FGF23-related hypophosphatemic rickets preceding the onset of systemic lupus erythematosus: A juvenile case.

Key Clinical Message: This case report describes the clinical course of a juvenile female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. Our study demonstrates the possibility of hypophosphatemic rickets as an early symptom of SLE. Abstract: Fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets is observed in both genetic and acquired disorders. Various reports describe FGF23-related hypophosphatemia with systemic lupus erythematosus (SLE), although FGF23-related hypophosphatemia preceding the onset of SLE has never been described. Here, we report the case of a 9-year-old female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. The patient presented to us with arthralgia in the lower extremities and abnormality of gait lasting for 8 months. She was diagnosed with FGF23 hypophosphatemic rickets due to the presence of hypophosphatemic rickets symptoms and high serum levels of FGF23. Additional examination excluded hereditary diseases and tumor-induced osteomalacia. Three months after diagnosis of FGF23-related hypophosphatemic rickets, she developed nephritis and was diagnosed with SLE. She was treated with prednisolone, hemodialysis, and disease-modifying drugs, as well as oral sodium phosphate to improve hypophosphatemia. Serum anti-double-stranded DNA antibody (dsDNAab) and plasma tumor necrosis factor-α (TNF-α) were elevated at FGF23-related hypophosphatemic rickets diagnosis. During the clinical course, serum FGF23 correlated with dsDNAab and TNF-α serum levels, which are involved in SLE disease activity. In this case, FGF23-related hypophosphatemic rickets without hereditary diseases or tumor-induced osteomalacia occurred before the appearance of juvenile SLE symptoms, and serum FGF23 represented disease activity in SLE.

Feasibility and Usability of the Job Adjustment Mobile App for Pregnant Women: Longitudinal Observational Study.

BACKGROUND: Working pregnant women often need to adjust their physically demanding jobs for a healthy pregnancy. However, uncertainty about the extent of these adjustments can hinder their effectiveness. To address this, we developed the Job Adjustment mobile app, which allows users to input job and health details to generate a variety of personalized action plans. As this is the first version of the app, assessing its feasibility and usability is crucial. OBJECTIVE: This study aims to verify the feasibility and usability of the Job Adjustment mobile app. METHODS: A longitudinal observational study was conducted on pregnant Japanese women who were allowed to use the app anytime from 12 to 34 weeks of gestation; they received reminder emails every 2 weeks encouraging app use. A questionnaire was administered before app use and at 20 and 32 weeks of gestation. Feasibility was evaluated across 4 domains: implementation, demand, acceptability, and adverse events. Implementation was evaluated based on 3 parameters: dropout rate, initial reminder email receipt rate, and adherence rate (measured as pregnant women who used the app at intervals of 2.5 weeks or less). Demand was measured by intervals between use and intervals between log-in, and participants answered 15 questions to assess acceptability. Adverse events were assessed by analyzing the degree of anxiety related to work. Demographic data were analyzed to determine any statistically significant differences in intervals between uses. Usability was evaluated using the System Usability Scale. RESULTS: The analysis included 66 pregnant women, and 61% (n=40) of them were multipara. The dropout rate, adherence rate, and initial reminder email receipt rate were 18% (13/71), 44% (29/66), and 79% (52/66) respectively. The median intervals between use and intervals between log-in were 2.94 (IQR 2.00-5.13) weeks and 2.28 (IQR 1.81-4.00) weeks, respectively. Overall, 60% (35/58) to 90% (52/58) of the participants responded positively to all 15 questions assessing acceptability, and no anxiety regarding work was recorded. The mean System Usability Scale score was 66.1 points. Multipara women had significantly longer intervals between app use compared to primipara women (P=.01). CONCLUSIONS: The results demonstrated acceptable levels of feasibility and usability of the app. However, the low adherence rates, especially among multipara women, suggest the need for modifications to reduce the time burden of the app. Further research should explore more effective and acceptable intervals between use and timing, involving a larger sample and accounting for diverse characteristics of pregnant women. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000042943; https://tinyurl.com/ydrchfas.

Phytochemistry and Biological Studies of Endemic Hawaiian Plants.

