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Yammani RD, Leyva MA, Jennings RN, Haas KM.
J Immunol. 2014 Dec 1;193(11):5434-43.
PMID: 25339671
Reductions in C4 levels may predispose individuals to infection with encapsulated bacteria as well as autoimmunity. In this study, we examined the role C4 has in protection against Streptococcus pneumoniae-induced autoimmunity. Mild respiratory infection with serotype 19F pneumococci selectively induced systemic anti-dsDNA IgA production in naive C4(-/-) mice, but not in C3(-/-) or wild-type mice. Systemic challenge with virulent serotype 3 pneumococci also induced anti-dsDNA IgA production in immune C4(-/-) mice. Remarkably, pneumococcal polysaccharide (PPS) vaccination alone induced C4(-/-) mice to produce increased anti-dsDNA IgA levels that were maintained in some mice for months. These effects were most pronounced in female C4(-/-) mice. Importantly, immunization-induced increases in anti-dsDNA IgA levels were strongly associated with increased IgA deposition in kidneys. Cross-reactivity between pneumococcal Ags and dsDNA played a partial role in the induction of anti-dsDNA IgA, but a major role for PPS-associated TLR2 agonists was also revealed. Administration of the TLR2/4 antagonist, OxPAPC, at the time of PPS immunization completely blocked the production of anti-dsDNA IgA in C4(-/-) mice without suppressing PPS-specific Ab production. The TLR2 agonist, Pam3CSK4, similarly induced anti-dsDNA IgA production in C4(-/-) mice, which OxPAPC also prevented. LPS, a TLR4 agonist, had no effect. Pam3CSK4, but not LPS, also induced dsDNA-specific IgA production by C4(-/-) splenic IgA(+) B cells in vitro, indicating that TLR2 agonists can stimulate autoantibody production via B cell-intrinsic mechanisms. Collectively, our results show an important role for C4 in suppressing autoantibody production elicited by cross-reactive Ags and TLR2 agonists associated with S. pneumoniae.
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Goeritzer M, Schlager S, Radovic B, Madreiter CT, Rainer S, Thomas G, Lord CC, Sacks J, Brown AL, Vujic N, Obrowsky S, Sachdev V, Kolb D, Chandak PG, Graier WF, Sattler W, Brown JM, Kratky D.
J Lipid Res. 2014 Dec ;55(12):2562-75.
PMID: 25316883
Cellular TG stores are efficiently hydrolyzed by adipose TG lipase (ATGL). Its coactivator comparative gene identification-58 (CGI-58) strongly increases ATGL-mediated TG catabolism in cell culture experiments. To investigate the consequences of CGI-58 deficiency in murine macrophages, we generated mice with a targeted deletion of CGI-58 in myeloid cells (macCGI-58(-/-) mice). CGI-58(-/-) macrophages accumulate intracellular TG-rich lipid droplets and have decreased phagocytic capacity, comparable to ATGL(-/-) macrophages. In contrast to ATGL(-/-) macrophages, however, CGI-58(-/-) macrophages have intact mitochondria and show no indications of mitochondrial apoptosis and endoplasmic reticulum stress, suggesting that TG accumulation per se lacks a significant role in processes leading to mitochondrial dysfunction. Another notable difference is the fact that CGI-58(-/-) macrophages adopt an M1-like phenotype in vitro. Finally, we investigated atherosclerosis susceptibility in macCGI-58/ApoE-double KO (DKO) animals. In response to high-fat/high-cholesterol diet feeding, DKO animals showed comparable plaque formation as observed in ApoE(-/-) mice. In agreement, antisense oligonucleotide-mediated knockdown of CGI-58 in LDL receptor(-/-) mice did not alter atherosclerosis burden in the aortic root. These results suggest that macrophage function and atherosclerosis susceptibility differ fundamentally in these two animal models with disturbed TG catabolism, showing a more severe phenotype by ATGL deficiency.
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Wright LD, McKeon-Fischer KD, Cui Z, Nair LS, Freeman JW.
J Tissue Eng Regen Med. 2014 Dec ;8(12):946-54.
