The success of total joint replacements has led to consistent growth in the use of arthroplasty in progressively younger patients. However, more than 10 percent of patients require revision surgeries ...due to implant failure caused by osteolytic loosening. These failures are classified as either aseptic or septic and are associated with the presence of particulate wear debris generated by mechanical action between implant components. Aseptic loosening results from chronic inflammation caused by activation of resident immune cells in contact with implant wear debris. In contrast, septic loosening is defined by the presence of chronic infection at the implant site. However, recent findings suggest that subclinical biofilms may be overlooked when evaluating the cause of implant failure, leading to a misdiagnosis of aseptic loosening. Many of the inflammatory pathways contributing to periprosthetic joint infections are also involved in bone remodeling and resorption. In particular, wear debris is increasingly implicated in the inhibition of the innate and adaptive immune response to resolve an infection or prevent hematogenous spread. This review examines the interconnectivity of wear particle- and infection-associated mechanisms of implant loosening, as well as biomaterials-based strategies to combat infection-related osteolysis.
Women with type 2 diabetes mellitus are at a higher risk of pregnancy complications. Although traditional beliefs and practices influence diabetes management and breastfeeding, recommendations ...integrating Thai cultural beliefs in maternal care are lacking. The purpose of this study is to describe diabetes self-management in pregnancy and breastfeeding experiences in women with preexisting type 2 diabetes mellitus from Thailand. A convergent parallel mixed-methods study will be conducted. Data will be collected from 20 pregnant women with preexisting type 2 diabetes mellitus in Thailand who are either primigravida or multigravida, aged 20-44 years old, speak the Thai language, and provide consent. The National Institute on Minority Health and Health Disparities Framework's sociocultural and behavioral domains guides the research aims. Data will be collected two times. The first time is during pregnancy (T1); study participants will complete questionnaires and engage in an interview about diabetes self-management, breastfeeding confidence, and breastfeeding intention. The second time is at 4-6 weeks postpartum (T2); study participants will be interviewed about their breastfeeding experiences. We will review and extract maternal health outcomes including body mass index, gestational weight gain, and glycated hemoglobin for T1 as well as fasting plasma glucose for T2. Qualitative data will be analyzed using directed content analysis. Quantitative data will be analyzed using descriptive statistics. Data sources will be triangulated with relative convergence in the results. This proposed study is significant because the findings will be used as a preliminary guide to developing a culturally tailored approach to enhance health outcomes of Thai women with diabetes in pregnancy and postpartum periods.
Segregation of homologs at the first meiotic division (MI) is facilitated by crossovers and by a physical constraint imposed on sister kinetochores that facilitates monopolar attachment to the MI ...spindle. Recombination failure or premature separation of homologs results in univalent chromosomes at MI, and univalents constrained to form monopolar attachments should be inherently unstable and trigger the spindle assembly checkpoint (SAC) 1. Although univalents trigger cell-cycle arrest in the male 2–5, this is not the case in mammalian oocytes 6, 7. Because the spindle assembly portion of the SAC appears to function normally 8–10, two hypotheses have been proposed to explain the lack of response to univalents: (1) reduced stringency of the oocyte SAC to aberrant chromosome behavior 7, and (2) the ability of univalents to satisfy the SAC by forming bipolar attachments 6. The present study of Mlh1 mutant mice demonstrates that metaphase alignment is not a prerequisite for anaphase onset and provides strong evidence that MI spindle stabilization and anaphase onset require stable bipolar attachment of a critical mass—but not all—of chromosomes. We postulate that subtle differences in SAC-mediated control make the human oocyte inherently error prone and contribute to the age-related increase in aneuploidy.