The Hawaiian Islands are renowned for their exceptional biodiversity and are host to a plethora of endemic plant species, which have been utilized in traditional Hawaiian medicine. This scientific review provides an in-depth analysis of the phytochemistry and biological studies of selected endemic Hawaiian plants, highlighting their medicinal properties and therapeutic potential. A literature search was conducted, utilizing major academic databases such as SciFinder, Scopus, Web of Science, PubMed, Google Scholar, Science Direct, and the Scientific Information Database. The primary objective of this search was to identify relevant scholarly articles pertaining to the topic of the review, which focused on the phytochemistry and biological studies of endemic Hawaiian plants. Utilizing these databases, a comprehensive range of literature was obtained, facilitating a comprehensive examination of the subject matter. This review emphasizes the rich phytochemical diversity and biological activities found in Endemic Hawaiian plants, showcasing their potential as sources of novel therapeutic agents. Given the unique biodiversity of Hawaii and the cultural significance of these plants, continued scientific exploration, conservation, and sustainable utilization of these valuable resources is necessary to unlock the full potential of these plant species in drug discovery and natural product-based therapeutics.

Microwell culture platform maintains viability and mass of human pancreatic islets.

Background: Transplantation of the human pancreatic islets is a promising approach for specific types of diabetes to improve glycemic control. Although effective, there are several issues that limit the clinical expansion of this treatment, including difficulty in maintaining the quality and quantity of isolated human islets prior to transplantation. During the culture, we frequently observe the multiple islets fusing together into large constructs, in which hypoxia-induced cell damage significantly reduces their viability and mass. In this study, we introduce the microwell platform optimized for the human islets to prevent unsolicited fusion, thus maintaining their viability and mass in long-term cultures. Method: Human islets are heterogeneous in size; therefore, two different-sized microwells were prepared in a 35 mm-dish format: 140 µm × 300 µm-microwells for <160 µm-islets and 200 µm × 370 µm-microwells for >160 µm-islets. Human islets (2,000 islet equivalent) were filtered through a 160 µm-mesh to prepare two size categories for subsequent two week-cultures in each microwell dish. Conventional flat-bottomed 35 mm-dishes were used for non-filtered islets (2,000 islet equivalent/2 dishes). Post-cultured islets are collected to combine in each condition (microwells and flat) for the comparisons in viability, islet mass, morphology, function and metabolism. Islets from three donors were independently tested. Results: The microwell platform prevented islet fusion during culture compared to conventional flat bottom dishes, which improved human islet viability and mass. Islet viability and mass on the microwells were well-maintained and comparable to those in pre-culture, while flat bottom dishes significantly reduced islet viability and mass in two weeks. Morphology assessed by histology, insulin-secreting function and metabolism by oxygen consumption did not exhibit the statistical significance among the three different conditions. Conclusion: Microwell-bottomed dishes maintained viability and mass of human islets for two weeks, which is significantly improved when compared to the conventional flat-bottomed dishes.

Occupational stress is associated with job performance among pregnant women in Japan: comparison with similar age group of women.

BACKGROUND: Pregnancy results in physical and psychological changes in women; however, pregnant women hesitate to take a break from work even when they feel the need. Since working while physically ill leads to decreased job performance, it is important to determine the factors that lead to this phenomenon. AIM: To study the occupational stress associated with job performance and absenteeism of pregnant women compared with non-pregnant women. METHODS: In 2019, non-pregnant and pregnant employed women in their 20-40 s in Japan completed an online survey examining job performance (Work Limitation Questionnaire - Short Form), absenteeism, occupational stress (Brief Job Stress Questionnaire), and working situations. RESULTS: Of 918 respondents who met the inclusion criteria, 904 were included in the final analysis (454 non-pregnant and 450 pregnant women). Logistic regression analyses showed that absenteeism was significantly higher for pregnant women. However, for women who were absent, there was no significant difference between non-pregnant and pregnant women. After adjusting for attributes and working conditions, pregnant women had significantly higher (p < .001) work productivity losses than non-pregnant women, but only in the physical tasks domain; their physical stress response was also higher compared to non-pregnant women (p = .048). However, pregnant women reported significantly less interpersonal conflict stress (p < .001) and psychological stress (p = .026), as well as better workplace support as a buffering factor for stress (p = .021), than non-pregnant women. CONCLUSION: Clarifying the physical burden associated with pregnancy and assisting women in coordinating their work duties while considering the physical demands of pregnancy may minimize work productivity losses among pregnant women.

Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Generation of Tetrafluoroethylene-Propylene Elastomer-Based Microfluidic Devices for Drug Toxicity and Metabolism Studies.

Polydimethylsiloxane (PDMS) is widely used to fabricate microfluidic organs-on-chips. Using these devices (PDMS-based devices), the mechanical microenvironment of living tissues, such as pulmonary respiration and intestinal peristalsis, can be reproduced in vitro. However, the use of PDMS-based devices in drug discovery research is limited because of their extensive absorption of drugs. In this study, we investigated the feasibility of the tetrafluoroethylene-propylene (FEPM) elastomer to fabricate a hepatocyte-on-a-chip (FEPM-based hepatocyte chip) with lower drug absorption. The FEPM-based hepatocyte chip expressed drug-metabolizing enzymes, drug-conjugating enzymes, and drug transporters. Also, it could produce human albumin. Although the metabolites of midazolam and bufuralol were hardly detected in the PDMS-based hepatocyte chip, they were detected abundantly in the FEPM-based hepatocyte chip. Finally, coumarin-induced hepatocyte cytotoxicity was less severe in the PDMS-based hepatocyte chip than in the FEPM-based hepatocyte chip, reflecting the different drug absorptions of the two chips. In conclusion, the FEPM-based hepatocyte chip could be a useful tool in drug discovery research, including drug metabolism and toxicity studies.

Factors Associated With the Work Productivity of Japanese Working Pregnant Women: A Cross-Sectional Study.

OBJECTIVES: Working pregnant women experience physical and psychosocial changes, which are associated with two aspects of work productivity: presenteeism and absenteeism. We examined the factors that affect these two aspects. METHODS: This cross-sectional study was conducted in April to May 2019 through an online survey. Participants were 450 working women who were pregnant for the first time. RESULTS: Occupational stress (job overload sß: 0.14, suitable jobs sß: 0.16); physical conditions, such as pregnancy complications (sß: 0.32) and gestational period (sß: 0.18); and adjustment status in the workplace due to pregnancy, such as pregnancy disclosure (sß: 0.11) and pregnancy discrimination (sß: 0.18), were related to presenteeism. Meanwhile, pregnancy complications were the only factor associated with absenteeism (sß: 0.32; all P < 0.05). CONCLUSIONS: In addition to physical condition support, support for psychosocial conditions in the workplace is required.

Late-onset argininosuccinic aciduria associated with hyperammonemia triggered by influenza infection in an adolescent: A case report.

Hyperammonemia is a typical symptom of urea cycle disorders. While early-onset argininosuccinic aciduria (ASA) can often be detected by hyperammonemia, patients with late-onset ASA predominantly present with psychomotor retardation and mental disorders. However, in late-onset ASA that develops during early childhood, hyperammonemia can sometimes be caused by acute infections, stress, and reduced dietary intake. Here, we report the case of a 14-year-old boy with late-onset ASA associated with hyperammonemia that was triggered by an influenza A infection. Due to the infection, he presented with a fever and was unable to eat food or take oral medication. He then experienced restlessness, a disturbance in his level of consciousness, and seizures. Hyperammonemia (3286 µg/dL, reference value ≤100 µg/dL) was detected. He was biochemically diagnosed with ASA based on increased serum and urinary argininosuccinic acid levels. Additionally, genetic testing revealed compound heterozygous mutations in the ASL gene: c.91G > A(p.Asp31Asn) and c.1251-1G > C. This case revealed that in late-onset ASA, hyperammonemia can occur not only in early childhood but also during adolescence. Late-onset ASA may have a very broad clinical spectrum that includes hyperammonemia. We suggest that urea cycle disorders such as ASA must be considered when patients present with hyperammonemic decompensation during adolescence.

