The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects.

Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by Trip11) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect. A possible explanation for the tissue specificity of ACG1A is that cartilage and bone are highly secretory tissues with a high use of the membrane trafficking machinery. The perinatal lethality of ACG1A prevents investigating this hypothesis. We therefore generated mice with conditional Trip11 knockout alleles and inactivated Trip11 in chondrocytes, osteoblasts, osteoclasts and pancreas acinar cells, all highly secretory cell types. We discovered that the ACG1A skeletal phenotype is solely due to absence of GMAP-210 in chondrocytes. Mice lacking GMAP-210 in osteoblasts, osteoclasts and acinar cells were normal. When we inactivated Trip11 in primary chondrocyte cultures, GMAP-210 deficiency affected trafficking of a subset of chondrocyte-expressed proteins rather than globally impairing membrane trafficking. Thus, GMAP-210 is essential for trafficking specific cargoes in chondrocytes but is dispensable in other highly secretory cells.

Recognizing global disparities in health and in health transitions in the 21st century: what can nurses do?

PURPOSE: To examine changes in patterns of health and disease in global context between rich countries (USA, Korea, South Africa) and poor countries (Cambodia, Malawi) by using the framework of epidemiology theory developed by Orman (1971, 2005), and to raise awareness of global health disparities thereby prompting actions to reduce such disparities. FINDINGS: 1) Life expectancy has increased across all selected countries except South Africa; 2) Korea and the USA have substantially lower mortality rates than other countries; 3) Infant and maternal mortality are still high in the poor countries; 4) The major cause of mortality in the poor countries is still communicable disease with evidence of the onset of non-communicable disease; and 5) The health transition theory provides a description and explanation of the differences in progress in economic development between countries but fails to explain differences in health status within and between countries. CONCLUSIONS: Life expectancy and mortality are enormously different among the five selected countries. This excessive health disparity is primarily due to the higher risk of communicable diseases in low-income countries. Social determinants of health are mainly responsible for the health disparities observed within and between countries. CLINICAL RELEVANCE: Future health care development and global research priorities will not be the same for all countries because the pattern of health transitions in the developing countries is not the same as the developed countries. Actions to reduce global health disparities need to recognize the conditions and social context in which persons live. An effective strategic approach to global health equality should develop a shared system of values, priorities, and delivery infrastructures with the populations who are targeted, aligning delivery within the local social contexts.

Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins.

Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.

Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia.

Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder.

Molecular profiles of pyramidal neurons in the superior temporal cortex in schizophrenia.

Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30-100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-ß) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.

Obesity shapes selection for driver mutations in cancer.

Obesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.

Introductory Chemistry: A Molar Relaxivity Experiment in the High School Classroom.

Dotarem and Magnevist, two clinically available magnetic resonance imaging (MRI) contrast agents, were assessed in a high school science classroom with respect to which is the better contrast agent. Magnevist, the more efficacious contrast agent, has negative side effects because its gadolinium center can escape from its ligand. However, Dotarem, though a less efficacious contrast agent, is a safer drug choice. After the experiment, students are confronted with the FDA warning on Magnevist, which enabled a discussion of drug efficacy versus safety. We describe a laboratory experiment in which NMR spin lattice relaxation rate measurements are used to quantify the relaxivities of the active ingredients of Dotarem and Magnevist. The spin lattice relaxation rate gives the average amount of time it takes the excited nucleus to relax back to the original state. Students learn by constructing molar relaxivity curves based on inversion recovery data sets that Magnevist is more relaxive than Dotarem. This experiment is suitable for any analytical chemistry laboratory with access to NMR.

Developing an Audit and Feedback Dashboard for Family Physicians: User-Centered Design Process.

