♦ Background: The aim of the present study was to investigate the effect of oral pioglitazone (PIO) on lipid metabolism, insulin resistance, inflammation, and adipokine metabolism in continuous ambulatory peritoneal dialysis (CAPD) patients.
♦ Methods: In this randomized crossover trial, 36 CAPD patients with serum triglyceride levels above 1.8 mmol/L were randomly assigned to receive either oral PIO 15 mg once daily or no PIO for 12 weeks. Then, after a 4-week washout, the patients were switched to the alternative regimen. The primary endpoint was change in serum triglycerides during the PIO regimen compared with no PIO. Secondary endpoints included changes in other lipid levels, homeostatic model assessment of insulin resistance (HOMA-IR), adipocytokines, and C-reactive protein (CRP).
♦ Results: All 36 CAPD patients (age: 64 ± 11 years; 33% men; 27.8% with diabetes mellitus) completed the study. Comparing patients after PIO and no PIO therapy, we found no significant differences in mean serum triglycerides (3.83 ± 1.49 mmol/L vs 3.51 ± 1.98 mmol/L, p = 0.2). However, mean high-density lipoprotein (0.94 ± 0.22 mmol/L vs 1.00 ± 0.21 mmol/L, p = 0.004) and median total adiponectin [10.34 μg/mL (range: 2.59 - 34.48 μg/mL) vs 30.44 μg/mL (3.47 - 93.41 μg/mL), p < 0.001] increased significantly. Median HOMA-IR [7.51 (1.39 - 45.23) vs 5.38 (0.97 - 14.95), p = 0.006], mean fasting blood glucose (7.31 ± 2.57 mmol/L vs 6.60 ± 2.45 mmol/L, p = 0.01), median CRP [8.78 mg/L (0.18 - 53 mg/L) vs 3.50 mg/L (0.17 - 26.30 mg/L), p = 0.005], and mean resistin (32.70 ± 17.17 ng/mL vs 28.79 ± 11.83 ng/mL, p = 0.02) all declined. The PIO was well tolerated, with only one adverse event: lower-extremity edema in a patient with low residual renal function.
♦ Conclusions: Blood triglycerides were not altered after 12 weeks of PIO 15 mg once daily in CAPD patients, but parameters of dysmetabolism were markedly improved, including insulin resistance, inflammation, and adipokine balance, suggesting that PIO could be of value for this high-risk patient group. Larger, more definitive studies are needed to confirm these findings.
Pioglitazone; lipid dysmetabolism; insulin resistance; inflammation; adipocytokines
The development of pulmonary hypertension is a common accompaniment of congenital heart disease (CHD) with increased pulmonary blood flow. Our recent evidence suggests that asymmetric dimethylarginine (ADMA)-induced mitochondrial dysfunction causes endothelial nitric oxide synthase (eNOS) uncoupling secondary to a proteasome-dependent degradation of GTP cyclohydrolase I (GCH1) that results in a decrease in the NOS co-factor, tetrahydrobiopterin (BH4). Decreases in NO signaling are thought to be an early hallmark of endothelial dysfunction. As L-carnitine plays an important role in maintaining mitochondrial function in this study we examined the protective mechanisms and the therapeutic potential of L-carnitine on NO signaling in pulmonary arterial endothelial cells (PAEC) and in a lamb model of CHD and increased pulmonary blood flow (Shunt). Acetyl L-carnitine (ALC) attenuated the ADMA-mediated proteasomal degradation of GCH1. This preservation was associated with a decrease in the association of GCH1 with the Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) and a decrease in its ubiquitination. This in turn prevented the decrease in BH4 levels induced by ADMA and preserved NO signaling. Treatment of Shunt lambs with L-carnitine also reduced GCH1/CHIP interactions, attenuated the ubiquitination and degradation of GCH1, and increased BH4 levels compared to vehicle treated Shunt lambs. The increases in BH4 were associated with decreased NOS uncoupling and enhanced NO generation. Thus, we conclude that L-carnitine may have a therapeutic potential in the treatment of pulmonary hypertension in children with CHD with increased pulmonary blood flow.
