloroform-methanol solvent, fractionated into neutral and polar fractions, and composition determined by gas chromatography-mass spectrometry. Thirty-four fatty acids were quantified and their concentrations and percentages within each lipid fraction were calculated. Overall, saturated fatty acids (SFA) were predominant, accounting for 71 to 80% of fatty acids in neutral and polar lipid factions. There were marked differences in fatty acid composition between the lipid fractions (P < 0.001). The branched chain fatty acid (BCFA) concentration (15 to 18 µg) was almost twice as much as polyunsaturated fatty acids (PUFA) concentration found in the polar lipid fraction (8 to 9 µg; P < 0.001). Sperm with different freezability phenotypes only had a few differences in 22:0, 18:1 cis 9, and 14:0 13-methyl fatty acids (P ≤ 0.011). These results are significant because they reveal key understandings of fatty acid composition of sperm membrane and lay a foundation for the manipulation of membrane integrity, fluidity, and stability to advance the assisted reproductive technologies.

The objective of this study was to ascertain cellular characteristics and the dynamics of the sperm chromatin proteins protamine 1 (PRM1) and protamine 2 (PRM2) in the sperm of Holstein bulls having a different fertility status. Important sperm variables were analyzed using computer-assisted sperm analysis (CASA). Sperm membrane, acrosome status, DNA integrity were also assessed using propidium iodide (PI), fluorescein isothiocyanate conjugated to Arachis hypogaea (FITC-PNA), and acridine orange (AO) followed by flow cytometry. In addition, abundances of PRM1 and PRM2 were analyzed using flow cytometry experiments. Differences in sperm decondensation capacity were assessed in bulls of varying fertility using a decondensation assay. As determined using CASA, average pathway velocity, amplitude of lateral head displacement and straightness were different (P < 0.05) for sperm from high and low fertility bulls. There, however, were no differences between the high and low fertility bulls for characteristics of sperm plasma membrane, acrosome, and DNA integrity (P >  0.05). Relative abundances of PRM1 and PRM2 in sperm from the high and low fertility bulls were inversely related (P <  0.0001). Percentages of decondensed sperm were different between high and low fertility bulls (P < 0.0001) and total numbers of decondensed sperm were greater in low fertility bulls than high fertility bulls (R 2  = 0.72). Results of the present study are significant because molecular and morphological phenotypes of sperm that were detected affect fertility in livestock species., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.

Objective: Bone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass., Methods: The skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing., Results: Bones from juvenile and Pyy KO mice were longer (P < 0.001), with decreased bone mineral content (P < 0.001). Whereas, bones from adult Pyy KO mice had increased bone mineral content (P < 0.05) with increased mineralisation of both cortical (P < 0.001) and trabecular (P < 0.001) compartments. Long bones from adult Pyy KO mice were stronger (maximum load P < 0.001), with increased stiffness (P < 0.01) and toughness (P < 0.05) compared to wild-type (WT) control mice despite increased cortical vascularity and porosity (P < 0.001). The increased bone mass and strength in Pyy KO mice resulted from increases in trabecular (P < 0.01) and cortical bone formation (P < 0.05)., Conclusions: These findings demonstrate that PYY acts as a negative regulator of osteoblastic bone formation, implicating increased PYY levels in the pathogenesis of bone loss during anorexia or following bariatric surgery., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance.

Four species of ticks known to parasitize humans (Amblyomma americanum (lone star tick), Dermacentor variabilis (American dog tick), Amblyomma maculatum (Gulf Coast tick), and Ixodes scapularis (black-legged tick)) were collected at Joint Base Langley-Eustis, Fort Eustis, Virginia during 2009. These ticks were tested individually (adults and nymphs) and in pools of 15 (larvae) for pathogens of public health importance within the genera: Rickettsia, Borrelia, and Ehrlichia, by quantitative real-time polymerase chain reaction (qPCR) assays and, where appropriate, multilocus sequence typing (MLST). Of the 340 A americanum ticks tested, a minimum of 65 (19%), 4 (1%), 4 (1%), and one (<1%) were positive for Rickettsia amblyommii, B lonestari, E ewingii and E chaffeensis, respectively. One of 2 (50%) A maculatum ticks collected was found to be positive for R parkeri by MLST and qPCR analyses. All 33 D variabilis ticks were negative for evidence of rickettsial infections. Likewise, no pathogenic organisms were detected from the single Ixodes scapularis tick collected. Pathogenic rickettsiae and ehrlichiae are likely emerging and cause under-recognized diseases, which threaten people who live, work, train, or otherwise engage in outdoor activities at, or in the vicinity of, Fort Eustis, Virginia.

