Influence of smoking on gingival crevicular fluid cytokines in severe chronic periodontitis

The aim of this study was to compare the expression of 22 chemokines and cytokines in gingival crevicular fluid (GCF) from smokers and non-smokers with periodontitis and periodontally healthy control subjects

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors

A Qualitative Exploration of Seriously Ill Patients’ Experiences of Goals of Care Discussions in Australian Hospital Settings

© 2020, Society of General Internal Medicine. Background: Goals of care (GOC) is a communication and decision-making process that occurs between a clinician and a patient (or surrogate decision-maker) during an episode of care to facilitate a plan of care that is consistent with the patient’s preferences and values. Little is known about patients’ experiences of these discussions. Objective: This study explored patients’ perspectives of the GOC discussion in the hospital setting. Design: An explorative qualitative design was used within a social constructionist framework. Participants: Adult patients were recruited from six Australian hospitals across two states. Eligible patients had had a GOC discussion and they were identified by the senior nurse or their doctor for informed consent and interview. Approach: Semi-structured individual or dyadic interviews (with the carer/family member present) were conducted at the bedside or at the patient’s home (for recently discharged patients). Interviews were audio-recorded and transcribed verbatim. Data were analysed for themes. Key Results: Thirty-eight patient interviews were completed. The key themes identified were (1) values and expectations, and (2) communication (sub-themes: (i) facilitators of the conversation, (ii) barriers to the conversation, and (iii) influence of the environment). Most patients viewed the conversation as necessary and valued having their preferences heard. Effective communication strategies and a safe, private setting were facilitators of the GOC discussion. Deficits in any of these key elements functioned as a barrier to the process. Conclusions: Effective communication, and patients’ values and expectations set the stage for goals of care discussions; however, the environment plays a significant role. Communication skills training and education designed to equip clinicians to negotiate GOC interactions effectively are essential. These interventions must also be accompanied by systemic changes including building a culture supportive of GOC, clear policies and guidelines, and champions who facilitate uptake of GOC discussions

ApoE isoform does not influence skeletal muscle regeneration in adult mice

Introduction: Apolipoprotein E (ApoE) has been shown to be necessary for proper skeletal muscle regeneration. Consistent with this finding, single-cell RNA-sequencing analyses of skeletal muscle stem cells (MuSCs) revealed that Apoe is a top marker of quiescent MuSCs that is downregulated upon activation. The purpose of this study was to determine if muscle regeneration is altered in mice which harbor one of the three common human ApoE isoforms, referred to as ApoE2, E3 and E4.Methods: Histomorphometric analyses were employed to assess muscle regeneration in ApoE2, E3, and E4 mice after 14 days of recovery from barium chloride-induced muscle damage in vivo, and primary MuSCs were isolated to assess proliferation and differentiation of ApoE2, E3, and E4 MuSCs in vitro.Results: There was no difference in the basal skeletal muscle phenotype of ApoE isoforms as evaluated by section area, myofiber cross-sectional area (CSA), and myonuclear and MuSC abundance per fiber. Although there were no differences in fiber-type frequency in the soleus, Type IIa relative frequency was significantly lower in plantaris muscles of ApoE4 mice compared to ApoE3. Moreover, ApoE isoform did not influence muscle regeneration as assessed by fiber frequency, fiber CSA, and myonuclear and MuSC abundance. Finally, there were no differences in the proliferative capacity or myogenic differentiation potential of MuSCs between any ApoE isoform.Discussion: Collectively, these data indicate nominal effects of ApoE isoform on the ability of skeletal muscle to regenerate following injury or the in vitro MuSC phenotype

Quantitation of SPLUNC1 in saliva with an xMAP particle-based antibody capture and detection immunoassay

The short palate lung and nasal epithelial clone 1 (SPLUNC1) protein may be differentially expressed in oral infections, oral inflammatory disorders, or oral malignancies and may be involved in innate immune responses in the oral cavity. However, the actual concentration of SPLUNC1 in saliva has not previously been determined. In this study, we determined the concentrations of SPLUNC1 in saliva using a particle-based antibody capture and detection immunoassay. A commercial goat anti-rhSPLUNC1 polyclonal antibody (AF1897) was linked to fluorescent polystyrene microspheres and used as the capture antibody. A commercial mouse IgG2b anti-rhSPLUNC1 monoclonal antibody (MAB1897) was biotinylated and used as the detection antibody. Western blot and 2-dimensional fluorescence difference gel electrophoresis (2-D DIGE) analysis of immunoprecipitated rhSPLUNC1 and SPLUNC1 from saliva were used to show that the capture AF1897 and detection MAB1897 antibodies both recognized SPLUNC1. Protein concentrations in saliva from 20 subjects ranged from 0.9 to 23.9 mg/ml; SPLUNC1 concentrations ranged from 34.7 ng/ml to 13.8 μg/ml; and SPLUNC concentrations normalized per mg of total salivary protein ranged from 4.7 ng/ml to 5.3 μg/ml. These results show that SPLUNC1 is detected in saliva in a variety of concentrations. This immunoassay may prove to be useful in determining the concentration of SPLUNC1 in saliva for assessing its role in the pathogenesis of oral infections, oral inflammatory disorders, or oral malignancies

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Treatment of Periodontitis by Local Administration of Minocycline Microspheres: A Controlled Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141491/1/jper1535.pd

Using mobile health technology to assess childhood autism in low-resource community settings in India: an innovation to address the detection gap

A diagnosis of autism typically depends on clinical assessments by highly-trained professionals. This high resource demand poses a challenge in low-resource settings. Digital assessment of neurodevelopmental symptoms by non-specialists provides a potential avenue to address this challenge. In this study, we provide the proof of principle for such a digital assessment, with a cross-sectional case control field study using mixed methods. We developed and tested an app, START, that can assess autism phenotypic domains (social, sensory, motor) through child performance and parent reports. N=131 children (2-7 years old; 48 autistic, 43 intellectually disabled, and 40 non-autistic typically developing) from low-resource settings in India were assessed using START in home settings by non-specialist health workers. The two groups of children with neurodevelopmental disorders manifested lower social preference, higher sensory sensitivity, and lower fine-motor accuracy compared to their typically developing counterparts. Machine-learning analysis combining all START-derived measures demonstrated 78% classification accuracy for the three groups. Qualitative analysis of the interviews with health workers and families of the participants demonstrated high acceptability and feasibility of the app. These results provide feasibility, acceptability, and proof of principle for START, and demonstrate the potential of a scalable, mobile tool for assessing neurodevelopmental conditions in low-resource settings