mitochondrial dysfunction; BH4; Hsp90; Hsp70; CHIP; ubiquitination
C-Jun has been proved as playing an important role in the pathogenesis of tumors, as a main component of Activator protein 1 and c-Jun gene polymorphisms are associated with colorectal cancer. However, the relationship between the c-Jun gene polymorphism and the susceptibility to systemic lupus erythematosus (SLE) has not been known. Our purpose is to evaluate whether the c-Jun gene polymorphism (SNP rs3748814) is associated with susceptibility to SLE in a Chinese population. In this study, we enrolled 502 SLE patients and 652 healthy controls. The c-Jun polymorphism (rs3748814) was specified from genomic DNA using the TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. We found that the frequency of the A/G genotype in SLE patients was lower than in healthy controls, whereas the frequency of the G/G genotype was significantly higher in SLE patients than in healthy controls (A/G vs. G/G p=8.670e-08, odds ratio [OR]=0.290, 95% confidence interval [CI]=0.184–0.456). In addition, the frequency of allele A in the patients group was significantly lower than in the control group (A vs. G p=5.221e-09, OR=0.308, 95% CI=0.212–0.466). The distribution of genotype and allele frequency in SLE patients with lupus nephritis (LN) compared with SLE patients without LN was not statistically significant (A/G vs. G/G p=0.744, OR=1.157, 95% CI=0.481–2.785; A vs. G p=0.748, OR=1.152, 95% CI=0.486–2.734; A/A+A/G vs. G/G p=0.744, OR=1.157, 95% CI=0.481–2.785). Furthermore, we did not find any significant association between other clinical features and genotypes. Our findings suggest that the c-Jun polymorphism (rs3748814) may be significantly associated with the susceptibility to SLE in a Chinese population.
Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer′s disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu), a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET), coimmunoprecipitation (co-IP), and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co-overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with β-amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Aβ with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention.
A large number of scientific researches and industrial applications commonly suffer from missing data. Some inappropriate techniques of missing value treatment compromise data quality, which detrimentally influences the knowledge discovery. In this paper, we propose a missing data completion method named CBGMI. Firstly, it separates the nonmissing data instances into several clusters by excluding the missing-valued entries. Then, it utilizes the entropy of the proximal category for each incomplete instance in terms of the similarity metric based on gray relational analysis. Experiments on UCI datasets and aerospace datasets demonstrate that the superiority of our algorithm to other approaches on validity.
We examined performance in the antisaccade task for younger and older adults by comparing latencies and errors in what we defined as high attentional focus (mixed antisaccades and prosaccades in the same block) and low attentional focus (antisaccades and prosaccades in separate blocks) conditions. Shorter saccade latencies for correctly executed eye movements were observed for both groups in mixed, compared to blocked, antisaccade tasks, but antisaccade error rates were higher for older participants across both conditions. The results are discussed in relation to the inhibitory hypothesis, the goal neglect theory and attentional control theory.
To determine the efficacy and toxicity of Pemetrexed plus Oxaliplatin in patients suffering from stage IIIb or IV lung adenocarcinoma and being treated with Erlotinib as second-line treatment, a total of 45 patients were randomly divided into two groups. One group was treated with 500 mg/m2 Pemetrexed plus 100 mg/m2 Oxaliplatin, and the other was treated with 500 mg/m2 Pemetrexed plus 75 mg/m2 Cisplatin. All drugs were administered on day one of a 21-day cycle. In the Oxaliplatin group, 3 patients (13.6 %) experienced partial response (PR), 9 patients (41.0 %) showed stable disease (SD), and 10 patients (45.5 %) had progressive disease (PD). In the Cisplatin group, 2 patients (8.7 %) experienced PR, 7 patients (30.4 %) showed SD, and 14 patients (60.9 %) had PD. The PFS of the Oxaliplatin group and the Cisplatin group was 4.45 months (95 % CI 4.10–4.80) and 3.96 months (95 % CI 3.68–4.24) (P = 0.03), respectively. The median overall survival (OS) was 10.8 months (95 % CI 10.2–11.5) and 10.7 months (95 % CI 10.2–11.3) (P = 0.72), respectively. There was no statistically significant difference in the occurrence rate of grades 3 and 4 myelotoxicity between the two groups. However, there was a significant difference in the occurrence rate of grades 3 and 4 gastrointestinal reactions and peripheral neurotoxicity between the two groups (P < 0.05). A regime combining Pemetrexed and Oxaliplatin was marginally effective and well tolerated in patients with stage IIIb or IV lung adenocarcinoma who have received Erlotinib as second-line treatment.