BACKGROUND: Audit and feedback (A&F), the summary and provision of clinical performance data, is a common quality improvement strategy. Successful design and implementation of A&F-or any quality improvement strategy-should incorporate evidence-informed best practices as well as context-specific end user input. OBJECTIVE: We used A&F theory and user-centered design to inform the development of a web-based primary care A&F dashboard. We describe the design process and how it influenced the design of the dashboard. METHODS: Our design process included 3 phases: prototype development based on A&F theory and input from clinical improvement leaders; workshop with family physician quality improvement leaders to develop personas (ie, fictional users that represent an archetype character representative of our key users) and application of those personas to design decisions; and user-centered interviews with family physicians to learn about the physician's reactions to the revised dashboard. RESULTS: The team applied A&F best practices to the dashboard prototype. Personas were used to identify target groups with challenges and behaviors as a tool for informed design decision-making. Our workshop produced 3 user personas, Dr Skeptic, Frazzled Physician, and Eager Implementer, representing common users based on the team's experience of A&F. Interviews were conducted to further validate findings from the persona workshop and found that (1) physicians were interested in how they compare with peers; however, if performance was above average, they were not motivated to improve even if gaps compared to other standards in their care remained; (2) burnout levels were high as physicians are trying to catch up on missed care during the pandemic and are therefore less motivated to act on the data; and (3) additional desired features included integration within the electronic medical record, and more up-to-date and accurate data. CONCLUSIONS: We found that carefully incorporating data from user interviews helped operationalize generic best practices for A&F to achieve an acceptable dashboard that could meet the needs and goals of physicians. We demonstrate such a design process in this paper. A&F dashboards should address physicians' data skepticism, present data in a way that spurs action, and support physicians to have the time and capacity to engage in quality improvement work; the steps we followed may help those responsible for quality improvement strategy implementation achieve these aims.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

Characteristics and 10 key components of interpersonal caring: a narrative review

This paper aims to help people understand better the lives of people who are mentally ill by describing the general concept of the Interpersonal Caring Theory (ICT) and deducing 10 key components of interpersonal caring. The literature review described the definition of interpersonal caring, and its assumptions and characteristics. Furthermore, the authors' experience with patient care suggested the critical components of interpersonal caring, which is the compassion-based therapeutic actions/behaviors through the collaborative partnership developed between nurse and client. Essential characteristics of interpersonal caring include the following: person-to-person interaction between nurse and patient, genuine love and concern toward the person, conveying trust and hope, transcending space, time, and culture, holistic approach expressed through a comprehensive and dynamic mode of communication, helping the patient focus on their self-worth, and providing culturally relevant and sensitive nursing. Ten key components of interpersonal caring in ICT include noticing, participating, sharing, active listening, companioning, complimenting, comforting, hoping, forgiving, and accepting. Interpersonal caring results from the blended understanding of the empirical, aesthetic, ethical, and intuitive aspects of a given clinical situation, and a nexus of pre-conditions, content, feelings, and sense of self-worth/self-esteem.

Comparison of the effects of NADH- and NADPH-perturbation stresses on the growth of Escherichia coli.

To better understand how the reducing power of either NADH or NADPH affects cell growth, Escherichia coli strains expressing either NADH-dependent or NADPH-dependent azoreductase (EC 1.6.5.2), which mediates the reduction of an azo dye, were cultured in glucose minimal medium in the presence of 200 muM methyl red. Growth rates in NADH-perturbed, NADPH-perturbed, and control cells were 0.05, 0.12, and 0.13 h(-1), respectively. In addition, glucose consumption in NADH-perturbed cells was 10.8 g glucose/g cell, while that of control and NADPH-perturbed cells was very similar (3.6 vs 3.8 g glucose/g cell) during the perturbation phase. Therefore, NADH perturbation had a larger effect than NADPH on cellular growth.

Potential application of the recombinant Escherichia coli-synthesized heme as a bioavailable iron source.

To investigate the potential use of microbial heme as an iron source, recombinant Escherichia coli coexpressing ALA synthase (HemA) as well as the NADP-dependent malic enzyme (MaeB) and dicarboxylic acid transporter (DctA) were cultured. The typical red pigment extracted from the recombinant E. coli after 38 h showed highest absorbance at 407 nm, and the amount of iron in 38.4 mg of microbial heme extract derived from 6-l fermentation broth was 4.1 mg. To determine the commercial potential of the recombinant E.coli-synthesized iron-associated heme as an iron source, mice were fed the iron-free provender with the microbial heme extract. The average body weight reduction of mice fed non-iron provender was 2.3%, whereas no detectable weight loss was evident in mice fed microbial heme addition after 15 days. The heme content of the blood from microbial heme fed mice was 4.2 mg/ml whereas that of controls was 2.4 mg/ml, which implies that the microbial heme could be available for use as an animal iron source.

Spirituality, depression, living alone, and perceived health among Korean older adults in the community.

