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Background/Objectives: Three-dimensional accelerometry data from the lower trunk during running is associated with intervertebral disc degeneration. The kinematic function known as the lumbo–pelvic–hip complex involves movements in the sagittal plane during running. If pelvic movement and acceleration in the anteroposterior direction are correlated, improving running mechanics may reduce the load on the intervertebral disc. This study investigated the relationship between the anteroposterior acceleration of the lower lumbar spine and pelvic tilt movements during running. Methods: Sixteen healthy male college students were enrolled and asked to run on a treadmill for 1 min at 16 km/h, and the acceleration data for their lower lumbar region and running motion in the sagittal plane were recorded. The pelvic tilt angle during running was calculated through two-dimensional motion analysis. Subsequently, a simple linear regression analysis was employed to clarify the relationship between the acceleration data of the lower lumbar region and the pelvic tilt angle during running. Results: The simple linear regression analysis indicated that the root mean squares of the anteroposterior acceleration of the lower lumbar spine were associated with the maximum pelvic tilt angle (r = 0.32, p = 0.003, adjusted R2 = 0.09) and its range (r = 0.42, p = 0.0001, adjusted R2 = 0.16). Conclusions: However, the adjusted R2 value was low, indicating that although the pelvic tilt angle during running may be related to acceleration in the anteroposterior direction, the effect is small.

In the veterinary field, the utility of disease-identification models that use comprehensive circulating microRNA (miRNA) profiles produced through measurements based on next-generation sequencing (NGS) remains unproven. To integrate NGS technology with automated machine learning (autoML) to create a comprehensive circulating miRNA profile and to assess the clinical utility of a disease-screening model derived from this profile. The study involved dogs diagnosed with or being treated for various diseases, including tumors, across multiple veterinary clinics (n = 254), and healthy dogs without apparent diseases (n = 91). miRNA was extracted from EDTA-treated plasma, and a comprehensive analysis was conducted of one million reads per sample using NGS. Then autoML technology was applied to develop a diagnostic model based on miRNA. Among these models, the one with the highest performance was chosen for evaluation. The diagnostic model, based on the comprehensive circulating miRNA profile developed in this study, achieved an AUC score of 0.89, with a sensitivity of 85 % and a specificity of 88 % for the disease samples. The miRNA-based diagnostic model demonstrated high sensitivity for disease groups and has the potential to be an effective screening test. This study indicates that a comprehensive miRNA profile in dog plasma could serve as a highly sensitive blood biomarker.

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

Abstract The psychological theory argues that serious threats cause negative attitudes from ingroups to outgroups. However, the factors that can reduce such outgroup bias caused by the health threats of a pandemic are unknown. Here, we provide evidence that health certifications to prove immunity or negative test result for COVID-19 reduce outgroup bias. Using a discrete choice experiment with a randomized conjoint design in Japan, we investigated public attitudes towards inbound travelers entering the country, including foreigners, immigrants, and tourists. We found that travelers carrying a vaccination certificate or a negative test result for COVID-19 have a higher probability or rating of being admitted to the country. These effects are the same size as those for travelers undergoing self-isolation. Thus, our results demonstrate that health certification can mitigate outgroup bias among ingroup members experiencing threats to health due to the COVID-19 pandemic. We anticipate that the findings would support the combined usage of vaccine passports and negative certificates to reopen the international borders.

BackgroundsThe effectiveness of citizens’ behavioral changes to prevent the spread of SARS-CoV-2, such as avoiding large social events, relies on science communication from policymakers and collective action among peer citizens. Extant studies recognize the potential effects of information stimuli on citizens’ behavioral changes, including what epidemiological experts request (injunctive information) and what surrounding people behave (descriptive information). Yet, they have insufficiently assessed the co-occurrence and possible interaction of multiple information stimuli.Methods1,819 Japanese citizens aged 18 or over were recruited for an experimental survey during March 1–3, 2021 and asked their views on a hypothetical wedding attendance in Japan while being exposed to randomly assigned normative information stimuli. Their willingness to attend a wedding asked before and after the intervention was measured. Infection risk perception was also asked as a mediating variable.ResultsFindings suggest the constant supremacy of descriptive information and no synergistic effects in the interaction of multiple information stimuli. We also report that the effects of injunctive and descriptive information vary according to participants’ risk perception, age, and trust in experts.ConclusionOur experimental test enables a systematic assessment of multiple normative information and confirms the primacy of descriptive information as the main driver of behavioral change. Communication by medical experts has limitations but is still effective in specific categories of the population.

