Arthritis Rheumatol. 2020 Sep 17;:
Authors: Kazmers NH, Meeks HD, Novak KA, Yu Z, Fulde GL, Thomas JL, Barker T, Jurynec MJ
Abstract
OBJECTIVES: Erosive hand osteoarthritis (EOA) is a severe and rapidly progressing subset of hand osteoarthritis. Its etiology remains largely unknown, which has hindered development of successful treatments. Our goals were to test the hypothesis that EOA would demonstrate familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with EOA.
METHODS: Patients diagnosed with EOA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of EOA as defined by a Familial Standardized Incidence Ratio (FSIR) of ≥ 2.0. The magnitude of familial risk of EOA in related individuals was calculated using Cox regression models. Association of potential EOA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models.
RESULTS: We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of EOA (FSIR ≥ 2.0). The relative risk of developing EOA was significantly elevated in first-degree relatives. There was a significant association with the diagnosis of EOA and age, sex, diabetes, and obesity.
CONCLUSIONS: Familial clustering of EOA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for EOA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to EOA onset and progression.
PMID: 32940959 [PubMed - as supplied by publisher]
J Appl Physiol (1985). 2020 Sep 17;:
Authors: Ratchford SM, Clifton HL, La Salle DT, Broxterman RM, Lee JF, Ryan JJ, Hopkins PN, Wright JB, Trinity JD, Richardson RS, Wray DW
Abstract
While the contribution of non-cardiac complications to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) have been increasingly recognized, disease-related changes in peripheral vascular control remain poorly understood. We utilized small muscle mass handgrip exercise to concomitantly evaluate exercising muscle blood flow and conduit vessel endothelium-dependent vasodilation in individuals with HFpEF (n = 25) compared to hypertensive controls (HTN) (n = 25). Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), brachial artery blood velocity, and brachial artery diameter were assessed during progressive intermittent handgrip (HG) exercise (15-30-45% MVC). Forearm blood flow (FBF) and vascular conductance (FVC) were determined to quantify the peripheral hemodynamic response to HG exercise, and changes in brachial artery diameter were evaluated to assess endothelium-dependent vasodilation. HR, SV, and CO were not different between groups across exercise intensities. However, although FBF was not different between groups at the lowest exercise intensity, FBF was significantly lower (20-40%), in individuals with HFpEF at the two higher exercise intensities (30% MVC: 229±8 vs. 274±23 ml/min; 45% MVC: 283±17 vs. 399±34 ml/min, HFpEF vs. HTN). FVC was not different between groups at 15 and 30% MVC, but was ≈20% lower in HFpEF at the highest exercise intensity. Brachial artery diameter increased across exercise intensities in both HFpEF and HTN, with no difference between groups. These findings demonstrate an attenuation in muscle blood flow during exercise in HFpEF in the absence of disease-related changes in central hemodynamics or endothelial function.
PMID: 32940557 [PubMed - as supplied by publisher]
J Nutr. 2020 Sep 16;:
Authors: Ilozumba MN, Cheng TD, Neuhouser ML, Miller JW, Beresford SAA, Duggan DJ, Toriola AT, Song X, Zheng Y, Bailey LB, Shadyab AH, Liu S, Malysheva O, Caudill MA, Ulrich CM
Abstract
BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites.
OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites.
METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined.
RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration.
CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.
PMID: 32939549 [PubMed - as supplied by publisher]
Mol Pharmacol. 2020 Sep 16;:
Authors: Nguyen ND, Memon TA, Burrell KL, Almestica-Roberts M, Rapp E, Sun L, Scott AF, Deering-Rice C, Rower JE, Reilly CA
Abstract
This study investigated the roles of Transient Receptor Potential Ankyrin-1 (TRPA1) and TRP Vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) and cytotoxicity in human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) and chemical agonists of each channel. Functions of TRPA1 and TRPV3 in pulmonary epithelial cells remain largely undefined. This study shows that TRPA1 activity localizes to the plasma membrane and ER of cells, whereas TRPV3 resides primarily in the ER. Additionally, treatment of cells using moderately cytotoxic concentrations of pine WSPM, carvacrol, and other TRPA1 agonists, caused ERS as a function of both TRPA1 and TRPV3 activities. Specifically, ERS and cytotoxicity were attenuated by TRPA1 inhibition, while inhibiting TRPV3 exacerbated ERS and cytotoxicity. Interestingly, following treatment with pine WSPM, TRPA1 transcription was suppressed, while TRPV3 was increased. TRPV3 overexpression in HBECs conferred resistance to ERS and an attenuation of ERS-associated cell cycle arrest caused by WSPM and multiple prototypical ERS-inducing agents. Alternatively, shRNA-mediated knockdown of TRPV3, like the TRPV3 antagonist, exacerbated ERS. This study reveals previously undocumented roles for TRPA1 in promoting pathological ERS and cytotoxicity elicited by pneumotoxic WSPM and TRPA1 agonists, and a unique role for TRPV3 in fettering pathological facets of the integrated ERS response. Significance Statement These findings provide new insights into how WSPM and other TRPA1 and TRPV3 agonists can affect HBECs, and highlight novel physiological and pathophysiological roles for TRPA1 and TRPV3 in these cells.
PMID: 32938721 [PubMed - as supplied by publisher]
Infect Control Hosp Epidemiol. 2020 Sep 17;:1-7
Authors: Jones TW, Fino N, Olson J, Hersh AL
Abstract
BACKGROUND AND OBJECTIVES: Antibiotic allergy labels are common and are frequently inaccurate. Previous studies among adults demonstrate that β-lactam allergy labels may lead to adverse outcomes, including prescription of broader-spectrum antibiotics, increased costs, and increased lengths of stay, among others. However, data among pediatric patients are lacking, especially in the United States. In this study, we sought to determine the impact of β-lactam allergy labels in hospitalized children with regards to clinical and economic outcomes.