Both theoretical and empirical studies have documented the protective effect of religiosity and spirituality on general health in older adults in community and hospital settings; however, no study has documented the relationship between spirituality and depression among older adults living alone in communities in Korea. We tested two hypotheses: Hypothesis 1: Korean older adults living alone would be more depressed and less healthy than older adults living with family, and Hypothesis 2: Individuals who are more religious and spiritual would report a lower level of depression and a higher level of general health even when other demographic and living status variables are controlled. A descriptive, comparative, and correlational design with a convenience sampling method was conducted among community-dwelling Korean older adults in Chounbook Providence, South Korea. This study included 152 men and women older than 65 years old. Hypothesis 1 was supported as Korean older adults living alone were significantly more depressed than were older adults living with family (P<.01). However, for Hypotheses 2, only spirituality activities and Spirituality Index of Well-Being scores were significantly associated with general health and/or depression (P<.01), but there were no relationships between the variables of attendance and importance of religion with general health and depression.

Onychomadesis following hand, foot, and mouth disease in a pregnant woman: A case report.

Hand, foot, and mouth disease is an enteroviral infection characterized by vesicles on the hands, feet, and oral mucosa. Given its rising incidence among adults, it is important to recognize its variable presentations and sequelae. These include onychomadesis, a complication of hand, foot, and mouth disease that is well described in children, with limited reports in adults. We present the unique case of a pregnant woman who developed onychomadesis following hand, foot, and mouth disease, with no adverse pregnancy outcomes. This case illustrates that (1) onychomadesis can occur in pregnant women with hand, foot, and mouth disease; (2) onychomadesis is typically a benign change that can occur following hand, foot, and mouth disease; and (3) onychomadesis is not necessarily associated with more severe disease or adverse pregnancy outcomes.

Kindlin-2 is required for myocyte elongation and is essential for myogenesis.

BACKGROUND: Integrins are required for normal muscle differentiation and disruptions in integrin signaling result in human muscle disease. The intracellular components that regulate integrin function during myogenesis are poorly understood. Unc-112 is an integrin-associated protein required for muscle development in C. elegans. To better understand the intracellular effectors of integrin signaling in muscle, we examined the mammalian homolog of Unc-112, kindlin-2. RESULTS: Kindlin-2 expression is upregulated during differentiation and highly enriched at sites of integrin localization. RNAi knockdown of kindlin-2 in C2C12 cells results in significant abnormalities during the early stages of myogenesis. Specifically, differentiating myocytes lacking kindlin-2 are unable to elongate and fail to fuse into multinucleated myotubes. These changes are correlated with decreased cell substratum adhesion and increased cell motility. They are also associated with redistribution of a known kindlin-2 binding partner, integrin linked kinase (ILK), to the membrane insoluble subcellular fraction. CONCLUSION: In all, our study reveals kindlin-2 as a novel integrin adaptor protein important for muscle differentiation, and identifies it particularly as a critical regulator of myocyte elongation.

Understanding disparities in aggressive care preferences between patients with terminal illness and their family members.

We examined the factors associated with the disparity in aggressive care preferences between patients with terminal cancer and their family members. Two hundred forty-four consecutive pairs recruited from three university hospitals participated in this study. Each pair completed questionnaires that measured two major aggressive care preferences-admission to the intensive care unit (ICU) and the use of cardiopulmonary resuscitation (CPR). Sixty-eight percent of patients and their family members were in agreement regarding admission to the ICU and 71% agreed regarding CPR. Regarding admission to the ICU, younger, unmarried patients and patients who preferred to die in an institution were more likely to have a different preference from their family caregivers. Regarding CPR, younger patients and patients from severely dysfunctional families were more likely to have a different preference from their family caregivers. Elucidation of the factors associated with such disparities should help reduce them.

Interventions for prevention of childhood obesity in primary care: a qualitative study.

BACKGROUND: Preventing childhood obesity is a public health priority, and primary care is an important setting for early intervention. Authors of a recent national guideline have identified a need for effective primary care interventions for obesity prevention and that parent perspectives on interventions are notably absent from the literature. Our objective was to determine the perspectives of primary care clinicians and parents of children 2-5 years of age on the implementation of an obesity prevention intervention within team-based primary care to inform intervention implementation. METHODS: We conducted focus groups with interprofessional primary care clinicians (n = 40) and interviews with parents (n = 26). Participants were asked about facilitators and barriers to, and recommendations for implementing a prevention program in primary care. Data were recorded and transcribed, and we used directed content analysis to identify major themes. RESULTS: Barriers existed to addressing obesity-related behaviours in this age group and included a gap in well-child primary care between ages 18 months and 4-5 years, lack of time and sensitivity of the topic. Trust and existing relationships with primary care clinicians were facilitators to program implementation. Offering separate programs for parents and children, and addressing both general parenting topics and obesity-related behaviours were identified as desirable. INTERPRETATION: Despite barriers to addressing obesity-related behaviours within well-child primary care, both clinicians and parents expressed interest in interventions in primary care settings. Next steps should include pilot studies to identify feasible strategies for intervention implementation.

