Mortality outcomes in 35,433 patients admitted for acute haemorrhagic stroke in Australia: A population-linkage study.

Background: Haemorrhagic stroke (HS) is an important cardiovascular cause of mortality worldwide. Trends in admission rates and outcomes, and predictors of outcomes, post-HS in Australia remain unclear. Methods: All New South Wales residents, Australia, hospitalized with HS from 2002 to 2017 were identified from the Admitted-Patient-Data-Collection database. Admission rates were adjusted to population size by sex, age-groups and calendar-year. Mortality was tracked from the death registry to 31-Dec-2018 and adjusted for admission calendar-year, age, gender, referral source, surgical evacuation following HS and comorbidities. Results: The cohort comprised 35,433 patients (51.1% males). Overall age-adjusted mean(±SD) admission rates were higher for males (63.6 ± 6.2 vs 49.9 ± 4.4 admissions-per-100,000-persons-per-annum). Annual admission rates declined for both sexes from 2002 to 2017 especially in those ≥60yo. In-hospital and 1-year mortality rates were higher for females than males (25.0% vs 20.0% and 40.6% vs 35.9% respectively, all p < 0.001). Adjusted in-hospital and 1-year mortality declined for men and women, overall decreasing by 45% (odds ratio 0.55, 95% confidence interval [CI] = 0.47-0.64), and 31% (hazard ratio 0.69,95%CI = 0.63-0.76) respectively between 2002 and 2017. Independent predictors of increased in-hospital and 1-year mortality included increasing age and Charlson comorbidity index, while male sex, a history of hyperlipidaemia and current smoking, and surgical evacuation following HS were associated with reduced mortality (all p < 0.001). Conclusion: HS incidence increases markedly with age. Although age-adjusted HS admission rates and post HS mortality have fallen, HS remains associated with high early and 1-year mortality, with females consistently associated with worse outcomes. Strategies to improve outcomes of these patients remain a clinical priority.

Interleukin 17A Contributes to Blood-Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction.

BACKGROUND: Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood-brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction-induced HF. METHODS AND RESULTS: Male Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno-associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate-dextran 10 kDa+rhodamine-dextran 70 kDa). Compared with sham-operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate-dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin-1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin-1 and tight junction-associated proteins in the PVN. CONCLUSIONS: Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.

Tocilizumab Exerts Anti-Tumor Effects on Colorectal Carcinoma Cell Xenografts Corresponding to Expression Levels of Interleukin-6 Receptor.

The use of tocilizumab against the interleukin-6 receptor (IL-6R) has been demonstrated as inhibiting the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels remains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as human CRC xenograft models with anti-IL-6R antibody (tocilizumab) therapy. The IL-6R expression levels, histology of CRC growth/invasiveness, and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels showed better responsiveness in tocilizumab therapy than in the treated HT-29 group. Likewise, therapeutic effects of tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, invasiveness with MMP-9 proteinase expressions, and ERK 1/2 and STAT3 signaling transduction in the SW480 treatment group were superior to the HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, tocilizumab may serve as a targeted and promising anti-CRC therapy.

Outcomes Following Implantable Cardioverter-Defibrillator Insertion in Patients 80 Years of Age or Older: A Statewide Population Cohort Study.

BACKGROUND: Patients ≥ 80 years of age are underrepresented in major implantable cardioverter-defibrillator (ICD) trials, and real-world data are lacking. In this study, we sought to assess ICD utilisation, outcomes, and their predictors, in an unselected statewide population including patients ≥ 80 years old. METHODS: We extracted details of ICDs implanted from 2009 to 2018 in New South Wales (NSW), Australia from the Centre for Health Record Linkage administrative data sets. Analysis was stratified into age groups of < 60 years, 60-79 years, and ≥ 80 years. RESULTS: A total of 9304 patients (mean age 66.1 ± 13.1 years; 12.1% ≥ 80 years) had de novo ICD placement at an average rate of 1163 ± 122 patients per annum, with more implants in men in all age groups. After adjusting for NSW population size by sex, age group, and calendar year, mean implantation rates were 5.5 ± 0.6, 63.2 ± 8.6, and 52.7 ± 10.8 per 100,000 persons per annum in patients aged < 60 years, 60-79 years, and ≥ 80 years, respectively. In-hospital mortality was 0.4% and did not differ among age groups. However, 1-year mortality was 2.1%, 5.9%, and 10.7%, in those < 60 years, 60-79 years, and ≥ 80 years of age, respectively (P < 0.001), with hazard ratios for those aged ≥ 80 years of 4.3 (95% confidence interval [CI] 3.1-6.0) and those aged 60-79 years of 2.6 (95% CI 1.9-3.5) relative to those aged < 60 years (both P < 0.001) after adjusting for ICD indications, sex, implantation year, referral source, and comorbidities. In those aged ≥ 80 years, age > 83 years, congestive cardiac failure, chronic renal failure, neurodegenerative disease, and a higher Charlson comorbidity index score were each independent predictors of 1-year mortality. CONCLUSIONS: ICD use in patients aged ≥ 80 years and 60-79 years was 10-fold that in patients aged < 60 years, and perioperative outcomes were good in all ages, but there was substantially increased 1-year mortality in those aged ≥ 80 years. Careful selection based on age and comorbidity may further reduce 1-year mortality in patients ≥ 80 years old receiving ICDs.

