Search

Riad Taher,1 Jaskanwal D Sara,1 Behnam Heidari,1 Takumi Toya,1 Lilach O Lerman,2 Amir Lerman11Division of Cardiovascular Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; 2Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USAPurpose: Metabolic syndrome (MetS) and peripheral endothelial dysfunction (PED) are both independently associated with an increased risk of cardiovascular disease (CVD). PED provides prognostic information beyond that provided by conventional risk factors. However, the association between MetS and PED remains uncertain. We evaluated the association between MetS and PED.Patients and methods: We performed a retrospective analysis of patients who were referred to Mayo Clinic between 2006 and 2014 for evaluation of chest pain and/or an assessment of CVD risk that included an assessment of PED measured with reactive hyperemia peripheral arterial tonometry. MetS was defined as the presence of at least 3 of the following: body mass index≥25 kg/m,2 impaired fasting glucose or diabetes, high blood pressure or hypertension, hypertriglyceridemia, or low high-density lipoprotein cholesterol.Results: Six hundred seventy-eight patients were included (mean age 51.9±13.5 years, 418 (61.6%) women), of which 293 (43.2%) had PED, and 249 (36.7%) had MetS. In multivariable analyses adjusted for age, sex, CVD, smoking status, and elevated low-density lipoprotein, MetS was significantly associated with PED (Odds Ratio (OR) 2.06; P=0.0090). Of the individual MetS components, only being overweight and MetS range high-density lipoprotein had a similar association. After stratifying by sex, the association between MetS and PED persisted only in men (OR 3.16, P=0.0094).Conclusions: MetS is associated with PED in men undergoing an assessment of chest pain and/or CVD risk. Identifying PED in individuals with MetS could provide an abridged assessment of risk, potentially allowing for earlier and more intensive management of risk factors.Keywords: metabolic syndrome, peripheral endothelial dysfunction, reactive hyperemia peripheral arterial tonometry, cardiovascular disease

Currently, personal mobility vehicles (PMVs) are attracting attention as intermediate- or short-range transportation. Bicycles are familiar PMVs that are also environmentally friendly and convenient. A small-wheel bicycle saves space and is easy to carry. However, a small-wheel bicycle running at low speed has poor upright stability and maneuverability. The purpose of this study is to improve its running stability by adopting a steer-by-wire system, which independently operates the steering gear and the tire. Sensors obtain the handle angle and actuators, instead of force from a mechanical connection, change the steering wheel angle. In this study, we carried out two experiments. First, we carried out straight running experiments to confirm the steering accuracy, upright stability, and maneuverability on a straight course. Second, we carried out turning experiments to confirm the upright stability and maneuverability on a course requiring changes in driving direction. It was confirmed that the proposed mechanism enhanced the upright stability compared with that of a conventional small-wheel bicycle. However, the maneuverability evaluations by the drivers showed that a conventional small wheel bicycle was better than the proposed steer-by-wire bicycle. The delay of motor control and the moment of inertia of the gearing might be the causes of this performance issue.

Human mesenchymal stem cells (hMSC) expressing paracrine factors may enhance therapeutic benefits when transplanted. Here, the authors show that hMSCs stably expressing prostacyclin enhance host regeneration and muscle mass gain in a mouse hindlimb ischaemia model, mediated by the long noncoding RNA H19.

