Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the ...dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.
Thioacetamide (100mg/kg IP)-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ) (n = 5-10). Bleomycin (0.25U, SubQ)-treated mice were treated with vehicle or tenofovir (75mg/kg, IP) (n = 5-10). Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.
Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.
These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.
Skin color evaluation contributes to assessment of an individual’s cutaneous phenotype. Skin color changes provide important clues to disease progression or treatment response. Skin color is also a ...predictor of skin cancer risk. Melanin pigment, blood flow, skin thickness, and photoaging contribute to skin color. Melanin, hemoglobin, bilirubin, and carotene are the primary chromophores of skin color. Their concentrations vary depending on the individual’s phenotype, anatomic location, external insults of chemical irritants and UVR, and physiological changes. The evaluation and perception of skin color are often subjective. Objective quantification of skin color can be achieved with colorimetric devices such as tristimulus colorimeters. These devices compute the intensity of light reflected from skin and correlate with pigmentation and erythema. Cutaneous color and color changes can be quantified under color organization systems, such as the CIELAB color space, which is standardized by the Commission Internationale de l’Eclairage (CIE). The CIELAB expresses color’s lightness, red/green intensity, and yellow/blue intensity, as L*, a*, and b* values, respectively. Additionally, skin color’s full spectral characteristics and cutaneous physiology can be measured with spectrophotometers. This article outlines basic principles of the CIELAB color system and how to optimally use colorimetric devices as a skin research tool.
► A substantial proportion of children with autism spectrum disorder have sensory processing atypicalities, including unusual responses to tactile stimuli. ► This study used both parent-report and ...direct-observation measures to evaluate tactile processing and core diagnostic symptoms. ► Increased tactile seeking and hypo-responsive behaviors were associated with more severe social impairment and increased restricted and repetitive behaviors. ► Tactile hyper-responsiveness, or defensiveness, was not found to relate to core social, communication, or behavioral symptoms in this sample. ► Our findings of strong relations between tactile and diagnostic symptoms underscore the need for additional research on sensory processing in ASD.
Autism spectrum disorders (ASD) are often associated with aberrant responses to sensory stimuli, which are thought to contribute to the social, communication, and repetitive behavior deficits that define ASD. However, there are few studies that separate aberrant sensory responses by individual sensory modality to assess modality-specific associations between sensory features and core symptoms. Differences in response to tactile stimuli are prevalent in ASD, and tactile contact early in infancy is a foundation for the development of social and communication skills affected by ASD. We assessed the association between three aberrant patterns of tactile responsiveness (hyper-responsiveness, hypo-responsiveness, sensory seeking) and core symptoms of ASD. Both sensory and core features were measured with converging methods including both parent-report and direct observation. Our results demonstrate that for the tactile modality, sensory hypo-responsiveness correlates strongly with increased social and communication impairments, and to a lesser degree, repetitive behaviors. Sensory seeking was found to correlate strongly with social impairment, nonverbal communication impairment, and repetitive behaviors. Surprisingly, tactile hyper-responsiveness did not significantly correlate with any core features of ASD. This differential association between specific tactile processing patterns and core features provides an important step in defining the significance of sensory symptoms in ASD, and may be useful in the development of sensory-based approaches for early detection and intervention.
While leisure-time physical activity (PA) has been associated with reduced risk of cardiometabolic disease, less is known about the relationship between work-related PA and health. Work-related PA is ...often not a chosen behavior and may be associated with lower socioeconomic status and less control over job-related activities. This study examined whether high work-related PA and leisure-time PA reported by hospital employees were associated with healthier dietary intake and reductions in cardiometabolic risk.
This was a cross-sectional analysis of 602 hospital employees who used workplace cafeterias and completed the baseline visit for a health promotion study in 2016-2018. Participants completed the International Physical Activity Questionnaire and clinical measures of weight, blood pressure, HbA1c, and lipids. Healthy Eating Index (HEI) scores were calculated from two 24-h dietary recalls, and a Healthy Purchasing Score was calculated based on healthfulness of workplace food/beverage purchases. Regression analyses examined Healthy Purchasing Score, HEI, and obesity, hypertension, hyperlipidemia, and diabetes/prediabetes by quartile of work-related PA, leisure-time PA, and sedentary time.
Participants' mean age was 43.6 years (SD = 12.2), 79.4% were female, and 81.1% were white. In total, 30.3% had obesity, 20.6% had hypertension, 26.6% had prediabetes/diabetes, and 32.1% had hyperlipidemia. Median leisure-time PA was 12.0 (IQR: 3.3, 28.0) and median work-related PA was 14.0 (IQR: 0.0, 51.1) MET-hours/week. Higher leisure-time PA was associated with higher workplace Healthy Purchasing Score and HEI (p's < 0.01) and lower prevalence of obesity, diabetes/prediabetes, and hyperlipidemia (p's < 0.05). Work-related PA was not associated with Healthy Purchasing Score, HEI, or cardiometabolic risk factors. Increased sedentary time was associated with lower HEI (p = 0.02) but was not associated with the workplace Healthy Purchasing Score.
Employees with high work-related PA did not have associated reductions in cardiometabolic risk or have healthier dietary intake as did employees reporting high leisure-time PA. Workplace wellness programs should promote leisure-time PA and healthy food choices for all employees, but programs may need to be customized and made more accessible to meet the unique needs of employees who are physically active at work.