Trends in Isolated Mitral Valve Repair or Replacement Surgery in Australia: A Statewide Cohort Linkage Study.

BACKGROUND: Global trends in mitral valve surgery (MVSx) suggest increasing repair compared with replacement, especially in the United States and European countries. The relative use, and outcomes of, MV repair and replacement in Australia are unknown. METHODS: New South Wales residents who underwent isolated MVSx between 2001 and 2017 were identified from the Admitted-Patient-Data-Collection database. Mortality outcomes were tracked to 31 Dec 2018 and adjusted based on age, sex, urgency of operation, and comorbidity status. RESULTS: The study cohort comprised 5,693 patients: 2020 (35%) underwent repair (MVr), 1,656 (29%) underwent mechanical replacement (mech.MVR), and 2017 (35%) underwent bioprosthetic replacement (bio.MVR). Respective median ages [interquartile range] were 67 yo [59-75 yo], 64 yo [55-71 yo], and 75 yo [68-80 yo] (p<0.001 across groups). Between 2001 and 2017, total MVSx increased steadily with population growth. Whereas the relative use of MVr remained static (34% to 38%), that for bio.MVR (22% to 50%) and mech.MVR (45% to 13%) changed significantly. MVr had the best outcome with 1.2% in-hospital, 2.5% 1-year, and 21.6% total cumulative mortality during a median follow-up of 6.5 years. Compared to MVr, the adjusted hazard ratio (aHR) for mech.MVR and bio.MVR for long-term mortality were 1.41 (95% confidence interval [CI]=1.24-1.61) and 1.73 (95% CI=1.53-1.95), respectively. Heart failure and sepsis were the main cardiovascular and noncardiovascular causes of death in all groups. CONCLUSION: In this statewide Australian cohort examined over 17 years, MVr is potentially underutilised despite having superior outcomes to MVR. Access to quality dataset which provides the indication for MVSx and quantitative clinical factors is critical to further improve MVr coverage and outcome MVSx.

Interactive Game-Based Platform System for Assessing and Improving Posture Control in the Elderly.

Inadequate response to balance perturbations lead to posture instability in the elderly. The fall risks are increased by a reduced capacity to control the center of pressure (COP) displacement within the safety limit of the supporting base. This study developed an interactive evaluation and training platform. The system incorporated a computerized program with instantaneous force plate evaluation. Ten young subjects underwent a baseline evaluation and twenty-nine community-dwelling elderly received pre- and post-intervention testing. The ability to reach the stability limit was assessed by measuring the maximum voluntary excursion of the COP in anterior-posterior and medial-lateral directions. Functional mobility tests including Berg Balance Scale, Timed-Up-and-Go and functional reach were used as functional outcomes. The experimental group (n = 15) received a 40 min intervention three times a week for six weeks. The interactive game-based training focused on multi-directional weight shifting by tracing a COPcontrolled target to challenge an individual's stability limit. The control group (n = 14) maintained daily activities as usual. The young group revealed a superior COP displacement through active ankle control than the elderly, especially in the anterior-posterior direction. The experimental group improved their COP displacement control more in the medial-lateral direction due to the predominant side-to-side gameplay movement. The functional outcome measures were also significantly improved after training. Using the COPcontrolled game-based program, the stability limit was challenged to facilitate dynamic posture control by an incremental increase in self-initiated perturbations. The platform system could assist in transferring the immediate training effects into daily functional mobility in the elderly.

Effects of sling exercises on pain, function, and corticomuscular functional connectivity in individuals with chronic low back pain- preliminary study.

