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Pace LA, Plate JF, Smith TL, Van Dyke ME.
Biomaterials. 2013 Aug ;34(24):5907-14.
PMID: 23680369
Peripheral nerve injuries requiring surgery can be repaired by autograft, the clinical "gold standard", allograft, or nerve conduits. Most published clinical studies show the effectiveness of nerve conduits in small size defects in sensory nerves. Many preclinical studies suggest that peripheral nerve regeneration through conduits can be enhanced and repair lengths increased with the use of a biomaterial filler in the conduit lumen. We have previously shown that a luminal hydrogel filler derived from human hair keratin (HHK) can improve electrophysiological and histological outcomes in mouse, rabbit, and non-human primate nerve injury models, but insight into potential mechanisms has been lacking. Based on the premise that a keratin biomaterial (KOS) hydrogel provides an instantaneous structural matrix within the lumen, the current study compares the cellular behavior elicited by KOS hydrogel to Matrigel (MAT) and saline (SAL) conduit fillers in a 1 cm rat sciatic nerve injury model at early stages of regeneration. While there was little difference in initial cellular influx, the KOS group showed earlier migration of dedifferentiated Schwann cells (SC) from the proximal nerve end compared to the other groups. The KOS group also showed faster SC dedifferentiation and myelin debris clearance, and decreased macrophage infiltration during Wallerian degeneration of the distal nerve tissue.
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Orlando G, Booth C, Wang Z, Totonelli G, Ross CL, Moran E, Salvatori M, Maghsoudlou P, Turmaine M, Delario G, Al-Shraideh Y, Farooq U, Farney AC, Rogers J, Iskandar SS, Burns A, Marini FC, De Coppi P, Stratta RJ, Soker S.
Biomaterials. 2013 Aug ;34(24):5915-25.
PMID: 23680364
In the United States, more than 2600 kidneys are discarded annually, from the total number of kidneys procured for transplant. We hypothesized that this organ pool may be used as a platform for renal bioengineering and regeneration research. We previously showed that decellularization of porcine kidneys yields renal extracellular matrix (ECM) scaffolds that maintain their basic components, support cell growth and welfare in vitro and in vivo, and show an intact vasculature that, when such scaffolds are implanted in vivo, is able to sustain physiological blood pressure. The purpose of the current study was to test if the same strategy can be applied to discarded human kidneys in order to obtain human renal ECM scaffolds. The results show that the sodium dodecylsulfate-based decellularization protocol completely cleared the cellular compartment in these kidneys, while the innate ECM framework retained its architecture and biochemical properties. Samples of human renal ECM scaffolds stimulated angiogenesis in a chick chorioallantoic membrane assay. Importantly, the innate vascular network in the human renal ECM scaffolds retained its compliance. Collectively, these results indicate that discarded human kidneys are a suitable source of renal scaffolds and their use for tissue engineering applications may be more clinically applicable than kidneys derived from animals.
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Dalton GD, Peterson LJ, Howlett AC.
Cell Signal. 2013 Aug ;25(8):1665-77.
