We propose a randomized phase II clinical trial design based on Bayesian adaptive randomization and predictive probability monitoring. Adaptive randomization assigns more patients to a more efficacious treatment arm by comparing the posterior probabilities of efficacy between different arms. We continuously monitor the trial by using the predictive probability. The trial is terminated early when it is shown that one treatment is overwhelmingly superior to others or that all the treatments are equivalent. We develop two methods to compute the predictive probability by considering the uncertainty of the sample size of the future data. We illustrate the proposed Bayesian adaptive randomization and predictive probability design by using a phase II lung cancer clinical trial, and we conduct extensive simulation studies to examine the operating characteristics of the design. By coupling adaptive randomization and predictive probability approaches, the trial can treat more patients with a more efficacious treatment and allow for early stopping whenever sufficient information is obtained to conclude treatment superiority or equivalence. The design proposed also controls both the type I and the type II errors and offers an alternative Bayesian approach to the frequentist group sequential design.
Adaptive randomization; Bayesian inference; Clinical trial ethics; Group sequential method; Posterior predictive distribution; Randomized trial; Type I error; Type II error
Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the PI3K/Akt/mTOR pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor suppressive and promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, ATG depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, over-expression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the ERK/MAPK pathway, and to promote EGF-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.
Autophagy; oncogenic PI3K; proliferation; 3D culture
Primary focal segmental glomerulosclerosis (FSGS) is pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. Currently, there is no practical noninvasive technique to predict different pathological types of glomerulopathies. In this study, the role of urinary metabolomics in the diagnosis and pathogenesis of FSGS was investigated.
NMR-based metabolomics was applied for the urinary metabolic profile in the patients with FSGS (n = 25), membranous nephropathy (MN, n = 24), minimal change disease (MCD, n = 14) and IgA nephropathy (IgAN, n = 26), and healthy controls (CON, n = 35). The acquired data were analyzed using principal component analysis (PCA) followed by orthogonal projections to latent structure discriminant analysis (OPLS-DA). Model validity was verified using permutation tests.
FSGS patients were clearly distinguished from healthy controls and other three types of glomerulopathies with good sensitivity and specificity based on their global urinary metabolic profiles. In FSGS patients, urinary levels of glucose, dimethylamine and trimethylamine increased compared with healthy controls, while pyruvate, valine, hippurate, isoleucine, phenylacetylglycine, citrate, tyrosine, 3-methylhistidine and β-hydroxyisovalerate decreased. Additionally, FSGS patients had lower urine N-methylnicotinamide levels compared with other glomerulopathies.
NMR-based metabonomic approach is amenable for the noninvasive diagnosis and differential diagnosis of FSGS as well as other glomerulopathies, and it could indicate the possible mechanisms of primary FSGS.
Rosiglitazone (RGL), a synthetic agonist for peroxisome proliferator activated receptor γ (PPARγ), exhibits a potent anti-inflammatory activity by attenuating local infiltration of neutrophils and monocytes in the renal interstitium. To evaluate the mechanisms that account for inhibiting inflammatory cells infiltration, we investigated the effect of RGL on chemokines secretion and nuclear factor-kappa B (NF-κB) activation in human renal proximal tubular cells (PTCs). We demonstrated that RGL significantly inhibited lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production in a dose-dependent manner, without appreciable cytotoxicity. Chromatin immunoprecipitation (ChIP) assays clearly revealed that, RGL inhibited p65 binding to IL-8/MCP-1 gene promoters in LPS-stimulated PTCs. Interestingly, further experiments showed RGL reversed LPS-induced nuclear receptor corepressor (NCoR) degradation. In addition, knockdown of protein inhibitor of activated STAT1 (PIAS1), an indispensable small ubiquitin-like modiﬁer (SUMO) ligase, abrogated the effects of RGL on antagonizing LPS-induced IL-8/MCP-1 overexpression and NCoR degradation. These findings suggest that, RGL activates PPARγ SUMOylation, inhibiting NCoR degradation and NF-κB activation in LPS-stimulated PTCs, which in turn decrease chemokines expression. The results unveil a new mechanism triggered by RGL for prevention of tubular inflammatory injury.