BACKGROUND: Individuals with chronic low back pain (CLBP) exhibit altered brain function and trunk muscle activation. AIM: This study examined the effects of sling exercises on pain, function, and corticomuscular coherence (CMC) in healthy adults and individuals with CLBP. METHODS: Eight individuals with CLBP and 15 healthy adults received sling exercise training for 6 weeks. Before and after training, participants performed two motor tasks: rapid arm lifts and repeated trunk flexion-extension tasks, and electromyography of the trunk muscles and electroencephalography of the sensorimotor cortex were recorded. Chi-squared test and Mann-Whitney U tests were used for between group comparison, and Wilcoxon signed-rank tests were used for pre- and post-training comparison. Spearman's Rank Correlation Coefficient (Rs) was used to identify for the relationship between motor performance and Corticomuscular coherence. RESULTS: Sling exercises significantly improved pain (median from 3 to 1, p = .01) and Oswestry Disability Index scores (median from 2.5 to 2, p = .03) in the CLBP group. During rapid arm lifts, individuals with CLBP showed lower beta CMC of the transverse abdominis and internal oblique (Tra/IO) (0.8 vs. 0.49, p = .01) and lumbar erector spinae (0.70 vs. 0.38, p = .04) than the control group at baseline. During trunk flexion-extension, the CLBP group showed higher gamma CMC of the left Tra/IO than the control group at baseline (0.28 vs. 0.16 , p = .001). After training, all CMC became statistically non-significant between groups. The training induced improvement in anticipatory activation of the Tra/IO was positively correlated with the beta CMC (rs = 0.7851, p = .02). CONCLUSION: A 6-week sling exercises diminished pain and disability in patients with CLBP and improved the anticipatory activation and CMC in some trunk muscles. These improvements were associated with training induced changes in corticomuscular connectivity in individuals with CLBP.

Veronica persica ameliorates acetaminophen-induced murine hepatotoxicity via attenuating oxidative stress and inflammation.

Excess acetaminophen (APAP) commonly causes severe acute liver injury (ALI), characterized by oxidative stress, pro-inflammatory responses, and hepatocyte damage. Veronica persica (VP) is a traditional medicine with antioxidant and anti-inflammatory properties. There is a paucity of information on its medicinal value, especially its potential mechanisms for alleviating ALI. This study aimed to clarify the ameliorative effects and intracellular mechanisms of VP on APAP-induced ALI via attenuating oxidative stress and inflammation. Mice were given VP for 7 days before exposure to APAP (300 mg/kg). The HPLC and radical scavenging assay found that VP contains 12 phenolic acids and 6 flavonoids, as well as show robust antioxidant capacity. In the APAP-induced ALI model, pre-treatment with VP significantly reduces APAP-induced hepatotoxicity by observing improved hepatocyte pathological injury and further confirmed by serum biochemical indicator. Also, the reduction of TUNEL-positive regions and the regulation of Bcl-2-associated X protein indicated that VP attenuates hepatocytotoxicity. Moreover, VP pre-intervention inhibits the formation of liver pro-inflammatory cytokines, the expression of inflammatory response genes, and increases in myeloperoxidase (MPO) in APAP-exposed mice. The elevated reduced glutathione (GSH) levels and decreased oxidative stress markers indicate that VP reduces APAP-promoted oxidative stress. Further study revealed that VP inhibited the phosphorylation of NF-κB/STAT3 cascade, blocked ERK and JNK phosphorylation, and activated AMP-activated protein kinase (AMPK). To sum up, this study demonstrated that VP exists hepatoprotective abilities on APAP-induced ALI, primarily by suppressing the phosphorylation of NF-κB/STAT3 cascade and ERK-JNK and inducing AMPK activation to alleviate oxidative stress and inflammation.

Roux-en-Y and One-Anastomosis Gastric Bypass Surgery Are Superior to Sleeve Gastrectomy in Lowering Glucose and Cholesterol Levels Independent of Weight Loss: a Propensity-Score Weighting Analysis.