PMID: 23571270
Tyrosine phosphorylation (Tyr-P) of focal adhesion kinase (FAK) regulates FAK activation. Phosphorylated FAK Tyr 397 binds Src family kinases (Src), which in turn directly phosphorylate FAK Tyr 576/577 to produce maximal FAK enzymatic activity. CB1 cannabinoid receptors (CB1) are abundantly expressed in the nervous system and influence FAK activation by presently unknown mechanisms. The current investigation determined that CB1-stimulated maximal FAK catalytic activity is mediated by Gi/o proteins in N18TG2 neuronal cells, and that G12/13 regulation of Rac1 and RhoA occurs concomitantly. Immunoblotting analyses using antibodies against FAK phospho-Tyr 397 and phospho-Tyr 576/577 demonstrated that the time-course of CB1-stimulated FAK 576/577 Tyr-P occurred in three phases: Phase I (0-2min) maximal Tyr-P, Phase II (5-20min) rapid decline in Tyr-P, and Phase III (>20min) plateau in Tyr-P at submaximal levels. In contrast, FAK 397 Tyr-P was monophasic and significantly lower in magnitude. FAK 397 Tyr-P and Phase I FAK 576/577 Tyr-P involved protein tyrosine phosphatase (PTP1B and Shp1/Shp2)-mediated Src activation, Protein Kinase A (PKA) inhibition, and integrin activation. Phase I maximal FAK 576/577 Tyr-P also required cooperative signaling between receptor tyrosine kinases (RTKs) and integrins. The integrin antagonist RGDS peptide, Flk-1 vascular endothelial growth factor receptor (VEGFR) antagonist SU5416, and epidermal growth factor receptor (EGFR) antagonist AG 1478 blocked Phase I FAK 576/577 Tyr-P. CB1 agonists failed to stimulate FAK Tyr-P in the absence of integrin activation upon suspension in serum-free culture media. In contrast, cells grown on the integrin ligands fibronectin and laminin displayed increased FAK 576/577 Tyr-P that was augmented by CB1 agonists and blocked by the Src inhibitor PP2 and Flk-1 VEGFR antagonist SU5416. Taken together, these studies have identified a complex integrative pathway utilized by CB1 to stimulate maximal FAK 576/577 Tyr-P in neuronal cells.
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Welker ME, Kulik G.
Bioorg Med Chem. 2013 Jul 15;21(14):4063-91.
PMID: 23735831
This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.
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Aston ER, Neiberg RH, Liguori A.
Alcohol Alcohol. 2013 Jul-Aug;48(4):396-401.
PMID: 23695976
Breath alcohol concentration (BrAC) estimation training has been effective in increasing estimation accuracy in social drinkers. Predictors of estimation accuracy may identify populations to target for training, yet potential predictors typically are not evaluated. In addition, the therapeutic efficacy of estimation training as a preventive strategy for problematic drinking is unknown.
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Pirkle JL, Freedman BI, Fogo AB.
Am J Kidney Dis. 2013 Jul ;62(1):159-64.
PMID: 23548558
Immune complex-mediated glomerulonephritis can be caused by a multitude of disease processes and may manifest in a variety of histologic patterns. Lupus nephritis is an immune complex disease, the diagnosis of which requires that the affected patient have systemic lupus erythematosus (SLE). In the absence of SLE, the finding of glomerulonephritis with certain patterns of immune complex deposition characteristic of lupus nephritis has been referred to as lupus-like glomerulonephritis. Immunoglobulin G (IgG), IgA, IgM, complement C3, and C1q deposition in glomerular immune deposits is one such pattern. We report a case of immune complex disease in a primarily membranous distribution with mesangial, subendothelial, and tubular basement membrane deposits with IgG, IgA, IgM, C3, and C1q deposition in a patient with proteinuria, photosensitive dermatitis, and a positive lupus anticoagulant test. The patient had 3 of the clinical criteria for SLE, thus failing to meet the diagnosis based on the American College of Rheumatology definition. In this case, a diagnosis of lupus-like glomerulonephritis was made after other causes of membranous glomerulopathy were excluded. This teaching case highlights the broad differential diagnosis of this pattern of injury and reviews similar cases in the literature.
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Palmer NR, Geiger AM, Felder TM, Lu L, Case LD, Weaver KE.
Am J Public Health. 2013 Jul ;103(7):1306-13.
PMID: 23678936
Objectives. We examined racial/ethnic disparities in health care receipt among a nationally representative sample of male cancer survivors. Methods. We identified men aged 18 years and older from the 2006-2010 National Health Interview Survey who reported a history of cancer. We assessed health care receipt in 4 self-reported measures: primary care visit, specialist visit, flu vaccination, and pneumococcal vaccination. We used hierarchical logistic regression modeling, stratified by age (< 65 years vs ≥ 65 years). Results. In adjusted models, older African American and Hispanic survivors were approximately twice as likely as were non-Hispanic Whites to not see a specialist (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.19, 2.68 and OR = 2.09; 95% CI = 1.18, 3.70, respectively), not receive the flu vaccine (OR = 2.21; 95% CI = 1.45, 3.37 and OR = 2.20; 95% CI = 1.21, 4.01, respectively), and not receive the pneumococcal vaccine (OR = 2.24; 95% CI = 1.54, 3.24 and OR = 3.10; 95% CI = 1.75, 5.51, respectively). Conclusions. Racial/ethnic disparities in health care receipt are evident among older, but not younger, cancer survivors, despite access to Medicare. These survivors may be less likely to see specialists, including oncologists, and receive basic preventive care.
