A class of anti-inflammatory lipids decrease with aging in the central nervous system.

Lipids contribute to the structure, development, and function of healthy brains. Dysregulated lipid metabolism is linked to aging and diseased brains. However, our understanding of lipid metabolism in aging brains remains limited. Here we examined the brain lipidome of mice across their lifespan using untargeted lipidomics. Co-expression network analysis highlighted a progressive decrease in 3-sulfogalactosyl diacylglycerols (SGDGs) and SGDG pathway members, including the potential degradation products lyso-SGDGs. SGDGs show an age-related decline specifically in the central nervous system and are associated with myelination. We also found that an SGDG dramatically suppresses LPS-induced gene expression and release of pro-inflammatory cytokines from macrophages and microglia by acting on the NF-κB pathway. The detection of SGDGs in human and macaque brains establishes their evolutionary conservation. This work enhances interest in SGDGs regarding their roles in aging and inflammatory diseases and highlights the complexity of the brain lipidome and potential biological functions in aging.

Elevated White Blood Cell Count Resultant Atherogenesis is Associated With Panoramic-Imaged Carotid Plaque.

PURPOSE: Atherosclerotic plaques develop as a result of a low-grade, chronic, systemic inflammatory response to the injury of endothelial cells arising from lipid deposition within the intima. Increased white blood cell count (WBCC) is both a validated "biologic marker" of the extent of this inflammatory process and a key participant in the development of subsequent atherosclerotic ischemic heart disease manifesting as myocardial infarction. We sought to determine if calcified carotid artery plaque (CCAP) on a panoramic image (PI), also a validated risk indicator of future myocardial infarction, is associated with increased WBCC. PATIENTS AND METHODS: We retrospectively evaluated the PI and medical records of White male military veterans aged 55 years and older treated by a VA dental service. Established were 2 cohorts of patients, 50 having plaques (CCAP+) and 50 without plaques (CCAP-). Predictor variable was CCAP+; outcome variable was WBCC. Bootstrapping analysis determined the differences in mean WBCCs between groups. Statistical significance set at ≤ 0.05. RESULTS: The study group, (mean age 74; range 59 to 91 years) demonstrated a mean WBCC of 8,062 per mm3. The control group, (mean age 72 range; 57 to 94) evidenced a mean WBCC of 7,058 per mm3. Bootstrapping analysis of WBCC values demonstrated a significant (P = .012) difference (95% confidence interval of difference of mean, -806, 742; observed effect size, 1004) between groups. CONCLUSIONS: The presence of CCAP demonstrated on PIs of older Caucasian men is associated with elevated WBCC. Concomitant presence of CCAP on PI and increased WBCC (≥7,800 per mm3) amplifies need for medical consultation before intravenous anesthesia and maxillofacial surgical procedures.

Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids. Here we identify the linoleic acid ester of 13-hydroxy linoleic acid (13-LAHLA) as an anti-inflammatory lipid. An oat oil fraction and FAHFA-enriched extract from this fraction showed anti-inflammatory activity in a lipopolysaccharide-induced cytokine secretion assay. Structural studies identified three LAHLA isomers (15-, 13-, and 9-LAHLA) as being the most abundant FAHFAs in the oat oil fraction. Of these LAHLAs, 13-LAHLA is the most abundant LAHLA isomer in human serum after ingestion of liposomes made of fractionated oat oil, and it is also the most abundant endogenous LAHLA in mouse and human adipose tissue. As a result, we chemically synthesized 13-LAHLA for biological assays. 13-LAHLA suppresses lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells.

Severe Obstructive Sleep Apnea With Imaged Carotid Plaque Is Significantly Associated With Systemic Inflammation.

