With parallels to concussive mild traumatic brain injury (mTBI) occurring in humans, anesthetized mice subjected to a single 30 g weight drop mTBI event to the right parietal cortex exhibited significant diffuse neuronal degeneration that was accompanied by delayed impairments in recognition and spatial memory. To elucidate the involvement of reversible p53-dependent apoptosis in this neuronal loss and associated cognitive deficits, mice were subjected to experimental mTBI followed by the systemic administration of the tetrahydrobenzothiazole p53 inactivator, PFT-α, or vehicle. Neuronal loss was quantified immunohistochemically at 72 hr. post-injury by the use of fluoro-Jade B and NeuN within the dentate gyrus on both sides of the brain, and recognition and spatial memory were assessed by novel object recognition and Y-maze paradigms at 7 and 30 days post injury. Systemic administration of a single dose of PFT-α 1 hr. post-injury significantly ameliorated both neuronal cell death and cognitive impairments, which were no different from sham control animals. Cellular studies on human SH-SY5Y cells and rat primary neurons challenged with glutamate excitotoxicity and H2O2 induced oxidative stress, confirmed the ability of PFT-α and a close analog to protect against these TBI associated mechanisms mediating neuronal loss. These studies suggest that p53-dependent apoptotic mechanisms underpin the neuronal and cognitive losses accompanying mTBI, and that these are potentially reversible by p53 inactivation.
Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in TH2 priming and polarization.
We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection.
Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12.
OX40L was expressed mainly on CD11c+MHC class II (MHCII)+CD11b+ DCs but not CD103+ DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection.
In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and TH2 polarization, accounting for the enhanced response on reinfection.
Respiratory syncytial virus; OX40 ligand; thymic stromal lymphopoietin
Heat shock proteins (HSPs), produced in response to stress are suppressive in disease models. We previously showed that Mycobacterium leprae HSP65 prevented development of airway hyperresponsiveness and inflammation in mice. Our goal here was to define the mechanism responsible for the suppressive effects of HSP. In one in vivo approach, BALB/c mice were sensitized to ovalbumin (OVA) followed by primary OVA challenges. Several weeks later, HSP65 was administered prior to a single, provocative secondary challenge. In a second in vivo approach, the secondary challenge was replaced by intratracheal instillation of allergen-pulsed bone marrow-derived dendritic cells (BMDCs). The in vitro effects of HSP65 on BMDCs were examined in co-culture experiments with CD4+ T cells. In vivo, HSP65 prevented development of airway hyperresponsiveness and inflammation. As well, Th1 cytokine levels in bronchoalveolar lavage (BAL) fluid were increased. In vitro, HSP65 induced notch receptor ligand Delta1 expression on BMDCs and HSP65-treated BMDCs skewed CD4+ T cells to Th1 cytokine production. Thus, HSP65-induced effects on allergen-induced airway hyperresponsiveness and inflammation were associated with increased Delta 1 expression on DCs, modulation of DC function, and CD4+ Th1 cytokine production.
HSP65; asthma; dendritic cells; T cells
Vitamin D is suggested to have protective effects against type 1 diabetes. However, the results from observational studies have been inconsistent. We aimed to examine their association by conducting a meta-analysis of observational studies. Multiple databases were searched in June 2013 to identify relevant studies including both case-control and cohort studies. Either a fixed- or random-effects model was used to calculate the pooled risk estimate. We identified eight studies (two cohort studies and six case-control studies) on vitamin D intake during early life and three studies (two cohort studies and one case-control study) on maternal vitamin D intake during pregnancy. The pooled odds ratio for type 1 diabetes comparing vitamin D supplementation with non-supplementation during early life was 0.71 (95% confidence interval [CI], 0.51–0.98). Similar results were observed in the case-control subgroup analysis but not in the cohort subgroup analysis. The pooled odds ratio with maternal intake of vitamin D during pregnancy was 0.95 (95% CI, 0.66–1.36). In conclusion, vitamin D intake during early life may be associated with a reduced risk of type 1 diabetes. However, there was not enough evidence for an association between maternal intake of vitamin D and risk of type 1 diabetes in the offspring.
vitamin D; type 1 diabetes; early life; pregnancy; meta-analysis
Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. There is evidence that dihydrocapsaicin (DHC) can exert multiple pharmacological and physiological effects. Here, we explored the effect of DHC in atherosclerotic plaque progression in apoE−/− mice fed a high-fat/high-cholesterol diet.