Case series summary Two Japanese domestic cats with GM2 gangliosidosis variant 0, diagnosed at different times, are included in this case series. Both cats were diagnosed by genetic analysis and had the HEXB :c.667C>T pathogenic genetic variant, which have been previously reported in Japanese domestic cats with GM2 gangliosidosis variant 0. Clinical signs and the identification of vacuolation in circulating lymphocytes were consistent with those in previous reports of feline GM2 gangliosidosis variant 0. Radiography showed that both cases had similar skeletal radiographic manifestations, which has not been previously reported in Japanese domestic cats with GM2 gangliosidosis variant 0. Radiographic findings included abnormally shaped vertebral bodies, obscure or irregular endplates (both of which were seen especially in the cervical and thoracic vertebrae), generalised osteopenia and new bone proliferation around articular facets. Relevance and novel information To the best of our knowledge, this is the first report to present the skeletal radiographic abnormalities of Japanese domestic cats with GM2 gangliosidosis variant 0 caused by the HEXB :c.667C>T pathogenic genetic variant. Furthermore, together with a report published in 2015 on the radiographic findings of feline GM2 gangliosidosis variant 0 caused by another pathogenic genetic variant, this report suggests that these findings may be indicators of feline GM2 gangliosidosis variant 0. The easily obtained radiographic findings described in this report may be useful as a finding suggestive of feline GM2 gangliosidosis variant 0, in addition to the cytological finding of the vacuolated cells. The report emphasises the utility of radiography for diagnosis of cases with suspected progressive neurodegenerative diseases.

We aimed to uncover which rectus femoris strain injury types affect regional activation within the rectus femoris. The rectus femoris has a region-specific functional role; the proximal region of the rectus femoris contributes more than the middle and distal regions during hip flexion. Although a history of strain injury modifies the region-specific functional role within the rectus femoris, it was not obvious which rectus femoris strain injury types affect regional activation within it. We studied 12 soccer players with a history of rectus femoris strain injury. Injury data were obtained from a questionnaire survey and magnetic resonance imaging. To confirm the region-specific functional role of the rectus femoris, surface multichannel electromyographic signals were recorded. Accordingly, eight legs had a history of central tendon injury, four had a history of myofascial junction injury, and four had a healed strain injury. When the injury was limited to the central tendon, the region-specific functional role disappeared. The region-specific functional role was confirmed when the injury was outside the central part. The neuromuscular function was also inhibited when the longitudinal range of the injured region was long. Our findings suggest that a central tendon injury with a long injury length impairs regional neuromuscular activation of the rectus femoris muscle.

Background Cutaneous malignant melanoma has a poor prognosis. The detrimental effect of incisional biopsies on the outcome of malignant melanoma has been debated. The aim of this study was to determine the effect of the presence and type of biopsy on the prognosis of malignant melanoma. Methods The medical records of 109 malignant melanoma patients treated at Tokushima University Hospital from 1983 to 2007 were reviewed. After excluding 28 cases with stage 0 disease or incomplete data, 81 cases were analyzed in detail with respect to patient sex, age, tumor site, clinical stage at diagnosis, presence of ulceration or lymph node metastasis, and prognosis. The five-year survival and five-year disease-free survival rates of patients who underwent incisional or excisional biopsies were compared with those who did not undergo a biopsy. Results The male-to-female ratio was 1:1.19. The mean age was 61.3 years (range, 19-93 years). The most common site was a lower extremity, and the most common clinical stage was stage II. No significant differences in clinicopathological features, five-year survival rates, and five-year disease-free survival rates were observed among the three groups. Conclusions The presence and type of biopsy neither affected the metastatic rate nor the prognosis of malignant melanoma. The use of incisional biopsies is not encouraged because tumor thickness cannot be measured accurately. However, they may be helpful for confirming the diagnosis if an excisional biopsy cannot be performed.