PMID: 23109502
Osteoarthritis (OA) is the most prevalent musculoskeletal disease in humans, causing pain, loss of joint motility and function, and severely reducing the standard of living of patients. Cartilage tissue engineering attempts to repair the damaged tissue of individuals suffering from OA by providing mechanical support to the joint as new tissue regenerates. The aim of this study was to create composite three dimensional scaffolds comprised of electrospun poly(D,L-lactide)/poly(L-lactide) (PDLA/PLLA) or poly(D,L-lactide)/polycaprolactone (PDLA/PCL) with salt leached pores and an embedded chitosan hydrogel to determine the potential of these scaffolds for cartilage tissue engineering. PDLA/PLLA-hydrogel scaffolds displayed the largest compressive moduli followed by PDLA/PCL-hydrogel scaffolds. Dynamic mechanical tests showed that the PDLA/PLLA scaffolds had no appreciable recovery while PDLA/PCL scaffolds did exhibit some recovery. Primary canine chondrocytes produced both collagen type II and proteoglycans (primary components of extracellular matrix in cartilage) while being cultured on scaffolds composed of electrospun PDLA/PCL. As a result, a composite electrospun embedded hydrogel scaffold shows promise for treating individuals suffering from OA.
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Blumenfeld YJ, Momirova V, Rouse DJ, Caritis SN, Sciscione A, Peaceman AM, Reddy UM, Varner MW, Malone FD, Iams JD, Mercer BM, Thorp JM, Sorokin Y, Carpenter MW, Lo J, Ramin SM, Harper M, .
J Ultrasound Med. 2014 Dec ;33(12):2187-92.
PMID: 25425377
To evaluate the accuracy of sonographic classification of chorionicity in a large cohort of twins and investigate which factors may be associated with sonographic accuracy.
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Christiaanse E, Jager T, Lenchik L, Buls N, Van Hedent E, De Maeseneer M.
J Ultrasound Med. 2014 Dec ;33(12):2099-103.
PMID: 25425365
An important sign of proximal intersection syndrome is thickening of the tendons at the area where the first extensor compartment tendons cross over the second compartment. Normal values for the thickness of the tendons have not been reported. Our purpose was to measure the thickness of the tendons with sonography at the level of the intersection in healthy volunteers and assess differences between men and women, dominant and nondominant sides, and different tendons.
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Reboussin BA, Green KM, Milam AJ, Furr-Holden CD, Ialongo NS.
J Urban Health. 2014 Dec ;91(6):1189-201.
PMID: 25323775
African American male high school students have the highest rates of marijuana use among all racial, ethnic, and gender groups, yet there is limited research examining contextual factors salient to the African American community. The purpose of this study was to examine how neighborhood environment measured in 8th grade is related to longitudinal transitions in marijuana use during high school (9th to 12th grades) in a sample of urban African Americans. Four hundred and fifty-two African American children were interviewed annually beginning in 1st grade as part of a longitudinal field study in Baltimore city. Latent transition analysis indicated early in high school posed the greatest risk for initiation and progression of marijuana use. Community violence exposure was associated with an increased likelihood of transitioning from no marijuana use to infrequent use (adjusted odds ratios (AOR) = 2.40, p < 0.001). Higher perceived neighborhood disorder (AOR = 3.20, p = 0.004), drug activity and sales in the neighborhood (AOR = 2.28, p = 0.028), and community violence exposure (AOR = 4.54, p < 0.001) were associated with an increased risk of transitioning from no use to frequent/problematic marijuana use. There was evidence for partial mediation of these associations by perceptions of harm and depressed mood. Drug activity and sales was associated with progression from infrequent to frequent and problematic use (AOR = 2.87, p = 0.029). African American youth living in urban environments with exposure to drug activity, violence, and neighborhood disorder are at increased risk for both initiation and progression to more frequent and problematic marijuana use during high school. These findings highlight the need to develop interventions for African American youth that are mindful of the impact of the additional stressors of living in a high-risk urban environment during a critical developmental transition period. Reducing exposure to drug activity and violence in high-risk urban neighborhoods may be the first step to potentially halt increasing rates of marijuana use among African Americans.
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Jennings RN, Grayson JM, Barton ES.
J Virol. 2014 Dec ;88(24):14040-9.
PMID: 25253356
CD8(+) T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8(+) T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1(-/-) mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8(+) T cell response. To test this, IFNAR1(-/-) mice were infected with MHV68 and the CD8(+) T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8(+) T cells, and MHV68-specific CD8(+) T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-α), gamma IFN (IFN-γ), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8(+) T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1(-/-) mice failed to improve CD8(+) T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8(+) T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8(+) T cell response.
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Williams J, Stafford E, Williams K, Hartsell Z.
JAAPA. 2014 Dec ;27(12):18-22.
PMID: 25383581
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is a common diagnosis in outpatient and inpatient settings. COPD exacerbations account for more than 800,000 hospital admissions annually and are most commonly caused by viral or bacterial infections. This article reviews management of patients with COPD exacerbations, including recommended diagnostic evaluations and treatments.
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Shah RV, Murthy VL, Abbasi SA, Blankstein R, Kwong RY, Goldfine AB, Jerosch-Herold M, Lima JA, Ding J, Allison MA.