Methods and Results
apoE−/− mice were randomly divided into two groups and fed a high-fat/high-cholesterol diet with or without DHC for 12 weeks. We demonstrated that cellular cholesterol content was significantly decreased while apoA1-mediated cholesterol efflux was significantly increased following treatment with DHC in THP-1 macrophage-derived foam cells. We also observed that plasma levels of TG, LDL-C, VLDL-C, IL-1β, IL-6, TNF-α and CRP were markedly decreased while plasma levels of apoA1 and HDL-C were significantly increased, and consistent with this, atherosclerotic lesion development was significantly inhibited by DHC treatment of apoE−/− mice fed a high-fat/high-cholesterol diet. Moreover, treatment with both LXRα siRNA and PPARγ siRNA made the up-regulation of DHC on ABCA1, ABCG1, ABCG5, SR-B1, NPC1, CD36, LDLR, HMGCR, apoA1 and apoE expression notably abolished while made the down-regulation of DHC on SRA1 expression markedly compensated. And treatment with PPARγ siRNA made the DHC-induced up-regulation of LXRα expression notably abolished while treatment with LXRα siRNA had no effect on DHC-induced PPARγ expression.
These observations provide direct evidence that DHC can significantly decrease atherosclerotic plaque formation involving in a PPARγ/LXRα pathway and thus DHC may represent a promising candidate for a therapeutic agent for the treatment or prevention of atherosclerosis.
This study aims to investigate the clinicopathologic significance of lymphatic vessel invasion (LVI) labeled by D2-40 monoclonal antibody in esophageal squamous cell carcinoma (ESCC).
Immunohistochemical assay was used to detect the expression of D2-40 and LVI in 107 ESCC patients. Then, the correlation between the clinicopathologic feature and the overall survival time of the patients was analyzed.
The lymph node metastasis rates were 70% and 21% in the LVI-positive and LVI-negative groups, respectively. The nodal metastasis rate was higher in the LVI-positive group than in the LVI-negative group. Multivariate regression analysis showed that LVI was related to nodal metastasis (P<0.001). The median survival time of the patients was 26 and 43 months in the LVI-positive and LVI-negative groups, respectively. Although univariate regression analysis showed significant difference between the two groups (P=0.014), multivariate regression analysis revealed that LVI was not an independent prognostic factor for overall survival in the ESCC patients (P=0.062). Lymphatic node metastasis (P=0.031), clinical stage (P=0.019), and residual tumor (P=0.026) were the independent prognostic factors.
LVI labeled by D2-40 monoclonal antibody is a risk factor predictive of lymph node metastasis in ESCC patients.
Esophageal squamous cell carcinoma; lymphatic vessel invasion; D2-40; lymph node metastasis; prognosis
We evaluated retrospectively the early and midterm results of using veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support in patients undergoing valvular surgery.
A total of 87 patients undergoing valvular surgery received VA-ECMO due to refractory postcardiotomy cardiogenic shock (PCS), who were eligible for inclusion were enrolled in this study. Preoperative, perioperative, and postoperative variables were assessed and analyzed for possible associations with mortality in hospital and after discharge.
The mean age, additive EuroSCORE, and left ventricular ejection fraction (LVEF) for all patients was 65±7 years, 6.1±1.9 points, and 46% ±12%, respectively. The mean duration of VA-ECMO support was 61±37 hours. Intra-aortic balloon pumps (IABP) were implanted in 47.1% of patients. Weaning from VA-ECMO was successful in 59% of patients, and 49% were discharged. Multivariate analysis revealed that being >65 years old (odds ratio [OR], 2.75), receiving postoperative renal replacement treatment (OR, 2.47), having a peak lactate level ≥12 mmol L–1 (OR, 2.18), and receiving VA-ECMO for >60 hours (OR, 3.2) were independent predictors of in-hospital mortality. IABP support (OR, 0.46) was protective. In addition, persistent heart failure with an LVEF <40% was an independent predictor of mortality after discharge.