Abstract Aims Sleep‐disordered breathing (SDB) is closely related to cardiovascular diseases. The higher the apnoea–hypopnoea index (AHI), the higher the prevalence of cardiovascular diseases. Despite these findings suggesting a close link between SDB and heart failure, the relationship between the severity of SDB and the onset of heart failure symptoms in individuals without apparent heart failure symptoms (Heart Failure Stage A + B) remains poorly understood. Methods and results Between December 2010 and June 2017, we conducted full‐night polysomnography (PSG) at the Nippon Medical School Chiba Hokusoh Hospital, extracting patients who were at risk of heart failure (Stage A or B in the Heart Failure Guidelines). Using a median cut‐off of AHI ≥ 41.6 events/hour, we divided the patients into two groups and examined the composite endpoint of all‐cause mortality plus hospitalization due to heart failure as the primary endpoint. We included 230 patients (mean age 63.0 ± 12.5 years, 78.3% males) meeting the selection criteria. When comparing the two groups, those with AHI

Adaptive governance is increasingly known as a salient factor in enhancing capacity particularly in sustainable development in small islands. Considering how small islands are vulnerable to changes, it is important to determine how islandness influence both social and ecological components of a socio-ecological system and what are the various types of governance contexts in islands that are existing in literature. With that aim in mind, we conducted a systematic review of adaptive governance research in small islands based on 43 peer-reviewed articles. We generated research clusters and gaps based on content analysis and examine the key dimensions where adaptive governance principles are used or adopted. Our main findings include: dominant research field (i.e., island resource governance, climate risk governance), adaptive governance dimensions (i.e., governance structure and framework, stakeholder capacity, planning and development), scale/level of research, most common methodologies (questionnaire survey, interviews, and group workshops, mixed methods, action research) and most frequent typology of risk (climate change, variability and impacts). Based on the result, future directions for adaptive governance research in small islands are identified--most of which covers stakeholder characterization and clarification of the diverse set of actors and capacities that support implementation of adaptive governance in multiple scales and processes. Furthermore, in-depth analysis of the present and future risks and uncertainties in small islands, coupled with cross-scale linkages, are needed. Finally, we recommend that island's geographical and cultural contexts be considered in institutionalization of adaptive governance principles and approaches in small island settings. [ABSTRACT FROM AUTHOR]

Summary: Ischemia and pathological angiogenesis in retinal vascular diseases cause serious vision-related problems. However, the transcriptional regulators of vascular repair remain unidentified. Thus, the factors and mechanisms involved in angiogenesis must be elucidated to develop approaches for restoring normal blood vessels. Here, we investigated the effects of the stress response activating transcription factor 3 (ATF3) on angiogenesis and vascular regeneration in vitro and in vivo. ATF3 was expressed specifically in retinal vascular endothelial cells (ECs) during vascular development. Vascular endothelial growth factor stimulation upregulated ATF3 expression in cultured ECs. The downregulated ATF3 expression in ECs caused the deterioration of vascular network formation in vitro and in vivo. Moreover, ATF3 deletion in a model of oxygen-induced retinopathy inhibited retinal vascular repair but not pathological neovascularization. Transcriptome analysis confirmed that high ATF3 expression upregulated the expression of angiogenesis-related genes in ECs. ATF3 may aid vascular repair therapy in retinal vascular diseases.

Abstract Aims Fractional excretion of urea nitrogen (FEUN), used to differentiate the cause of acute kidney injury, has emerged as a useful fluid index in patients with heart failure (HF). We hypothesized that FEUN could be useful in identifying worsening renal function (WRF) associated with poor outcomes in patients with acute HF (AHF). Methods and results Overall, 1103 patients with AHF (median age, 78 years; male proportion, 60%) were categorized into six groups according to the presence of WRF and FEUN values (low, ≤32.1%; medium, >32.1% and ≤38.0%; and high, >38.0%) at discharge. WRF was defined as an increase of ≥0.3 mg/dL in the serum creatinine level from admission to discharge. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). The cut‐off values for low, medium, and high FEUN were based on a previous study. The primary outcome of this study was HF readmission after hospital discharge. During the 1 year follow‐up, 170 HF readmissions occurred. Kaplan–Meier analysis revealed significantly higher HF readmission rates in patients with WRF than in those without WRF (log‐rank test, P