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Mirmalek-Sani SH, Orlando G, McQuilling JP, Pareta R, Mack DL, Salvatori M, Farney AC, Stratta RJ, Atala A, Opara EC, Soker S.
Biomaterials. 2013 Jul ;34(22):5488-95.
PMID: 23583038
Emergent technologies of regenerative medicine have the potential to overcome the limitations of organ transplantation by supplying tissues and organs bioengineered in the laboratory. Pancreas bioengineering requires a scaffold that approximates the biochemical, spatial and vascular relationships of the native extracellular matrix (ECM). We describe the generation of a whole organ, three-dimensional pancreas scaffold using acellular porcine pancreas. Imaging studies confirm that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. The scaffold was seeded with human stem cells and porcine pancreatic islets, demonstrating that the decellularized pancreas can support cellular adhesion and maintenance of cell functions. These findings advance the field of regenerative medicine towards the development of a fully functional, bioengineered pancreas capable of establishing and sustaining euglycemia and may be used for transplantation to cure diabetes mellitus.
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Liu W, Xie CC, Thomas CY, Kim ST, Lindberg J, Egevad L, Wang Z, Zhang Z, Sun J, Sun J, Koty PP, Kader AK, Cramer SD, Bova GS, Zheng SL, Grönberg H, Isaacs WB, Xu J.
Cancer. 2013 Jul 1;119(13):2405-12.
PMID: 23609948
This study sought to identify novel effectors and markers of localized but potentially life-threatening prostate cancer (PCa), by evaluating chromosomal copy number alterations (CNAs) in tumors from patients who underwent prostatectomy and correlating these with clinicopathologic features and outcome.
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Sukhtankar DD, Zaveri NT, Husbands SM, Ko MC.
J Pharmacol Exp Ther. 2013 Jul ;346(1):11-22.
PMID: 23652222
Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.
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Walker FO.
Lancet Neurol. 2013 Jul ;12(7):624-5.
PMID: 23664845
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Kavanagh K, Flynn DM, Jenkins KA, Wilson MD, Chilton FH.
Prostaglandins Leukot Essent Fatty Acids. 2013 Jul ;89(1):39-45.
PMID: 23664597
Echium oil (EO) contains stearidonic acid (18:4), a n-3 polyunsaturated fatty acids (PUFAs), and gamma-linolenic acids (18:3), a n-6 PUFA that can be converted to long chain (LC)-PUFAs. We aimed to compare a safflower oil (SO)-enriched diet to EO- and fish oil (FO)-enriched diets on circulating and tissue PUFAs levels and glycemic, inflammatory, and cardiovascular health biomarkers in insulin resistant African green monkeys. In a Latin-square cross-over study, eight monkeys consumed matched diets for 6 weeks with 3-week washout periods. Monkeys consuming FO had significantly higher levels of n-3 LC-PUFAs and EO supplementation resulted in higher levels of circulating n-3 LC-PUFAs and a significant increase in dihomo-gamma linolenic acid (DGLA) in red blood cells and muscle. Glucose disposal was improved after EO consumption. These data suggest that PUFAs in EO supplementation have the capacity to alter circulating, RBC and muscle LC-PUFA levels and improve glucose tolerance in insulin-resistant monkeys.
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Votanopoulos KI, Newman NA, Russell G, Ihemelandu C, Shen P, Stewart JH, Levine EA.