JACC Cardiovasc Imaging. 2014 Dec ;7(12):1221-35.
PMID: 25440591
This study sought to evaluate differential effects of visceral fat (VF) and subcutaneous fat and their effects on metabolic syndrome (MetS) risk across body mass index (BMI) categories.
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Taheri A, Mansoori P, Alinia H, Lewallen R, Feldman SR.
JAMA Dermatol. 2014 Dec 1;150(12):1359-1360.
PMID: 25188750
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Mays AC, Moustafa F, Worley M, Waltonen JD, D'Agostino R.
JAMA Otolaryngol Head Neck Surg. 2014 Dec 1;140(12):1198-206.
PMID: 25321077
Identifying high-risk patients in the preoperative period can allow physicians to optimize nutritional status early for better outcomes after head and neck cancer resections.
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Izawa KP, Watanabe S, Brubaker PH, Tochimoto S, Hirano Y, Matsushima S, Suzuki T, Oka K, Saito T, Omori Y, Suzuki K, Osada N, Omiya K, Shimizu H, Akashi YJ.
Medicine (Baltimore). 2014 Dec ;93(29):e306.
PMID: 25546676
This study aimed to determine the relation between the regression slope relating minute ventilation to carbon dioxide output (V˙E/V˙CO2 slope) and maximum phonation time (MPT), and the MPT required to attain a threshold value for V˙E/V˙CO2 slope of ≤34 in chronic heart failure (CHF) patients.This cross-sectional study enrolled 115 CHF patients (mean age, 54.5 years; men, 84.9%). V˙E/V˙CO2 slope was assessed during cardiopulmonary exercise testing (CPX). Thereafter, patients were divided into 2 groups according to exercise capacity: V˙E/V˙CO2 slope ≤34 (V˙E/V˙CO2 ≤34 group, n = 81) and V˙E/V˙CO2 slope >34 (V˙E/V˙CO2 >34 group, n = 34). For MPT measurements, all patients produced a sustained vowel/a:/ for as long as possible during respiratory effort from the seated position.All subjects showed significant negative correlation between V˙E/V˙CO2 slope and MPT (r = -0.51, P < 0.001). After adjustment for clinical characteristics, MPT was significantly higher in the V˙E/V˙CO2 ≤34 group vs V˙E/V˙CO2 >34 group (21.4 ± 6.4 vs 17.4 ± 4.3 s, F = 7.4, P = 0.007). The appropriate MPT cut-off value for identifying a V˙E/V˙CO2 slope ≤34 was 18.12 seconds.An MPT value of 18.12 seconds may be a useful target value for identifying CHF patients with a V˙E/V˙CO2 slope ≤34 and for risk management in these patients.
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Zhao Y, Li Q, Katzenellenbogen BS, Lau LF, Taylor RN, Bagchi IC, Bagchi MK.
Mol Endocrinol. 2014 Dec ;28(12):1934-47.
PMID: 25321413
Endometriosis is a prevalent gynecological disorder in which endometrial tissue proliferates in extrauterine sites, such as the peritoneal cavity, eventually giving rise to painful, invasive lesions. Dysregulated estradiol (E) signaling has been implicated in this condition. However, the molecular mechanisms that operate downstream of E in the ectopic endometrial tissue are unknown. To investigate these mechanisms, we used a mouse model of endometriosis. Endometrial tissue from donor mice was surgically transplanted on the peritoneal surface of immunocompetent syngeneic recipient mice, leading to the establishment of cystic endometriosis-like lesions. Our studies revealed that treatment with E led to an approximately 3-fold increase in the lesion size within a week of transplantation. E also caused a concomitant stimulation in the expression of connective tissue growth factor/Cyr61/Nov (CCN1), a secreted cysteine-rich matricellular protein, in the lesions. Interestingly, CCN1 is highly expressed in human ectopic endometriotic lesions. To address its role in endometriosis, endometrial tissue from Ccn1-null donor mice was transplanted in wild-type recipient mice. The resulting ectopic lesions were reduced up to 75% in size compared with wild-type lesions due to diminished cell proliferation and cyst formation. Notably, loss of CCN1 also disrupted the development of vascular networks in the ectopic lesions and reduced the expression of several angiogenic factors, such as vascular endothelial growth factor-A and vascular endothelial growth factor-C. These results suggest that CCN1, acting downstream of E, critically controls cell proliferation and neovascularization, which support the growth and survival of endometriotic tissue at ectopic sites. Blockade of CCN1 signaling during the early stages of lesion establishment may provide a therapeutic avenue to control endometriosis.