METHOD: This retrospective cohort study included pediatric patients 30 days to 17 years old, hospitalized at Intermountain Healthcare facilities from 2007 to 2017, who received ≥1 dose of an antibiotic during their admission. Patients with β-lactam allergies were matched to nonallergic patients based on age, sex, clinical service line, admission date, academic children's hospital or other hospital admission, and the presence of chronic, comorbid conditions. Outcomes included receipt of broader-spectrum antibiotics, clinical outcomes including length of stay and readmission, and antibiotic and hospitalization costs.
RESULTS: In total, 38,906 patients were identified. The prevalence of antibiotic allergy increased from 0.9% among those < 1 year peaked at 10.6% by age 17. Patients with β-lactam allergy received broader-spectrum antibiotics and experienced higher antibiotic costs than nonallergic controls. However, there were no differences in the length of stay, readmission rates, or total number of days of antibiotics between allergic and nonallergic patients.
CONCLUSIONS: Hospitalized pediatric patients with β-lactam allergy labels receive broader-spectrum antibiotics and experience increased antibiotic costs. This represents an important opportunity for allergy delabeling and antibiotic stewardship.
PMID: 32938517 [PubMed - as supplied by publisher]
Clin Exp Rheumatol. 2020 May-Jun;38 Suppl 125(3):132-136
Authors: Radic M, Snow M, Frech TM, Saketkoo LA, Cutolo M, Smith V
Abstract
OBJECTIVES: Nailfold videocapillaroscopy (NVC) is the current gold standard for detection and quantification of capillary abnormalities in Raynaud's phenomenon (RP). The objective of this study is to evaluate the role of dermatoscopy as a further screening tool in RP.
METHODS: Nailfold capillaries of RP patients were examined by a hand-held non-contact polarised dermatoscope connected to the digital camera (D1) and connected to an iPad (D2). Both dermatoscopic images were marked with an arrowhead. NVC examination was evaluated at the arrowhead. Single blinded reader performed all examinations. NVC was graded as per standard of European League against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases. Consensus evaluation of dermatoscopy characteristics/grade was determined and each dermatoscopic image was given a final impression of 'normal', 'non-specific' or 'scleroderma' pattern. The final interpretation by both techniques was compared after completion of the blinded reading.
RESULTS: Classification of 100 consecutive dermatoscopic images resulted in 37 (wide view) 'non-interpretable', 2 'normal', 48 'non-specific' and 13 'scleroderma' pattern with D1; 23 'non-interpretable', 4 'normal', 52 'non-specific' and 21 'scleroderma' pattern by the experts with D2; 0 non-interpretable, 4 normal, 13 non-specific and 83 'scleroderma' pattern with NVC.
CONCLUSIONS: Overall, 50% of dermatoscopic images were classified as non-specific and 30% were classified as non-interpretable in RP patients. However, all images classified by dermatoscopy as "normal" or as overt "scleroderma" pattern were confirmed by concomitant NVC analysis. These findings demonstrate tenuous promise for dermatoscopy as a tool for the initial screening of nailfold capillaries in RP. Further regular work up with NVC is needed to further clarify non-interpretable and non-specific findings possibly related to non-scleroderma patterns.
PMID: 32865167 [PubMed - indexed for MEDLINE]
Curr Opin Hematol. 2019 09;26(5):336-342
Authors: Montenont E, Rondina MT, Campbell RA
Abstract
PURPOSE OF REVIEW: Platelets are specialized effector cells that rapidly respond to sites of vascular injury. However, emerging data demonstrate that platelets possess diverse functions that also mediate inflammatory responses and neurological diseases. These functions are relevant to disease processes prevalent among older adults and likely influence susceptibility to thrombotic and inflammatory disorders.
RECENT FINDINGS: Platelet counts decrease in aged individuals whereas platelet reactivity increases. The platelet transcriptome is altered in aged individuals resulting in altered platelet function and exaggerated inflammation. Platelet signaling to monocytes in aging results in significantly more cytokines because of increased platelet-derived granzyme A. Platelet activation in aging appears to be driven, in part, because of increased reactive oxygen species and activation of the mammalian target of rapamycin pathway. Increased platelet hyperactivity in diseases is associated with aging, such cardiovascular disease and sepsis, exaggerate inflammation and thrombosis. Noncanonical functions of platelets influence the development of neurological diseases including Alzheimer's disease.
SUMMARY: Although there have been advances dissecting the molecular mechanisms regarding aging-related changes in platelets, many knowledge gaps still remain. Studies filling these gaps are likely to identify new mechanisms driving aging-related changes in platelet gene expression and function, and contributing to injurious thrombo-inflammation in older adults.
PMID: 31348047 [PubMed - indexed for MEDLINE]
J Child Neurol. 2019 03;34(3):148-152
Authors: Aaen G, Waltz M, Vargas W, Makhani N, Ness J, Harris Y, Casper TC, Benson L, Candee M, Chitnis T, Gorman M, Graves J, Greenberg B, Lotze T, Mar S, Tillema JM, Rensel M, Rodriguez M, Rose J, Rubin J, Schreiner T, Waldman A, Weinstock-Guttman B, Belman A, Waubant E, Krupp L
Abstract
Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan (P = .002), reading assistance (P = .0003), and math assistance (P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.
PMID: 30556452 [PubMed - indexed for MEDLINE]