Ann Surg Oncol. 2013 Jun 19. [Epub ahead of print]
PMID: 23780382
BACKGROUND: Cytoreductive surgery (CRS)/Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is associated with prolonged survival in selected patients with peritoneal surface disease. Yet, for elderly patients (older than 70 years of age) CRS/HIPEC is controversial, due to associated morbidity. METHODS: A retrospective analysis of a prospective database of 950 procedures was performed. Type of malignancy, demographics, performance and resection status, hospitalization, morbidity, mortality, and survival were reviewed. RESULTS: A total of 81 patients (median age 73, range 70-87) underwent CRS/HIPEC between 1991 and 2011. Median follow-up was 48.1 months. Complete cytoreduction was achieved in 44 %. Median survival was 31.8 months for appendiceal cancer, 41.5 for mesothelioma, 54.0 for ovarian cancer, 13.2 for colon cancer, and 7.6 for gastric cancer. The 30-day mortality was 13.6 %. The combined grade III and IV morbidity was 38 %. Median ICU and hospital stay for uncomplicated patients was 1 and 8 days, respectively. The 3-month mortality was 27.4 %. There were no deaths in the octogenarian group. In stepwise multivariate analysis, type of primary (p = 0.03), albumin (p = 0.02), and R status (p = 0.007) were predictive of survival only in the absence of complications. Splitting the data at the midpoint of surgical experience, there was a drop in 1- and 3-month mortality over time to 9.5 and 19.3 %, respectively, while the median survival increased from 11.2 (N = 39) to 46.9 months (N = 42). CONCLUSIONS: HIPEC in the elderly is associated with a steep learning curve and considerable morbidity and mortality. However, age alone is not a contraindication for the procedure. Institutional experience and stringent patient selection are key factors for prolonged survival.
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Calipari ES, Ferris MJ, Zimmer BA, Roberts DC, Jones SR.
Neuropsychopharmacology. 2013 Jun 19. [Epub ahead of print]
PMID: 23719505
The dopamine transporter (DAT) is responsible for terminating dopamine (DA) signaling and is the primary site of cocaine's reinforcing actions. Cocaine self-administration has been shown previously to result in changes in cocaine potency at the DAT. To determine whether the DAT changes associated with self-administration are due to differences in intake levels or temporal patterns of cocaine-induced DAT inhibition, we manipulated cocaine access to produce either continuous or intermittent elevations in cocaine brain levels. Long-access (LgA, 6 h) and short-access (ShA, 2 h) continuous self-administration produced similar temporal profiles of cocaine intake that were sustained throughout the session; however, LgA had greater intake. ShA and intermittent-access (IntA, 6 h) produced the same intake, but different temporal profiles, with 'spiking' brain levels in IntA compared with constant levels in ShA. IntA consisted of 5-min access periods alternating with 25-min timeouts, which resulted in bursts of high responding followed by periods of no responding. DA release and uptake, as well as the potency of cocaine for DAT inhibition, were assessed by voltammetry in the nucleus accumbens slices following control, IntA, ShA, and LgA self-administration. Continuous-access protocols (LgA and ShA) did not change DA parameters, but the 'spiking' protocol (IntA) increased both release and uptake of DA. In addition, high continuous intake (LgA) produced tolerance to cocaine, while 'spiking' (IntA) produced sensitization, relative to ShA and naive controls. Thus, intake and pattern can both influence cocaine potency, and tolerance seems to be produced by high intake, while sensitization is produced by intermittent temporal patterns of intake.Neuropsychopharmacology advance online publication, 19 June 2013; doi:10.1038/npp.2013.136.
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Manny TB, Krane LS, Hemal AK.
J Endourol. 2013 Jun 18. [Epub ahead of print]
PMID: 23442199
Abstract Introduction: Indocyanine green (ICG) is emerging as a potential adjunct to robot-assisted partial nephrectomy by its ability to aid in the real-time identification of renal vasculature, renal masses, and the renal mass-parenchymal margin. The fluorescence patterns of renal masses have not been adequately described according to histology, and it remains unknown if fluorescence pattern can reliably predict histology or malignancy. We therefore describe the ICG fluorescence pattern of our first 100 robot-assisted partial nephrectomies (RAPN) and correlate with histology. Materials and Methods: We reviewed our prospective RAPN database and categorized fluorescence pattern as isofluorescent (same as surrounding parenchyma), hypofluorescent (less than surrounding parenchyma, but with uptake), or afluorescent (no visible uptake of dye). Descriptive statistics were applied. Results: All 14 cystic lesions were afluorescent and comprised 9 malignant and 5 benign masses. Eighty-six lesions were solid, of which 3 were isofluorescent including two clear-cell and one translocation tumor. The remaining 83 solid lesions were hypofluorescent and included 65 malignant and 18 benign lesions. Clear-cell was the most common histology of which 96% were hypofluorescent and 4% isofluorescent. In determining malignant vs benign lesions, hypofluorescence had a positive predictive value of 87%, negative predictive value of 52%, sensitivity of 84%, and specificity of 57%. Conclusions: A three-grade classification of renal mass ICG fluorescence pattern is correlated with some histologic findings but unable to reliably predict malignant vs benign lesions.