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Zaitlen N, Pasaniuc B, Sankararaman S, Bhatia G, Zhang J, Gusev A, Young T, Tandon A, Pollack S, Vilhjálmsson BJ, Assimes TL, Berndt SI, Blot WJ, Chanock S, Franceschini N, Goodman PG, He J, Hennis AJ, Hsing A, Ingles SA, Isaacs W, Kittles RA, Klein EA, Lange LA, Nemesure B, Patterson N, Reich D, Rybicki BA, Stanford JL, Stevens VL, Strom SS, Whitsel EA, Witte JS, Xu J, Haiman C, Wilson JG, Kooperberg C, Stram D, Reiner AP, Tang H, Price AL.
Nat Genet. 2014 Dec ;46(12):1356-62.
PMID: 25383972
Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).
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Freedman BI, Robinson TW.
Nat Rev Nephrol. 2014 Dec ;10(12):677-8.
PMID: 25266211
A new population-based study of a Norwegian registry containing data on more than 5 million individuals has confirmed the existence of powerful familial clustering of complex aetiologies of end-stage renal disease. Novel strategies for identifying additional nephropathy risk genes will benefit from such large familial registries.
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Strowd RE, Swett K, Harmon M, Carter AF, Pop-Vicas A, Chan M, Tatter SB, Ellis T, Blevins M, High K, Lesser GJ.
Neuro Oncol. 2014 Dec ;16(12):1639-44.
PMID: 24714522
Patients with central nervous system (CNS) malignancies represent an "at-risk" population for contracting influenza, particularly if they are receiving ongoing chemotherapy, radiation, and/or glucocorticoid treatment. The Centers for Disease Control endorses vaccination for these patients, although data are not available to indicate whether they mount an immunologic response adequate to achieve clinical protection.
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Nader MA, Balster RL, Henningfield JE.
Neuropharmacology. 2014 Dec ;87():4-8.
PMID: 24859612
Clinical findings suggest that the most promising strategy for cocaine addiction is a combination of indirect-acting monoamine agonists with some form of behavioral intervention. This approach can be traced back to preclinical research, some of which was conducted by William L. Woolverton. The goal of this brief review is to provide readers with an appreciation for the experimental breadth involving both behavior and pharmacology that encompassed Woolverton's amazing career, from the evaluation of abuse liability of drugs to the use of complex behavioral contingencies to better model the human condition. We begin with Woolverton's research using simple and complex schedules of reinforcement to evaluate abuse liability and how that has impacted current animal models. We also discuss his use of cocaine vs. food choice schedules of reinforcement as a model to evaluate potential medications for treating cocaine use disorders. Woolverton concluded that drug taking behavior was not "impulsive" and "out of control" as has often been proposed, but rather directly determined by the environmental contingencies and the context of its availability, providing a nuanced understanding of drug-behavior interactions. This article is part of the Special Issue entitled 'CNS Stimulants'
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Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, Genuth S, Goff DC, Leiter LA, Ismail-Beigi F, Ambrosius WT, .
Ophthalmology. 2014 Dec ;121(12):2443-51.
PMID: 25172198
To report additional ocular outcomes of intensive treatment of hyperglycemia, blood pressure, and dyslipidemia in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.
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Boada MD, Martin TJ, Peters CM, Hayashida K, Harris MH, Houle TT, Boyden ES, Eisenach JC, Ririe DG.
Pain. 2014 Dec ;155(12):2646-55.
PMID: 25267211
Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury-induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an adeno-associated virus-type 8 viral vector with the CAG promoter and was administered by intrathecal injection resulting in expression in myelinated neurons. Optical inhibition of peripheral neurons at the soma and transcutaneously was possible in the neurons expressing ArchT, but not in neurons from control animals. Receptive field characteristics and electrophysiology determined that inhibition was neuronal subtype-specific with only AHTMR neurons being inhibited. One week after nerve injury the AHTMR are hyperexcitable, but can still be inhibited at the soma and transcutaneously. Withdrawal thresholds to mechanical stimuli in normal and in hyperalgesic nerve-injured animals also were increased by transcutaneous light to the affected hindpaw. This suggests that AHTMR neurons play a role not only in threshold-related withdrawal behavior in the normal animal, but also in sensitized states after nerve injury. This is the first time this subpopulation of neurons has been reversibly modulated to test their contribution to withdrawal-related behaviors before and after nerve injury. This technique may prove useful to define the role of selective neuronal populations in different pain states.
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Nahman-Averbuch H, Martucci KT, Granovsky Y, Weissman-Fogel I, Yarnitsky D, Coghill RC.
Pain. 2014 Dec ;155(12):2491-501.
PMID: 25047783
The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information.
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