Abstract Aims Plasma volume status (PVS), a measure of plasma volume, has been evaluated as a prognostic marker for chronic heart failure. Although the prognostic value of PVS has been reported, its significance in patients with acute decompensated heart failure (ADHF) admitted to the cardiovascular intensive care unit (CICU) remains unclear. In this study, we examined the relationship between PVS and long‐term mortality in patients with ADHF admitted to the CICU. Methods Between January 2018 and December 2020, 363 consecutive patients with ADHF were admitted to the Nippon Medical School Hospital CICU. Of the 363 patients, 206 (mean age, 74.9 ± 12.9 years; men, 64.6%) were enrolled in this study. Patients who received red blood cell transfusions, underwent dialysis, were discharged from the CICU or died in the hospital were excluded from the study. We measured the PVS of the patients at admission, transfer to the general ward (GW) and discharge using the Kaplan–Hakim formula. The patients were assigned to four groups according to the quartiles of their PVS measured at each of the three abovementioned timepoints. We examined the association between PVS and all‐cause mortality during the observation period (1134 days). The primary endpoint of this study was all‐cause mortality. Results The Kaplan–Meier analysis showed that the high PVS group had a significantly higher mortality rate at admission, transfer to the GW and discharge than the other groups (log‐rank test: P = 0.016, P = 0.005 and P

Abstract Background Guideline-directed medical therapy (GDMT) is important in heart failure management; however, polypharmacy itself may impact heart failure. Although measures against polypharmacy are needed, current discussion on unilateral drug tapering (including the drugs that should be tapered) is insufficient. In this study, we investigated the relationship between the number of prescribed GDMT drugs and prognosis in patients with heart failure. Methods In this single-centre retrospective study, 3,146 eligible patients with heart failure were included and divided into four groups based on the median number of prescribed GDMT drugs and the median number of drugs not included in the GDMT (ni-GDMT) at the time of hospital discharge. The definition of GDMT was based on various Japanese guidelines. The primary outcome was all-cause mortality within 3 years of hospital discharge. Results A total of 252 deaths were observed during the 3-year follow-up period. Kaplan–Meier analysis revealed that groups with GDMT drug count ≥ 5 and ni-GDMT drug count

Acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT), secondary to cardiovascular disease and sepsis, is associated with high in-hospital mortality. Although studies have examined cardiovascular disease and sepsis in AKI, the association between AKI and hepatic functional impairment remains unclear. We hypothesized that hepatic function markers would predict mortality in patients undergoing CRRT. We included 1,899 CRRT patients from a multi-centre database. In Phase 1, participants were classified according to the total bilirubin (T-Bil) levels on the day of, and 3 days after, CRRT initiation: T-Bil < 1.2, 1.2 ≤ T-Bil < 2, and T-Bil ≥ 2 mg/dL. In Phase 2, propensity score matching (PSM) was performed to examine the effect of a T-Bil cutoff of 1.2 mg/dL (supported by the Sequential Organ Failure Assessment score); creating two groups based on a T-Bil cutoff of 1.2 mg/dL 3 days after CRRT initiation. The primary endpoint was total mortality 90 days after CRRT initiation, which was 34.7% (n = 571). In Phase 1, the T-Bil, aspartate transaminase (AST), alanine transaminase (ALT), and AST/ALT (De Ritis ratio) levels at CRRT initiation were not associated with the prognosis, while T-Bil, AST, and the De Ritis ratio 3 days after CRRT initiation were independent factors. In Phase 2, T-Bil ≥1.2 mg/dL on day 3 was a significant independent prognostic factor, even after PSM [hazard ratio: 2.41 (95% CI; 1.84-3.17), p

Abstract Background Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. Methods A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. Results In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. Conclusions Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. Trial registration IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