VA-ECMO is an acceptable technique for the treatment of PCS in patients undergoing valvular surgery, who would otherwise die. It is justified by the good long-term outcomes of hospital survivors, but the use of VA-ECMO must be decided on an individual risk profile basis because of high morbidity and mortality rates.
Calmodulin (CaM) is a major calcium sensor in all eukaryotes. It binds calcium and modulates the activity of a wide range of downstream proteins in response to calcium signals. However, little is known about the CaM gene family in Solanaceous species, including the economically important species, tomato (Solanum lycopersicum), and the gene silencing model plant, Nicotiana benthamiana. Moreover, the potential function of CaM in plant disease resistance remains largely unclear.
We performed genome-wide identification of CaM gene families in Solanaceous species. Employing bioinformatics approaches, multiple full-length CaM genes were identified from tomato, N. benthamiana and potato (S. tuberosum) genomes, with tomato having 6 CaM genes, N. benthamiana having 7 CaM genes, and potato having 4 CaM genes. Sequence comparison analyses showed that three tomato genes, SlCaM3/4/5, two potato genes StCaM2/3, and two sets of N. benthamiana genes, NbCaM1/2/3/4 and NbCaM5/6, encode identical CaM proteins, yet the genes contain different intron/exon organization and are located on different chromosomes. Further sequence comparisons and gene structural and phylogenetic analyses reveal that Solanaceous species gained a new group of CaM genes during evolution. These new CaM genes are unusual in that they contain three introns in contrast to only a single intron typical of known CaM genes in plants. The tomato CaM (SlCaM) genes were found to be expressed in all organs. Prediction of cis-acting elements in 5' upstream sequences and expression analyses demonstrated that SlCaM genes have potential to be highly responsive to a variety of biotic and abiotic stimuli. Additionally, silencing of SlCaM2 and SlCaM6 altered expression of a set of signaling and defense-related genes and resulted in significantly lower resistance to Tobacco rattle virus and the oomycete pathogen, Pythium aphanidermatum.
The CaM gene families in the Solanaceous species tomato, N. benthamiana and potato were identified through a genome-wide analysis. All three plant species harbor a small set of genes that encode identical CaM proteins, which may manifest a strategy of plants to retain redundancy or enhanced quantitative gene function. In addition, Solanaceous species have evolved one new group of CaM genes during evolution. CaM genes play important roles in plant disease resistance to a variety of pathogens.
Calcium; Calmodulin; Gene Structure; Phylogenetic Analysis; Defense; Resistance; Tomato; Nicotiana Benthamiana; Potato
Malignancy with liver metastasis plays an important role in daily oncology practice, especially for primary cancers of the gastrointestinal tract and hepatopancreatobiliary system. On account of the dual vascular supply system and the fact that most metastatic liver tumors are supplied by the hepatic artery, hepatic artery infusion chemotherapy (HAIC) is an appealing method for the treatment of liver metastases. Herein, we summarize recent study results reported in the literature regarding the use of HAIC for metastatic liver tumors, with special focus on colorectal cancer.
This study explores whether caregivers follow the discourse-pragmatic principle of information status of referents (given vs. new) in their gestures and how children respond to their caregivers’ gestures. Chinese and American caregivers were videotaped while interacting spontaneously with their children. Their speech and gestures were coded for referential expressions. Even though Chinese caregivers gestured more often than American caregivers, we found that both groups produced more gestures when asking their children to identify new referents than when asking their children to identify given referents. In addition, both groups of children were sensitive to the gestures accompanying new referents and using these gestures to identify the referents. Thus, we conclude that gesture serves as a potential cue for both caregivers and children to identify referents according to the discourse-pragmatic principle of information status.
