The aim of the present study was to investigate the effects of three blood purification methods on fibroblast growth factor-23 (FGF-23) clearance in patients with hyperphosphatemia undergoing maintenance hemodialysis (MHD). In addition, the correlation between serum FGF-23 and phosphorus (Pi) levels and the clinical implications were identified. Sixty-five MHD patients with hyperphosphatemia were randomly divided into three groups: Hemodialysis, HD (n=23); hemodiafiltration, HDF (n=21); and hemodialysis+hemoperfusion, HD+HP (n=21) groups. Serum Pi, FGF-23, blood urea nitrogen, serum creatinine and associated bio-marker levels were measured prior to and following treatment. The expression level of serum FGF-23 was observed to be positively correlated with Pi (r=0.45, P<0.01). The three blood purification methods that were adopted for the present study exhibited significant and effective clearance of serum Pi (P<0.05). The post-treatment serum FGF-23 levels were significantly decreased in the HDF and HD+HP groups (P<0.05). Therefore, HDF may be an effective method for clearing serum FGF-23 in MHD patients exhibiting hyperphosphatemia.
hyperphosphatemia; fibroblast growth factor-23; hemodialysis; hemodiafiltration; hemoperfusion
Although the chemopreventive effect of 5-aminosalicylates on patients with ulcerative colitis has been extensively studied, the results remain controversial. This updated review included more recent studies and evaluated the effectiveness of 5-aminosalicylates use on colorectal neoplasia prevention in patients with ulcerative colitis.
Up to July 2013, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant observational studies (case-control and cohort) about the effect of 5-aminosalicylates on the risk of colorectal neoplasia among patients with ulcerative colitis. The Newcastle-Ottawa Scale was used to assess the quality of studies. Adjusted odds ratios (ORs) were extracted from each study. A random-effects model was used to generate pooled ORs and 95% confidence intervals (95%CI). Publication bias and heterogeneity were assessed.
Seventeen studies containing 1,508 cases of colorectal neoplasia and a total of 20,193 subjects published from 1994 to 2012 were analyzed. 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis (OR 0.63; 95%CI 0.48–0.84). Pooled OR of a higher average daily dose of 5-aminosalicylates (sulfasalazine ≥ 2.0 g/d, mesalamine ≥ 1.2 g/d) was 0.51 [0.35–0.75]. Pooled OR of 5-aminosalicylates use in patients with extensive ulcerative colitis was 1.00 [0.53–1.89].
Our pooled results indicated that 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis, especially in the cases with a higher average daily dose of 5-aminosalicylates use. However, the chemopreventive benefit of 5-aminosalicylates use in patients with extensive ulcerative colitis was limited.
Ventricular tachycardia (VT) is the second most common cause of death in patients with Duchenne muscular dystrophy (DMD). Recent studies have implicated enhanced sarcoplasmic reticulum (SR) Ca2+ leak via ryanodine receptors (RyR2) as a cause of VT in the mdx mouse model of DMD. However, the signaling mechanisms underlying induction of SR Ca2+ leak and VT are poorly understood.
To test whether enhanced CaMKII phosphorylation of RyR2 underlies SR Ca2+ leak and induction of VT in mdx mice.
Programmed electrical stimulation (PES) was performed on anesthetized mice, and confocal imaging of calcium release events in isolated ventricular myocytes.
PES revealed inducible VT in mdx mice, which was inhibited by CaMKII inhibition or mutation S2814A in RyR2. Myocytes from mdx mice exhibited more Ca2+ sparks and Ca2+ waves compared with wild type (WT) mice, in particular at faster pacing rates. Arrhythmogenic Ca2+ waves were inhibited by CaMKII but not PKA inhibition. Moreover, mutation S2814A but not S2808A in RyR2 suppressed spontaneous Ca2+ waves in myocytes from mdx mice.
CaMKII blockade and genetic inhibition of RyR2-S2814 phosphorylation prevent VT induction in a mouse model of DMD. In ventricular myocytes from mdx mice, spontaneous Ca2+ sparks and Ca2+ waves can be suppressed by CaMKII inhibition or mutation S2814A in RyR2. Thus, inhibition of CaMKII-induced SR Ca2+ leak might be a new strategy to prevent arrhythmias in patients with DMD without heart failure.
Cardiac arrhythmias; Ca2+/calmodulin kinase II; mouse model; ryanodine receptor; Duchenne muscular dystrophy; ventricular tachycardia
Peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1α expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1α mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1α expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1α and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1α and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1α in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.
Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist.
Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses.
Decreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP.
Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.
Epithelial-mesenchymal transition (EMT); Lung epithelial cells; Non-neuronal cholinergic system; Signaling pathway
High-fat diets may promote growth, partly through their protein-sparing effects. However, high-fat diets often lead to excessive fat deposition, which may have a negative impact on fish such as poor growth and suppressive immune. Therefore, this study investigated the effects of a fat-rich diet on the mechanisms of fat deposition in the liver. Three-hundred blunt snout bream (Megalobrama amblycephala) juveniles (initial mass 18.00±0.05 g) were fed with one of two diets (5% or 15% fat) for 8 weeks. β-Oxidation capacity and regulation of rate-limiting enzymes were assessed. Large fat droplets were present in hepatocytes of fish fed the high-fat diet. This observation is thought to be largely owing to the reduced capacity for mitochondrial and peroxisomal β-oxidation in the livers of fish fed the high-fat diet, as well as the decreased activities of carnitine palmitoyltransferase (CPT) I and acyl-CoA oxidase (ACO), which are enzymes involved in fatty-acid metabolism. Study of CPT I kinetics showed that CPT I had a low affinity for its substrates and a low catalytic efficiency in fish fed the high-fat diet. Expression of both CPT I and ACO was significantly down-regulated in fish fed the high-fat diet. Moreover, the fatty-acid composition of the mitochondrial membrane varied between the two groups. In conclusion, the attenuated β-oxidation capacity observed in fish fed a high-fat diet is proposed to be owing to decreased activity and/or catalytic efficiency of the rate-limiting enzymes CPT I and ACO, via both genetic and non-genetic mechanisms.
The lymphotoxin-α (LTA), as one of the mediators of inflammation, may play an important role in the pathogenesis of myocardial infarction (MI). Genetic association studies (GAS) that have investigated the association between three common polymorphisms (A252G, G10A and C804A) of the LTA gene and susceptibility to MI have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association of these polymorphisms with susceptibility to MI.
A literature search for eligible GAS published before October 15, 2013 was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and CNKI (China National Knowledge Infrastructure) databases. We performed a meta-analysis of fifteen case-control studies with a total of 22,549 MI patients and 16,105 healthy controls.
For LTA A252G, a borderline significant overall association was found, indicating that GG genotype may confer an increased susceptibility to MI compared to AA and AG genotypes. Based on an ethnicity stratification analysis, a significant association was observed in Asians, but not in Caucasians. For LTA G10A, no significant overall association was found. However, subgroup analysis based on ethnicity suggested that the 10A allele may confer a significant increased susceptibility to MI only in Asian populations. For LTA C804A, the combined results revealed a significantly increased susceptibility to MI for carriers of the 804A allele in both overall analysis and stratified analyses.
This meta-analysis shows that LTA C804A may be associated with an increased susceptibility to MI, whereas LTA A252G and G10A may confer a significant increased susceptibility to MI only in Asians. Thus, these polymorphisms of the LTA gene can probably be used with other genetic markers together to identify individuals at high susceptibility to MI especially in Asians.
The signaling pathway for tumor necrosis factor-α (TNF-α) and its receptors is up-regulated during extracorporeal circulation (ECC), and recruits blood neutrophil into the lung tissue, which results in acute lung injury (ALI). In this study, we evaluated the role of tumor necrosis factor receptor 1 (TNFR1) in ECC-induced ALI by blocking TNF-α binding to TNFR1 with CAY10500. Anesthetized Sprague-Dawley (SD) rats were pretreated intravenously with phosphate buffered saline (PBS) or vehicle (0.3 ml ethanol IV) or CAY10500, and then underwent ECC for 2 h. The oxygenation index (OI) and pulmonary inflammation were assessed after ECC. OI was significantly decreased, while TNF-α and neutrophil in bronchoalveolar lavage fluid (BALF) and plasma TNF-α increased after ECC. Pretreatment of CAY10500 decreased plasma TNF-α level, but did not decrease TNF-α levels and neutrophil counts in BALF or improve OI. Lung histopathology showed significant alveolar congestion, infiltration of the leukocytes in the airspace, and increased thickness of the alveolar wall in all ECC-treated groups. CAY10500 pretreatment slightly reduced leukocyte infiltration in lungs, but did not change the wet/dry ratio in the lung tissue. Blocking TNF-α binding to TNFR1 by CAY10500 intravenously slightly mitigates pulmonary inflammation, but cannot improve the pulmonary function, indicating the limited role of TNFR1 pathway in circulating inflammatory cell in ECC-induced ALI.