Based on ab initio calculations of both the ABC- and AB-stacked graphites, interlayer potentials (i.e., graphene-graphene interaction) are obtained as a function of the interlayer spacing using a modified Möbius inversion method, and are used to calculate basic physical properties of graphite. Excellent consistency is observed between the calculated and experimental phonon dispersions of AB-stacked graphite, showing the validity of the interlayer potentials. More importantly, layer-related properties for nonideal structures (e.g., the exfoliation energy, cleave energy, stacking fault energy, surface energy, etc.) can be easily predicted from the interlayer potentials, which promise to be extremely efficient and helpful in studying van der Waals structures.
The purpose of this work was to evaluate a previously proposed approach that aims to improve the point-spread-function (PSF) of MR spectroscopic imaging (MRSI) in order to avoid corruption by lipid signal arising from neighboring voxels. Retrospective spatial filtering can be used to alter the PSF, however, this either reduces spatial resolution or requires extending the acquisition in k-space at the cost of increased imaging time. Alternatively, the method evaluated here, PSF-Choice, can modify the PSF localization to reduce the contamination from adjacent lipids by conforming the signal response more closely to the desired MRSI voxel grid. This is done without increasing scan time or degrading SNR of important metabolites. PSF-Choice achieves improvements in spatial localization through modifications to the RF excitation pulses. An implementation of this method is reported for MRSI of the prostate, where it is demonstrated that, in 13 of 16 pilot prostate MRSI scans, intra-voxel spectral contamination from lipid was significantly reduced when using PSF-Choice. Phantom studies were also performed that demonstrate, compared to MRSI with standard Fourier phase encoding, out-of-voxel signal contamination of spectra was significantly reduced in MRSI with PSF-Choice.
point-spread-function (PSF); MR spectroscopic imaging (MRSI); prostate imaging; truncation artifact
Multi-shot spiral imaging is a promising alternative to echo-planar imaging for high-resolution diffusion-weighted imaging and diffusion tensor imaging. However, subject motion in the presence of diffusion-weighting gradients causes phase inconsistencies among different shots, resulting in signal loss and aliasing artifacts in the reconstructed images. Such artifacts can be reduced by using a variable-density spiral trajectory or a navigator echo, however at the cost of a longer scan time. Here, a novel iterative phase correction method is proposed to inherently correct for the motion-induced phase errors without requiring any additional scan time. In this initial study, numerical simulations and in vivo experiments are performed to demonstrate that the proposed method can effectively and efficiently correct for spatially linear phase errors caused by rigid-body motion in multi-shot spiral diffusion-weighted imaging of the human brain.
inherent; motion correction; multi-shot; spiral; diffusion-weighted imaging
Maternal executive function and household regulation both are critical aspects of optimal childrearing, but their interplay is not understood. We tested the hypotheses that 1) the link between challenging child conduct problems and harsh parenting would be strongest for mothers with poorer executive function and weakest among those with better executive function, and 2) this mechanism would be further moderated by the degree of household chaos.
The socioeconomically diverse sample included 147 mothers of 3-to-7 year old children. Mothers completed questionnaires and a laboratory assessment of executive function.
Consistent with hypotheses, harsh parenting was linked with child conduct problems only among mothers with poorer executive function. This effect was particularly strong in calm, predictable environments, but was not evident in chaotic environments.
Maternal executive function is critical to minimizing harsh parenting in the context of challenging child behavior, but this self-regulation process may not operate well in chaotic environments.
parenting; executive function; emotion regulation; conduct problems
Parallel MRI techniques reconstruct full-FOV images from undersampled k-space data by using the uncorrelated information from RF array coil elements. One disadvantage of parallel MRI is that the image signal-to-noise ratio (SNR) is degraded because of the reduced data samples and the spatially correlated nature of multiple RF receivers. Regularization has been proposed to mitigate the SNR loss originating due to the latter reason. Since it is necessary to utilize static prior to regularization, the dynamic contrast-to-noise ratio (CNR) in parallel MRI will be affected. In this paper we investigate the CNR of regularized sensitivity encoding (SENSE) acquisitions. We propose to implement regularized parallel MRI acquisitions in functional MRI (fMRI) experiments by incorporating the prior from combined segmented echo-planar imaging (EPI) acquisition into SENSE reconstructions. We investigated the impact of regularization on the CNR by performing parametric simulations at various BOLD contrasts, acceleration rates, and sizes of the active brain areas. As quantified by receiver operating characteristic (ROC) analysis, the simulations suggest that the detection power of SENSE fMRI can be improved by regularized reconstructions, compared to unregularized reconstructions. Human motor and visual fMRI data acquired at different field strengths and array coils also demonstrate that regularized SENSE improves the detection of functionally active brain regions.