PURPOSE: Persons with obstructive sleep apnea (OSA) are at heightened risk of myocardial infarction (MI) and stroke caused by adiposity and intermittent hypoxia, which provoke proinflammatory cytokines to induce systemic and vascular inflammation, resulting in endothelial dysfunction and development of atherosclerotic plaque. This study compared levels of systemic inflammation, as indexed by the neutrophil-to-lymphocyte ratio (NLR), between groups of patients with severe OSA with and without carotid artery calcified plaque (CACP+ and CACP-, respectively) on their panoramic image (PI). MATERIALS AND METHODS: This study had a retrospective cross-sectional study design. Medical records and PIs of men with severe OSA treated by the dental service (January 1, 2017 to December 31, 2017) were reviewed. The predictor variable was the presence or absence of CACP on PIs and the outcome variable was NLR. The t test was used to analyze differences in mean NLRs between groups. Atherogenic risk factors (age, body mass index, hypertension, and diabetes) were assessed for independence by descriptive and logistic regression analyses. Significance set at .05 for all tests. RESULTS: The study group (n = 39) of patients with CACP+ (mean age, 63 ± 7.4 yr) showed a mean NLR of 3.09 ± 1.42. The control group (n = 46) of patients with CACP- (mean age, 62 ± 6.8 yr) showed a mean NLR of 2.10 ± 0.58. The difference between groups was significant (P < .001). Logistic regression for NLR and CACP failed to show meaningful correlations with covariates. CONCLUSION: Older men with severe OSA and carotid atheromas on PIs show substantially greater systemic inflammation measured by NLRs. The combination of severe OSA, atheroma formation, and markedly increased NLR suggests a higher risk of MI and stroke and greater need for cardiovascular and cerebrovascular evaluation.

Severity of Obstructive Sleep Apnea Is Positively Associated With the Presence of Carotid Artery Atheromas.

PURPOSE: Hypoxemia and hypertension caused by obstructive sleep apnea (OSA) often result in atherosclerosis of the carotid and coronary vessels and heightened risk of stroke and myocardial infarction (MI). Therefore, this study investigated whether severity of OSA, based on the apnea-hypopnea index (AHI), is associated with the presence of calcified carotid artery (atherosclerotic) plaque (CCAP) seen on panoramic images (PIs). MATERIALS AND METHODS: Using a cross-sectional study design, the electronic medical records and PIs of all male patients referred from the sleep medicine service to the dental service from 2010 through 2016 were reviewed. The predictor variable was the patients' OSA intensity level as defined by the American Academy of Sleep Medicine based on the AHI score. The outcome variable was the presence of CCAP on the PI. Other variables of interest, that is, demographic and atherogenic risk factors (age, body mass index, diabetes, hypertension, and hyperlipidemia), were included in a multivariate analysis to assess the association of OSA with CCAP. RESULTS: The study sample consisted of 108 men (mean age, 54.7 ± 13.5 yr). Approximately one third (n = 33; 30.6%) presented with CCAP and this group was significantly older with greater odds of co-diagnosis of diabetes (P < .05). Patients with more "severe" OSA showed significantly greater odds of having CCAP on their PIs compared with those with "milder" OSA (odds ratio = 1.035; 95% confidence interval, 1.008-1.062; P = .010) when adjusted for confounders. CONCLUSION: There is a significant association between severity of OSA and the presence of CCAP visible on PI. These atherosclerotic plaques are "risk factors" for stroke and "risk indicators" for future MI; therefore, clinicians providing corrective airway surgery for these patients and noting concomitant CCAP on PI should refer these patients for a thorough cerebrovascular and cardiovascular workup.

Positive Association Between Neutrophil-Lymphocyte Ratio and Presence of Panoramically Imaged Carotid Atheromas Among Men.