Pim kinases are a family of serine/threonine kinases whose activity can be induced by cytokines involved in allergy and asthma. These kinases play a role in cell survival and proliferation, but have not been examined, to the best of our knowledge, in the development of allergic disease. This study sought to determine the role of Pim1 kinase in the development of allergic airway responses. Mice were sensitized and challenged with antigen (primary challenge), or were sensitized, challenged, and rechallenged with allergen in a secondary model. To assess the role of Pim1 kinase, a small molecule inhibitor was administered orally after sensitization and during the challenge phase. Airway responsiveness to inhaled methacholine, airway and lung inflammation, cell composition, and cytokine concentrations were assessed. Lung Pim1 kinase concentrations were increased after ovalbumin sensitization and challenge. In the primary allergen challenge model, treatment with the Pim1 kinase inhibitor after sensitization and during airway challenges prevented the development of airway hyperresponsiveness, eosinophilic airway inflammation, and goblet cell metaplasia, and increased Th2 cytokine concentrations in bronchoalveolar fluid in a dose-dependent manner. These effects were also demonstrated after a secondary allergen challenge, where lung allergic disease was established before treatment. After treatment with the inhibitor, a significant reduction was evident in the number of CD4+ and CD8+ T cells and concentrations of cytokines in the airways. The inhibition of Pim1 kinase was effective in preventing the development of airway hyperresponsiveness, airway inflammation, and cytokine production in allergen-sensitized and allergen-challenged mice. These data identify the important role of Pim1 kinase in the full development of allergen-induced airway responses.
airway hyperresponsiveness; inflammation; Pim1 kinase; T cells
Nanoporous materials such as Mobil composite material number 41 (MCM-41) are attractive for applications such as catalysis, adsorption, supports, and carriers. Green synthesis of MCM-41 is particularly appealing because the chemical reagents are useful and valuable. We report on the eco-friendly synthesis of MCM-41 nanoporous materials via multi-cycle approach by re-using the non-reacted reagents in supernatant as mother liquor after separating the solid product. This approach was achieved via minimal requirement of chemical compensation where additional fresh reactants were added into the mother liquor followed by pH adjustment after each cycle of synthesis. The solid product of each successive batch was collected and characterized while the non-reacted reagents in supernatant can be recovered and re-used to produce subsequent cycle of MCM-41. The multi-cycle synthesis is demonstrated up to three times in this research. This approach suggests a low cost and eco-friendly synthesis of nanoporous material since less waste is discarded after the product has been collected, and in addition, product yield can be maintained at the high level.
MCM-41; Green synthesis; Mother liquor; Chemical compensation; Chemical waste
Serum preptin levels among subjects with different bone mineral densities (BMD) were measured and investigated to determine the correlation between BMD and bone-metabolic markers.
Approximately 52 elderly male patients with osteoporosis, 50 elderly men with osteopaenia, and 31 age-matched normal bone mass controls participated in the study. The serum preptin levels and bone metabolic markers were measured by enzyme-linked immunosorbent assay. The relationships between preptin levels, BMD, and metabolic parameters were also assessed.
The serum preptin level was the lowest in the osteoporosis group and positively correlated with BMD. All the bone formation markers in the osteoporosis and osteopaenia groups were significantly reduced compared with those in the normal group. Serum preptin level was positively correlated with all the bone formation markers, whereas no correlation was observed with the bone resorption marker TRACP-5b.
Serum preptin levels are decreased in osteoporosis and osteopaenia patients and positively correlated with BMD. Therefore, preptin is involved in the pathogenesis of osteoporosis, probably through bone formation rather than bone resorption.
Preptin; Osteoporosis; Bone density; Bone metabolic marker
MicroRNAs (miRNAs, miRs) have the potential to control stem cells fate decisions. The cardiac- and skeletal-muscle-specific miRNA, miR-1, can regulate embryonic stem cells differentiation to cardiac lineage by suppressing gene expression of alternative lineages. Accordingly, we hypothesized that overexpression of miR-1 may also promote cardiac gene expression in mesenchymal stem cells. Since Notch signaling could inhibit muscle differentiation, a process in contrast with the effect of miR-1, miR-1-mediated repression of Notch signaling may contribute to the observed effects of miR-1 in mesenchymal stem cells. Thus, mesenchymal stem cells were infected by lentiviral vectors carrying miR-1, and cells expressing miR-1 were selected. Alterations in Notch signaling and cardiomyocyte markers, Nkx2.5, GATA-4, cTnT, and CX43, were identified by Western blot in the infected cells on days 1, 7, and 14. Our study showed that the downstream target molecule of Notch pathway, Hes-1, was obviously decreased in mesenchymal stem cells modified with miR-1, and overexpression of miR-1 promotes the specific cardiac gene expression in the infected cells. Knockdown of Hes-1 leads to the same effects on cell lineage decisions. Our results indicated that miR-1 promotes the differentiation of MSCs into cardiac lineage in part due to negative regulation of Hes-1.