Lung adenocarcinoma; Oxaliplatin; Pemetrexed; Erlotinib as second-line treatment
The Agrobacterium-mediated transformation system is the most commonly used method in soybean transformation. Screening of soybean genotypes favorable for Agrobacterium-infection and tissue regeneration is the most important step to establish an efficient genetic transformation system. In this study, twenty soybean genotypes that originated from different soybean production regions in China were screened for transient infection, regeneration capacity, and stable transgenic efficiency. Three genotypes, Yuechun 04-5, Yuechun 03-3, and Tianlong 1, showed comparable stable transgenic efficiencies with that of the previously reported American genotypes Williams 82 and Jack in our experimental system. For the Tianlong 1, the average stable transformation efficiency is 4.59%, higher than that of control genotypes (Jack and Williams 82), which is enough for further genomic research and genetic engineering. While polymerase chain reaction (PCR), LibertyLink strips, and β-glucuronidase (GUS) staining assays were used to detect the insertion and expression of the transgene, leaves painted with 135 mg/L Basta could efficiently identify the transformants.
Soybean; Agrobacterium-mediated transformation; Genotypes; Stable transgenic efficiency
The development of transgenic mouse lines that selectively label a subset of neurons provides unique opportunities to study detailed neuronal morphology and morphological changes under experimental conditions. In the present study, a mouse line in which a small number of retinal ganglion cells (RGCs) express yellow fluorescent protein (YFP) under control of the Thy-1 promoter was used (Feng et al., 2000). We characterized the number, distribution by retinal region and eccentricity of YFP-labeled RGCs using fluorescence microscopy and StereoInvestigator software (MicroBrightField, VT, USA). Then, we captured images of 4–6 YFP-expressing RGCs from each of 8 retinal regions by confocal microscopy, producing 3-dimensional and flattened data sets. A new semi-automated method to quantify the soma size, dendritic length and dendritic arbor complexity was developed using MetaMorph software (Molecular Devices, PA, USA). Our results show that YFP is expressed in 0.2% of all RGCs. Expression of YFP was not significantly different in central versus peripheral retina, but there were higher number of YFP expressing RGCs in the temporal quadrant than in the nasal. By confocal-based analysis, 58% of RGCs expressing YFP did so at a high level, with the remainder distributed in decreasing levels of brightness. Variability in detailed morphometric parameters was as great between two fellow retinas as in retinas from different mice. The analytic methods developed for this selective YFP expressing RGC model permit quantitative comparisons of parameters relevant to neuronal injury.
mouse; retina; ganglion cell; glaucoma; optic nerve; neuropathy; yellow fluorescent protein
Selenium (Se) deficiency is associated with the occurrence of many diseases. However, excessive Se supplementation, especially with inorganic Se, can result in toxicity. Selenoproteins are the major forms of Se in vivo to exert its biological function. Expression of those selenoproteins, especially with the application of a newly developed system, is thus very important for studying the mechanism of Se in nutrition. The use of Chlamydomonas reinhardtii (C. reinhardtii) as a biological vector to express an heterogeneous protein is still at the initial stages of development. In order to investigate the possibility of using this system to express selenoproteins, human 15-KDa selenoprotein (Sep15), a small but widely distributed selenoprotein in mammals, was chosen for the expression platform test. Apart from the wild-type human Sep15 gene fragment, two Sep15 recombinants were constructed containing Sep15 open reading frame (ORF) and the selenocysteine insertion sequence (SECIS) element from either human Sep15 or C. reinhardtii selenoprotein W1, a highly expressed selenoprotein in this alga. Those Sep15-containing plasmids were transformed into C. reinhardtii CC-849 cells. Results showed that Sep15 fragments were successfully inserted into the nuclear genome and expressed Sep15 protein in the cells. The transgenic and wild-type algae demonstrated similar growth curves in low Se culture medium. To our knowledge, this is the first report on expressing human selenoprotein in green alga.
15-KDa selenoprotein (Sep15); alga; Chlamydomonas reinhardtii (C. reinhardtii); selenium (Se); selenocysteine insertion sequence (SECIS)
Enhanced Depth Imaging (EDI) optical coherence tomography (OCT) provides high-definition cross-sectional images of the choroid in vivo, and hence is used in many clinical studies. However, the quantification of the choroid depends on the manual labelings of two boundaries, Bruch’s membrane and the choroidal-scleral interface. This labeling process is tedious and subjective of inter-observer differences, hence, automatic segmentation of the choroid layer is highly desirable. In this paper, we present a fast and accurate algorithm that could segment the choroid automatically. Bruch’s membrane is detected by searching the pixel with the biggest gradient value above the retinal pigment epithelium (RPE) and the choroidal-scleral interface is delineated by finding the shortest path of the graph formed by valley pixels using Dijkstra’s algorithm. The experiments comparing automatic segmentation results with the manual labelings are conducted on 45 EDI-OCT images and the average of Dice’s Coefficient is 90.5%, which shows good consistency of the algorithm with the manual labelings. The processing time for each image is about 1.25 seconds.
