PRO-FIT-CARE study: the feasibility assessment of a pilot online exercise intervention for persons living with obesity and female infertility.

Introduction: Moderate-to-high physical activity participation is associated with a reduced risk of infertility. Yet, exercise interventions that target cardiorespiratory fitness, independent of weight loss, are lacking in obesity and female fertility research. Purpose: The primary objective of the PRO-FIT-CARE (PROmoting FITness for CArdiometabolic & REproductive Health) study was to assess the feasibility of a moderate-to-high-intensity online exercise program for persons with obesity and female infertility. Methods: Feasibility, safety, acceptability, and efficacy were assessed by examining: (1) recruitment and consent rate, (2) study retention, (3) adverse events, (4) participant satisfaction, (5) adherence, and (6) cardiorespiratory fitness. Results: Eleven of thirty-two women contacted agreed to participate in the program (34.4% consent rate). Eight participants (72.7%) completed the study. One musculoskeletal injury was reported. There was a 30% adherence rate based on prescribed exercise intensity (60%-80% of heart rate maximum). One of eleven participants attended 80% of the exercise intervention. Based on a weekly satisfaction survey, the program had an overall high level of satisfaction. Compared to sex and age normative data, post-intervention, two of eight participants improved their cardiorespiratory fitness percentile rank. Conclusion: The study highlights challenges with adherence to an online exercise program. While the program was safe and participants reported high levels of program satisfaction, approaches to improve adherence must be incorporated.

The LW blood group system: not just "tagging along" with D.

This update of the Landsteiner-Wiener (LW) blood group system (Grandstaff Moulds MK. The LW blood group system: a review. Immunohematology 2011;27:136-42. Storry JR. Review: the LW blood group system. Immunohematology 1992;8:87-93) reports new information on the distribution of genetic variants in ICAM4 and reviews the complex serologic identification of the high-prevalence LWEM antigen. The role of ICAM4 in sickle cell disease and malaria susceptibility is discussed.

Modelling growth in Suffolk and Charollais sheep populations using random regression models and validation of constrained polynomial correlation values.

Random regression modelling has been used across multiple animal species to model longitudinal data. The random regression model for growth accounts for the genetic correlation between measures of the same trait over time and the wide environmental variability in growth, but this requires adequate weight records across the age range. However, contemporary management practices in sheep in the United Kingdom generally focus on growing lambs and neglect mature weight recordings. This study examined modelling strategies for growth data in Suffolk and Charollais sheep, provided by the Agriculture and Horticulture Development Board, with polynomial random regression modelling with many early life weight recordings but limited weight recordings in mature animals. Two methods were employed to model the data. In Method A, missing mature weight records were predicted for those animals that did not have a recorded mature weight. The animals were sorted into groups based on the identity of their sires and the year in which the animal was born. Mature weight values were predicted within each group with a multiple regression model. The dataset, including predicted values, was analysed with random regression models using polynomials and simple linear regression for animal and permanent environmental (PE) effects. In Method B, the dataset with missing mature weight records was analysed using a random linear regression animal model with random animal and PE effects. Due to problems of convergence because the parameters were close to the boundary space, fixing the correlation between the intercept and slope of the Legendre polynomial at different levels was investigated. The heritability values resulting from the model with a fixed correlation between intercept and slope parameters at 0.5 for the Suffolk dataset resulted in heritability values ranging from 0.2 to 0.5 from 1 to 619 days of age. Corresponding estimates for the Charollais dataset ranged from 0.18 to 0.49 from 1 to 640 days of age. For the Suffolk data, the genetic correlations ranged from 1.00 to 0.08 between weight at day 1 to weight at day 619, while for the Charollais, the correlations ranged from 1.00 to 0.05 from 1 to 640 days of age. Validation procedures were undertaken using a multitrait approach to examine the estimated breeding values when the correlation between the intercept and slope are fixed at different levels. The results indicated that fixing the correlation at 0.5 gave the most appropriate estimates for the Suffolk and Charollais datasets.

Leadership capabilities of physiotherapy leaders in Ireland: Part 2. Clinical specialists and advanced physiotherapy practitioners.