This trial was prospectively registered with clinicaltrials.gov (Identifier: NCT02660086) on January 21, 2016. The first participant was enrolled on September 16, 2016.
Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic ...inflammation, remain unknown. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin-1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation.
Staphylococcal scalded skin syndrome causes widespread skin denudation primarily in infants < 1 year old. Selection of empiric therapy is complicated by rising rates of antibiotic resistance in ...community‐acquired staphylococcal infections. Consistent with a previous study, this retrospective review found that SSSS‐associated isolates were more likely to be clindamycin‐resistant and less likely to be methicillin‐resistant compared to overall staphylococcal infections. We favor cephalosporins and penicillinase‐resistant penicillins (eg, oxacillin) for empiric management of SSSS, with consideration of adding MRSA coverage in communities with high MRSA prevalence or failure to improve following several days of treatment.
On the basis of studies that extend back to the early 1900s, regression and stabilization of atherosclerosis in humans has progressed from being a concept to one that is achievable. Successful ...attempts at regression generally applied robust measures to improve plasma lipoprotein profiles. Possible mechanisms responsible for lesion shrinkage include decreased retention of atherogenic apolipoprotein B within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of lesional foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris as well as other components of the plaque. Currently available clinical agents, however, still fail to stop most cardiovascular events. For years, HDL has been considered the 'good cholesterol.' Clinical intervention studies to causally link plasma HDL-C levels to decreased progression or to the regression of atherosclerotic plaques are relatively few because of the lack of therapeutic agents that can selectively and potently increase HDL-C. The negative results of studies that were carried out have led to uncertainty as to the role that HDL plays in atherosclerosis. It is becoming clearer, however, that HDL function rather than quantity is most crucial and, therefore, discovery of agents that enhance the quality of HDL should be the goal.
Abstract The idea that atheroma can regress is no longer a dream. We and others have discovered that decreasing the lipid content can directly lead to macrophage egress and plaque healing. The ...question, however, has remained as to how to translate these findings to the bedside. Taking advantage of imaging modalities such as intravascular ultrasound (IVUS) and near infrared spectroscopy (NIRS), we demonstrated in the YELLOW (Reduction in Yellow Plaque by Intensive Lipid Lowering Therapy) trial that short term treatment of high dose rosuvastatin treatment can lead to a decrease in lipid content in plaques. It is important to note that optical coherence tomography (OCT), a high resolution imaging modality, was not performed during the first study and therefore, only a very limited assessment of the effect of statin therapy on measures of plaque stabilization could be made. The YELLOW II trial is the first to our knowledge to determine whether these data can be extrapolated and how it relates to HDL function, alterations in macrophage gene expression, and plaque morphology. While tremendous progress has been made, our research serves as a reminder that angiography is simply luminography and it is features such as thin cap fibroatheroma and lipid burden, for example, that likely modulate the syndromes seen in clinical practice. Ongoing studies such as ours may provide novel pathways for diagnosis and therapy, with the ultimate goal of reducing the burden of cardiovascular disease.
In the rubber hand illusion, perceived hand ownership can be transferred to a rubber hand after synchronous visual and tactile stimulation. Perceived body ownership and self–other relation are ...foundational for development of self-awareness, imitation, and empathy, which are all affected in autism spectrum disorders (ASD). We examined the rubber hand illusion in children with and without ASD. Children with ASD were initially less susceptible to the illusion than the comparison group, yet showed the effects of the illusion after 6 minutes. Delayed susceptibility to the illusion may result from atypical multisensory temporal integration and/or an unusually strong reliance on proprioception. Children with ASD who displayed less empathy were significantly less likely to experience the illusion than those with more intact ability to express empathy. A better understanding of body representation in ASD may elucidate neural underpinnings of social deficits, thus informing future intervention approaches.
The pathogenesis of Huntington's disease (HD) remains elusive. The identification of increasingly early pathophysiological abnormalities in HD suggests the possibility that impairments of striatal ...medium spiny neuron (MSN) specification and maturation may underlie the etiology of HD. In fact, we demonstrate that HD knock-in (Hdh-Q111) mice exhibited delayed acquisition of early striatal cytoarchitecture with aberrant expression of progressive markers of MSN neurogenesis (Islet1, DARPP-32, mGluR1, and NeuN). Hdh-Q111 striatal progenitors also displayed delayed cell cycle exit between E13.5-15.5 (BrdU birth-dating) and an enhanced fraction of abnormal cycling cells in association with expansion of the pool of intermediate progenitors and over expression of the core pluripotency (PP) factor, Sox2. Clonal analysis further revealed that Hdh-Q111 neural stem cells (NSCs) displayed: impaired lineage restriction, reduced proliferative potential, enhanced late-stage self-renewal, and deregulated MSN subtype specification. Further, our analysis revealed that in addition to Sox2, the core PP factor, Nanog is expressed within the striatal generative and mantle regions, and in Hdh-Q111 embryos the fraction of Nanog-expressing MSN precursors was substantially increased. Moreover, compared to Hdh-Q18 embryos, the Hdh-Q111 striatal anlagen exhibited significantly higher levels of the essential PP cofactor, Stat3. These findings suggest that Sox2 and Nanog may play roles during a selective window of embryonic brain maturation, and alterations of these factors may, in part, be responsible for mediating the aberrant program of Hdh-Q111 striatal MSN specification and maturation. We propose that these HD-associated developmental abnormalities might compromise neuronal homeostasis and subsequently render MSNs more vulnerable to late life stressors.
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