(100.0100) Image processing; (110.4500) Optical coherence tomography; (100.2960) Image analysis; (170.4470) Ophthalmology
The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex®, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9® and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
prostate cancer stem cells; androgen receptor; combination therapy
To evaluate the impacts of the negative lymph nodes (NLNs) count on the prognostic prediction of the ratio of positive and removed lymph nodes (RPL) in cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RHPL).
The positive and negative lymph node counts were calculated for 609 postoperative cervical cancer patients. The 5-year survival rate (5-YSR) was examined according to clinicopathologic variables. Cox regression was used to identify independent prognostic factors.
The NLNs count cutoffs were determined to be 10 and 25 with 5-YSR of 62.8% and 80.5%. The RPL of 13 patients who had the NLNs count of 10 or fewer was >20%. Among 242 patients who had 10 < NLNs count ≤ 25, 194 without positive nodes had the 5-YSR of 77.8%, 31 with 0% < RPL ≤ 5% had the 5-YSR of 3.2%, 15 with RPL > 20% had died when follow-up was completed. Among 354 patients who had NLNs count >25, 185 without positive nodes had the 5-YSR of 87.6%, 6 with 0% < RPL ≤ 5% had the 5-YSR of 25%, 15 with 5% < RPL ≤ 20% had the 5-YSR of 4.5%, and 2 with RPL >20% had died when follow-up was completed. Furthermore, stage, histologic grade and RPL were independently correlated with overall survival of cervical cancer patients after RHPL in the multivariate analysis.
RPL was an independent prognostic factor. The NLNs count is a key factor for improvement of survival prediction of RPL in cervical cancer.
Cervical cancer; Lymph node; Pelvic lymphadenectomy; Prognosis
To study sequential changes in retinal ganglion cell (RGC) morphology in mice after optic nerve crush and after induction of experimental glaucoma.
Nerve crush or experimental glaucoma was induced in mice that selectively express yellow fluorescent protein (YFP) in RGCs. Mice were euthanized 1, 4, and 9 days after crush and 1, 3, and 6 weeks after induction of glaucoma by bead injection. All YFP-RGCs were identified in retinal whole mounts. Then confocal images of randomly selected RGCs were quantified for somal fluorescence brightness, soma size, neurite outgrowth, and dendritic complexity (Sholl analysis).
By 9 days after crush, 98% of RGC axons died and YFP-RGCs decreased by 64%. After 6 weeks of glaucoma, 31% of axons died, but there was no loss of YFP-RGC bodies. All crush retinas combined had significant decreases in neurite outgrowth parameters (P ≤ 0.036, generalized estimating equation [GEE] model) and dendritic complexity was lower than controls (P = 0.017, GEE model). There was no change in RGC soma area after crush. In combined glaucoma data, the RGC soma area was larger than control (P = 0.04, GEE model). At 3 weeks, glaucoma RGCs had significantly larger values for dendritic structure and complexity than controls (P = 0.044, GEE model), but no statistical difference was found at 6 weeks.
After nerve crush, RGCs and axons died rapidly, and dendritic structure decreased moderately in remaining RGCs. Glaucoma caused an increase in RGC dendrite structure and soma size at 3 weeks.
Retinal ganglion cell morphology after optic nerve crush and experimental glaucoma.
Doxorubicin (DOX) is considered as one of the best antineoplastic agents. However, its clinical use is restricted by its associated cardiotoxicity, which is mediated by the production of reactive oxygen species. In this study, 20(S)-ginsenoside Rh2 (Rh2) was explored whether it had protective effects against DOX-induced cardiotoxicity. In vitro study on H9C2 cell line, as well as in vivo investigation in one mouse and one rat model of DOX-induced cardiomyopathy, was carried out. The results showed that pretreatment with Rh2 significantly increased the viability of DOX-injured H9C2 cells. In the mouse model, Rh2 could suppress the DOX-induced release of the cardiac enzymes into serum and improved the occurred pathological changes through ameliorating the decreased antioxidant biomolecules and the cumulated lipid peroxidation malondialdehyde in heart tissues. In the rat model, Rh2 could attenuate the change of ECG resulting from DOX administration. Furthermore, Rh2 enhanced the antitumor activity of DOX in A549 cells. Our findings thus demonstrated that Rh2 pretreatment could effectively alleviate heart injury induced by DOX, and Rh2 might act as a novel protective agent in the clinical usefulness of DOX.