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Beavers KM, Ambrosius WT, Nicklas BJ, Rejeski WJ.
J Am Geriatr Soc. 2013 Jun 17. [Epub ahead of print]
PMID: 23772804
OBJECTIVES: To determine the independent effect of long-term physical activity (PA) and the combined effects of long-term PA and weight loss (WL) on inflammation in overweight and obese older adults. DESIGN: Eighteen-month randomized, controlled trial. SETTING: The community infrastructure of cooperative extension centers. PARTICIPANTS: Overweight and obese (body mass index >28.0 kg/m(2) ) community-dwelling men and women aged 60 to 79 at risk for cardiovascular disease (CVD). INTERVENTION: Physical activity + weight loss (PA + WL) (n = 98), PA only (n = 97), or successful aging (SA) health education (n = 93) intervention. MEASUREMENTS: Biomarkers of inflammation (adiponectin, leptin, high-sensitivity interleukin (hsIL)-6, IL-6sR, IL-8, and soluble tumor necrosis factor receptor 1) were measured at baseline and 6 and 18 months. RESULTS: After adjustment for baseline biomarker, wave, sex, and visit, leptin and hsIL-6 showed a significant intervention effect. Specifically, leptin was significantly lower in the PA + WL group (21.3 ng/mL, 95% confidence interval (CI) = 19.7-22.9 ng/mL) than in the PA (29.3 ng/mL, 95% CI = 26.9-31.8 ng/mL) or SA (30.3 ng/mL, 95% CI = 27.9-32.8 ng/mL) group (both P < .001), and hsIL-6 was significantly lower in the PA + WL group (2.1 pg/mL, 95% CI = 1.9-2.3 pg/mL) than in the PA (2.5 pg/mL, 95% CI = 2.3-2.7 pg/mL) or SA (2.4 pg/mL, 95% CI = 2.2-2.6 pg/mL) group (P = .02). CONCLUSION: Addition of dietary-induced WL to PA reduced leptin and hsIL-6 more than PA alone and more than a SA intervention in older adults at risk for CVD. Results suggest that WL, rather than increased PA, is the lifestyle factor primarily responsible for improvement in the inflammatory profile.
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Huang SY, Murai J, Dalla Rosa I, Dexheimer TS, Naumova A, Gmeiner WH, Pommier Y.
Nucleic Acids Res. 2013 Jun 17. [Epub ahead of print]
PMID: 23775789
Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs-acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)-we show that TDP1 is capable of removing the covalently linked corresponding CTNAs from DNA 3'-ends. We also show that Tdp1(-/-) cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1(-/-) cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs.
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Mofidi A, Lu B, Plate JF, Lang JE, Poehling GG, Jinnah RH.
Eur J Orthop Surg Traumatol. 2013 Jun 16. [Epub ahead of print]
PMID: 23771595
The purpose of this study is to evaluate the outcome of robotic-assisted (MAKO Surgical Corp.) unicondylar replacement in the treatment for knee osteoarthritis after the initial surgical insult is worn off to evaluate the impact of residual patellofemoral and lateral osteoarthritis on the outcome of medial unicompartmental knee replacement. One hundred and thirty-four patients who underwent uncomplicated 144 robotic-assisted medial unicondylar replacements for knee arthritis were identified and studied. Original radiographs were used to classify severity of patellofemoral and lateral compartmental osteoarthritis in these patients. Severity of patellofemoral and lateral compartmental osteoarthritis was analyzed against Oxford and Knee Society scores and amount of ipsilateral residual knee symptoms at 6 months postoperative period. Preoperative Oxford and Knee Society scores, other comorbidities and long-term disability were studied as confounding variables. We found significant improvement in symptoms and scores in spite of other compartment diseases. Poorer outcome was seen in association with comorbidities and long-term disability but not when radiographic signs of arthritis in the other compartments were present. Six patients required revision of which three had (lateral facet) patellofemoral disease in the original X-rays. In conclusion, there is a higher amount of postoperative retained symptoms, but similar outcome when there is radiographic disease in the other compartments. However, when symptoms are severe enough to necessitate revision, this is due to the lateral facet of patellofemoral compartment and not lateral compartment disease.