Combining carbon nanotubes (CNTs), graphene or conducting polymers with conventional silicon wafers leads to promising solar cell architectures with rapidly improved power conversion efficiency until recently. Here, we report CNT-Si junction solar cells with efficiencies reaching 15% by coating a TiO2 antireflection layer and doping CNTs with oxidative chemicals, under air mass (AM 1.5) illumination at a calibrated intensity of 100 mW/cm2 and an active device area of 15 mm2. The TiO2 layer significantly inhibits light reflectance from the Si surface, resulting in much enhanced short-circuit current (by 30%) and external quantum efficiency. Our method is simple, well-controlled, and very effective in boosting the performance of CNT-Si solar cells.
Emerging epidemiological evidence suggests that higher magnesium intake may reduce diabetes incidence. We aimed to examine the association between magnesium intake and risk of type 2 diabetes by conducting a meta-analysis of prospective cohort studies.
RESEARCH DESIGN AND METHODS
We conducted a PubMed database search through January 2011 to identify prospective cohort studies of magnesium intake and risk of type 2 diabetes. Reference lists of retrieved articles were also reviewed. A random-effects model was used to compute the summary risk estimates.
Meta-analysis of 13 prospective cohort studies involving 536,318 participants and 24,516 cases detected a significant inverse association between magnesium intake and risk of type 2 diabetes (relative risk [RR] 0.78 [95% CI 0.73–0.84]). This association was not substantially modified by geographic region, follow-up length, sex, or family history of type 2 diabetes. A significant inverse association was observed in overweight (BMI ≥25 kg/m2) but not in normal-weight individuals (BMI <25 kg/m2), although test for interaction was not statistically significant (Pinteraction = 0.13). In the dose-response analysis, the summary RR of type 2 diabetes for every 100 mg/day increment in magnesium intake was 0.86 (95% CI 0.82–0.89). Sensitivity analyses restricted to studies with adjustment for cereal fiber intake yielded similar results. Little evidence of publication bias was observed.
This meta-analysis provides further evidence supporting that magnesium intake is significantly inversely associated with risk of type 2 diabetes in a dose-response manner.
Maternal nutrition has critical effects on the developing structures and functions of the fetus. Malnutrition during pregnancy can result in low birth weight and small for gestational age babies, increase risk for infection, and impact the immune system. Long-chain polyunsaturated fatty acids (PUFAs) have been reported to have immunomodulatory effects. Decreased consumption of omega-6 PUFAs, in favor of more anti-inflammatory omega-3 PUFAs in modern diets, has demonstrated the potential protective role of omega-3 PUFAs in allergic and respiratory diseases. In this paper, we examine the role of PUFAs consumption during pregnancy and early childhood and its influence on allergy and respiratory diseases. PUFAs act via several mechanisms to modulate immune function. Omega-3 PUFAs may alter the T helper (Th) cell balance by inhibiting cytokine production which in turn inhibits immunoglobulin E synthesis and Th type 2 cell differentiation. PUFAs may further modify cellular membrane, induce eicosanoid metabolism, and alter gene expression. These studies indicate the benefits of omega-3 PUFAs supplementation. Nevertheless, further investigations are warranted to assess the long-term effects of omega-3 PUFAs in preventing other immune-mediated diseases, as well as its effects on the later immunodefense and health status during early growth and development.
The effect of reaction temperature on the synthesis of graphitic thin film on nickel substrate was investigated in the range of 400°C to 1,000°C. Amorphous carbon (a-C) film was obtained at 400°C on nickel foils by chemical vapor deposition; hybrid films of multilayer graphene (MLG) and a-C were synthesized at a temperature of 600°C, while MLG was obtained at temperatures in excess of 800°C. Schottky-junction solar cell devices prepared using films produced at 400°C, 600°C, 800°C, and 1,000°C coupled with n-type Si demonstrate power conversion efficiencies of 0.003%, 0.256%, 0.391%, and 0.586%, respectively. A HNO3 treatment has further improved the efficiencies of the corresponding devices to 0.004%, 1.080%, 0.800%, and 0.820%, respectively. These films are promising materials for application in low-cost and simple carbon-based solar cells.