The objective of this study was to measure the biomechanical response of the human posterior sclera in vitro and to estimate the effects of age and glaucoma.
Scleral specimens from 22 donors with no history of glaucoma and 11 donors with a history of glaucoma were excised 3 mm posterior to the equator and affixed to an inflation chamber. Optic nerve cross-sections were graded to determine the presence of axon loss. The time-dependent inflation response was measured in a series of pressure-controlled load–unload tests to 30 mm Hg and creep tests to 15 and 30 mm Hg. Circumferential and meridional strains were computed from the digital image correlation displacements, and midposterior stresses were determined from pressure and deformed geometry.
Among normal specimens, older age was predictive of a stiffer response and a thinner sclera. In the age group 75 to 93, diagnosed glaucoma eyes with axon damage were thicker than normal eyes. Both damaged and undamaged glaucoma eyes had a different strain response in the peripapillary sclera characterized by a stiffer meridional response. Undamaged glaucoma eyes had slower circumferential creep rates in the peripapillary sclera than normal eyes. Glaucoma eyes were not different from normal eyes in stresses and strains in the midposterior sclera.
The observed differences in the biomechanical response of normal and glaucoma sclera may represent baseline properties that contribute to axon damage, or may be characteristics that result from glaucomatous disease.
This work represents the first characterization of the mechanical response of the human normal and glaucoma sclera under near physiological loading conditions. Older age was predictive of a stiffer response. Glaucoma eyes had a stiffer meridional response in the peripapillary sclera than normal eyes.
Hypoxia acts as a plant stress factor, particularly in cucumbers plants under hydroponic culture. Calcium is involved in stress signal transmission and in the growth of plants. To determine the effect of exogenous calcium on hypoxic-responsive proteins in cucumber (Cucumis sativus L. cv. Jinchun No.2) roots, proteomic analysis was performed using two-dimensional electrophoresis (2-DE) and mass spectrometry.
Cucumber roots were used to analyze the influence of hypoxia on plants. The expressions of 38 protein spots corresponding to enzymes were shown to change in response to hypoxia. Of these, 30 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/TOF MS analysis). The proteins were categorized according to functional groups, including glycolysis, the tricarboxylic acid (TCA) cycle, fermentative metabolism, nitrogen metabolism, energy metabolism, protein synthesis and defense against stress. Exogenous calcium appeared to alleviate hypoxic stress via these metabolic and physiological systems. Western blotting was used to analyze the accumulation of alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC); calcium further increased the expression of ADH and PDC under hypoxia. In addition, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the transcript levels of differentially expressed proteins.
Exogenous calcium enhanced the expression of enzymes involved in glycolysis, the TCA cycle, fermentative metabolism, nitrogen metabolism, and reactive oxygen species (ROS) defense in plants under hypoxia. Calcium appears to induce hypoxic tolerance of cucumber seedlings. These phenomena have prompted us to further investigate the mechanisms by which cucumbers respond to exogenous calcium under hypoxia.
Cucumber; Calcium; Hypoxic stress; Proteomics
We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), are elevated, whereas the NOS cofactor tetrahydrobiopterin (BH4) is decreased in Shunt lambs. Our previous studies demonstrated that ADMA decreases heat shock protein–90 (Hsp90) chaperone activity, whereas other studies suggest that guanosine-5′-triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the generation of BH4, may be a client protein for Hsp90. Thus, we determined whether increases in ADMA could alter GCH1 protein and activity. Our data demonstrate that ADMA decreased GCH1 protein, but not mRNA concentrations, in pulmonary arterial endothelial cells (PAECs) because of the ubiquitination and proteasome-dependent degradation of GCH1. We also found that Hsp90–GCH1 interactions were reduced, whereas the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) increased in ADMA-exposed PAECs. The overexpression of CHIP potentiated, whereas a CHIP U-box domain mutant attenuated, ADMA-induced GCH1 degradation and reductions in cellular BH4 concentrations. We also found in vivo that Hsp90/GCH1 interactions are decreased, whereas GCH1–Hsp70 and GCH1–CHIP interactions and GCH1 ubiquitination are increased. Finally, we found that supplementation with l-arginine restored Hsp90–GCH1 interactions and increased both BH4 and NOx concentrations in Shunt lambs. In conclusion, increased concentrations of ADMA can indirectly alter NO signaling through decreased cellular BH4 concentrations, secondary to the disruption of Hsp90–GCH1 interactions and the CHIP-dependent proteasomal degradation of GCH1.
proteasome; ubiquitination; Hsp90; Hsp70; mitochondrial dysfunction
To examine the impact of educational attainment on the incidence of preclinical mobility disability (PCD).