► Metaphase alignment is not a prerequisite for anaphase onset in the mouse oocyte ► Chromosome behavior influences MI spindle formation and stabilization ► Insensitivity to misaligned chromosomes renders the oocyte error prone
The present research used resting-state functional magnetic resonance imaging (fMRI) to examine whether the ability to generate creative ideas corresponds to differences in the intrinsic organization ...of functional networks in the brain. We examined the functional connectivity between regions commonly implicated in neuroimaging studies of divergent thinking, including the inferior prefrontal cortex and the core hubs of the default network. Participants were prescreened on a battery of divergent thinking tests and assigned to high- and low-creative groups based on task performance. Seed-based functional connectivity analysis revealed greater connectivity between the left inferior frontal gyrus (IFG) and the entire default mode network in the high-creative group. The right IFG also showed greater functional connectivity with bilateral inferior parietal cortex and the left dorsolateral prefrontal cortex in the high-creative group. The results suggest that the ability to generate creative ideas is characterized by increased functional connectivity between the inferior prefrontal cortex and the default network, pointing to a greater cooperation between brain regions associated with cognitive control and low-level imaginative processes.
•Participants completed divergent thinking tasks and resting-state fMRI•Higher creative ability was related to greater rs-fc in the IFG and default network•Seed-to-voxel analysis further revealed greater rs-fc in the IFG and DLPFC•Controlled and spontaneous processes may cooperate more in the creative brain
A chronic mismatch of caregiver responsiveness to infant-feeding cues, such as feeding when the infant is not hungry, is hypothesized to have a role in the development of overweight by impairing an ...infant's response to internal states of hunger and satiation. Although this concept of mismatch or discordance has long been acknowledged in scholarly writings, a systematic assessment of the evidence supporting the role of discordant responsiveness during infant feeding in the early origins of overweight is lacking. This review was undertaken to assess evidence for this hypothesized relationship between discordant responsiveness in feeding and overweight in infancy and toddlerhood, framed within the larger social-environmental context of the infant–caregiver dyad. A systematic method was used to extract articles from three databases of the medical, psychology and nursing fields. The quality of evidence collected was assessed using Oxford University Centre for Evidence Based Medicine's level of evidence and through a narrative review. The systematic search resulted in only nine original research studies, which met a priori inclusion/exclusion criteria. Several studies provide support for the conceptual model, but most were cross-sectional or lower quality prospective studies. The need for consistent definitions, improved measures and longitudinal work is discussed. In conclusion, this review reveals preliminary support for the proposed role of discordant responsiveness in infant/child overweight and at the same time highlights the need for rigorous investigation of responsive feeding interactions in the first years of life.
CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR ...promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival.
The absence or reduction of CFTR function causes CF and results in a pulmonary milieu characterized by bacterial colonization and unresolved inflammation. The ineffectiveness at controlling infection ...by species such as Pseudomonas aeruginosa suggests defects in innate immunity. Macrophages, neutrophils, and DCs have all been shown to express CFTR mRNA but at low levels, raising the question of whether CFTR has a functional role in these cells. Bone marrow transplants between CF and non-CF mice suggest that these cells are inherently different; we confirm this observation using conditional inactivation of Cftr in myeloid-derived cells. Mice lacking Cftr in myeloid cells overtly appear indistinguishable from non-CF mice until challenged with bacteria instilled into the lungs and airways, at which point, they display survival and inflammatory profiles intermediate in severity as compared with CF mice. These studies demonstrate that Cftr is involved directly in myeloid cell function and imply that these cells contribute to the pathophysiological phenotype of the CF lung.
Many heritable genetic disorders arise from nonsense mutations, which generate premature termination codons (PTCs) in transcribed mRNA. PTCs ablate protein synthesis by prematurely terminating the ...translation of mutant mRNA, as well as reducing mutant mRNA quantity through targeted degradation by nonsense-mediated decay (NMD) mechanisms. Therapeutic strategies for nonsense mutations include facilitating ribosomal readthrough of the PTC and/or inhibiting NMD to restore protein function. However, the efficacy of combining readthrough agents and NMD inhibitors has not been thoroughly explored. In this study, we examined combinations of known NMD inhibitors and readthrough agents using functional analysis of the
protein in primary cells from a mouse model carrying a G542X nonsense mutation in
. We observed synergy between an inhibitor of the NMD component SMG-1 (SMG1i) and the readthrough agents G418, gentamicin, and paromomycin, but did not observe synergy with readthrough caused by amikacin, tobramycin, PTC124, escin, or amlexanox. These results indicate that treatment with NMD inhibitors can increase the quantity of functional protein following readthrough, and that combining NMD inhibitors and readthrough agents represents a potential therapeutic option for treating nonsense mutations.
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