Calcifying characteristics of peripheral vascular smooth muscle cells of chronic kidney disease patients with critical limb ischemia.

The role of vascular smooth muscle cells (VSMCs) in vascular calcification, which is related to chronic kidney disease (CKD), has been studied in greater detail in the major arteries relative to the peripheral arteries. We compared the calcifying characteristics of peripheral VSMCs relative to non-pathologic major VSMCs in patients with severe peripheral artery disease (PAD). We isolated peripheral VSMCs from the posterior tibial artery of 10 patients with CKD who underwent below-knee amputation for critical limb ischemia (CLI). Using normal human aortic VSMCs as a control group, we cultured the cells in normal and high phosphate media for 10 days, and subsequently tested by immunofluorescence staining. We compared the calcification levels between the two groups using various assays, tests for cell viability, and scanning electron microscopy. As a result, calcification of pathologic peripheral VSMCs increased significantly with time (p = 0.028) and was significantly higher than that in human aortic VSMCs in calcium assays (p = 0.043). Dead cells in the pathologic VSMC group were more distinct in high phosphate media than in human aortic VSMCs. In conclusion, VSMCs from the peripheral artery of patients with severe CKD and CLI who underwent amputation surgery showed marked calcifying characteristics compared to normal human aortic VSMCs.

CLIF-SOFA scoring system accurately predicts short-term mortality in acutely decompensated patients with alcoholic cirrhosis: a retrospective analysis.

BACKGROUND & AIMS: Accurate prognostication of acute-on-chronic liver failure (ACLF) is essential for therapeutic decisions. Our aim was to validate a novel scoring system for predicting mortality, the chronic liver failure-sequential organ failure assessment (CLIF-SOFA), in a population of Asian patients with ACLF. METHODS: A total of 345 patients with acutely decompensated alcoholic cirrhosis were selected for study, comparing areas under the receiver operating characteristic (AUROC) curves of CLIF-SOFA and five existing scoring systems for end-stage liver disease [model for end-stage liver disease (MELD), MELD-Na, Refit-MELD, Refit-MELD-Na, and Child-Turcotte-Pugh]. RESULTS: CLIF-SOFA displayed the highest AUROC of 0.943 significantly outperforming all five reference methods in predicting short-term mortality at Week 4 (all P < 0.001) by competing risk analysis. In 262 patients given supportive care only, the power of CLIF-SOFA to predict short-term mortality was high (AUROC: 0.952 at Week 1; 0.959 at Week 4), again surpassing the other methods (all P < 0.001). For the remaining 83 liver transplant recipients, CLIF-SOFA also excelled in predicting 12-week mortality (AUROC: 0.978); and high-grade ACLF by CLIF-SOFA was associated with prolonged postoperative mechanical support (i.e. mechanical ventilation and renal replacement therapy) and ICU stays (all P < 0.05). CONCLUSIONS: CLIF-SOFA enables more accurate prediction of short-term mortality in patients with acutely decompensated alcoholic cirrhosis than other available scoring systems and is useful in predicting both 12-week mortality and the need for mechanical support after liver transplantation.

Caregiver's education level and child's dental caries in African Americans: a path analytic study.

The objective of this study was to investigate the influence of caregiver education level on children's dental caries mediated by both caregiver and child oral health behaviors. Participants were 423 low-income African American kindergarteners and their caregivers who were part of a school-based randomized clinical trial. Path analysis tested the hypothesis that caregiver education level affected untreated dental caries and cumulative overall caries experience (decayed or filled teeth) through the mediating influence of frequency of dental visits, use of routine care, and frequency of toothbrushing for both the caregiver and the child. The results supported the hypothesis: caregivers who completed high school were 1.76 times more likely to visit dentists compared with those who did not complete high school (e(0.56) = 1.76, 95% CI: 1.03-2.99), which in turn was associated with 5.78 times greater odds of dental visits among their children (e(1.76) = 5.78, 95% CI: 3.53-9.48). Children's dental visits, subsequently, were associated with 26% fewer untreated decayed teeth compared with children without dental visits (e(-0.31) = 0.74, 95% CI: 0.60-0.91). However, this path was not present in the model with overall caries experience. Additionally, caregiver education level was directly associated with 34% less untreated decayed teeth (e(-0.42) = 0.66, 95% CI: 0.54-0.79) and 28% less decayed or filled teeth (e(-0.32) = 0.72, 95% CI: 0.60-0.88) among the children. This study overcomes important conceptual and analytic limitations in the existing literature. The findings confirm the role of caregiver education in child dental caries and indicate that caregiver's behavioral factors are important mediators of child oral health.