PURPOSE: Heightened levels of systemic inflammation documented by increased neutrophil-to-lymphocyte ratios (NLRs) characterize a robust atherosclerosis processes evidenced by carotid and coronary artery plaques at ultrasound and angiography with associated strokes and myocardial infarctions (MIs). Therefore, this study investigated whether calcified carotid artery plaques (CCAPs) on panoramic images (PIs), known to herald future stroke and MI, are associated with increased NLRs. MATERIALS AND METHODS: Using a cross-sectional study design, electronic medical records and PIs of non-Hispanic white men at least 55 years old who were treated by the dental service (January 1, 2017 to December 31, 2017) were retrieved. Two groups of patients (n = 50 per group) with plaque (CCAP+) and without plaque (CCAP-) were constituted. The predictor variable was CCAP+ and the outcome variable was the NLR. A t test analyzed the differences in mean NLRs between groups. Other variables of interest, that is, atherogenic risk factors (hypertension, hyperlipidemia, and diabetes mellitus), were included in a logistic regression analysis to assess their influence on the association of CCAP with the NLR. Significance was set at .05 for all tests. RESULTS: The study group of 50 men with CCAP+ (mean age, 71.7 ± 7.47 yr) evidenced a mean NLR of 3.07 ± 1.43. The control group of 50 men with CCAP- (mean age, 69.8 ± 9.29 yr) evidenced a mean NLR of 2.13 ± 0.68. A t test analysis comparison showed a significant (P = .00007) difference (95% confidence interval, 0.49-1.39). Logistic regression failed to show any relevant relation of the NLR with the covariate and other variables of interest. CONCLUSION: There is a strong association between CCAP+ in older non-Hispanic white men and extent of systemic inflammation as evidenced by increased NLRs. These plaques are "risk factors or indicators" for future stroke and MI. Therefore, maxillofacial surgeons providing care for patients with CCAP+ should consider referring them for a comprehensive cerebrovascular and cardiovascular workup.

Severe Sleep Apnea Associated With Increased Systemic Inflammation and Decreased Serum Bilirubin.

PURPOSE: Obstructive sleep apnea hypopnea syndrome (OSAHS) among older men has been associated with increased systemic inflammation, as evidenced by an increased neutrophil/lymphocyte ratio (NLR) and provocation of coronary artery atherosclerosis, potentially resulting in myocardial infarction (MI). The total serum bilirubin levels (TSBLs; formed primarily from senescent red blood cells via the catabolic pathway in the reticuloendothelial system) at the higher end of the normal reference range are anti-inflammatory. However, at the lower end of the physiologic range, they have been associated with increased adverse vascular events. We compared the relationship between NLR and TSBL among subjects with "severe" OSAHS. MATERIALS AND METHODS: We used a retrospective, cross-sectional study design. The electronic medical records of older male subjects (age range, 55 to 74 years) with "severe" OSAHS treated by the dental service (January 1, 2017 to December 31, 2017) were examined. The predictor variable was the NLR, and the outcome variable was the TSBL; both were analyzed using continuous scales. Spearman's rank order correlation analysis explicated the relationship between the NLR and TBSL. Traditional proatherogenic risk factors (ie, age, body mass index, hypertension, hyperlipidemia, diabetes) were evaluated for independence using descriptive and logistic regression analysis. Significance was set at P = .05 for all tests. RESULTS: A total sample size of 47 subjects (mean age, 63.74 ± 4.12 years) was enrolled in the present study. The Spearman rank order correlation analysis determined that the NLR is significantly (P = .038) and inversely related to the TSBL (rs = -0.304). CONCLUSIONS: Older men with "severe" OSAHS demonstrated an inverse relationship between NLR and TSBL. This combination of a heightened severity marker of systemic inflammation (ie, elevated NLR) and an indicator of amplified atherosclerotic activity (ie, diminished TSBL) will identify patients potentially at increased risk of future MI and the need for cardiovascular evaluation.