Extracorporeal circulation (ECC); Acute lung injury (ALI); Tumor necrosis factor receptor 1 (TNFR1); Tumor necrosis factor-α (TNF-α)
An ovotesticular disorder of sex development (OT-DSD) was rarely found in human. The mechanism causing such condition is poorly understood. We hereby reported a 11-year-old child with OT-DSD and a karyotype 46,XX/46,XY, a single maternal and double paternal genetic contribution to the patient.
Fluorescence in situ hybridization (FISH), blood grouping, HLA (human leukocyte antigen) haplotyping and a genome-wide scanning of lymphocytes with 398 short tandem repeat microsatellite markers were performed to investigate the origin of the cell lines concerned. ABO typing revealed that two populations of red cells were in the patient, which were group A and group B, both from paternal alleles. HLA haplotyping showed the patient had three haplotypes. Haplotype 1 was inherited from maternity, haplotype 2 and 3 were from paternity. The STR microsatellite analysis showed 25 of the 74 fully informative markers in both parents, three alleles were inherited: one of them was from mother, another two were from father. Seventeen of the thirty-eight paternal markers, the patient inherited two paternal alleles. For 121 informative maternal markers, the patient had a single maternal allele. There were two distinct alleles in locus DXS6810 and DXS1073 on X-chromosome, in which one was from the mother and the other from the father.
The patient was a single maternal and double paternal genetic, which was a type of a parthenogenetic division of a maternal haploid nucleus into two identical nuclei, followed by fertilization by two spermatozoa and fusion of the two zygotes into a single individual at the early embryonic stage. To the best of our knowledge, this is the oldest OT-DSD case of parthenogenetic chimerism. These data provide additional evidence that a parthenogenetic maternal and double paternal contribution causes 46,XX/46,XY OT-DSD.
Ovotesticular disorder of sex development; Parthenogenetic chimera; Molecular genetics
To evaluate the expression of dendritic cell-associated C-type lectin-1 (dectin-1) in human corneal epithelial (HCE) cells infected by fungus.
A total of 20 cases of healthy donor corneas were group A, and 20 patients (20 eyes) suffered from fungal keratitis (FK) composed group B. Real-time qPCR and immunohistochemistry were applied to detect dectin-1 expression in corneal epithelium of both groups. HCE cells were cultured with aspergillus fumigatus (AF) antigens in vitro. The expression of dectin-1 mRNA was measured by real-time qPCR at the stimulation of 0, 4, 8 and 24h separately. Dectin-1 protein was detected by immunocytochemistry at 0 and 24h separately.
Dectin-1 expressed in corneal epithelium of normal persons and FK patients. Vitro cellular experiment showed that the expression of dectin-1 mRNA in HCE cells began to increase after stimulation of AF antigens at 4h, and dectin-1 protein expression increased after stimulation at 24h.
Dectin-1 expressed in corneal epithelium of normal persons. AF antigens stimulation can elevate the expression of dectin-1 in HCE cells in vitro.
dectin-1; corneal epithelial cells; fungal keratitis; human
As a photochemical reaction that can stiffen the cornea, corneal collagen cross-linking (CXL) is the only promising method of preventing the progress of keratectasia, such as keratoconus and secondary ectasia following refractive surgery. The aim of CXL is to stabilize the underlying condition, with a small chance of visual improvement. Combining CXL with refractive surgery targeting both stabilization and reshaping of the corneal tissue for visual function improvement is a good treatment option. This review aims to provide a comprehensive and unbiased summary of the published research regarding combined CXL and refractive surgery, including measures and results, to help elucidate the future direction of CXL.
cornea; cross-linking; refractive surgery; keratoconus; ectasia
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, against all class I phosphatidylinositol3-kinase (PI3K) and other members of the PI3K-like kinase family. The study was to determine the effect of AZD8055 on proliferation and apoptosis on Hep-2, a human laryngeal cancer cell line and to investigate the underlying mechanism(s) of action. Hep-2 cells were treated with AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Rhodamine 123 and TUNEL staining were used to determine mitochondrial membrane potential and cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Protein expressions were examined by western blotting. Treatment with AZD8055 inhibited proliferation and induced apoptosis in Hep-2 cells in a dose- and time-dependent manner. During the prolonged treatment with AZD8055, AZD8055 inhibits the mammalian target of rapamycin mTOR. Further experiments showed which signaling cascade p-4EBP1 and substrate EIF4E as well as downstream proteins were down regulated. Furthermore, our study showed that the expression profiles of various BH3-only proteins including Bid, Bad, and Bim, apoptosis regulatory protein cleaved caspase3 was up regulated in a time-dependent manner in Hep-2 cells treated with AZD8055. Thus, in vitro, AZD8055 potently inhibits proliferation and induces apoptosis in head and neck squamous cell carcinoma.