BACKGROUND: The superior effects of gastric bypass surgery in preventing cardiovascular diseases compared with sleeve gastrectomy are well-established. However, whether these effects are independent of weight loss is not known. METHODS: In this retrospective cohort study, we compared the change in cardiometabolic risks of 1073 diabetic patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 265), one-anastomosis gastric bypass (OAGB) (n = 619), and sleeve gastrectomy (SG) (n = 189) with equivalent weight loss from the Min-Shen General Hospital. Propensity score-weighting, multivariate regression, and matching were performed to adjust for baseline differences. RESULTS: After 12 months, OAGB and, to a lesser extent, RYGB exhibited superior effects on glycemic control compared with SG in patients with equivalent weight loss. The effect was significant in patients with mild-to-modest BMI reduction but diminished in patients with severe BMI reduction. RYGB and OAGB had significantly greater effects in lowering total and low-density lipoprotein cholesterol than SG, regardless of weight loss. The results of matching patients with equivalent weight loss yielded similar results. The longer length of bypassed biliopancreatic (BP) limbs was correlated with a greater decrease in glycemic levels, insulin resistance index, lipids, C-reactive protein (CRP) levels, and creatinine levels in patients receiving RYBG. It was correlated with greater decreases in BMI, fasting insulin, insulin resistance index, and C-reactive protein levels in patients receiving OAGB. CONCLUSION: Diabetic patients receiving OAGB and RYGB had lower glucose and cholesterol levels compared with SG independent of weight loss. Our results suggest diabetic patients with cardiovascular risk factors such as hypercholesterolemia to receive bypass surgery.

Promoting plasmonic photocatalysis with ligand-induced charge separation under interband excitation.

Plasmonic nanoparticles have been demonstrated to enhance photocatalysis due to their strong photon absorption and efficient hot-carrier generation. However, plasmonic photocatalysts suffer from a short lifetime of plasmon-generated hot carriers that decay through internal relaxation pathways before being harnessed for chemical reactions. Here, we demonstrate the enhanced photocatalytic reduction of gold ions on gold nanorods functionalized with polyvinylpyrrolidone. The catalytic activities of the reaction are quantified by in situ monitoring of the spectral evolution of single nanorods using a dark-field scattering microscope. We observe a 13-fold increase in the reduction rate with the excitation of d-sp interband transition compared to dark conditions, and a negligible increase in the reduction rate when excited with intraband transition. The hole scavenger only plays a minor role in the photocatalytic reduction reaction. We attribute the enhanced photocatalysis to an efficient charge separation at the gold-polyvinylpyrrolidone interface, where photogenerated d-band holes at gold transfer to the HOMO of polyvinylpyrrolidone, leading to the prolonged lifetime of the electrons that subsequently reduce gold ions to gold atoms. These results provide new insight into the design of plasmonic photocatalysts with capping ligands.

Comparison of three-dimensional motion of bacteria with and without wall accumulation.

A comparison of the movement characteristics between bacteria with and without wall accumulation could potentially elucidate the mechanisms of biofilm formation. However, authors of previous studies have mostly focused on the motion of bacteria that exhibit wall accumulation. Here, we applied digital holographic microscopy to compare the three-dimensional (3D) motions of two bacterial strains (Shewanella japonica UMDC19 and Shewanella sp. UMDC1): one exhibiting higher concentrations near the solid surfaces, and the other showing similar concentrations in near-wall and bulk regions. We found that the movement characteristics of the two strains are similar in the near-wall region but are distinct in the bulk region. Near the wall, both strains have small velocities and mostly perform subdiffusive motions. In the bulk, however, the bacteria exhibiting wall accumulation have significantly higher motility (including faster swimming speeds and longer movement trajectories) than the one showing no wall accumulation. Furthermore, we found that bacteria exhibiting wall accumulation slowly migrate from the bulk region to the near-wall region, and the hydrodynamic effect alone is insufficient to generate this migration speed. Future studies are required to test if the current findings apply to other bacterial species and strains.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

["Huayu Tongluo" moxibustion improves learning-memory ability and promotes myelin regeneration by regulating Sonic Hedgehog signaling pathway in vascular dementia rats].