The Women's Health and Aging II Study is a prospective observational cohort study of 436 initially high-functioning community-dwelling women aged 70–79 years at baseline in Baltimore, Maryland. We measured the association of highest attained education level with preclinical mobility disability (PCD) over an 11-year period. PCD is defined as self-reported modification in any of four tasks without reporting difficulty in those tasks. The tasks were walking ½ mile, climbing up steps, doing heavy housework, and getting in/out of bed or chair.
Participants with less than 9 years of education were more likely to acquire incident PCD (hazard ratio: 3.1, 95% confidence interval = 1.2–7.7) than their counterparts with more education after adjusting for income, marital status, number of diseases, and high self-efficacy.
Lower education level is an independent predictor of incident preclinical mobility disability. This association has important implications for primary and secondary prevention and can be easily assessed in clinical encounters.
Health disparities; Mobility; Preclinical disability
When we applied a single pulse of transcranial magnetic stimulation (TMS) to any part of the human head during a saccadic eye movement, the ongoing eye velocity was reduced starting as early as 45ms after the TMS, and lasted around 32ms. The perturbation to the saccade trajectory was not due to a mechanical effect of the lid on the eye (e.g., from blinks). When the saccade involved coordinated movements of both the eyes and the lids, e.g., in vertical saccades, TMS produced a synchronized inhibition of the motor commands to both eye and lid muscles. The TMS induced perturbation of the eye trajectory did not show habituation with repetition, and was present in both pro- and anti-saccades. Despite the perturbation, the eye trajectory was corrected within the same saccade with compensatory motor commands that guided the eyes to the target. This within-saccade correction did not rely on visual input, suggesting that the brain monitored the oculomotor commands as the saccade unfolded, maintained a real time estimate of the position of the eyes, and corrected for the perturbation. TMS disrupted saccades regardless of the location of the coil on the head, suggesting that the coil discharge engages a non-habituating startle-like reflex system. This system affects ongoing motor commands upstream of the oculomotor neurons, possibly at the level of the superior colliculus or omnipause neurons. Therefore, a TMS pulse centrally perturbs saccadic motor commands, which are monitored possibly via efference copy, and are corrected via internal feedback.
saccade accuracy; pause; TMS; startle; omnipause neuron; forward model
Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies.
We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors were identified for twelve symptoms from medical records and the same four factors emerged from analysis of structured interviews. Factor congruencies were high but the correlation of factors between interviews and records were modest (i.e. +0.2 to +0.4).
Structured interviews and medical records are highly concordant for age of onset, and the number and length of episodes, but agree more modestly for individual symptoms and symptom factors. The modesty of these correlations probably arises from multiple factors including i) inconsistency in the definition of the worst episode, ii) inaccuracies in self-report and iii) difficulties in coding medical records where symptoms were recorded solely for clinical purposes.
When environmental or sensory conditions change suddenly, the brain must be capable of learning different behavioral modes to produce accurate movements under multiple circumstances. A form of this dual-state adaptation known as “context-specific adaptation” has been widely investigated using the saccade gain adaptation paradigm in humans. In this study, we asked whether or not context-specific adaptation of saccade gain exists in monkeys and if so to explore its properties. Here, vertical eye position was used as a context cue for adaptation of horizontal saccade gain. We asked for a gain increase in one context and gain decrease in another context, and then determined if a change in the context would invoke switching between the adapted states. After training, our monkeys developed context-specific adaptation: in most cases gain-decrease adaptation could be induced, but there was little or no gain-increase adaptation. This context-specific adaptation developed gradually and switching of gains was evident on the first saccades with each change in context. Along with these results, the retention of an adaptation aftereffect overnight indicates that contextual-specific adaptation in monkeys is not a strategy, but involves a true adaptive process of reorganization in the brain. We suggest that context-specific adaptation in monkeys could be an important tool to provide insights into the mechanisms of saccade adaptation that occurs during the more natural circumstances of daily life.
Saccade; Adaptation; Context; Motor learning; Monkey