Faster Protocol for Endogenous Fatty Acid Esters of Hydroxy Fatty Acid (FAHFA) Measurements.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of endogenous lipids with antidiabetic and anti-inflammatory activities. Interest in these lipids is due to their unique biological activites and the observation that insulin-resistant people have lower palmitic acid esters of hydroxystearic acid (PAHSA) levels, suggesting that a FAHFA deficiency may contribute to metabolic disease. Rigorous testing of this hypothesis will require the measurement of many clinical samples; however, current analytical workflows are too slow to enable samples to be analyzed quickly. Here we describe the development of a significantly faster workflow to measure FAHFAs that optimizes the fractionation and chromatography of these lipids. We can measure FAHFAs in 30 min with this new protocol versus 90 min using the older protocol with comparable performance in regioisomer detection and quantitation. We also discovered through this optimization that oleic acid esters of hydroxystearic acids (OAHSAs), another family of FAHFAs, have a much lower background signal than PAHSAs, which makes them easier to measure. Our faster workflow was able to quantify changes in PAHSAs and OAHSAs in mouse tissues and human plasma, highlighting the potential of this protocol for basic and clinical applications.

Males With Rheumatoid Arthritis Often Evidence Carotid Atheromas on Panoramic Imaging: A Risk Indicator of Future Cardiovascular Events.

PURPOSE: Males with rheumatoid arthritis (RA) are at an exceedingly high risk of adverse intraoperative ischemic events, given the role of systemic inflammation in the atherogenic process. We hypothesized that their panoramic images would demonstrate calcified carotid artery atheromas (CCAPs) significantly more often than those from a general population of similarly aged men. PATIENTS AND METHODS: We implemented a retrospective observational study. The sample was composed of male patients older than 55 years of age who had undergone panoramic imaging studies. The predictor variable was the diagnosis of RA confirmed by a positive rheumatoid factor (RF) titer, and the outcome variable was the prevalence rate of CCAPs. The other major study variable was the level of RF among the patients evidencing CCAPs. The prevalence of CCAPs among the patients with RA was then compared with that of a historical general population of similarly aged men. Descriptive and bivariate statistics were computed, and the P value was set at .05. RESULTS: Of the 100 men (mean age 69.89 ± 8.927 years) with RA, 29 (29%; mean age 72.10 ± 7.68 years) had atheromas (CCAP+). Of these 29 men, 25 (86%; mean age 71.88 ± 7.43 years) had a RF titer of ≥41 IU/mL, twice that of normal. A statistically significant (P < .05) association was found between a diagnosis of RA and the presence of an atheroma on the panoramic image compared with the 3% rate found in the historical cohort. CONCLUSIONS: The results of the present study suggest that CCAP, a risk indicator of future adverse cardiovascular events, is frequently seen on panoramic images of male patients with RA and that these individuals routinely manifest high titer levels of RF, a biologic marker of inflammation. Oral and maxillofacial surgeons planning surgery for male patients with RA must be uniquely vigilant for the presence of these lesions.

Prevalence of Panoramically Imaged Carotid Atheromas in Alcoholic Patients With Chronic Pancreatitis and Comorbid Diabetes.

PURPOSE: Men with alcohol-related chronic pancreatitis (ARCP) resulting in type 3c diabetes mellitus (DM) are at a uniquely elevated risk of adverse ischemic events given the role of inflammation in both the underlying disease processes and atherosclerosis. We hypothesized that their panoramic images would show a prevalence of calcified carotid artery atheromas (calcified carotid artery plaques [CCAPs]) significantly more often than a general population of similarly aged men. PATIENTS AND METHODS: We implemented a retrospective observational study. The sample was composed of male patients older than 30 years having panoramic images. The predictor variable was a diagnosis of ARCP-DM, and the outcome variable was the prevalence rate of CCAPs. The prevalence of CCAPs among the patients with ARCP-DM was then compared with that of a historical general population composed of similarly aged men. Descriptive and bivariate statistics were computed, and the P value was set at .05. RESULTS: Of the 32 men (mean age, 61.7 ± 11.2 years) with ARCP-DM, 8 (25%) (mean age, 63.3 ± 4.80 years) had atheromas (CCAPs). There was a statistically significant (P < .05) association between a diagnosis of ARCP-DM and the presence of an atheroma on the panoramic image in comparison with the 3% rate manifested by the historical general-population cohort. The presence or absence of classic atherogenic risk factors within the ARCP-DM cohort failed to distinguish between individuals with and individuals without atheroma formation on their panoramic images. CONCLUSIONS: The results of this study suggest that CCAP, a risk indicator for future adverse cardiovascular events, is frequently seen on the panoramic images of male patients with ARCP-DM. Dentists treating male patients with the disorder must be uniquely vigilant for the presence of these lesions.