Graphene; Amorphous carbon; Temperature effect; Nickel foil; Solar cell; HNO3 treatment
Human platelet antigens (HPA) are determinant in several platelet-specific alloimmune disorders, such as neonatal alloimmune thrombocytopenia, post-transfusion purpura and platelet transfusion refractoriness. The distribution of HPA systems in the Malaysian population is not known. Defining the patterns of HPA systems provides a basis for risk assessment and management of the above complications.
Materials and methods.
The aim of this study was to investigate the distribution of HPA -1 to -6 and -15 in the three major ethnic groups (Malay, Chinese and Indian) in the Malaysian population. A total of 600 random donor samples, 200 from each of the three ethnic groups, were genotyped by means of real time polymerase chain reaction (PCR) with hydrolysis probes and PCR-restriction fragment length polymorphism (PCR-RFLP).
The most common genotype observed in this study was HPA-1a/1a-2a/2a-3a/3b-4a/4a-5a/5a-6a/6a-15a/15b (17%) followed by HPA-1a/1a-2a/2a-3a/3a-4a/4a-5a/5a-6a/6a-15a/15b (14.33%). The allele frequencies of HPA in Malays and Chinese were found to be similar those of other East and South-East Asian populations, while those of Indians were comparable to the frequencies found in Europeans.
The results of this study have been useful for determining the distribution of HPA polymorphisms in this region and for potential clinical implications.
HPA; genotyping; Malay; Southeast Asia
Vernalization-induced flowering is a cold-relevant adaptation in many species, but little is known about the genetic basis behind in Orchidaceae species. Here, we reported a collection of 15017 expressed sequence tags (ESTs) from the vernalized axillary buds of an Orchidaceae species, Dendrobium nobile, which were assembled for 9616 unique gene clusters. Functional enrichment analysis showed that genes in relation to the responses to stresses, especially in the form of low temperatures, and those involving in protein biosynthesis and chromatin assembly were significantly overrepresented during 40 days of vernalization. Additionally, a total of 59 putative flowering-relevant genes were recognized, including those homologous to known key players in vernalization pathways in temperate cereals or Arabidopsis, such as cereal VRN1, FT/VRN3, and Arabidopsis AGL19. Results from this study suggest that the networks regulating vernalization-induced floral transition are conserved, but just in a part, in D. nobile, temperate cereals, and Arabidopsis.
We present the photovoltaic properties of heterojunctions made from single-walled carbon nanotube (SWNT) fibers and n-type silicon wafers. The use of the opaque SWNT fiber allows photo-generated holes to transport along the axis direction of the fiber. The heterojunction solar cells show conversion efficiencies of up to 3.1% (actual) and 10.6% (nominal) at AM1.5 condition. In addition, the use of strong, environmentally benign carbon nanotube fibers provides excellent structural stability of the photovoltaic devices.
carbon nanotubes; fibers; heterojunction; solar cells
Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route.
ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 μg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry.
Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 μg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 μg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-α, IL-1β, and IL-6 production 1, 3 and 7 days post-ICH.
Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen.
anti-neuroinflammation; brain edema; intracerebral hemorrhage; urocortin
Epigenetic variation describes heritable differences that are not attributable to changes in DNA sequence. There is the potential for pure epigenetic variation that occurs in the absence of any genetic change or for more complex situations that involve both genetic and epigenetic differences. Methylation of cytosine residues provides one mechanism for the inheritance of epigenetic information. A genome-wide profiling of DNA methylation in two different genotypes of Zea mays (ssp. mays), an organism with a complex genome of interspersed genes and repetitive elements, allowed the identification and characterization of examples of natural epigenetic variation. The distribution of DNA methylation was profiled using immunoprecipitation of methylated DNA followed by hybridization to a high-density tiling microarray. The comparison of the DNA methylation levels in the two genotypes, B73 and Mo17, allowed for the identification of approximately 700 differentially methylated regions (DMRs). Several of these DMRs occur in genomic regions that are apparently identical by descent in B73 and Mo17 suggesting that they may be examples of pure epigenetic variation. The methylation levels of the DMRs were further studied in a panel of near-isogenic lines to evaluate the stable inheritance of the methylation levels and to assess the contribution of cis- and trans- acting information to natural epigenetic variation. The majority of DMRs that occur in genomic regions without genetic variation are controlled by cis-acting differences and exhibit relatively stable inheritance. This study provides evidence for naturally occurring epigenetic variation in maize, including examples of pure epigenetic variation that is not conditioned by genetic differences. The epigenetic differences are variable within maize populations and exhibit relatively stable trans-generational inheritance. The detected examples of epigenetic variation, including some without tightly linked genetic variation, may contribute to complex trait variation.