fMRI; SENSE; EPI; parallel MRI; brain
Outcome-adaptive randomization (AR) allocates more patients to the better treatments as the information accumulates in the trial. Is it worth to apply outcome-AR in clinical trials? Different views permeate the medical and statistical communities. We provide additional insights to the question by conducting extensive simulation studies. Trials are designed to maintain the type I error rate, achieve a specified power, and provide better treatment to patients. Generally speaking, equal randomization (ER) requires a smaller sample size and yields a smaller number of non-responders than AR by controlling type I and type II errors. Conversely, AR produces a higher overall response rate than ER with or without expanding the trial to the same maximum sample size. When there exist substantial treatment differences, AR can yield a higher overall response rate as well as a lower average sample size and a smaller number of non-responders. Similar results are found for the survival endpoint. The differences between AR and ER quickly diminish with early stopping of a trial due to efficacy or futility. In summary, ER maintains balanced allocation throughout the trial and reaches the specified statistical power with a smaller number of patients in the trial. If the trial’s result is positive, ER may lead to early approval of the treatment. AR focuses on treating patients best in the trial. AR may be preferred when the difference in efficacy between treatments is large or when limited patients are available.
Adaptive and fixed randomization; Bayesian clinical trial design; Efficacy and futility early stopping; Type I error and statistical power; Patient population; Sample size
Previous neuroimaging research has documented that patterns of intrinsic (resting-state) functional connectivity (FC) among brain regions covary with individual measures of cognitive performance. Here, we examined the relation between intrinsic FC and a reaction time (RT) measure of performance, as a function of both age group and task demands. We obtained filtered, event-related functional magnetic resonance imaging (fMRI) data, and RT measures of visual search performance, from 21 younger adults (19–29 years) and 21 healthy, older adults (60–87 years). Age-related decline occurred in the connectivity strength in multiple brain regions, consistent with previous findings. Among eight pairs of regions, across somatomotor, orbitofrontal, and subcortical networks, increasing FC was associated with faster responding (lower RT). Relative to younger adults, older adults exhibited a lower strength of this RT-connectivity relation and greater disruption of this relation by a salient but irrelevant display item (color singleton distractor). Age-related differences in the covariation of intrinsic FC and cognitive performance vary as a function of task demands.
brain connectivity; fMRI; resting state; default mode; behavior-based connectivity analysis; aging; attention; cognition; visual search; reaction time
Ischemic stroke (IS) is a prevalent disease causing a body disability, the third leading cause of death in Taiwan. It shows that the level of intercellular adhesion molecular-1 (ICAM-1) in IS patients is higher than control subjects.
This study is to investigate the possible association of ICAM-1 (G1548A) polymorphism in IS patients.
Materials and Methods:
A total of 646 subjects were enrolled in this study, including 312 IS patients, and 334 controls without a history of symptomatic IS. The ICAM-1 (G1548A) polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. Clinical factors were also determined.
The frequencies of the ICAM-1 (G1548A) polymorphism for G/G, G/A, and A/A were 74.8%, 23.9%, and 0.3%, respectively, in healthy controls, and 62.8%, 32.1%, and 5.1%, respectively, in patients. The frequency of the ICAM-1 (G1548A) A allele (21.2% versus 13.2%, respectively; P = 0.007) and the carriers of the ICAM-1 (G1548A) A allele (37.2% versus 25.2%; P = 0.019, OR 1.76, 95% CI 1.1-2.83) are great in IS patients compared with healthy controls. There is a higher risk of IS associated with homozygosity for the ICAM-1 (G1548A) A allele (AA genotype) compared with the control population (5.1% vs. 0.3%, respectively, P = 0.04; OR 5.1, 95% CI 1.19-21.66). We also observed both hypertension and diabetes has shown a positive association with IS.