The effectiveness of xylitol in a school-based cluster-randomized clinical trial.

OBJECTIVE: The purpose of this double-blind, cluster-randomized clinical trial was to examine the effects of xylitol gummy bear snacks on dental caries progression in primary and permanent teeth of inner-city school children. METHODS: A total of 562 children aged 5-6 years were recruited from five elementary schools in East Cleveland, Ohio. Children were randomized by classroom to receive xylitol (7.8 g/day) or placebo (inulin fiber 20 g/day) gummy bears. Gummy bears were given three times per day for the 9-month kindergarten year within a supervised school environment. Children in both groups also received oral health education, toothbrush and fluoridated toothpaste, topical fluoride varnish treatment and dental sealants. The numbers of new decayed, missing, and filled surfaces for primary teeth (dmfs) and permanent teeth (DMFS) from baseline to the middle of 2nd grade (exit exam) were compared between the treatment (xylitol/placebo) groups using an optimally-weighted permutation test for cluster-randomized data. RESULTS: The mean new d(3-6)mfs at the exit exam was 5.0 ± 7.6 and 4.0 ± 6.5 for the xylitol and placebo group, respectively. Similarly, the mean new D(3-6)MFS was 0.38 ± 0.88 and 0.48 ± 1.39 for the xylitol and placebo group, respectively. The adjusted mean difference between the two groups was not statistically significant: new d(3-6)mfs: mean 0.4, 95% CI -0.25, 0.8), and new D(3-6)MFS: mean 0.16, 95% CI -0.16, 0.43. CONCLUSION: Xylitol consumption did not have additional benefit beyond other preventive measures. Caries progression in the permanent teeth of both groups was minimal, suggesting that other simultaneous prevention modalities may have masked the possible beneficial effects of xylitol in this trial.

Plexin-A4 mediates amyloid-ß-induced tau pathology in Alzheimer's disease animal model.

Amyloid-ß (Aß) and tau are major pathological hallmarks of Alzheimer's disease (AD). Several studies have revealed that Aß accelerates pathological tau transition and spreading during the disease progression, and that reducing tau can mitigate pathological features of AD. However, molecular links between Aß and tau pathologies remain elusive. Here, we suggest a novel role for the plexin-A4 as an Aß receptor that induces aggregated tau pathology. Plexin-A4, previously known as proteins involved in regulating axon guidance and synaptic plasticity, can bound to Aß with co-receptor, neuropilin-2. Genetic downregulation of plexin-A4 in neurons was sufficient to prevent Aß-induced activation of CDK5 and reduce tau hyperphosphorylation and aggregation, even in the presence of Aß. In an AD mouse model that manifests both Aß and tau pathologies, genetic downregulation of plexin-A4 in the hippocampus reduced tau pathology and ameliorated spatial memory impairment. Collectively, these results indicate that the plexin-A4 is capable of mediating Aß-induced tau pathology in AD pathogenesis.

Relationship between talofibular impingement and increased talar tilt in incongruent varus ankle osteoarthritis.

PurposeThis study aimed to evaluate the relationship between talofibular impingement and increased talar tilt in incongruent varus ankle osteoarthritis. Methods: Incongruent varus ankle osteoarthritis was defined as a talar tilt of more than 4° on standard ankle anteroposterior radiographs. We retrospectively reviewed 30 patients with unilateral incongruent varus ankle osteoarthritis with normal alignment of the contralateral ankle. All patients underwent bilateral weightbearing computed tomography and standing plain radiographs. The talar tilt and the distance between the talar lateral process and lateral malleolar tip were measured from a standing ankle anteroposterior radiograph of both sides. Talar and fibular spurs were assessed on the coronal and axial views of weightbearing computed tomography. After simulating the correction of the talar tilt in varus ankle osteoarthritis, talofibular bony impingement was reassessed. Results: On the varus side, the distance between the talar lateral process and the lateral malleolar tip was significantly shorter than that on the contralateral side (p < .001). Talar spur was present in the varus side of all 30 patients on the axial view of weightbearing computed tomography and in the control side of 10 patients. After the simulation of talar tilt correction, talofibular impingement (overlap) occurred in all 30 patients with a larger extent in the severe talar tilt subgroup (p < .001). Conclusion: Talofibular impingement by lateral gutter osteophytes is closely related to increased talar tilt in patients with incongruent varus ankle osteoarthritis. Therefore, lateral gutter osteophytes should be resected to stabilize mortise and improve clinical outcomes.