Background: Investigation of the leadership capabilities of physiotherapy managers found that they report predominantly demonstrating capabilities associated with the human resource and structural frames. However, little is known about the leadership capabilities of clinical specialists and advanced physiotherapy practitioners (APPs) who also are identified as having responsibility for leadership. Objective: To explore clinical specialists´ and APPs' perceptions of their leadership capabilities and compare them with the reported leadership capabilities of physiotherapy managers. Methods: Semi-structured interviews were conducted with a purposive sample of 17 physiotherapy clinical specialists and APPs from a range of practice settings across Ireland. The interviews were analyzed using template analysis and the coding template was based on the Bolman and Deal Leadership framework. Results: The participants described demonstrating leadership capabilities associated with each of the four leadership frames. However, the language used by the clinical specialists/APPs suggested that they work predominantly through the human resource frame. Structural frame capabilities were reported by the clinical specialists/APPs and there were some differences to those reported by the managers. In keeping with the reported leadership capabilities of the physiotherapy managers, the employment of capabilities associated with the political frame varied between participants and symbolic frame capabilities were underused. Conclusion: There are many similarities in the self-reported leadership capabilities of managers and clinical specialists/APPs. However, differences were also noted. Both cohorts of physiotherapy leaders may benefit from specific development programs to develop leadership capabilities associated with the political and symbolic frames.

Effects of a transition home program on preterm infant emergency room visits within 90 days of discharge.

OBJECTIVE: To evaluate effects of a transition home program (THP) and risk factors on emergency room (ER) use within 90 days of discharge for preterm (PT) infants <37 weeks gestation. STUDY DESIGN: This is a prospective 3-year cohort study of 804 mothers and 954 PT infants. Mothers received enhanced neonatal intensive care unit transition support services until 90 days postdischarge. Regression models were run to identify the effects of THP implementation year and risk factors on ER visits. RESULTS: Of the 954 infants, 181 (19%) had ER visits and 83/181 (46%) had an admission. In regression analysis, THP year 3 vs year 1 and human milk at discharge were associated with decreased risk of ER visits, whereas increased odds was associated with non-English speaking, maternal mental health disorders and bronchopulmonary dysplasia. CONCLUSION: Enhanced THP services were associated with a 33% decreased risk of all ER visits by year 3. Social and environmental risk factors contribute to preventable ER visits.

Diverse and novel RHD variants in Australian blood donors with a weak D phenotype: implication for transfusion management.

BACKGROUND AND OBJECTIVES: Variant RHD genes associated with the weak D phenotype can result in complete or partial D-epitope expression on the red cell. This study examines the genetic classification in Australian blood donors with a weak D phenotype and correlates RHD variants associated with the weak D phenotype against D-epitope profile. MATERIALS AND METHODS: Following automated and manual serology, blood samples from donors reported as 'weak D' (n = 100) were RHD genotyped by a commercial SNP-typing platform and Sanger sequencing. Two commercial anti-D antibody kits were used for extended serological testing for D-epitope profiles. RESULTS: Three samples had wild-type RHD exonic sequences, and 97 samples had RHD variants. RHD*weak D type 1, RHD*weak D type 2 or RHD*weak D type 3 was detected in 75 donors. The remaining 22 samples exhibited 17 different RHD variants. One donor exhibited a novel RHD*c.939+3A>C lacking one D-epitope. Weak D types 1·1, 5, 15, 17 and 90 showed a partial D-epitope profile. CONCLUSION: The array of RHD variants detected in this study indicated diversity in the Australian donor population that needs to be accommodated for in future genotyping strategies.

Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus.

UNLABELLED: Zika virus (ZIKV) is a mosquito-borne flavivirus responsible for thousands of cases of severe fetal malformations and neurological disease since its introduction to Brazil in 2013. Antibodies to flaviviruses can be protective, resulting in lifelong immunity to reinfection by homologous virus. However, cross-reactive antibodies can complicate flavivirus diagnostics and promote more severe disease, as noted after serial dengue virus (DENV) infections. The endemic circulation of DENV in South America and elsewhere raises concerns that preexisting flavivirus immunity may modulate ZIKV disease and transmission potential. Here, we report on the ability of human monoclonal antibodies and immune sera derived from dengue patients to neutralize contemporary epidemic ZIKV strains. We demonstrate that a class of human monoclonal antibodies isolated from DENV patients neutralizes ZIKV in cell culture and is protective in a lethal murine model. We also tested a large panel of convalescent-phase immune sera from humans exposed to primary and repeat DENV infection. Although ZIKV is most closely related to DENV compared to other human-pathogenic flaviviruses, most DENV immune sera (73%) failed to neutralize ZIKV, while others had low (50% effective concentration [EC50], <1:100 serum dilution; 18%) or moderate to high (EC50, >1:100 serum dilution; 9%) levels of cross-neutralizing antibodies. Our results establish that ZIKV and DENV share epitopes that are targeted by neutralizing, protective human antibodies. The availability of potently neutralizing human monoclonal antibodies provides an immunotherapeutic approach to control life-threatening ZIKV infection and also points to the possibility of repurposing DENV vaccines to induce cross-protective immunity to ZIKV. IMPORTANCE: ZIKV is an emerging arbovirus that has been associated with severe neurological birth defects and fetal loss in pregnant women and Guillain-Barré syndrome in adults. Currently, there is no vaccine or therapeutic for ZIKV. The identification of a class of antibodies (envelope dimer epitope 1 [EDE1]) that potently neutralizes ZIKV in addition to all four DENV serotypes points to a potential immunotherapeutic to combat ZIKV. This is especially salient given the precedent of antibody therapy to treat pregnant women infected with other viruses associated with microcephaly, such as cytomegalovirus and rubella virus. Furthermore, the identification of a functionally conserved epitope between ZIKV and DENV raises the possibility that a vaccine may be able to elicit neutralizing antibodies against both viruses.