The ICAM-1 (G1548A) polymorphism was associated with independent risk factor for the development of IS.
Allele; intercellular adhesion molecular-1; ischemic stroke; polymorphism
We examined the link between household chaos (i.e., noise, clutter, disarray, lack of routines) and maternal executive function (i.e., effortful regulation of attention and memory), and whether it varied as a function of socioeconomic risk (i.e., single parenthood, lower mother and father educational attainment, housing situation, and father unemployment). We hypothesized that: 1) higher levels of household chaos would be linked with poorer maternal executive function, even when controlling for other measures of cognitive functioning (e.g., verbal ability), and 2) this link would be strongest in the most socioeconomically distressed or lowest-socioeconomic status households. The diverse sample included 153 mothers from urban and rural areas who completed a questionnaire and a battery of cognitive executive function tasks and a verbal ability task in the laboratory. Results were mixed for hypothesis 1, and consistent with hypothesis 2. Two-thirds of the variance overlapped between household chaos and maternal executive function, but only in families with high levels of socioeconomic risk. This pattern was not found for chaos and maternal verbal ability, suggesting that the potentially deleterious effects of household chaos may be specific to maternal executive function. The findings implicate household chaos as a powerful statistical predictor of maternal executive function in socioeconomically distressed contexts.
parenting; executive function; environment; socioeconomic status
Aberrant accumulation of transition metals in the brain may have an early and important role in the pathogenesis of several neurodegenerative disorders, including Huntington disease (HD).
To comprehensively evaluate and validate the distribution of metal deposition in the brain using advanced magnetic resonance imaging methods from the premanifest through symptomatic stages of HD.
University imaging center.
Twenty-eight HD expanded gene carriers, 34 patients with symptomatic HD, and 56 age- and sex-matched healthy control subjects were included in the study.
Participants underwent magnetic resonance imaging for the quantification of the phase evolution of susceptibility-weighted images.
Main Outcome Measures
To verify the identity of the metals responsible for the changes in the phase evolution of the susceptibility signal in the brain and to assess correlations with systemic levels. Inductively coupled plasma mass spectrometry was used to measure transition metal concentrations in postmortem brains.
In the basal ganglia, progressive increases in the phase evolution were found in HD, beginning in pre-manifest individuals who were far from expected onset and increasing with proximity to expected onset and thereafter. Increases in the cerebral cortex were regionally selective and present only in symptomatic HD. Increases were verified by excessive deposition of brain iron, but a complex alteration in other transition metals was found.
An important and early role of altered metal homeostasis is suggested in the pathogenesis of HD.
A technique suitable for diffusion tensor imaging (DTI) at high field strengths is presented in this work. The method is based on a periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) k-space trajectory using EPI as the signal readout module, and hence is dubbed PROPELLER EPI. The implementation of PROPELLER EPI included a series of correction schemes to reduce possible errors associated with the intrinsically higher sensitivity of EPI to off-resonance effects. Experimental results on a 3.0 Tesla MR system showed that the PROPELLER EPI images exhibit substantially reduced geometric distortions compared with single-shot EPI, at a much lower RF specific absorption rate (SAR) than the original version of the PROPELLER fast spin-echo (FSE) technique. For DTI, the self-navigated phase-correction capability of the PROPELLER EPI sequence was shown to be effective for in vivo imaging. A higher signal-to-noise ratio (SNR) compared to single-shot EPI at an identical total scan time was achieved, which is advantageous for routine DTI applications in clinical practice.
PROPELLER imaging; EPI; geometric distortions; specific absorption rate; diffusion tensor imaging
In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity.