Abstract In pulmonary hypertension (PH) associated with chronic lung disease (CLD), identifying patients who would benefit from pulmonary vasodilators is a significant clinical challenge because the presence of PH is associated with poorer survival. This study evaluated the severity of pulmonary circulation impairment in patients with CLD‐PH using pulmonary perfusion single‐photon emission computed tomography/computed tomography (SPECT/CT). This single‐center, observational study enrolled patients with CLD‐PH who had a mean pulmonary arterial pressure (PAP) ≥ 25 mmHg, as confirmed by right heart catheterization. The primary outcome was to measure the percentage of pulmonary perfusion defect (%PPD), calculated by dividing the perfusion defect volume from perfusion SPECT images by the lung volume from CT scan images. The secondary outcome was to assess the correlation between %PPD and baseline characteristics. The median %PPD was 52.4% (interquartile range, 42.5%–72.3%) in 22 patients. In multivariate linear regression analysis, both forced vital capacity (β = 0.58, p = 0.008) and mean PAP (β = 0.68, p = 0.001) were significantly correlated with %PPD. In conclusion, significant correlation between mean PAP and %PPD in patients with CLD‐PH was observed. This noninvasive assessment of %PPD may be useful for evaluating the severity of pulmonary circulation impairment in CLD‐PH.

Abstract Alveologenesis is a spatially coordinated morphogenetic event, during which alveolar myofibroblasts surround the terminal sacs constructed by epithelial cells and endothelial cells (ECs), then contract to form secondary septa to generate alveoli in the lungs. Recent studies have demonstrated the important role of alveolar ECs in this morphogenetic event. However, the mechanisms underlying EC-mediated alveologenesis remain unknown. Herein, we show that ECs regulate alveologenesis by constructing basement membranes (BMs) acting as a scaffold for myofibroblasts to induce septa formation through activating mechanical signaling. Rap1, a small GTPase of the Ras superfamily, is known to stimulate integrin-mediated cell adhesions. EC-specific Rap1-deficient (Rap1 iECKO ) mice exhibit impaired septa formation and hypo-alveolarization due to the decreased mechanical signaling in myofibroblasts. In Rap1 iECKO mice, ECs fail to stimulate integrin β1 to recruit Collagen type IV (Col-4) into BMs required for myofibroblast-mediated septa formation. Consistently, EC-specific integrin β1-deficient mice show hypo-alveolarization, defective mechanical signaling in myofibroblasts, and disorganized BMs. These data demonstrate that alveolar ECs promote integrin β1-mediated Col-4 recruitment in a Rap1-dependent manner, thereby constructing BMs acting as a scaffold for myofibroblasts to induce mechanical signal-mediated alveologenesis. Thus, this study unveils a mechanism of organ morphogenesis mediated by ECs through intrinsic functions.

Abstract Hyperuricemia is reportedly associated with the progression of carotid intima-media thickness (IMT), a surrogate of cardiovascular risks and events. However, factors associated with carotid IMT progression in patients with asymptomatic hyperuricemia are largely unknown. In this post-hoc analysis of the multicenter, randomized PRIZE study, we analyzed data from a total of 326 patients who underwent carotid ultrasonography in a blind manner at baseline and 24 months to evaluate carotid IMT. Mean and maximum IMT at the common carotid artery (CCA) were measured at a central core laboratory. Factors related to the absolute change in mean and maximum IMT from baseline to 24 months were explored. Overall, the adjusted mean [0.0032 (− 0.0214 to 0.0278) mm] and maximum [0.0011 (− 0.0327 to 0.0351) mm] CCA-IMT increased numerically from baseline to 24 months. Multivariable analysis identified higher body mass index, history of atherosclerotic cardiovascular disease (ASCVD), and lower mean CCA-IMT at baseline as significant factors associated with the increase in mean CCA-IMT. In addition, older age and lower mean CCA-IMT at baseline were significant factors for an increased absolute change in the maximum CCA-IMT at 24 months. The present sub-analysis of the PRIZE study showed higher body mass index, history of ASCVD, and older age as significant factors associated with CCA-IMT progression in patients with asymptomatic hyperuricemia. These factors may be considered when identifying the possible risk of atherosclerotic progression in this specific patient population of hyperuricemia. Trial registration: UMIN000012911 and UMIN000041322.

