Normative values for grip strength, gait speed, timed up and go, single leg balance, and chair rise derived from the Canadian longitudinal study on ageing.

BACKGROUND: decreased muscle strength and physical function often precede disability, nursing home admission, home care use and mortality in older adults. Normative values for commonly used physical performance-based tests are not widely available for older adults but are required for clinicians and researchers to easily identify individuals with low performance. OBJECTIVE: to develop normative values for grip strength, gait speed, timed up and go, single-leg balance and five-repetition chair rise tests in a large population-based sample of Canadians aged 45-85 years. METHODS: baseline data (2011-2015) from the Canadian Longitudinal Study on Ageing was used to estimate age- and sex-specific normative values for each of the physical tests. Participants were without disability or mobility limitation (no assistance with activities of daily living or use of mobility devices). RESULTS: of the 25,470 participants eligible for the analyses 48.6% (n = 12,369) were female with a mean age of 58.6 ± 9.5 years. Sex-specific 5th, 10th, 20th, 50th, 80th, 90th and 95th percentile values for each physical performance-based test were estimated. Cross-validation (n = 100 repetitions) with a 30% holdout sample was used to evaluate model fit. CONCLUSIONS: the normative values developed in this paper can be used in clinical and research settings to identify individuals with low performance relative to their peers of the same age and sex. Interventions targeting these at-risk individuals including physical activity can prevent or delay mobility disability and the resulting cascade of increasing care requirements, health care costs and mortality.

Phenotypic Characterization and Comparison of Cystic Fibrosis Rat Models Generated Using CRISPR/Cas9 Gene Editing.

Animal models of cystic fibrosis (CF) are essential for investigating disease mechanisms and trialing potential therapeutics. This study generated two CF rat models using clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 gene editing. One rat model carries the common human Phe508del (ΔF508) CF transmembrane conductance regulator (CFTR) mutation, whereas the second is a CFTR knockout model. Phenotype was characterized using a range of functional and histologic assessments, including nasal potential difference to measure electrophysiological function in the upper airways, RNAscope in situ hybridization and quantitative PCR to assess CFTR mRNA expression in the lungs, immunohistochemistry to localize CFTR protein in the airways, and histopathologic assessments in a range of tissues. Both rat models revealed a range of CF manifestations, including reduced survival, intestinal obstruction, bioelectric defects in the nasal epithelium, histopathologic changes in the trachea, large intestine, and pancreas, and abnormalities in the development of the male reproductive tract. The CF rat models presented herein will prove useful for longitudinal assessments of pathophysiology and therapeutics.

Healthy eating interventions in adults living with and beyond colorectal cancer: a systematic review.

BACKGROUND: Rates of cancer survival are increasing, with more people living with and beyond cancer. Lifestyle recommendations for cancer survivors are based largely on extrapolation from cancer prevention recommendations. The present study aimed to systematically review the literature on randomised controlled trials (RCTs) focusing on healthy eating interventions in people with colorectal cancer (CRC). METHODS: A structured search of electronic databases was conducted in March 2018 using medical subject headings (MeSH) and text words related to CRC and diet. The results of the literature searches were uploaded to online software for data management. Titles and abstracts were screened based on the inclusion and exclusion criteria and data were extracted. Quality of data was assessed using the Cochrane Handbook. RESULTS: Seven studies were identified, including six RCTs and one RCT protocol, with a total of 2233 participants from six studies, of whom 1010 (45%) had CRC. Three studies assessed anthropometrics demonstrating participants who received dietary intervention had a greater reduction in measurements. Six studies assessed changes in dietary components; however, only one demonstrated an increase in dietary fibre. Two studies reported improvements in quality of life favouring dietary intervention groups. CONCLUSIONS: The quality of identified studies was variable, with limited evidence to support dietary intervention improving dietary intake in people living with or after CRC. Studies to date have not been based on robust study design that has combined all dietary interventions linked to CRC. As a result of the heterogeneity of the studies identified, it was difficult to draw strong conclusions.

Macrocyclic protease inhibitors with reduced peptide character.

There is a real need for simple structures that define a ß-strand conformation, a secondary structure that is central to peptide-protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting ß-strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C-terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X-ray crystallography.

Recent advances in reproductive research in Australia and New Zealand: highlights from the Annual Meeting of the Society for Reproductive Biology, 2022.