Magnetic resonance imaging; Brain; Behavior; Adult development; Neuroaxonal damage
BACKGROUND AND PURPOSE
Connectivity mapping based on resting-state fMRI is rapidly developing and this methodology has great potential for clinical applications. However, before resting-state fMRI can be applied for diagnosis, prognosis, and monitoring treatment for an individual patient with neurologic or psychiatric diseases, it is essential to assess its long-term reproducibility and between-subject variations among healthy individuals. The purpose of the study is to (1) quantify the long-term test-retest reproducibility of intrinsic connectivity network (ICN) measures derived from resting-state fMRI, and (2) assess the between-subject variation of ICN measures across the whole brain.
MATERIALS AND METHODS
Longitudinal resting-state fMRI data of six healthy volunteers were acquired from nine scan sessions over a period of more than one year. The within-subject reproducibility and between-subject variation of ICN measures, across 1) the whole brain and 2) major nodes of the default mode network, were quantified with intraclass correlation coefficient (ICC) and coefficient of variance (COV).
Our data show that the long-term test-retest reproducibility of ICN measures is outstanding, with over 70% of the connectivity networks showing an ICC greater than 0.60. COV across six healthy volunteers in this sample was greater than 0.2, suggesting significant between-subject variation.
Our data indicate that resting-state ICN measures (e.g., the correlation coefficients between fMRI signal profiles from two different brain regions) are potentially suitable as biomarkers for monitoring disease progression and treatment effects in clinical trials and individual patients. Because between-subject variation is significant, it may be difficult to use quantitative ICN measures, in their current state, as a diagnostic tool.
A total of 364 optical source–detector pairs were deployed uniformly over a 9 cm × 9 cm probe area initially, and then the total pairs were reduced gradually to 60 in experimental and simulation studies. For each source–detector configuration, three-dimensional (3-D) images of a 1-cm-diameter absorber of different contrasts were reconstructed from the measurements made with a frequency-domain system. The results have shown that more than 160 source–detector pairs are needed to reconstruct the absorption coefficient to within 60% of the true value and appropriate spatial and contrast resolution. However, the error in target depth estimated from 3-D images was more than 1 cm in all source–detector configurations. With the a priori target depth information provided by ultrasound, the accuracy of the reconstructed absorption coefficient was improved by 15% and 30% on average, and the beam width was improved by 24% and 41% on average for high- and low-contrast cases, respectively. The speed of reconstruction was improved by ten times on average.
We have constructed a near-real-time combined imager suitable for simultaneous ultrasound and near-infrared diffusive light imaging and coregistration. The imager consists of a combined hand-held probe and the associated electronics for data acquisition. A two-dimensional ultrasound array is deployed at the center of the combined probe, and 12 dual-wavelength laser source fibers (780 and 830 nm) and 8 optical detector fibers are deployed at the periphery. We have experimentally evaluated the effects of missing optical sources in the middle of the combined probe on the accuracy of the reconstructed optical absorption coefficient and assessed the improvements of a reconstructed absorption coefficient with the guidance of the coregistered ultrasound. The results have shown that, when the central ultrasound array area is in the neighborhood of 2 cm × 2 cm, which corresponds to the size of most commercial ultrasound transducers, the optical imaging is not affected. The results have also shown that the iterative inversion algorithm converges quickly with the guidance of a priori three-dimensional target distribution, and only one iteration is needed to reconstruct an accurate optical absorption coefficient.
To develop an ultrafast MRI-based temperature monitoring method for application during rapid ultrasound exposures in moving organs.
Materials and Methods
A slice selective 90° – 180° pair of RF pulses was used to solicit an echo from a column, which was then sampled with a train of gradient echoes. In a gel phantom, phase changes of each echo were compared to standard gradient-echo thermometry, and temperature monitoring was tested during focused ultrasound sonications. SNR performance was evaluated in vivo in a rabbit brain, and feasibility was tested in a human heart.
The correlation between each echo in the acquisition and MRI-based temperature measurements was good (R=0.98±0.03). A temperature sampling rate of 19 Hz was achieved at 3T in gel phantom. It was possible to acquire the water frequency in the beating heart muscle with 5-Hz sampling during a breath hold.