OBJECTIVE: To investigate the effect of "Huayu Tongluo" (resolving blood stagnation to dredge meridian-collaterals) moxibustion on remyelination and Sonic Hedgehog (Shh) signaling pathway in the corpus callosum of vascular dementia (VD) rats, so as to explore its mechanisms underlying improvement of VD. METHODS: Male Wistar rats were randomized into sham-operation, model, medication and moxibustion groups, with 12 rats in each group.The VD model was established by bilateral common carotid artery occlusion. Moxibustion was applied to "Shenting"(GV24), "Baihui"(GV20) and "Dazhui"(GV14) for 20 min once a day, 7 d as a treatment course, for 3 courses, with one day's rest between every two courses. Rats of the medication group were treated by gavage of 10 mg/kg of chloromastine solution once a day, and the course of treatment was the same as that of the moxibustion group. The rat's learning-memory ability was assessed by Morris water maze test (escape latency). The neurological deficits were evaluated by using Longa's scale.The mRNA and protein expressions of Shh and Gli1 in the corpus callosum were measured by quantitative real-time fluorescence PCR and Western blot, separately. The ultrastructure of the myelin sheath and myelinated axons was observed under transmission electron microscopy (TCM). RESULTS: Compared with the sham-operation group, the neurologic score and escape latency were significantly increased and prolonged (P<0.01), and the mRNA and protein expression levels of Shh and Gli1 and the number of myelinated axons were obviously decreased in the model group (P<0.01). In comparison with the model group, the escape latency was apparently shortened (P<0.05), while the mRNA and protein expression levels of Shh and Gli1 as well as the number of myelinated axons were strikingly increased in both moxibustion and medication groups (P<0.01). Results of TCM showed that in the model group, the arrangement of myelin coil structures was sparse and fuzzy, and some structures were bulged and disbanded. The oligodendrocytes were irregular, and the number of myelin sheath was rare. These situations were relatively milder in both moxibustion and medication groups. CONCLUSION: "Huayu Tongluo" moxibustion can promote the differentiation and maturation of oligodendrocyte precursor cells after cerebral ischemia by regulating the expressions of Shh and Gli1 in Shh signaling pathway, thus promoting the regeneration of cerebral white matter myelin sheaths in VD rats, which may contribute to improving learning-memory ability.

Effects of Noise Electrical Stimulation on Proprioception, Force Control, and Corticomuscular Functional Connectivity.

Sensory afferent inputs play an important role in neuromuscular functions. Subsensory level noise electrical stimulation enhances the sensitivity of peripheral sensory system and improves lower extremity motor function. The current study aimed to investigate the immediate effects of noise electrical stimulation on proprioceptive senses and grip force control, and whether there are associated neural activities in the central nervous system. Fourteen healthy adults participated in 2 experiments on 2 different days. In day 1, participants performed grip force and joint proprioceptive tasks with and without (sham) noise electrical stimulation. In day 2, participants performed grip force steady hold task before and after 30-min noise electrical stimulation. Noise stimulation was applied with surface electrodes secured along the course of the median nerve and proximal to the coronoid fossa EEG power spectrum density of bilateral sensorimotor cortex and coherence between EEG and finger flexor EMG were calculated and compared. Wilcoxon Signed-Rank Tests were used to compare the differences of proprioception, force control, EEG power spectrum density and EEG-EMG coherence between noise electrical stimulation and sham conditions. The significance level (alpha) was set at 0.05. Our study found that noise stimulation with optimal intensity could improve both force and joint proprioceptive senses. Furthermore, individuals with higher gamma coherence showed better force proprioceptive sense improvement with 30-min noise electrical stimulation. These observations indicate the potential clinical benefits of noise stimulation on individuals with impaired proprioceptive senses and the characteristics of individuals who might benefit from noise stimulation.

Substance P promotes epidural fibrosis via induction of type 2 macrophages.

In response to spinal surgery, neurons secrete a large amount of substance P into the epidural area. Substance P is involved in macrophage differentiation and fibrotic disease. However, the specific roles and mechanisms of substance P in epidural fibrosis remain unclear. In this study, we established a mouse model of L1-L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids. In vitro experiments revealed that type 1 macrophages secreted substance P, which promoted differentiation of type 1 macrophages towards a type 2 phenotype. High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P. Specifically, sphingomyelin synthase 2, a component of the sphingolipid metabolic pathway, promoted M2 differentiation in substance P-treated macrophages, while treating the macrophages with LY93, a sphingomyelin synthase 2 inhibitor, suppressed M2 differentiation. In addition, substance P promoted the formation of neutrophil extracellular traps, which further boosted M2 differentiation. Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis, as evidenced by decreased fibronectin, α-smooth muscle actin, and collagen I in the scar tissue. These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps. These findings provide a novel strategy for the treatment of epidural fibrosis.

Voice banking to support individuals who use speech-generating devices: development and evaluation of Singaporean-accented English synthetic voices and a Singapore Colloquial English recording inventory.