Myeloma bone disease results from an uncoupling of osteoclastic resorption and osteoblastic bone formation, but early changes in osteogenic function remain poorly defined. We used the KMS12BM xenograft model to investigate cellular and molecular events at early and late stages of disease. Lytic lesions and changes in osteoblast and osteoclast numbers occur late (8 weeks), however, micro-computed tomography of femora revealed significant reduction in bone volume at earlier disease stages (3 weeks) when tumour burden is low. Calcein labelling demonstrated reduced mineralization and bone formation at 3 weeks, suggesting functional impairment despite preserved osteoblast numbers. Osteo-progenitors from compact bone increased early (1 week), but fell at 3 weeks and were profoundly suppressed by 8 weeks. Exposure of osteoblast progenitors to multiple myeloma (MM) cells in vitro induced cell cycling, suggesting a mechanistic basis for early expansion of osteo-progenitors. We observed temporal changes in chemokine, osteogenic and osteoclastogenic genes in the stromal compartment. Notably, an early rise in CCL3 may underlie functional changes in mature osteoblasts at 3 weeks. Our data indicate that MM has distinct effects on mature osteoblasts and immature osteo-progenitors. Our findings argue for early clinical intervention to prevent bone changes that ultimately lead to the development of osteolytic disease., (© 2015 John Wiley & Sons Ltd.)

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.

Background: Allergen-specific immunotherapy (ASIT) is used to treat the symptoms of immediate type I hypersensitivity. The mechanisms driving establishment of allergen tolerance are not yet fully understood., Objective: The goal of this study was to develop and immunologically characterize 3 murine models of ASIT to simulate protocols currently used to treat patients with type I hypersensitivities., Methods: Ovalbumin (OVA)-sensitized mice were desensitized to OVA by means of repeated injections of OVA with a rapid, intermediate, or gradual protocol. After desensitization, mice were assessed for clinical sensitivity to OVA, and immunologic parameters were assessed., Results: Mice in all treatment protocols displayed decreased vascular permeability in response to OVA challenge after desensitization. Circulating OVA-specific IgE levels, as well as basophil activation in response to OVA stimulation and IgE cross-linking, were significantly decreased in all treatment groups. Intermediate and gradual protocols, but not rapid desensitization, suppressed splenocyte proliferation and production of IL-4, IL-5, and IFN-γ in response to OVA and polyclonal activation. Similarly, significant increases in IL-10 production, numbers of CD4(+)CD25(+) forkhead box protein 3-positive regulatory T cells, and OVA-specific IgG1 antibody levels were only observed in mice undergoing prolonged ASIT regimens., Conclusion: Suppression of IgE-mediated activation is a common feature of all desensitization schedules. Induction of immunoregulatory networks requires prolonged desensitization schedules., (Copyright © 2014. Published by Elsevier Inc.)

Helminth infections are associated with decreased rates of autoimmunity and allergy, and several clinical studies have demonstrated that intentional infection with helminths can reduce symptoms of autoimmune diseases. In contrast, though numerous animal studies have demonstrated that helminth infections ameliorate allergic diseases, clinical trials in humans have not shown benefit. In this article, we review in detail the 2 human studies that have prospectively tested whether helminth infections protect against allergy. We next review the research designs and results obtained from animal studies, and compare these to the human trials. We then postulate possible reasons for the lack of efficacy observed in clinical trials to date and discuss potential future areas of research in this field., (Copyright © 2014. Published by Elsevier Inc.)

A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1(PV/+) mice express a similar potent dominant-negative mutant TRα1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1(PV/+) mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1(PV/+) mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRα1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.

Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumors, respectively. ACTH secretion is stimulated by CRH, and we report a mouse model for Cushing's syndrome due to an N-ethyl-N-nitrosourea (ENU) induced Crh mutation at -120 bp of the promoter region, which significantly increased luciferase reporter activity and was thus a gain-of-function mutation. Crh(-120/+) mice, when compared with wild-type littermates, had obesity, muscle wasting, thin skin, hair loss, and elevated plasma and urinary concentrations of corticosterone. In addition, Crh(-120/+) mice had hyperglycemia, hyperfructosaminemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia but normal adiponectin. Crh(-120/+) mice also had low bone mineral density, hypercalcemia, hypercalciuria, and decreased concentrations of plasma PTH and osteocalcin. Bone histomorphometry revealed Crh(-120/+) mice to have significant reductions in mineralizing surface area, mineral apposition, bone formation rates, osteoblast number, and the percentage of corticoendosteal bone covered by osteoblasts, which was accompanied by an increase in adipocytes in the bone marrow. Thus, a mouse model for Cushing's syndrome has been established, and this will help in further elucidating the pathophysiological effects of glucocorticoid excess and in evaluating treatments for corticosteroid-induced osteoporosis.

Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T(3), which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2(-/-) mice and determined its skeletal expression in T(3) receptor (TR) knockout and thyroid-manipulated mice. Rcan2(-/-) mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T(3) treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.

Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3'-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.

Multimodal analgesia incorporates the use of analgesic adjuncts with different mechanisms of action to enhance postoperative pain management. Acetaminophen, anti-inflammatories, and gabapentinoids provide effective analgesia while reducing opioid requirements and opioid-related side effects. Intrathecal morphine and periarticular local anesthetic infiltration further enhance dynamic analgesia and improve postoperative mobilization. Epidural analgesia, peripheral nerve blocks, tramadol, ketamine, and/or clonidine can be added for improved benefit in opioid-tolerant individuals.