Quality and accuracy of publicly accessible cancer-related physical activity information on the Internet: a cross-sectional assessment.

In this study, we assessed the quality of publicly available cancer-related physical activity (PA) information appearing on reputable sites from Canada and other English-speaking countries. A cross-sectional Internet search was conducted on select countries (Canada, USA, Australia, New Zealand, UK) using Google to generate top 50 results per country for the keywords "'physical activity' AND 'cancer'". Top results were assessed for quality of PA information based on a coding frame. Additional searches were performed for Canadian-based sites to produce an exhaustive list. Results found that many sites offered cancer-related PA information (94.5%), but rarely defined PA (25.2%). Top 50 results from each country did not differ on any indicator examined. The exhaustive list of Canadian sites found that many sites gave information about PA for survivorship (78.3%) and prevention (70.0%), but rarely defined (6.7%) or referenced PA guidelines (28.3%). Cancer-related PA information is plentiful on the Internet but the quality needs improvement. Sites should do more than mention PA; they should provide definitions, examples and guidelines. With improvements, these websites would enable healthcare providers to effectively educate their patients about PA, and serve as a valuable resource to the general public who may be seeking cancer-related PA information.

Tau suppression in a neurodegenerative mouse model improves memory function.

Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.

Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity.

Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1-358), followed by an 18 kDa peptide-binding domain (amino acids 359-494) and a C-terminal 10 kDa fragment (amino acids 495-609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359-610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFalpha(tumour necrosis factor alpha), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70-CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.

The retinal degeneration (rd) gene seriously impairs spatial cognitive performance in normal and Alzheimer's transgenic mice.

To determine the effects of the recessive retinal degeneration (rd) gene on behavioral performance, three Alzheimer's transgenic lines (APPsw, P301L, APPsw + P301L) and non-transgenic littermates were evaluated in a comprehensive behavioral battery between 5 and 8.5 months of age. For all four genotypes collectively, rd homozygosity resulted in profound impairment in spatial cognitive tasks requiring visual acuity (Morris maze, platform recognition, and radial arm water maze). Non-transgenic and P301L mutant tau mice contributed most to this rd effect since heterozygous and wild type mice performed well. By contrast, spatial cognitive performance of both APPsw-expressing lines was often impaired, irrespective of rd status. Sensorimotor performance was unaffected by rd homozygosity, while rd effects on anxiety were genotype-dependent (less anxiety in NT, APPsw; more anxiety in P301L, APPsw + P301L). Our results strongly encourage rd screening of genetically manipulated mouse lines produced from rd-carrying strain backgrounds to avoid serious potential confounds in the interpretation of spatially based cognitive performance.

Effect of progesterone receptor a predominance on breast cancer cell migration into bone marrow fibroblasts.

Women exposed to exogenous progesterone have increased breast cancer risk, but the mechanisms of progesterone involvement in breast cancer development are unknown. In human breast and endometrium, progesterone receptor (PR) isoform expression is disrupted in premalignant lesions and predominance of one isoform, usually PRA, in invasive cancers is associated with poorer prognosis. Disrupted PR isoform expression results in disrupted progestin regulation of cell morphology, including rounded morphology and decreased adherence of cells to tissue culture flasks. The purpose of this study was to test the hypothesis that predominance of PRA affects the interaction of breast cancer cells with a physiologically relevant stromal tissue, bone marrow stroma. T-47D breast cancer cells demonstrated the ability to migrate into bone marrow fibroblasts and this was inhibited by progestin treatment. The antiprogestin RU38486 abrogated the progestin effect on migration, demonstrating that it was PR-mediated. In cells expressing a predominance of PRA, after induction of a stably integrated inducible PRA construct, the ability of progestin to inhibit breast cancer cell migration was lost. A number of integrins were progestin regulated in T-47D cells, but there was no difference in the progestin effect in cells with PRA predominance, nor were the levels of focal adhesion proteins altered in these cells. This suggested that the lack of inhibition by progestin of breast cancer cell migration in cells with PRA predominance was not mediated by PRA effects on the membrane components of the adherens junctions. In summary, this study has shown that PRA predominance has a striking functional effect on breast cancer cell migration into stromal layers. PRA predominance may render breast cancer cells relatively resistant to the inhibitory effects of progestins and one consequence of this may be increased invasion of stroma. If borne out in vivo, these findings suggest that tumours with PRA predominance may be predisposed to cancer progression and this may signal a poorer prognosis in patients.