Quantitative evaluation of posterior talar subluxation in posterior malleolar fractures: A preliminary study.

BACKGROUNDS: Although ankle posterior subluxation is one of the major mechanisms by which posterior malleolar fractures (PMF) contribute to a worse prognosis, there is no parameter to address it quantitatively. So, we suggest a method that can evaluate posterior talar subluxation quantitatively in PMF. METHODS: We retrospectively analyzed 37 patients with posterior malleolar fractures. The patients were divided into two groups: PMF without posterior talar subluxation (n = 18) and with posterior talar subluxation (n = 19). We measured the distance between the arc center of the talus and the anterior tibia (TAD), the percentage of articular involvement of the fracture fragment, the inter-fragment distance (IFD) and articular step-off. We analyzed significant differences and the correlations between the two groups for each index. The estimated area of the receiver operating characteristic (ROC) curve was calculated, and cutoff values were suggested to discriminate posterior talar subluxation. RESULTS: TAD, IFD, and articular step-off were significantly greater in patients with posterior talar subluxation. (TAD: 14.3 vs. 2.8 mm, p < 0.001, IFD: 7.8 vs. 4.0 mm, p < 0.001, articular step-off: 3.6 vs. 2.0 mm, p = 0.004). The ROC curve showed that TAD was most useful to determine cutoff values for posterior talar subluxation. The area under the curve for TAD was 1.000, and the appropriate cutoff value was 5 mm. When a TAD of > 5 mm was used as a threshold, a sensitivity of 100% and a specificity of 100% were achieved in determining the presence of posterior talar subluxation. Also, higher TAD was correlated with IFD and articular step-off. CONCLUSIONS: TAD can be a useful parameter for evaluating the posterior talar subluxation in PMF. It can reflect not only the degree of fracture displacement but also posterior talar subluxation quantitatively.

Acetylation changes tau interactome to degrade tau in Alzheimer's disease animal and organoid models.

Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT ) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice.

Clinical Utility of the Korean Version of the WHO Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale Screener.

OBJECTIVE: The aim of this study was to compare the performance of the 18-item Korean version of the World Health Organization adult attention-deficit/hyperactivity disorder self-report scale (ASRS) with the six-item ASRS Screener for predicting attention-deficit/hyperactivity disorder (ADHD) group. METHODS: The study sample included 51 adult patients with ADHD and 158 normal controls. All participants completed the ASRS and were interviewed individually using the Mini-International Neuropsychiatric Interview. Receiver operating characteristic (ROC) curves were used to compare the ASRS (ASRS-18) with the ASRS Screener (ASRS-6) in Korean samples. RESULTS: The ADHD group had higher ASRS and ASRS subscale scores than those of the control group. ROC curve analysis revealed the ASRS was more powerful to predict ADHD group than the ASRS Screener, but the ASRS Screener also had strong concordance with clinician diagnoses. CONCLUSION: This study shows that the 18-question ASRS outperforms the six-question ASRS Screener. However, the weighted Screener is also a valid and useful screening instrument both in epidemiological surveys and in clinical settings.

Annexin A1 restores Aß1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway.

The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that ß-Amyloid 1-42 (Aß42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aß42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aß42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aß42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aß42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.

Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Aß-induced impaired axonal transport.