In 2022, the Society for Reproductive Biology came together in Christchurch New Zealand (NZ), for its first face-to-face meeting since the global COVID-19 pandemic. The meeting showcased recent advancements in reproductive research across a diverse range of themes relevant to human health and fertility, exotic species conservation, and agricultural breeding practices. Here, we highlight the key advances presented across the main themes of the meeting, including advances in addressing opportunities and challenges in reproductive health related to First Nations people in Australia and NZ; increasing conservation success of exotic species, including ethical management of invasive species; improvements in our understanding of developmental biology, specifically seminal fluid signalling, ovarian development and effects of environmental impacts such as endocrine-disrupting chemicals; and leveraging scientific breakthroughs in reproductive engineering to drive solutions for fertility, including in assisted reproductive technologies in humans and agricultural industries, and for regenerative medicine.

Are radiographers suffering from symptoms of compassion fatigue due to occupational stress: A systematic review.

INTRODUCTION: Repeated exposure to challenging or traumatic situations can lead to a phenomenon called compassion fatigue (CF). This can present as increased stress and anxiety in staff and a reduced patient relationship. If untreated it can lead to sickness and attrition from the profession. This systematic review aims to investigate the evidence of stressors leading to CF in diagnostic radiographers. METHOD: A review protocol was developed and registered on PROSPERO. Database and grey literature searches were carried out. Studies were selected against pre-defined inclusion and exclusion criteria for review. No meta-analysis was possible therefore the data were presented as a narrative. RESULTS: Fifteen studies were selected for review published between 1982 and 2020. Evidence demonstrates that diagnostic radiographers suffer from high levels of occupational stress, however, stress is perceived rather than defined. Common causes of occupational stress were identified as poor patient interactions and a lack of time to spend with patients. There is a lack of evidence to show how this stress affects radiographer health or their ability to provide compassionate care. CONCLUSION: Diagnostic radiographers are prone to suffering from symptoms that can be attributed to CF. This has been present for an extended period, and the main changes have been a decrease in job satisfaction and accomplishment. Patient interaction was identified as a cause, but it is unclear if this affects staff ability to be compassionate. Further work is required to find ways to mitigate these effects and prevent continued deterioration. IMPLICATIONS FOR PRACTICE: This review has highlighted that the issue of CF may be getting worse for some radiographers and that work is required to design and implement workable interventions to try and mitigate these issues.

Toll-like receptor-4 null mutation causes fetal loss and fetal growth restriction associated with impaired maternal immune tolerance in mice.

Maternal immune adaptation to accommodate pregnancy depends on sufficient availability of regulatory T (Treg) cells to enable embryo implantation. Toll-like receptor 4 is implicated as a key upstream driver of a controlled inflammatory response, elicited by signals in male partner seminal fluid, to initiate expansion of the maternal Treg cell pool after mating. Here, we report that mice with null mutation in Tlr4 (Tlr4-/-) exhibit impaired reproductive outcomes after allogeneic mating, with reduced pregnancy rate, elevated mid-gestation fetal loss, and fetal growth restriction, compared to Tlr4+/+ wild-type controls. To investigate the effects of TLR4 deficiency on early events of maternal immune adaptation, TLR4-regulated cytokines and immune regulatory microRNAs were measured in the uterus at 8 h post-mating by qPCR, and Treg cells in uterus-draining lymph nodes were evaluated by flow cytometry on day 3.5 post-coitum. Ptgs2 encoding prostaglandin-endoperoxide synthase 2, cytokines Csf2, Il6, Lif, and Tnf, chemokines Ccl2, Cxcl1, Cxcl2, and Cxcl10, and microRNAs miR-155, miR-146a, and miR-223 were induced by mating in wild-type mice, but not, or to a lesser extent, in Tlr4-/- mice. CD4+ T cells were expanded after mating in Tlr4+/+ but not Tlr4-/- mice, with failure to expand peripheral CD25+FOXP3+ NRP1- or thymic CD25+FOXP3+ NRP1+ Treg cell populations, and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. We conclude that TLR4 is an essential mediator of the inflammation-like response in the pre-implantation uterus that induces generation of Treg cells to support robust pregnancy tolerance and ensure optimal fetal growth and survival.

High-fat Diet Alters Male Seminal Plasma Composition to Impair Female Immune Adaptation for Pregnancy in Mice.