Heritable variation within a species provides the basis for natural and artificial selection. A substantial portion of heritable variation is based on alterations in DNA sequence among individuals and is termed genetic variation. There is also evidence for epigenetic variation, which refers to heritable differences that are not caused by DNA sequence changes. Methylation of cytosine residues provides one molecular mechanism for epigenetic variation in many eukaryotic species. The genome-wide distribution of DNA methylation was assessed in two different inbred genotypes of maize to identify differentially methylated regions that may contribute to epigenetic variation. There are hundreds of genomic regions that have differences in DNA methylation levels in these two different genotypes, including methylation differences in regions without genetic variation. By studying the inheritance of the differential methylation in near-isogenic progeny of the two inbred lines, it is possible to demonstrate relatively stable inheritance of epigenetic variation, even in the absence of DNA sequence changes. The epigenetic variation among individuals of the same species may provide important contributions to phenotypic variation within a species even in the absence of genetic differences.
The effects of aging on the electroencephalogram (EEG) power spectra of 8- and 60-week-old Wistar–Kyoto rats were examined during the waking baseline and treadmill exercise. Using continuous and simultaneous recordings of EEG and electromyogram signals, this study demonstrated that the alpha (10–13 Hz), theta (6–10 Hz), and delta (0.5–4 Hz) powers of the EEG were significantly lower in older rats as compared with young rats during the waking baseline. In the young rats, treadmill exercise resulted promptly in a higher alpha power, higher theta power, and higher theta power percentage as compared with the waking baseline. In the aged rats, treadmill exercise only resulted in a higher theta power and higher theta power percentage. During the treadmill exercise, however, the aged rats still showed a significantly lower exercise-evoked theta power change than the young rats. These results suggested that aging is accompanied by lower EEG activities during waking and this also is accompanied by an attenuated response of the brain to exercise in the rat.
EEG spectra; Waking status; Treadmill exercise; Aging; During exercise; Theta power of the EEG
Rationale: Respiratory syncytial virus (RSV) bronchiolitis in infants may be followed by the development of asthma-like symptoms. Age at first infection dictates consequences upon reinfection. Reinfection of mice initially exposed as neonates to RSV enhanced development of airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus hyperproduction. RSV lower respiratory tract disease is associated with activation of the leukotriene pathway.
Objectives: To determine the effects of montelukast (MK), a cysteinyl leukotriene (cysLT) receptor antagonist, in primary and secondary RSV-infected newborn and adult mice.
Methods: BALB/c mice were infected with RSV at 1 week (neonate) or 6 to 8 weeks (adult) of age and reinfected 5 weeks later. MK was administered 1 day before the initial infection and through Day 6 after infection. Seven days after primary or secondary infection, airway function was assessed by lung resistance to increasing doses of inhaled methacholine; lung inflammation, goblet cell metaplasia, and cytokine levels in bronchoalveolar lavage fluid were monitored.
Measurements and Main Results: RSV infection induced cysLT release in bronchoalveolar lavage fluid. MK decreased RSV-induced AHR, airway inflammation, and increased IFN-γ production in primary infected adult and neonatal mice. MK, administered during initial infection of neonates but not during secondary infection, prevented subsequent enhancement of AHR, airway eosinophilia, and mucus hyperproduction upon reinfection.
Conclusions: MK attenuated the initial responses to primary RSV infection in both age groups and altered the consequences of RSV reinfection in mice initially infected as neonates. These data support an important role for cysLT in RSV-induced AHR and inflammation.
airway; inflammation; RSV; cysteinyl leukotrienes