BACKGROUND: Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer's disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood. METHODS AND RESULTS: Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aß treated cells, the brains of 5xFAD AD model mice and AD patients. Malfunctioning Prx1, caused by reduced Prx1 acetylation levels, was recovered by HDAC6 inhibition. Increasing acetylation levels of Prx1 by HDAC6 inhibition recovered elevated reactive oxygen species (ROS) levels, elevated Ca2+ levels and impaired mitochondrial axonal transport, sequentially, even in the presence of Aß. Prx1 mutant studies on the K197 site for an acetylation mimic or silencing mutation support the results showing that HDAC6 inhibitor restores Aß-induced disruption of ROS, Ca2+ and axonal transport. CONCLUSIONS: Taken together, increasing acetylation of Prx1 by HDAC6 inhibition has several beneficial effects in AD pathology. Here, we present the novel mechanism by which elevated acetylation of Prx1 rescues mitochondrial axonal transport impaired by Aß. Therefore, our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well.

Neonatal Serum Phosphorus Levels and Enamel Defects in Very Low Birth Weight Infants.

BACKGROUND: Very low birth weight (VLBW) infants miss out on the period of greatest mineral accretion that occurs during the last trimester of pregnancy and are at higher risk of enamel defects. No studies have well described the relationship between neonatal nutrition and dental outcomes in preterm, VLBW infants. The objective of this study was to assess the differences in nutrition biomarkers, feeding intake, and comorbidities among VLBW infants with and without enamel defects. METHODS: A retrospective chart review of VLBW infants recruited for an ongoing longitudinal dental study between 2007 and 2010 was done. Participants were classified as cases and controls according to the presence/absence of developmental defects of enamel at 8 and/or 18-20 and/or 36 months. Demographics and medical and nutrition data were abstracted from 76 subjects' medical charts. RESULTS: Of the 76 VLBW subjects, 62% had enamel defects (hypoplasia and/or opacity). The only significant variable in the logistic regression analysis was that infants with a 1-mg/dL increase in serum phosphorus levels had a 68% reduction in the odds of having enamel hypoplasia (odds ratio, 0.322; P = .024). CONCLUSION: Neonatal lower serum phosphorus levels are significantly associated with enamel hypoplasia in VLBW infants younger than 3 years.

Serious psychological distress as a barrier to dental care in community-dwelling adults in the United States.

OBJECTIVES: To examine whether serious psychological distress (SPD), a nonspecific indicator of past year mental health problems, was associated with subsequent dental care utilization, dental expenditures, and unmet dental needs. METHODS: We analyzed data from panel 13 thru 15 of the Medical Expenditure Panel Survey -Household Component (n=31,056). SPD was defined as a score of 13 or higher on the Kessler Psychological Distress Scale (K6). Logistic regression, zero-inflated negative binomial model, and generalized linear model (GLM) with a gamma distribution were used to test the study hypotheses. RESULTS: Adults with SPD had, in the subsequent year, 35 percent lower odds of adhering to annual dental checkups and a twofold increase in the odds of having unmet dental needs. Although adults with SPD did not have significantly more dental visits than those without SPD, they spent 20 percent more on dental care. CONCLUSIONS: SPD was a modest independent risk factor for lack of subsequent preventive dental care, greater unmet dental needs, and greater dental expenditures. In addition to expanding adult dental coverage, it is important to develop and evaluate interventions to increase the utilization of dental care particularly preventive dental services among people with mental illness in order to improve oral health and reduce dental expenditures among this vulnerable population.

Family Access to a Dentist Study (FADS): A multi-center randomized controlled trial.

INTRODUCTION: Many low-income parent/caregivers do not understand the importance of cavity-free primary (baby) teeth and the chronic nature of dental caries (tooth decay). As a consequence, dental preventive and treatment utilization is low even when children are screened in schools and referred for care. This study aims to test a referral letter and Dental Information Guide (DIG) designed using the Common-Sense Model of Self-Regulation (CSM) framework to improve caregivers' illness perception of dental caries and increase utilization of care by children with restorative dental needs. METHODS: A multi-site randomized controlled trial with caregivers of Kindergarten to 4th grade children in urban Ohio and rural Washington State will compare five arms: (1) CSM referral letter alone; (2) CSM referral letter+DIG; (3) reduced CSM referral letter alone; (4) reduced CSM referral letter+DIG; and (5) standard (control) referral. At baseline, children will be screened at school to determine restorative dental needs. If in need of treatment, caregivers will be randomized to study arms and an intervention packet will be sent home. The primary outcome will be dental care based on a change in oral health status by clinical examination 7 months post-screening (ICDAS sealant codes 1 and 2; restoration codes 3-8; extraction). Enrollment commenced summer 2015 with results in summer 2016. CONCLUSION: This study uses the CSM framework to develop and test behavioral interventions to increase dental utilization among low-income caregivers. If effective this simple intervention has broad applicability in clinical and community-based settings.