mTOR; AZD8055; Hep-2; apoptosis; laryngeal carcinoma
Context. Polygoni Multiflori Radix (PMR) is originated from the root of Polygonum multiflorum Thunb. and used in oriental countries for centuries. However, little researches pay close attention to the absorption of its major constituents. Objective. Transepithelial transport of TSG, RL, PL, and four anthraquinones is carried out. Materials and Methods. Caco-2 cell monolayer, which represented a well-established model for the study of intestinal transport of nutrients and xenobiotics, was used in this paper. Results. The apparent permeability coefficients (Papp) in the Caco-2 cell monolayers were TSG (2.372 × 10−9) < EG (2.391 × 10−9) < EN (2.483 × 10−9) < PL (4.917 × 10−9) < RN (1.707 × 10−8) < RL (1.778 × 10−8) < AE (1.952 × 10−8). Thus, RN, RL, and AE were considered partly absorbed, while other constituents were hardly absorbed. Discussion and Conclusion. Glycosides showed poor permeabilities than aglycones. In the meantime, TSG and EN gave out poor recovery rates in this assay, which indicated that TSG and EN may accumulate or metabolise in the Caco-2 cells. In silico prediction indicated that Gibbs energy (r = 0.751, p < 0.05) and heat of form (r = 0.701, p < 0.05) were strongly positively correlated with Papp.
Cryptosporidium ubiquitum is an emerging zoonotic pathogen. In the past, it was not possible to identify an association between cases of human and animal infection. We conducted a genomic survey of the species, developed a subtyping tool targeting the 60-kDa glycoprotein (gp60) gene, and identified 6 subtype families (XIIa–XIIf) of C. ubiquitum. Host adaptation was apparent at the gp60 locus; subtype XIIa was found in ruminants worldwide, subtype families XIIb–XIId were found in rodents in the United States, and XIIe and XIIf were found in rodents in the Slovak Republic. Humans in the United States were infected with isolates of subtypes XIIb–XIId, whereas those in other areas were infected primarily with subtype XIIa isolates. In addition, subtype families XIIb and XIId were detected in drinking source water in the United States. Contact with C. ubiquitum–infected sheep and drinking water contaminated by infected wildlife could be sources of human infections.
Cryptosporidiosis; Cryptosporidium; zoonoses; epidemiology; molecular typing,whole genome sequencing; genomics; ruminants; rodents; horse; raccoon; sifaka; parasites; humans
Mu opioid receptor (MOR) is the main site of interaction for major clinical analgesics, particularly morphine. MOR expression is regulated at the transcriptional and post-transcriptional levels. However, the protein expression of the MOR gene is relatively low and the translational control of MOR gene has not been well studied. The 5′-untranslated region (UTR) of the human MOR (OPRM1) mRNA contains four upstream AUG codons (uAUG) preceding the main translation initiation site. We mutated the four uAUGs individually and in combination. Mutations of the third uAUG, containing the same open reading frame, had the strongest inhibitory effect. The inhibitory effect caused by the third in-frame uAUG was confirmed by in vitro translation and receptor-binding assays. Toeprinting results showed that OPRM1 ribosomes initiated efficiently at the first uAUG, and subsequently re-initiated at the in-frame #3 uAUG and the physiological AUG site. This re-initiation resulted in negative expression of OPRM1 under normal conditions. These results indicate that re-initiation in MOR gene expression could play an important role in OPRM1 regulation.