BACKGROUND: Cell-based therapy shows promise in treating peripheral arterial disease (PAD); however, the optimal cell type and long-term efficacy are unknown. In this study, we identified a novel subpopulation of adult progenitor cells positive for CD34 and M-cadherin (CD34⁺/M-cad⁺ BMCs) in mouse and human bone marrow. We also examined the long-lasting therapeutic efficacy of mouse CD34⁺/M-cad⁺ BMCs in restoring blood flow and promoting vascularization in an atherosclerotic mouse model of PAD. METHODS AND FINDINGS: Colony-forming cell assays and flow cytometry analysis showed that CD34⁺/M-cad⁺ BMCs have hematopoietic progenitor properties. When delivered intra-arterially into the ischemic hindlimbs of ApoE⁻/⁻ mice, CD34⁺/M-cad⁺ BMCs alleviated ischemia and significantly improved blood flow compared with CD34⁺/M-cad⁻ BMCs, CD34⁻/M-cad⁺ BMCs, or unselected BMCs. Significantly more arterioles were seen in CD34⁺/M-cad⁺ cell-treated limbs than in any other treatment group 60 days after cell therapy. Furthermore, histologic assessment and morphometric analyses of hindlimbs treated with GFP⁺ CD34⁺/M-cad⁺ cells showed that injected cells incorporated into solid tissue structures at 21 days. Confocal microscopic examination of GFP⁺ CD34⁺/M-cad⁺ cell-treated ischemic legs followed by immunostaining indicated the vascular differentiation of CD34⁺/M-cad⁺ progenitor cells. A cytokine antibody array revealed that CD34⁺/M-cad⁺ cell-conditioned medium contained higher levels of cytokines in a unique pattern, including bFGF, CRG-2, EGF, Flt-3 ligand, IGF-1, SDF-1, and VEGFR-3, than did CD34⁺/M-cad⁻ cell-conditioned medium. The proangiogenic cytokines secreted by CD34⁺/M-cad⁺ cells induced oxygen- and nutrient-depleted endothelial cell sprouting significantly better than CD34⁺/M-cad⁻ cells during hypoxia. CONCLUSION: CD34⁺/M-cad⁺ BMCs represent a new progenitor cell type that effectively alleviates hindlimb ischemia in ApoE⁻/⁻ mice by consistently improving blood flow and promoting arteriogenesis. Additionally, CD34⁺/M-cad⁺ BMCs contribute to microvascular remodeling by differentiating into vascular cells and releasing proangiogenic cytokines and growth factors.

Primary vitreoretinal lymphoma (PVRL) is a rare malignant lymphoma subtype with an unfavorable prognosis due to frequent central nervous system (CNS) progression. Thus, identifying factors associated with CNS progression is essential for improving the prognosis of PVRL patients. Accordingly, we conducted a comprehensive genetic analysis using archived vitreous humor samples of 36 PVRL patients diagnosed and treated at our institution and retrospectively examined the relationship between genetic alterations and CNS progression. Whole-exome sequencing (N=2) and amplicon sequencing using a custom panel of 107 lymphomagenesis-related genes (N=34) were performed to assess mutations and copy number alterations. The median number of pathogenic genetic alterations per case was 12 (range, 0-22). Pathogenic genetic alterations of CDKN2A, MYD88, CDKN2B, PRDM1, PIM1, ETV6, CD79B, and IGLL5, as well as aberrant somatic hypermutations, were frequently detected. The frequency of ETV6 loss and PRDM1 alteration (mutation and loss) was 23% and 49%, respectively. Multivariate analysis revealed ETV6 loss (hazard ratio [HR]=3.26, 95% confidence interval [CI]: 1.08-9.85) and PRDM1 alteration (HR=2.52, 95% CI: 1.03-6.16) as candidate risk factors associated with CNS progression of PVRL. Moreover, these two genetic factors defined slow-, intermediate-, and rapid-progression groups (0, 1, and 2 factors, respectively), and the median period to CNS progression differed significantly among them (52 vs. 33 vs. 20 months, respectively). Our findings suggest that genetic factors predict the CNS progression of PVRL effectively, and the genetics-based CNS progression model might lead to stratification of treatment.