Tetrafluoroethylene-Propylene Elastomer for Fabrication of Microfluidic Organs-on-Chips Resistant to Drug Absorption.

Organs-on-chips are microfluidic devices typically fabricated from polydimethylsiloxane (PDMS). Since PDMS has many attractive properties including high optical clarity and compliance, PDMS is very useful for cell culture applications; however, PDMS possesses a significant drawback in that small hydrophobic molecules are strongly absorbed. This drawback hinders widespread use of PDMS-based devices for drug discovery and development. Here, we describe a microfluidic cell culture system made of a tetrafluoroethylene-propylene (FEPM) elastomer. We demonstrated that FEPM does not absorb small hydrophobic compounds including rhodamine B and three types of drugs, nifedipine, coumarin, and Bay K8644, whereas PDMS absorbs them strongly. The device consists of two FEPM layers of microchannels separated by a thin collagen vitrigel membrane. Since FEPM is flexible and biocompatible, this microfluidic device can be used to culture cells while applying mechanical strain. When human umbilical vein endothelial cells (HUVECs) were subjected to cyclic strain (~10%) for 4 h in this device, HUVECs reoriented and aligned perpendicularly in response to the cyclic stretch. Moreover, we demonstrated that this device can be used to replicate the epithelial-endothelial interface as well as to provide physiological mechanical strain and fluid flow. This method offers a robust platform to produce organs-on-chips for drug discovery and development.

Brainstem infarction associated with HHV-6 infection in an infant.

INTRODUCTION: The relevant literature includes several case reports on cerebral infarction in children with HHV-6 infection; however, there is no report of brain stem infarction. CASE: An 11-month-old girl was hospitalized because of fever. She was unable to stand up and meet her mother's gaze. Magnetic resonance imaging (MRI) indicated a right pons and mid-brain lesion; a diagnosis of brainstem infarction was made. After her fever subsided, a rash developed on her trunk and limbs; blood examination results indicated a primary HHV-6 infection. She was treated with aspirin, edaravone, and mannitol to prevent further complications. At the age of 18months, the auditory brainstem response (ABR) was unremarkable and she is developing well. DISCUSSION AND CONCLUSION: A limited number of studies have reported HHV-6 infection-associated infarction, and no cases of brainstem infarction have been reported. One possible cause of cerebral infarction is antiphospholipid antibody syndrome (APS) triggered by the infection. HHV-6 may also directly infect vascular endothelial cells and cause angiopathy. However, the real mechanism of infarction remains unclear. Our patient had a favorable prognosis despite brainstem infarction.

Transcription factor FoxO1 is essential for enamel biomineralization.

The Transforming growth factor ß (Tgf-ß) pathway, by signaling via the activation of Smad transcription factors, induces the expression of many diverse downstream target genes thereby regulating a vast array of cellular events essential for proper development and homeostasis. In order for a specific cell type to properly interpret the Tgf-ß signal and elicit a specific cellular response, cell-specific transcriptional co-factors often cooperate with the Smads to activate a discrete set of genes in the appropriate temporal and spatial manner. Here, via a conditional knockout approach, we show that mice mutant for Forkhead Box O transcription factor FoxO1 exhibit an enamel hypomaturation defect which phenocopies that of the Smad3 mutant mice. Furthermore, we determined that both the FoxO1 and Smad3 mutant teeth exhibit changes in the expression of similar cohort of genes encoding enamel matrix proteins required for proper enamel development. These data raise the possibility that FoxO1 and Smad3 act in concert to regulate a common repertoire of genes necessary for complete enamel maturation. This study is the first to define an essential role for the FoxO family of transcription factors in tooth development and provides a new molecular entry point which will allow researchers to delineate novel genetic pathways regulating the process of biomineralization which may also have significance for studies of human tooth diseases such as amelogenesis imperfecta.

Vessel formation is induced prior to the appearance of cartilage in BMP-2-mediated heterotopic ossification.