Knowledge and Attitudes toward HIV, Hepatitis B Virus, and Hepatitis C Virus Infection among Health-care Workers in Malawi.

OBJECTIVE: The highest prevalence of HIV infection occurs in Sub-Saharan Africa and hepatitis B virus (HBV), and hepatitis C virus (HCV) prevalence are the second highest in Sub-Saharan Africa including Malawi. Health-care workers (HCWs) play an important role in the prevention of, response to, and management of these infectious diseases. There is, however, no published research about the level of knowledge and attitudes toward HIV, HBV, and HCV infection among Malawian HCWs. The purpose of this study was to explore and determine the knowledge of and attitudes toward HIV, HBV, and HCV among a targeted population of Malawian HCWs. METHODS: A cross-sectional community-based participatory research with 194 HCWs was completed employing health survey method. The project was a collaborative effort between nursing faculties in the USA and Malawian. A one-way analysis of variance (ANOVA) with the Bonferroni adjustment for multiple comparisons was used to assess the differences in knowledge and attitude among three subgroups of HCWs. RESULTS: Of 194 of Malawian HCWs surveyed, 41% were support staff, 37% were nursing students, and 22% were health-care professionals. Both health-care professionals and support staff had high knowledge scores related to HIV/AIDS, and their attitudes were mainly positive. However, a series of one-way ANOVAs revealed significant differences in knowledge and attitude toward HIV/AIDs, HBV, and HCV among HCWs (P < 0.01). The majority had less knowledge about HBV and HCV and more negative attitudes toward hepatitis. CONCLUSIONS: This study highlights the ongoing need for reducing negative attitudes toward HIV, HBV, and HCV; and providing health education among HCWs, especially focusing on HBV and HCV prevention. The findings of the research project can be used to develop interventions addressing low HBV- and HCV-related knowledge and attitudes.

Serum equol, bone mineral density and biomechanical bone strength differ among four mouse strains.

The extent of conversion of daidzein to its metabolite, equol, by intestinal microflora may be a critical step that determines if a diet rich in daidzein protects against the deterioration of bone after estrogen withdrawal. The objective was to determine the extent that daidzein is converted to equol. In addition, bone mineral content (BMC), bone mineral density (BMD) and strength of femurs and lumbar vertebrae (LV) in four mouse strains were measured. Mice were ovariectomized and fed control diet (AIN93G) with or without daidzein (200 mg daidzein/kg diet) for 3 weeks, after which serum, femurs and LV were collected. Serum daidzein and equol were elevated in all mice fed daidzein. Among mice fed daidzein, the CD-1 and Swiss-Webster (SW) mice had higher (P<.001) serum equol than C57BL/6 (C57) and C3H mice. Differences due to mouse strain were observed for all bone outcomes. C57 mice had lower femur BMC (P<.001), BMD (P<.001) and peak load at femur midpoint (P<.001) and neck (P<.001) than other mouse strains. C57 mice also had a lower femur midpoint yield load (P<.001) and resilience (P<.001) than C3H mice. C57 mice had a lower LV1-4 BMC (P<.001) and BMD (P<.001) compared with all mouse strains and peak load of LV3 was lower than CD-1 and SW mice. Differences in serum equol, BMD and bone strength properties should be considered when selecting a mouse strain for investigating whether dietary strategies that include isoflavones preserve bone tissue after ovariectomy.

Cross-cultural comparison of workplace stressors, ways of coping and demographic characteristics as predictors of physical and mental health among hospital nurses in Japan, Thailand, South Korea and the USA (Hawaii).

In an attempt to cross-culturally compare factors that may contribute to the nursing shortage within countries that have produced a limited number of research findings on role stress in nurses, this research examined work stressors, ways of coping and demographic characteristics as predictors of physical and mental health among hospital nurses from Japan, South Korea, Thailand and the USA (Hawaii). Subjects (n = 1554 hospital-based nurses) were administered four self-report questionnaires: Demographic Questionnaire, "Nursing Stress Scale", "Ways of Coping Questionnaire" and "SF-36 Health Survey". Findings suggested that nurses indicated similar workplace stressors, ways of coping, and levels of physical and mental health. While subjects, across countries, demonstrated a variety of predictors of physical and mental health, several predictors were found to be the same. Cross-culturally the role of nurses may vary; however, certain factors are predictive of the status of hospital nurses' physical health and mental health.