Ultrafast thermometry via phase or frequency monitoring along single columns was demonstrated. With a temporal resolution around 50 ms, it may be possible to monitor focal heating produced by short ultrasound pulses.
echo-planar magnetic resonance imaging; thermometry; proton resonance frequency shift; MR spectroscopy
Kidney fibrosis is a common process that leads to the progression of kidney diseases. We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have both tubulo-interstitial fibrosis and glomerulosclerosis. We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited SIAH1-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and expression of epithelial-mesenchymal trans-differentiation markers in kidney epithelial cells by activating p53, TGF-β/Smad3, and Wnt/Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 as well as in other animal models of kidney fibrosis. We conclude that HIPK2 is a potential target for anti-fibrosis therapy.
HIPK2; tubular epithelial cells; HIV; fibrosis; systems biology
Mineral and bone disorder (MBD) in patients with chronic kidney disease is associated with increased morbidity and mortality. Studies regarding the status of MBD treatment in developing countries, especially in Chinese dialysis patients are extremely limited.
A cross-sectional study of 1711 haemodialysis (HD) patients and 363 peritoneal dialysis (PD) patients were enrolled. Parameters related to MBD, including serum phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH) were analyzed. The achievement of MBD targets was compared with the results from the Dialysis Outcomes and Practice Study (DOPPS) 3 and DOPPS 4. Factors associated with hyperphosphatemia were examined.
Total 2074 dialysis patients from 28 hospitals were involved in this study. Only 38.5%, 39.6% and 26.6% of them met the Kidney Disease Outcomes Quality Initiative (K/DOQI) defined targets for serum P, Ca and iPTH levels. Serum P and Ca levels were statistically higher (P < 0.05) in the HD patients compared with those of PD patients, which was (6.3 ± 2.1) mg/dL vs (5.7 ± 2.0) mg/dL and (9.3 ± 1.1) mg/dL vs (9.2 ± 1.1) mg/dL, respectively. Serum iPTH level were statistically higher in the PD patients compared with those of HD patients (P = 0.03). The percentage of patients reached the K/DOQI targets for P (37.6% vs 49.8% vs 54.5%, P < 0.01), Ca (38.6% vs 50.4% vs 56.0%, P < 0.01) and iPTH (26.5% vs 31.4% vs 32.1%, P < 0.01) were lower among HD patients, compared with the data from DOPPS 3 and DOPPS 4. The percentage of patients with serum phosphorus level above 5.5 mg/dL was 57.4% in HD patients and 47.4% in PD patients. Age, dialysis patterns and region of residency were independently associated with hyperphosphatemia.
Status of MBD is sub-optimal among Chinese patients receiving dialysis. The issue of hyperphosphatemia is prominent and needs further attention.
End stage renal disease; Mineral and bone disorder; Epidemiology
Three decades ago, the marine-derived compound sinularin was shown to have anti-edematous effects on paw edema induced by carrageenan or adjuvant. To the best of our knowledge, no new studies were conducted to explore the bioactivity of sinularin until we reported the analgesic properties of sinularin based on in vivo experiments. In the present study, we found that sinularin significantly inhibits the upregulation of proinflammatory proteins, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and upregulates the production of transforming growth factor-β (TGF-β) in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells according to western blot analysis. We found that subcutaneous (s.c.) administration of sinularin (80 mg/kg) 1 h before carrageenan injection significantly inhibited carrageenan-induced nociceptive behaviors, including thermal hyperalgesia, mechanical allodynia, cold allodynia, and hindpaw weight-bearing deficits. Further, s.c. sinularin (80 mg/kg) significantly inhibited carrageenan-induced microglial and astrocyte activation as well as upregulation of iNOS in the dorsal horn of the lumbar spinal cord. Moreover, s.c. sinularin (80 mg/kg) inhibited carrageenan-induced tissue inflammatory responses, redness and edema of the paw, and leukocyte infiltration. The results of immunohistochemical studies indicate that s.c. sinularin (80 mg/kg) could upregulate production of TGF-β1 in carrageenan-induced inflamed paw tissue. The present results demonstrate that systemic sinularin exerts analgesic effects at the behavioral and spinal levels, which are associated with both inhibition of leukocyte infiltration and upregulation of TGF-β1.
sinularin; carrageenan; inflammatory pain; spinal neuroinflammation; transforming growth factor-β1; natural marine compound