Community factors predicting dental care utilization among older adults.

BACKGROUND: Few investigators have studied the influence of community factors on dental care utilization among older adults. The authors' objective in this study was to investigate the effect of community factors on dental care utilization after adjustment for individual factors. METHODS: Using data from a cross-sectional survey of Ohio residents, the authors assessed dental care utilization in a sample of 2,166 adults 65 years or older. They linked individual-level dental care utilization, predisposing factors (age, sex, race or ethnicity, marital status, education), enabling factors (poverty, dental insurance) and need-related factors (physical and mental health problems) with county-level data (socioeconomic environment and health resource environment) from the 2010 Area Health Resource Files (from the U.S. Department of Health and Human Services) and the American Community Survey (from the 2006-2010 U.S. census). By using multilevel logistic regression models, the authors evaluated the association between dental care utilization and community factors after adjustment for individual factors. RESULTS: The results indicated that individual factors such as being female, married and nonpoor and having a higher educational level and private dental insurance were associated with higher odds of having utilized dental care. Furthermore, older adults living in a county with a higher dentist-to-population ratio were more likely to use dental services even after the authors adjusted the results for the individual-level factors (odds ratio = 1.10; P = .03). CONCLUSIONS: County-level dentist-to-population ratio has independent effects on older adults' dental care utilization even after adjustment for individual-level characteristics. Practical Implications. A comprehensive policy plan is required to intervene at both the individual and community levels to improve dental care utilization among older adults. By understanding the factors influencing dental care utilization among older adults, U.S. dentists will be better positioned to meet the dental needs of this population.

Agreement between photographic and clinical examinations in detecting developmental defects of enamel in infants.

OBJECTIVES: This study assesses the reliability of photographic method with clinical examinations in detecting developmental defects of enamel (DDE) in the anterior primary teeth of infants. METHODS: The study sample was a part of an ongoing longitudinal study to assess risk factors for early childhood caries, and consisted of 138 and 238 infants who had scheduled follow-up visits at approximately 8 and 18-20 months corrected age, respectively. The modified DDE Index was used to record enamel defects (opacity, hypoplasia, and all types of defects) on anterior primary teeth by trained dentist examiners. Photographs of the teeth were taken using a digital camera. Statistical analysis included Cohen's Kappa for reliability, and McNemar test and paired t-test for comparison between photographic and clinical examinations. RESULTS: The level of agreement between clinical and photographic methods was fair to moderate with Kappa values ranging from 0.252 to 0.514. The photographic examination detected significantly more DDE than the clinical examination regardless of age group and type of DDE. The intra- and inter-examiner reliability of the photographic method was excellent with Kappa values ranging from 0.638 to 0.927. CONCLUSIONS: Within the limitation of this study, the photographic method can be a sound approach for verifying the diagnosis of DDE.

HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons.

Even though the disruption of axonal transport is an important pathophysiological factor in neurodegenerative diseases including Alzheimer's disease (AD), the relationship between disruption of axonal transport and pathogenesis of AD is poorly understood. Considering that α-tubulin acetylation is an important factor in axonal transport and that Aß impairs mitochondrial axonal transport, we manipulated the level of α-tubulin acetylation in hippocampal neurons with Aß cultured in a microfluidic system and examined its effect on mitochondrial axonal transport. We found that inhibiting histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, significantly restored the velocity and motility of the mitochondria in both anterograde and retrograde axonal transports, which would be otherwise compromised by Aß. The inhibition of HDAC6 also recovered the length of the mitochondria that had been shortened by Aß to a normal level. These results suggest that the inhibition of HDAC6 significantly rescues hippocampal neurons from Aß-induced impairment of mitochondrial axonal transport as well as mitochondrial length. The results presented in this paper identify HDAC6 as an important regulator of mitochondrial transport as well as elongation and, thus, a potential target whose pharmacological inhibition contributes to improving mitochondrial dynamics in Aß treated neurons.