Biallelic missense mutations in the nuclear-encoded, cytosolic isoleucyl-tRNA synthetase (IARS) gene are associated with a rare and complex multisystemic phenotype, including growth retardation, intellectual disability, muscular hypotonia, diabetes mellitus, and deafness. These mutations impact the cytosolic isoform of IARS, which plays a crucial role in protein synthesis. The pathogenesis involves mitochondrial dysfunction, despite IARS being primarily a cytosolic enzyme, potentially linking it to the observed clinical manifestations. The efficacy of cochlear implantation for deafness due to IARS mutations and the safety of general anesthesia in such patients remain unclear. This report describes a rare case of progressive sensorineural hearing loss caused by IARS mutation-associated mitochondrial disease, which was successfully treated with cochlear implantation. Additionally, we discuss the safety of general anesthesia in this patient. A Japanese woman with IARS mutation-associated mitochondrial disease was diagnosed with severe bilateral sensorineural hearing loss at five years of age and immediately received hearing aids. Her hearing progressively deteriorated to profound impairment, necessitating cochlear implantation at 26 years of age, which resulted in satisfactory hearing. Furthermore, no perioperative general anesthesia-related adverse events were reported. Our case demonstrates that cochlear implantation can effectively restore hearing. This suggests that sensorineural hearing loss caused by IARS deficiency is primarily due to cochlear dysfunction. This case demonstrated that hearing loss is a crucial feature of IARS mutation-associated mitochondrial disease, which can be mitigated by cochlear implantation. While general anesthesia can be safely administered, careful consideration of anesthetic choices, such as avoiding depolarizing muscle relaxants and prolonged use of propofol, is essential to prevent complications. In this case, general anesthesia was well tolerated without perioperative events, providing valuable insight into the potential safety of such procedures in similar patients. Nevertheless, further studies are needed to confirm these findings across a broader population., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board Affiliated with Jikei University School of Medicine issued approval 34-232[11383]). The Ethics Committee has reviewed the above application and hereby notifies that it has been approved. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Motegi et al.)

The rare sugar D-allulose (Alu), with ca. 10% calories of sucrose (Suc), is a promising alternative sugar that can be used to improve the quality of starch gels in storage. The effects of Alu (compared to Suc) on the hardening and microstructural and molecular order of amylopectin-rich (glutinous rice (GR) and corn amylopectin (CAP)) and amylose-rich (corn (C)) starch gels were investigated. Alu and Suc both suppressed hardening in C gels, while Alu but not Suc was effective in GR and CAP gels. SEM results showed that Alu-containing GR and CAP maintained a relatively large pore size compared to Suc-containing gels. The deconvolution of FTIR spectra revealed that Alu-containing GR and CAP gels had lower ratios of intermolecular hydrogen bonds and higher ratios of loose hydrogen bonds than Suc-containing gels. For amylose-rich C gels, on the other hand, such tendencies were not observed. The influence of Alu on amylopectin-rich gels could be because Alu reduced the ratio of intermolecular hydrogen bonds, which might be involved in amylopectin recrystallization, and increased that of loose hydrogen bonds. The results suggest that Alu is more effective than Suc in inhibiting the hardening of amylopectin-rich starch gels during refrigerated storage.

Asbestos, especially chrysotile, continues to be exposed to humans globally. Hence, it should be disposed properly to prevent asbestos-related diseases, including mesothelioma and lung cancer. This study aimed to verify whether forsterite, a heating product of chrysotile, can cause carcinogenicity, particularly mesothelioma. Forsterite (FO-1000) and enstatite (EN-1500) produced by heating chrysotile at 1000°C and 1500°C, respectively, were subjected. We injected 10 mg of chrysotile, FO-1000, or EN-1500 in rats intraperitoneally and observed the development of peritoneal mesothelioma until 24 months. The incidence of peritoneal mesothelioma in the chrysotile group was 91.2%, whereas in the FO-1000 and EN-1500 groups, peritoneal mesothelioma did not develop. Urinary 8-hydroxy-2'-deoxyguanosine and serum N-ERC/mesothelin concentrations significantly increased in the chrysotile group that developed peritoneal mesothelioma, while they only temporarily changed in the FO-1000 or EN-1500 groups during early treatment. Furthermore, there was a significant homozygous deletion of the CDKN2A/p16 gene in the chrysotile group compared to the control group, in contrast to no significant difference in the FO-1000 and EN-1500 groups. Therefore, this study provides clear evidence that forsterite is a nonmesothelioma carcinogen and suggests that forsterite and enstatite are sufficient substances for chrysotile detoxification.