Preventive Dental Treatment Workload/Costs to Mitigate Antiresorptive Bone Medication-related Osteonecrosis Risk.

PURPOSE: To determine the extent of dental disease and associated treatment costs designed to mitigate the risk of medication-related osteonecrosis of the jaws (MRONJ) among older, socially disadvantaged veterans prior to physician's administration of antiresorptive medication for osteoporosis or malignant bone disease. MATERIALS AND METHODS: This prospective study based on over seven years (2008-2015) of data describes the type and volume of disease, treatment, work-load measures, and costs using Veterans Affairs databases. RESULTS: One hundred fifty-two outpatients (94% male, mean age 69 ± 12 years) were referred by physicians for clinical/radiographic examination and treatment. Sixteen had a healthy dentition and 17 were completely edentulous with satisfactory prostheses. Three edentulous patients required prosthesis adjustment, 116 dentate individuals required restoration of carious teeth (mean 6.3 ± 5.7) and multiple quadrant (mean 3.1 ± 1.0) scaling/subgingival curettage. In the latter group, 75 required extractions (mean 6.0 teeth, range 1-23). Clinician's (dentist and dental assistant) costs for providing care and preventive education over the 7-year timespan came to almost $132,700. CONCLUSION: Older veterans requiring initiation of antiresorptive bone medication harbor extensive, untreated dental disease requiring immediate treatment. An appropriate physician-to-dentist referral network and provision of oral care and patient education prior to initiation of medication can potentially moderate the risk of jaw osteonecrosis.

Patients Receiving Parenteral Bisphosphonates for Malignant Disease and Having Developed an Atypical Femoral Fracture Are at Risk of Concomitant Osteonecrosis of the Jaw: An Evidence-Based Review.

PURPOSE: The risk of developing concomitant medication-related osteonecrosis of the jaw (MRONJ) in patients who have sustained an atypical femoral fracture (AFF) in association with parental administration of a bisphosphonate osteoclastic inhibitor medication for malignant disease is unclear. Published data were searched to determine the prevalence of these concomitant adverse medication events, if any. MATERIALS AND METHODS: A systematic review of published case series in the PubMed database was undertaken to ascertain the prevalence of patients having a concomitant history of AFF and MRONJ. The data were analyzed to provide prevalence rates of these events from the literature. RESULTS: Two case series were identified that delineated the risk (25 and 33%, respectively) of concomitant development of MRONJ and AFF in recipients of parenteral bisphosphonate medication administered for malignant disease. CONCLUSION: The published data suggest that approximately 30% of patients receiving parenteral bisphosphonates and having sustained an AFF could develop comorbid MRONJ.

Facial Trauma: Delayed Development of a Subluxated Traumatic Cataract as Visualized on a Panoramic Image.

The immediate and long-term consequences of blunt orbital trauma leading to a subluxated lens and its subsequent calcification and opacification are reviewed. The accompanying panoramic image documents the process.

High C-Terminal Cross-Linking Telopeptide Levels Are Associated With a Minimal Risk of Osteonecrosis of the Jaws in Patients Taking Oral Bisphosphonates and Having Exodontia.