human mu opioid receptor; post-transcriptional regulation; uORF
Sogatella furcifera and Laodelphax striatellus are economically important rice pests in China by acting as vectors of several rice viruses, sucking the phloem sap and blocking the phloem vessels. Ecdysteroid hormone 20-hydroxyecdysone regulates insect development and reproduction. A cytochrome P450 monooxygenase CYP302A1 (22-hydroxylase), encoded by the Halloween gene disembodied (dib), plays a critical role in ecdysteroidogenesis. The objective of this study is to test whether dib genes are potential targets for RNA interference-based management of S. furcifera and L. striatellus. We cloned and characterized Sfdib and Lsdib. The open reading frame regions of dib genes were generated and used for designing and constructing dsRNA fragments. Experiments were conducted using oral delivery of dsdib to investigate the effectiveness of RNAi in S. furcifera and L. striatellus nymphs. Real-time quantitative reverse transcriptase-PCR analysis demonstrated that continuous ingestion of dsdib at the concentration of 0.01, 0.05 and 0.50 mg/ml diminished Sfdib expression levels by 35.9%, 45.1% and 66.2%, and ecdysone receptor (SfEcR) gene mRNA levels by 34.0%, 36.2% and 58.5% respectively in S. furcifera, and decreased Lsdib expression level by 18.8%, 35.8% and 56.7%, and LsEcR mRNA levels by 25.2%, 46.8% and 68.8% respectively in L. striatellus. The reduction in dib and EcR transcript abundance resulted in observable phenotypes. The development of nymphs was impaired and the survival was negatively affected. Our data will enable the development of new insect control strategies and functional analysis of vital genes in S. furcifera and L. striatellus nymphs.
This study aimed to improve skin permeation and deposition of psoralen by using ethosomes and to investigate real-time drug release in the deep skin in rats. We used a uniform design method to evaluate the effects of different ethosome formulations on entrapment efficiency and drug skin deposition. Using in vitro and in vivo methods, we investigated skin penetration and release from psoralen-loaded ethosomes in comparison with an ethanol tincture. In in vitro studies, the use of ethosomes was associated with a 6.56-fold greater skin deposition of psoralen than that achieved with the use of the tincture. In vivo skin microdialysis showed that the peak concentration and area under the curve of psoralen from ethosomes were approximately 3.37 and 2.34 times higher, respectively, than those of psoralen from the tincture. Moreover, it revealed that the percutaneous permeability of ethosomes was greater when applied to the abdomen than when applied to the chest or scapulas. Enhanced permeation and skin deposition of psoralen delivered by ethosomes may help reduce toxicity and improve the efficacy of long-term psoralen treatment.
absorption enhancer; formulation vehicle; nanocarriers; nanoparticles; transdermal
Optical microscopy and multi-particle tracking are used to investigate the cross-correlated diffusion of quasi two-dimensional colloidal particles near an oil-water interface. The behaviors of the correlated diffusion along longitudinal and transverse direction are asymmetric. It is shown that the characteristic length for longitudinal and transverse correlated diffusion are particle diameter and the distance from particle center to the interface, respectively, for large particle separation . The longitudinal and transverse correlated diffusion coefficient and are independent of the colloidal area fraction when , which indicates that the hydrodynamic interactions(HIs) among the particles are dominated by HIs through the surrounding fluid for small . For high area fraction , the power law exponent for the spatial decay of begins to decrease, which suggests the HIs are more contributed from the 2D particle monolayer self for large .
Cyanuric chloride has been found to be an efficient catalyst for the synthesis of 2,3-unsaturated O-glycosides from the reaction of 3,4,6-tri-O-acetyl-D-glucal and a wide range of alcohols in dichloromethane at room temperature. The experimental procedure is simple, and the products are obtained in high yields.
In situ reduction of selenite to elemental selenium (Se(0)), by microorganisms in sediments and soils is an important process and greatly affects the environmental distribution and the biological effects of selenium. However, the mechanism behind such a biological process remains unrevealed yet. Here we use Shewanella oneidensis MR-1, a widely-distributed dissimilatory metal-reducing bacterium with a powerful and diverse respiration capability, to evaluate the involvement of anaerobic respiration system in the microbial selenite reduction. With mutants analysis, we identify fumarate reductase FccA as the terminal reductase of selenite in periplasm. Moreover, we find that such a reduction is dependent on central respiration c-type cytochrome CymA. In contrast, nitrate reductase, nitrite reductase, and the Mtr electron transfer pathway do not work as selenite reductases. These findings reveal a previously unrecognized role of anaerobic respiration reductases of S. oneidensis MR-1 in selenite reduction and geochemical cycles of selenium in sediments and soils.