Plant and animal conservation have benefited from the assistance of wildlife detection dogs (WDDs) since 1890, but their application to fungal conservation has not been trialed. In a world-first, we tested the effectiveness of WDDs and human surveyors when searching for experimentally outplanted fungi in natural habitat. We focused on a critically endangered fungus from Australia, Hypocreopsis amplectens, and showed that a WDD outperformed a human surveyor: our WDD detected a greater proportion of targets, had a faster time to first discovery, and had fewer false negatives. Our study highlights the tremendous potential for WDDs to enhance fungal conservation by demonstrating their utility in one of the most challenging fungal systems: a rare species with low population densities and low volatility. Our findings suggest that the application of WDDs to fungal conservation should enhance continuing efforts to document and conserve an understudied kingdom that is threatened by habitat loss and climate change., Competing Interests: The authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Inc.)

Abstract: Clinically significant cytomegalovirus infection (csCMVi) is frequently observed after allogeneic hematopoietic stem cell transplantation (HSCT) and prophylaxis with letermovir is commonly adopted. However, the clinical benefit of letermovir prophylaxis according to graft sources has not been sufficiently elucidated. We retrospectively analyzed 2194 recipients of HSCT who were CMV-seropositive (236 with letermovir prophylaxis and 1958 without prophylaxis against CMV). csCMVi was significantly less frequent in patients with letermovir prophylaxis than in those without (23.7% vs 58.7% at 100 days after HSCT, P < .001) and the same trend was seen when recipients of bone marrow (BM), peripheral blood stem cell (PBSC), or cord blood (CB) transplantation were separately analyzed. In recipients of BM, nonrelapse mortality (NRM) was significantly lower in the letermovir group at 6 months after HSCT (5.0% vs 14.9%, P = .018), and the same trend was observed in recipients of PBSCs (14.7% vs 24.8%, P = .062); however, there was no statistical significance at 1 year (BM, 21.1% vs 30.4%, P = .67; PBSCs, 21.2% vs 30.4%, P = .096). In contrast, NRM was comparable between recipients of CB with and without letermovir prophylaxis throughout the clinical course (6 months, 23.6% vs 24.3%, P =.92; 1 year, 29.3% vs 31.0%, P = .77), which was confirmed by multivariate analyses. In conclusion, the impact of letermovir prophylaxis on NRM and csCMVi should be separately considered according to graft sources., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Biological sex is one of the major factors characterizing the heart failure (HF) patient phenotype. Understanding sex-related differences in HF is crucial to implement personalized care for HF patients with various phenotypes. There are sex differences in left ventricular (LV) remodeling patterns in the HF setting, namely, more likely concentric remodeling and diastolic dysfunction in women and eccentric remodeling and systolic dysfunction in men. Recently supra-normal EF (snLVEF) has been recognized as a risk of worse outcome. This pathology might be more relevant in female patients. The possible mechanism may be through coronary microvascular dysfunction and sympathetic nerve overactivation from the findings of previous studies. Further, estrogen deficit might play a significant role in this pathophysiology. The sex difference in body composition may also be related to the difference in LV remodeling and outcome. Lower implementation in guideline-directed medical therapy (GDMT) in female HFrEF patients might also be one of the factors related to sex differences in relation to outcomes. In this review, we will discuss the sex differences in cardiac and clinical phenotypes and their relation to outcomes in HF patients and further discuss how to provide appropriate treatment strategies for female patients.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) show cardiovascular protective effects, regardless of the patient's history of diabetes mellitus (DM). SGLT2is suppressed cardiovascular adverse events in patients with type 2 DM, and furthermore, SGLT-2is reduced the risk of worsening heart failure (HF) events or cardiovascular death in patients with HF. Along with these research findings, SGLT-2is are recommended for patients with HF in the latest guidelines. Despite these benefits, the concern surrounding the increasing risk of body weight loss and other adverse events has not yet been resolved, especially for patients with sarcopenia or frailty. The DAPA-HF and DELIVER trials consistently showed the efficacy and safety of SGLT-2i for HF patients with frailty. However, the Rockwood frailty index that derived from a cumulative deficit model was employed for frailty assessment in these trials, which might not be suitable for the evaluation of physical frailty or sarcopenia alone. There is no fixed consensus on which evaluation tool to use or its cutoff value for the diagnosis and assessment of frailty in HF patients, or which patients can receive SGLT-2i safely. In this review, we summarize the methodology of frailty assessment and discuss the efficacy and safety of SGLT-2i for HF patients with sarcopenia or frailty., Competing Interests: The authors declare no conflicts of interest.