Heterotopic ossification (HO), or endochondral bone formation at nonskeletal sites, often results from traumatic injury and can lead to devastating consequences. Alternatively, the ability to harness this phenomenon would greatly enhance current orthopedic tools for treating segmental bone defects. Thus, understanding the earliest events in this process potentially would allow us to design more targeted therapies to either block or enhance this process. Using a murine model of HO induced by delivery of adenovirus-transduced cells expressing bone morphogenetic protein 2 (BMP-2), we show here that one of the earliest stages in this process is the establishment of new vessels prior to the appearance of cartilage. As early as 48 hours after induction of HO, we observed the appearance of brown adipocytes expressing vascular endothelial growth factors (VEGFs) simultaneous with endothelial progenitor replication. This was determined by using a murine model that possesses the VEGF receptor 2 (Flk1) promoter containing an endothelial cell enhancer driving the expression of nuclear-localized yellow fluorescent protein (YFP). Expression of this marker has been shown previously to correlate with the establishment of new vasculature, and the nuclear localization of YFP expression allowed us to quantify changes in endothelial cell numbers. We found a significant increase in Flk1-H2B::YFP cells in BMP-2-treated animals compared with controls. The increase in endothelial progenitors occurred 3 days prior to the appearance of early cartilage. The data collectively suggest that vascular remodeling and growth may be essential to modify the microenvironment and enable engraftment of the necessary progenitors to form endochondral bone.

Identification of a novel intracellular interaction domain essential for Bves function.

While Blood vessel epicardial substance (Bves) confers adhesive properties, the molecular mechanism of regulating this activity is unknown. No predicted functional motifs in this highly conserved integral membrane protein, other than the transmembrane domain, have been identified. Here, we report for the first time that Bves interacts with itself through an intracellular interaction domain that is essential for its intercellular adhesion activity. Glutathione-S-transferase (GST) pull-down and SPOTs analyses mapped this domain to amino acids 268-274 in the intracellular C-terminus. Site-directed mutagenesis revealed that lysines 272 and 273 are essential for homodimerization and cell adhesion. Human corneal cells transfected with wild-type Bves trafficked the protein to the cell surface, assembled junction complexes and formed epithelial sheets. In contrast, cells expressing Bves mutated at these positions did not form continuous epithelial sheets or maintain junctional proteins such as ZO-1 and E-cadherin at the membrane. A dramatic reduction in transepithelial electrical resistance was also observed indicating a functional loss of tight junctions. Importantly, expression of mutated Bves in epithelial cells promoted the transformation of cells from an epithelial to a mesenchymal phenotype. This study is the first to demonstrate the essential nature of any domain within Bves for maintenance of epithelial phenotype and function.

Coronary vessel development: a unique form of vasculogenesis.

Development of the coronary vascular system is an interesting model in developmental biology with major implications for the clinical setting. Although coronary vessel development is a form of vasculogenesis followed by angiogenesis, this system uses several unique developmental processes not observed in the formation of other blood vessels. This review summarizes the literature that describes the development of the coronary system, highlighting the unique aspects of coronary vessel development. It should be noted that many of the basic mechanisms that govern vasculogenesis in other systems have not been analyzed in coronary vessel development. In addition, we present recent advances in the field that uncover the basic mechanisms regulating the generation of these blood vessels and identify areas in need of additional studies.

Epicardial/Mesothelial cell line retains vasculogenic potential of embryonic epicardium.

Recent work has demonstrated the importance of the epicardium in the development of the heart. During embryogenesis, these epithelial cells provide the progenitors for the epicardium, coronary smooth muscle, endothelium, and cardiac fibroblasts. The epicardium sends important signals to the developing myocardium. Still, analysis of these epithelial cells has lagged behind that of other cardiac cell types largely because of the lack of a defined experimental cell system in which epicardial cell differentiation can be studied. The present report examines the developmental potential of a cell line derived from rat epicardial mesothelial cells. These analyses demonstrate that the cell line retains many characteristics of the intact epithelium, including the ability to form a polarized epithelium and express many epicardial genes. Our data show for the first time that these cells retain the ability to produce mesenchyme in response to specific growth factors and, importantly, to generate smooth muscle cells. Thus, this study provides evidence that these cells can serve as an important model system for the analysis of the cellular and molecular mechanisms that govern epicardial development and function.