Vitiligo is an acquired chronic depigmenting disorder of the skin and is characterized by the destruction of melanocytes. One of the clinical features of vitiligo is that damage to normal skin frequently results in the formation of depigmented macules, which is known as Köebner's phenomenon (KP). Here, we presented a case of vitiligo, in which depigmented macules followed the course of a dilated varicose vein. Dilatation of blood vessels was considered to contribute to the development of the vitiliginous lesions as a trigger for KP. Any kind of skin injury can trigger KP, but this is only the second case in which a dilated blood vessel caused KP in vitiligo. [ABSTRACT FROM AUTHOR]

Abstract Aims Maintenance of euvolaemia with diuretics is critical in heart failure (HF) patients with chronic kidney disease (CKD); however, it is challenging because no reliable marker of volume status exists. Fractional excretion of urea nitrogen (FEUN) is a useful index of volume status in patients with renal failure. We aimed to examine whether FEUN is a surrogate marker of volume status for risk stratification in HF patients with CKD. Methods and results We examined 516 HF patients with CKD (defined as discharge estimated glomerular filtration rate 43.7. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). During the 3 year follow‐up, 131 HF readmissions occurred. Kaplan–Meier analysis showed that the HF readmission rate was significantly lower in the medium‐FEUN group than in the other three groups (log‐rank test, P = 0.029). Multivariate Cox regression analysis identified the low‐FEUN, high‐FEUN, and extremely‐high‐FEUN values as independent factors associated with post‐discharge HF readmission. In the analysis of 130 patients who underwent right heart catheterization during hospitalization, a significant correlation between FEUN value and right atrial pressure was observed (R = 0.243, P = 0.005). Multivariate linear regression analysis revealed that FEUN value at discharge decreased in a dose‐dependent manner with loop diuretics. Conclusions In HF patients with CKD, FEUN is a potential marker of volume status for risk stratification of post‐discharge HF readmission. Low FEUN value (FEUN ≤ 32.1) may represent intravascular dehydration, whereas high FEUN value (FEUN > 38.0) may represent residual congestion; both of them were independent risk factors for HF readmission. FEUN may be useful to determine euvolaemia and guide fluid management in HF patients with CKD.

A 94 years old Japanese female was presented to our hospital with a skin lesion on her left foot. A physical examination found a markedly hyperkeratotic reddish-brown plaque, measuring 3 cm in diameter. A biopsy specimen showed prominent papillomatosis, hyperkeratosis, and atypical keratinocytes throughout the epidermis. Individual cell keratinization, multinucleated keratinocytes, and many keratinocytes with clear cytoplasm were seen. We excised the lesion, and the skin grafting was used for covering the skin defect. We investigated whether human papillomavirus (HPV) was present in the lesion, and HPV 16 DNA was detected using the polymerase chain reaction. Immunohistochemical analysis showed several HPV-positive cells in the upper epidermis. In addition, the tumor cells showed strong and diffuse expression of p16INK4a. Bowen disease (BD) is an intraepidermal squamous cell carcinoma. The precise pathogenesis of BD is unclear, but it involves various factors. HPV infection is one of these factors and is a well-known cause of BD of the genitalia and fingers. It has been shown that some BD lesions occurring at other locations are also associated with HPV. Dysregulation of the Rb / p16INK4a pathway is considered to play an important role in HPV-induced BD, but the precise mechanism remains to be elucidated. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhibition with cabozantinib plus Hx in mice also suppressed angiogenic response and exacerbated Hx-PH to the same extent as SuHx. Expression of endothelial proliferator-activated receptor γ coactivator 1α (PGC-1α) increased along with angiogenesis in lung of Hx-PH but not SuHx mice. In pulmonary endothelial cell–specific Ppargc1a-KO mice, the Hx-induced angiogenesis was suppressed, and PH was exacerbated along with increased oxidative stress, cellular senescence, and DNA damage. By contrast, treatment with baicalin, a flavonoid enhancing PGC-1α activity in endothelial cells, ameliorated Hx-PH with increased Vegfa expression and angiogenesis. Pulmonary endothelial PGC-1α–mediated angiogenesis is essential for adaptive responses to Hx and might represent a potential therapeutic target for PH.

Abstract Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.

Understanding blood and lymphatic vasculature networks is currently limited by existing imaging systems and quantification methods. Here the authors use the tissue clearing method CUBIC to generate 3D images, machine learning to capture the signals, and extract geometric features by topological data analysis.