Background: Alabama is one of seven priority states for the National Ending the HIV Epidemic Initiative due to a disproportionate burden of rural infections. To reverse growing infection rates, the state must increase its focus on prevention efforts, including novel strategies. One such approach is to utilize dashboards that visualize real-time data on the pre-exposure prophylaxis (PrEP) care continuum to assist in prioritizing evidence-based preventative care for those most vulnerable for HIV infection., Methods: We conducted a mixed methods evaluation to ascertain stakeholders' perceptions on the acceptability, feasibility, appropriateness, and usability of a PrEP care continuum dashboard, as well as gain insight on ways to improve the activities necessary to sustain it. Clinicians, administrators, and data personnel from participating sites in Alabama completed surveys (n = 9) and participated in key informant interviews (n = 10) to better understand their experiences with the prototype data dashboard and to share feedback on how it can be modified to best fit their needs., Results: Surveys and interviews revealed that all participants find the pilot data dashboard to be an acceptable, feasible, and appropriate intervention for clinic use. Overall, stakeholders find the pilot dashboard to be usable and helpful in administrative efforts, such as report and grant writing; however, additional refining is needed in order to reduce burden and optimize usefulness. Participants voiced concerns about their site's abilities to sustain the dashboard, including the lack of systematized PrEP protocols and limited funds and staff time dedicated to PrEP data collection, cleaning, and upload., Conclusion: Study participants from clinics providing HIV prevention services, including PrEP, in Alabama voiced interest in sustaining and refining a data dashboard that tracks clients across the PrEP care continuum. Despite viewing the platform itself as an acceptable, feasible, and appropriate intervention, participants agreed that efforts need to be focused on standardizing PrEP data collection protocols in order to ensure consistent, accurate data capture and that limited funds and staff time are barriers to the sustained implementation of the dashboard in practice., (© 2024. The Author(s).)

The vagus nerve crucially affects emotions and psychiatric disorders. However, the detailed neurophysiological dynamics of the vagus nerve in response to emotions and its associated pathological changes remain unclear. In this study, we demonstrated that the spike rates of the cervical vagus nerve change depending on anxiety behavior in an elevated plus maze test, and these changes were eradicated in stress-susceptible male mice. Furthermore, instantaneous spike rates of the vagus nerve were negatively and positively correlated with the power of 2-4 Hz and 20-30 Hz oscillations, respectively, in the prefrontal cortex and amygdala. The oscillations also underwent dynamic changes depending on the behavioral state in the elevated plus maze, and these changes were no longer observed in stress-susceptible and vagotomized mice. Chronic vagus nerve stimulation restored behavior-relevant neuronal oscillations with the recovery of altered behavioral states in stress-susceptible mice. These results suggested that physiological vagal-brain communication underlies anxiety and mood disorders., (© 2024. The Author(s).)