Paternal experiences and exposures before conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects through modulating the female reproductive tract immune response after mating. To investigate whether paternal obesity affects seminal plasma immune-regulatory activity, C57Bl/6 male mice were fed an obesogenic high-fat diet (HFD) or control diet (CD) for 14 weeks. Although HFD consumption caused only minor changes to parameters of sperm quality, the volume of seminal vesicle fluid secretions was increased by 65%, and the concentrations and total content of immune-regulatory TGF-ß isoforms were decreased by 75% to 80% and 43% to 55%, respectively. Mating with BALB/c females revealed differences in the strength and properties of the postmating immune response elicited. Transcriptional analysis showed >300 inflammatory genes were similarly regulated in the uterine endometrium by mating independently of paternal diet, and 13 were dysregulated by HFD-fed compared with CD-fed males. Seminal vesicle fluid factors reduced in HFD-fed males, including TGF-ß1, IL-10, and TNF, were among the predicted upstream regulators of differentially regulated genes. Additionally, the T-cell response induced by mating with CD-fed males was blunted after mating with HFD-fed males, with 27% fewer CD4+ T cells, 26% fewer FOXP3+CD4+ regulatory T cells (Treg) cells, and 19% fewer CTLA4+ Treg cells, particularly within the NRP1+ thymic Treg cell population. These findings demonstrate that an obesogenic HFD alters the composition of seminal vesicle fluid and impairs seminal plasma capacity to elicit a favorable pro-tolerogenic immune response in females at conception.

Investigator-initiated clinical trials in Malaysia and the role of the Clinical Research Centre of the Ministry of Health.

The objective of this review is to better understand the concept of investigator-initiated trials and its benefits. While investigator-initiated trials can be an invaluable tool, there are several challenges in its initiation and management. However, it is for these reasons that Clinical Research Centre (CRC) had developed the Investigator Initiated Trial (IIT) Programme where financial support and technical assistance are provided to local investigators embarking on their own clinical trials. In the course of preparing the review, we found that the inclination of investigator-initiated trials has yet to be well established in Ministry of Health, Malaysia. Given the potential and impact of such trials, clinicians should be aware of their ability as well as the availability of a supportive network in mobilising their concerted research efforts. Greater research collaboration among investigators could foster more innovative, insightful and constructive research.

The National Medical Research Register--a vital link between current and future research.

Registration of research proposal to a publicly accessible website with searchable function allows information sharing and ensures research transparency. The National Institutes of Health Malaysia, realising the importance of research registration, established the National Medical Research Register (NMRR) in 2007. The NMRR functions more than just a local register: it also links to ethics approval and MOH medical research grant application. It thus facilitates researchers in their application to the Ministry of Health Research and Ethics Committee (MREC) and for Ministry of Health research grant. In addition, MREC committee members can review research protocol on NMRR website, thus saving much time and resources. From May 2007 till December 2009, more than 3000 people have registered as NMRR public users and more than 1000 research proposals have been uploaded in NMRR. The number of registration of research proposals, clinical trials and industrial sponsored trials steadily increased from year 2007 to year 2009. The web-based NMRR is the first research register in the world that links research proposal registration to ethical review and research grant application. Its future plan is to be linked with publication. Therefore, it is indeed an innovation that Malaysians should be proud of.

Hypofractionated Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Tumours in Children and Young Adults.

AIMS: Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population. MATERIALS AND METHODS: We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged <25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented. RESULTS: Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5-20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2-49.5 months). The median follow-up was 3.4 years (range 0.28-6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8-82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04). CONCLUSION: Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules.

Quasiperiodic waves and asymptotic behavior for Bogoyavlenskii's breaking soliton equation in (2+1) dimensions.

Based on a multidimensional Riemann theta function, the Hirota bilinear method is extended to explicitly construct multiperiodic (quasiperiodic) wave solutions for the (2+1) -dimensional Bogoyavlenskii breaking soliton equation. Among these periodic waves, the one-periodic waves are well-known cnoidal waves, their surface pattern is one-dimensional, and often they are used as one-dimensional models of periodic waves in shallow water. The two-periodic (biperiodic) waves are a direct generalization of one-periodic waves, their surface pattern is two dimensional, that is, they have two independent spatial periods in two independent horizontal directions. The two-periodic waves may be considered to represent periodic waves in shallow water without the assumption of one dimensionality. A limiting procedure is presented to analyze asymptotic behavior of the one- and two-periodic waves in details. The exact relations between the periodic wave solutions and the well-known soliton solutions are established. It is rigorously shown that the periodic wave solutions tend to the soliton solutions under a "small amplitude" limit.

Prevalence of the JAK2-V617F mutation in Taiwanese patients with chronic myeloproliferative disorders.