Voice banking involves recording an inventory of sentences produced via natural speech. The recordings are used to create a synthetic text-to-speech voice that can be installed on speech-generating devices. This study highlights a minimally researched, clinically relevant issue surrounding the development and evaluation of Singaporean-accented English synthetic voices that were created using readily available voice banking software and hardware. Processes used to create seven unique synthetic voices that produce Singaporean-accented English, and the development of a custom Singaporean Colloquial English (SCE) recording inventory, are reviewed. The perspectives of adults who spoke SCE and banked their voices for this project are summarized and were generally positive. Finally, 100 adults familiar with SCE participated in an experiment that evaluated the intelligibility and naturalness of the Singaporean-accented synthetic voices, as well as the effect of the SCE custom inventory on listener preferences. The addition of the custom SCE inventory did not affect intelligibility or naturalness of the synthetic speech, and listeners tended to prefer the voice created with the SCE inventory when the stimulus was an SCE passage. The procedures used in this project may be helpful for interventionists who wish to create synthetic voices with accents that are not commercially available.

Microvascular reactivity using laser Doppler measurement in type 2 diabetes with subclinical atherosclerosis.

Microangiopathy should be noted in diabetes with subclinical vascular diseases. Little is known about whether various surrogate markers of systemic arterial trees exacerbate simultaneously in preclinical atherosclerosis. To clarify the association of skin microvascular reactivity with arterial stiffness is essential to elucidating early atherosclerotic changes. The post-occlusive reactive hyperemia of skin microcirculation was evaluated in 27 control and 65 type 2 diabetic subjects, including 31 microalbuminuria (MAU) and 34 normoalbuminuria (NAU) patients. The laser Doppler skin perfusion signals were transformed into three frequency intervals for the investigation of endothelial, neurogenic, and myogenic effects on basal and reactive flow motion changes. The analysis of spectral intensity and distribution provided insight into potential significance of microvascular regulation in subclinical atherosclerotic diseases. Systemic arterial stiffness was studied by the brachial ankle pulse wave velocity (baPWV). Following occlusive ischemia, the percent change of endothelial flow motion was lower in MAU than in NAU and control groups. The MAU group revealed a relative increase in myogenic activity and a decrease in endothelial activity in normalized spectra. The baPWV showed more significant associations with reactive endothelial change (r = - 0.48, P < 0.01) and normalized myogenic value (r = - 0.37, P < 0.05) than diabetes duration and HbA1c. By multivariate regression analysis, only endothelial vasomotor changes independently contributed to the decreased baPWV (OR 3.47, 95% CI 1.63-7.42, P < 0.05). Impaired microcirculatory control is associated with increased arterial stiffness in preclinical atherosclerosis. To identify the early manifestations is necessary for at-risk patients to prevent from further vascular damage.

ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking.

BACKGROUND: Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. METHODS: To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. RESULTS: In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. CONCLUSIONS: RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.

Outcomes after arthroscopic treatment for scaphoid nonunion using ipsilateral radius bone graft and a headless compression screw: a comparison between the patients with and without avascular necrosis.

PURPOSE: To determine whether avascular necrosis can affect clinical outcomes or the union incidence after arthroscopic bone grafting for the treatment of scaphoid nonunion. METHODS: This retrospective comparative study included thirty-four patients with scaphoid nonunion that underwent arthroscopic bone graft from the ipsilateral radius and internal fixation. The patients were divided into two cohorts (group A, with avascular necrosis, n = 15; group B, without avascular necrosis, n = 19) based on pre-operative magnetic resonance imaging findings. Additionally, the patients were grouped in accordance with the location of nonunion (waist, n = 27; proximal pole, n = 7). The mean follow-up was 20.7 months (range 12.0-40.0 months). Clinical outcomes, including the visual analog scale (VAS) pain score, grip strength, range of motion (ROM), Mayo Wrist Score (MWS), and Disabilities of the Arm, Shoulder, and Hand (DASH) score, were evaluated. Radiographic measurements for carpal bone alignment were assessed as well. RESULTS: Union rates did not differ between groups (group A, 93.3%; group B, 94.7%: p = 0.863), and the post-operative VAS pain score, ROM, and MWS were similar at follow-up for a minimum of one year. DASH and grip strength were significantly better in group B, but the intergroup differences were minimal (mean DASH 11.9 versus 9.6; mean grip strength 77.5% versus 95.4% of contralateral side). There was no significant intergroup difference in mean time to achieving union (group A, 14.9 weeks; group B, 14.6 weeks; p = 0.900). In post-operative radiographic assessments, no significant intergroup differences were noted in any of the parameters. Subgroup analysis regarding the location of nonunion showed there were no significant intergroup differences in union rates, mean time to achieving union, and clinical outcome measures at the last post-operative follow-up. CONCLUSIONS: Arthroscopic bone grafting and internal fixation in the treatment of scaphoid nonunion provided good union rates and satisfactory outcomes regardless of vascularity status.