Cytoskeletal responsiveness to progestins is dependent on progesterone receptor A levels.

Changes in the cell cytoskeleton occur in cell transformation and recent data suggest the involvement of ovarian hormones, which are implicated in cancer development and progression. In human breast and endometrial tumors, there is disrupted expression of progesterone receptor (PR) isoforms and predominance of one isoform, usually PRA. PRA predominance is an early event in carcinogenesis, and in cancers is associated with poor clinical features. Overexpression of PRA in vitro causes altered progestin regulation of cell morphology, suggesting that PRA overexpression may provoke deleterious changes in cell functioning. This study aimed to identify pathways of cytoskeleton regulation responsive to progestins and to determine whether these are perturbed when PRA is overexpressed to the levels seen in cancers. Progestin treatment of PR-positive breast cancer cells caused increased cell surface area whereas after induction of a stably integrated PRA construct, cells became rounded and the cell surface was decreased. The effect of PRA induction on cell rounding was reversed by the anti-progestin RU38486. Altered tropomyosin (Tm) isoforms were implicated in these morphological differences, as there was a PRA-mediated alteration in Tm5 isoform levels, and transfection of Tm5a mimicked progestin-mediated cell rounding in PRA-overexpressing cells. Ezrin was redistributed from the membrane to cytoplasmic locations in the presence of progestin, and discrete focal localization was evident in cells with PRA predominance. Progestin effects on the cytoskeleton in PRA-overexpressing cells provide evidence for novel endocrine regulation of aspects of actin microfilament composition, suggesting that changes in the cytoskeleton known to be associated with cancer development and progression may be regulated in part by altered PRA expression which develops early in carcinogenesis.

Analysis of tauopathies with transgenic mice.

Intraneuronal filamentous inclusions composed of the microtubule-associated protein tau are a feature of several neurodegenerative diseases (including Alzheimer's disease) known as tauopathies. A pivotal finding was the identification in 1998 of mutations in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. This demonstrated that tau dysfunction is sufficient to cause neurodegeneration, and indicated that tau is likely to play a crucial role in the pathogenesis of other tauopathies. However, the mechanism by which tau filamentous lesions form and their role in neurodegeneration remains uncertain. Recent progress in the development of transgenic mouse models of human tauopathy is allowing these questions to be addressed.

Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.

JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.

Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides.

In order to develop transgenic animal models that selectively overexpress various Abeta peptides, we have developed a novel expression system that selectively expresses Abeta40 or Abeta42 in the secretory pathway. This system utilizes fusion constructs in which the sequence encoding the 23-amino-acid ABri peptide at the carboxyl terminus of the 266-amino-acid type 2 transmembrane protein BRI is replaced with a sequence encoding either Abeta40 or Abeta42. Constitutive processing of the resultant BRI-Abeta fusion proteins in transfected cells results in high-level expression and secretion of the encoded Abeta peptide. Significantly, expression of Abeta42 from the BRI-Abeta42 construct resulted in no increase in secreted Abeta40, suggesting that the majority of Abeta42 is not trimmed by carboxypeptidase to Abeta40 in the secretory pathway.

Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.

alpha-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human alpha-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human alpha-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human alpha-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of alpha-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.

Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes.

The basalo-cortical cholinergic system was characterized in mice expressing mutant human genes for presenilin-1 (PS1), amyloid precursor protein (APP), and combined PS/APP. Dual immunocytochemistry for ChAT and A beta revealed swollen cholinergic processes within cortical plaques in both APP and PS/APP brains by 12 months, suggesting aberrant sprouting or redistribution of cholinergic processes in response to amyloid deposition. At 8 months, cortical and subcortical ChAT activity was normal (PS/APP) or elevated (PS, APP frontal cortex), while cholinergic cell counts (nBM/SI) and receptor binding were unchanged. ChAT mRNA was up-regulated in the nBM/SI of all three transgenic lines at 8 months. The data indicate that the basal forebrain cholinergic system does not degenerate in mice expressing AD-related transgenes, even in mice with extreme amyloid load. The