BACKGROUND: The Janus kinase-2 (JAK-2) V617F mutation has been recently reported in patients with myeloproliferative disorders (MPD), which is believed to underlie growth factor hypersensitivity displayed by haematopoietic progenitors in these disorders. However, its frequency has been rarely determined in Taiwanese patients. METHODS: The frequency of JAK2-V617F mutation in patients with polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis (IMF) was determined in the DNA from the peripheral blood leucocytes of 108 patients by genomic polymerase chain reaction and restriction enzyme-based assay. RESULTS: The JAK2-V617F mutation could be detected in 28 of 33 polycythaemia vera patients (85%), 29 of 49 essential thrombocythaemia patients (59%) and 2 of 6 IMF patients (33%), but was not detected in 11 patients with myelodysplastic syndrome or another 10 with other haematological diseases. The presence of the JAK2 mutation was associated with specific MPD disease subtypes (P = 0.007), longer disease duration (P = 0.005), splenomegaly (P = 0.019), a higher white blood cell count (P = 0.002) and a higher haemoglobin level (P = 0.036). However, the overall risk of thrombosis or bleeding was not affected by the presence of the JAK2 mutation (32 vs 17%; P = 0.22). CONCLUSION: The JAK2-V617F mutation can be frequently detected in the Taiwanese patients with MPD disorders and therefore should be incorporated into the initial evaluation of patients suspected of MPD.

miRNA Regulation of Immune Tolerance in Early Pregnancy.

To support embryo implantation, the female reproductive tract must provide a tolerogenic immune environment. Seminal fluid contact at conception contributes to activating the endometrial gene expression and immune cell changes required for robust implantation, influencing not only the quality of the ensuing pregnancy but also the health of offspring. miRNAs are small non-coding RNAs that play important regulatory roles in biological processes, including regulation of the immune environment. miRNAs are known to contribute to gene regulation in pregnancy and are altered in pregnancy pathologies. Recent studies indicate that miRNAs participate in establishing immune tolerance at conception, and may contribute to the regulatory effects of seminal fluid in generating tolerogenic dendritic cells and T regulatory cells. This review highlights those miRNAs implicated in programming immune cells that are critical during the peri-conception period and explores how seminal fluid may regulate female tract miRNA expression following coitus.

Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine.

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Solubilization and characterization of glutamate binding sites from porcine brain.

The majority of l-glutamate binding sites in the synaptic membranes isolated from porcine brain were solubilized by a mixture containing Triton X-100 and digitonin. The solubilized l-glutamate binding sites bind l-glutamate reversibly and with a K(d) value of 0.67 ?M. The solubilized sites also bind l-aspartate, cysteate, and homocysteate, but not N- methyl- d -aspartate , kainate or quisqualate. Various salts, sodium chloride, sodium acetate, potassium chloride, calcium chloride, and magnesium acetate, enhance the l-glutamate binding activity of the solubilized preparation. When solubilized preparations were fractionated by gel-filtration chromatography, no binding activity was detected in the resulting fractions, whereas activity could be partially recovered in the combinations of different fractions. l-Glutamate binding activity of the glutaraldehyde-treated solubilized preparation was eluted out of the gel-filtration column as a single peak. The results suggest that this l-glutamate binding site consists of at least two components and that phospholipids may play important roles in the receptor function.

Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults.

The Seville orange extract Citrus aurantium contains m-synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to "knock out" intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high-performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 +/- 0.52 microg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. Individuals with severe hypertension, tachyarrhythmias, and narrow-angle glaucoma and monoamine oxidase inhibitor recipients should avoid SOJ consumption. Persons taking decongestant-containing cold preparations should also refrain from SOJ intake.

Study of the stereoselectivity of L-glutamate receptors by synthetic 4(R)- and 4(S)-substituted L-glutamate analogues.

R- and S-stereoisomers of 4-substituted L-glutamate analogues are used to study the stereoselectivity of L-glutamate receptors. It is found that 4(R)-substituted analogues are more potent than their 4(S)-isomers in interacting with L-glutamate receptors both at porcine brain synaptic junctions and on drosophila muscles. This demonstrates that the ligand recognition site of L-glutamate receptors has chiral selectivity discriminating L-glutamate analogues with bulky 4(R)- and 4(S)-substituent groups.

A novel NMDA receptor antagonist protects against N-methyl-D-aspartate- and glutamate-induced neurotoxicity in the goldfish retina.

4(R)-(3-Phenylpropyl)-2(S)-glutamic acid, C(3), is a synthetic analogue of L-glutamate. This analogue reversibly inhibits the membrane depolarization of neurons in the CA1 region of rat hippocampal slices evoked by N-methyl-D-aspartate (NMDA), with an EC50 value of 3.6 microM, whereas the depolarization of these neurons evoked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid is not inhibited by C(3). Analyses of the inhibitory effect of C(3) on NMDA-evoked currents of dissociated rat hippocampal neurons further revealed that C(3) acts as a competitive antagonist of NMDA receptors and that the inhibitory action of C(3) is not use-dependent. Using goldfish retina as a model, we found that the neuronal damage produced by glutamate or by NMDA was effectively prevented by C(3). Incubation of retinas with high concentrations of C(3), up to 1 mM, did not induce pathomorphological changes in retinal neurons. These results suggest that C(3) is a useful neuroprotectant against excitotoxic damage of neurons.