Neural processes influenced by γ-aminobutyric acid B (GABAB) receptors appear to contribute to acute ethanol sensitivity, including the difference between lines of mice bred for extreme sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effect of ethanol. One goal of the current study was to determine whether selection of the FAST and SLOW lines resulted in changes in GABAB receptor function, since the lines differ in sensitivity to the GABAB receptor agonist baclofen and baclofen attenuates the stimulant response to ethanol in FAST mice. A second goal was to determine whether the baclofen-induced reduction in ethanol stimulation in FAST mice is associated with an attenuation of the mesolimbic dopamine response to ethanol. In Experiment 1, the FAST and SLOW lines were found to not differ in GABAB receptor function (measured by baclofen-stimulated [35S]GTP!S binding) in whole brain or in several regional preparations, except in the striatum in one of the two replicate sets of selected lines. In Experiment 2, baclofen-induced attenuation of the locomotor stimulant response to ethanol in FAST mice was not accompanied by a reduction in dopamine levels in the nucleus accumbens, as measured by microdialysis. These data suggest that, overall, GABAB receptor function does not play an integral role in the genetic difference in ethanol sensitivity between the FAST and SLOW lines. Further, although GABAB receptors do modulate the locomotor stimulant response to ethanol in FAST mice, this effect does not appear to be due to a reduction in tonic dopamine signaling in the nucleus accumbens.
alcohol; stimulation; catecholamine; animal model; selected line; drug abuse
Patients on anti-tuberculosis treatment may develop acute kidney injury (AKI), but little is known about the renal outcome and prognostic factors, especially in an aging population. This study aimed to calculate the incidence of AKI due to anti-TB drugs and analyze the outcomes and predictors of renal recovery.
From 2006 to 2010, patients on anti-TB treatment were identified and their medical records reviewed. Acute kidney injury was defined according to the criteria established by the AKI Network, while renal recovery was defined as a return of serum creatinine to baseline. Predictors of renal recovery were identified by Cox regression analysis.
Ninety-nine out of 1394 (7.1%) patients on anti-TB treatment had AKI. Their median age was 68 years and there was male predominance. Sixty (61%) developed AKI within two months of anti-TB treatment, including 11 (11%) with a prior history of rifampin exposure. Thirty (30%) had co-morbid chronic kidney disease or end-stage renal disease. The median time of renal recovery was 39.6 days (range, 1–180 days). Factors predicting renal recovery were the presence of fever, rash, and gastro-intestinal disturbance at the onset of AKI. Sixty-two of the 71 (87%) patients who recovered from AKI had successful re-introduction or continuation of rifampin.
Renal function impairment is not a rare complication during anti-TB treatment in an elderly population. The presence of fever and rash may be associated with renal recovery. Rifampin can still be used in most patients who recover from AKI.
Acute kidney injury; Anti-tuberculosis drug; Fever; Rash; Rifampin
Chinese menopausal women comprise a large population and the women in it experience menopausal symptoms in many different ways. Their health related quality of life (HRQOL) is not particularly well studied. Our study intends to evaluate the influence of menopause on HRQOL and explore other risk factors for HRQOL in rural China.
An interview study was conducted from June to August 2010 in Beijing based on cross-sectional design. 1,351 women aged 40–59 were included in the study. HRQOL was measured using the EuroQol Group’s 5-domain (EQ5D) questionnaire. Comparison of HRQOL measures (EQ5D index and EQ5D-VAS scores) was done between different menopausal groups. Logistic regression and multiple regression analysis were performed to adjust potential confounders and explore other risk factors for health problems and HRQOL measures.
Postmenopausal women who had menopause for 2–5 years (+1b stage) were more likely to suffer mobility problems (OR = 1.835, p = 0.008) after multiple adjustment. Menopause was also related to impaired EQ5D index and EQ5D-VAS scores after adjustment for age. Among menopausal groups categorized by menopausal duration, a consistent decrement in EQ5D index and EQ5D-VAS scores, that is, worsening HRQOL, was observed (p < 0.05). Multiple regression analysis revealed low education level and physical activity were associated with EQ5D index (β = -0.080, p = 0.003, and β = 0.056, p = 0.040, respectively). Cigarette smoking and chronic disease were associated with EQ5D index (β = -0.135, p < 0.001 and β = -0.104, p < 0.001, respectively) and EQ5D-VAS (β = -0.057, P = 0.034 and β = -0.214, p < 0.001, respectively).
Reduction in physical function was found within the first five years after menopause. Worsening EQ5D index and EQ5D-VAS scores were related to menopause. Education level, physical activity, cigarette smoking, and chronic disease history were associated with HRQOL in middle aged Chinese rural women.