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Rautaharju PM, Zhang ZM, Haisty WK, Prineas RJ, Kucharska-Newton AM, Rosamond WD, Soliman EZ.
Am J Cardiol. 2013 Jun 14. [Epub ahead of print]
PMID: 23768456
The risk of incident hospitalized heart failure (HF) was evaluated for 23 electrocardiographic (ECG) variables in men and women free from cardiovascular disease. The hazard ratios with 95% confidence intervals were determined from Cox regression analysis for 13,428 participants 45 to 65 years old in the Atherosclerosis Risk in Communities (ARIC) study. New-onset HF during a 14-year follow-up period occurred in 695 men (11.9%) and 721 women (9.5%). Several ECG variables were significant predictors of incident HF when evaluated as single ECG variables. Predominant among them were spatial angles, reflecting deviations of the direction of the repolarization sequence from the normal reference direction. After controlling for collinearity among the ECG variables, the spatial angle between T peak and normal T reference vectors, Ө(Tp|Tref), was a significant independent predictor in men (HF risk increased 31%) and women (HF risk increased 46%). Other independent predictors in men included epicardial repolarization time (62% increased risk) and T wave peak to T wave end (TpTe) interval, reflecting global dispersion of repolarization (27% increased risk). The independent predictors in women, in addition to Ө(Tp|Tref), were Ө(R|STT) the spatial angle between the mean QRS and STT vectors (54% increased risk) and QRS nondipolar voltage (46% increased risk). In conclusion, wide Ө(Tp|Tref), wide Ө(R|STT), and increased QRS nondipolar voltage in women and wide Ө(Tp|Tref), increased epicardial repolarization time, prolonged TpTe interval and T wave complexity in men were independent predictors of incident HF, and the presence of these abnormal findings could warrant additional diagnostic evaluation for possible preventive action for HF.
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Laxton AW, Neimat JS, Davis KD, Womelsdorf T, Hutchison WD, Dostrovsky JO, Hamani C, Mayberg HS, Lozano AM.
Biol Psychiatry. 2013 Jun 14. [Epub ahead of print]
PMID: 23773792
BACKGROUND: The subcallosal cingulate and adjacent ventromedial prefrontal cortex (collectively referred to here as the subcallosal cortex or SCC) have been identified as key brain areas in emotional processing. The SCC's role in affective valuation as well as severe mood and motivational disturbances, such as major depression, has been largely inferred from measures of neuronal population activity using functional neuroimaging. On the basis of imaging studies, it is unclear whether the SCC predominantly processes 1) negatively valenced affective content, 2) affective arousal, or 3) category-specific affective information. METHODS: To clarify these putative functional roles of the SCC, we measured single neuron activity in the SCC of 15 human subjects undergoing deep brain stimulation for depression while they viewed emotionally evocative images grouped into categories that varied in emotional valence (pleasantness) and arousal. RESULTS: We found that the majority of responsive neurons were modulated by specific emotion categories, rather than by valence or arousal alone. Moreover, although these emotion-category-specific neurons responded to both positive and negative emotion categories, a significant majority were selective for negatively valenced emotional content. CONCLUSIONS: These findings reveal that single SCC neuron activity reflects the automatic valuational processing and implicit emotion categorization of visual stimuli. Furthermore, because of the predominance of neuronal signals in SCC conveying negative affective valuations and the increased activity in this region among depressed people, the effectiveness of depression therapies that alter SCC neuronal activity may relate to the down-regulation of a previously negative emotional processing bias.
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