PURPOSE: The clinical significance of bone turnover marker C-terminal cross-linking telopeptide (CTX) levels less than 150 pg/mL among recipients of oral bisphosphonate (OBP) medications who develop osteonecrosis of the jaws (MRONJ) after exodontia is unclear. We searched the published data to determine the prevalence of such levels and the association, if any, with development of MRONJ. MATERIALS AND METHODS: A systematic review of published studies in the PubMed database was undertaken to ascertain the prevalence of preoperative, fasting CTX levels less than 150 pg/mL among recipients of OBP scheduled for exodontia and to determine whether such levels are associated with the development of postoperative MRONJ. The data were aggregated and analyzed to provide the sensitivity, specificity, and positive and negative predictive values of the association between low CTX levels and the development of MRONJ. RESULTS: Two studies were chosen for review. The first, with an enrollment of 21 patients, reported that 10 (48%) patients had a preoperative CTX level less than 150 pg/mL and that after exodontia, none developed MRONJ. The second study, with an enrollment of 950 patients, reported that approximately 282 (30%) had a preoperative CTX level less than 150 pg/mL. All the patients with depressed CTX levels were offered a "drug holiday"; however, only 101 accepted the offer. Of the remaining 181 patients, 4 developed MRONJ. The aggregated study data have demonstrated that 30% of patients evidence CTX levels less than 150 pg/mL and that the sensitivity and specificity of these levels in association with the development of MRONJ was 100% and 80.7%, respectively. The positive predictive value was 2.09% and the negative predictive value was 100%. CONCLUSION: The published data suggest that approximately one third of patients exposed to OBP will evidence depressed CTX levels and that only a very small minority (∼2%) will develop postexodontia MRONJ. Prudence would suggest that patients scheduled for exodontia and receiving OBPs should be informed about the strengths and weaknesses of the CTX test and that it should be offered during the consent process.

An Inner Mitochondrial Membrane Microprotein from the SLC35A4 Upstream ORF Regulates Cellular Metabolism.

Upstream open reading frames (uORFs) are cis-acting elements that can dynamically regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing downstream translation under stress conditions. Computational and empirical methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts, making uORFs one of the largest regulatory elements known. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides and small proteins, or microproteins, encoded by uORFs were rarely studied. We hypothesized that a uORF in the SLC35A4 mRNA is producing a functional microprotein (SLC35A4-MP) because of its conserved amino acid sequence. Through a series of biochemical and cellular experiments, we find that the 103-amino acid SLC35A4-MP is a single-pass transmembrane inner mitochondrial membrane (IMM) microprotein. The IMM contains the protein machinery crucial for cellular respiration and ATP generation, and loss of function studies with SLC35A4-MP significantly diminish maximal cellular respiration, indicating a vital role for this microprotein in cellular metabolism. The findings add SLC35A4-MP to the growing list of functional microproteins and, more generally, indicate that uORFs that encode conserved microproteins are an untapped reservoir of functional microproteins.

Prevalence of comorbid obstructive sleep apnea and metabolic syndrome: syndrome Z and maxillofacial surgery implications.

PURPOSE: To determine the prevalence of the recently identified syndrome Z (SZ), which is the co-occurrence of obstructive sleep apnea (OSA; hypoxia, systemic and pulmonary hypertension, nocturnal arrhythmias) and metabolic syndrome (MetS; increased abdominal girth, hypertriglyceridemia, decreased high-density lipoprotein, hypertension, increased fasting glucose), which places the surgical patient at heightened risk of perioperative complications (myocardial infarction, stroke, pneumonia, wound infection). MATERIALS AND METHODS: Electronic medical records of 296 male veterans were assessed for the presence of SZ using the American Academy of Sleep Medicine definition of OSA and a modified Adult Treatment Panel III definition of MetS, where obesity was defined by a body mass index of at least 30 kg/m(2) rather than by waist circumference. RESULTS: SZ was diagnosed in 59% of patients. These individuals commonly exhibited severe OSA and least commonly mild OSA. The more severe the OSA, the more likely (60%) that patients manifested moderate (4 risk markers) or severe (5 risk markers) MetS. Furthermore, with increasing apnea-hypopnea index values, the more severe were the MetS elements. CONCLUSIONS: The results of this study demonstrate the high prevalence rate of MetS in patients with OSA seeking treatment. Given the risk of perioperative complications, it is suggested that all patients scheduled for maxillofacial surgical procedures to treat OSA be evaluated for SZ.