Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action.
Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(−) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn).
Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(−) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration.
Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann–Whitney U test.
Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.001).
Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, in which pathogenesis is not clear. Many research demonstrated that fibroblast-like synoviocytes (FLSs) play a key role in RA pathogenesis, join in the cartilage injury and hyperplasia of the synovium, and contribute to the release of inflammatory cytokines. We used adjuvant arthritis (AA) rats as RA animal models. The methyl-CpG-binding protein 2 (MeCP2) enables the suppressed chromatin structure to be selectively detected in AA FLSs. Overexpression of this protein leads to an increase of integral methylation levels. Some research has confirmed the hedgehog (Hh) signaling pathway plays an important role in RA pathogenesis; furthermore, patched 1 (PTCH1) is a negative fraction of Hh signaling pathway. We used 5-aza-2′-deoxycytidine (5-azadc) as DNA methylation inhibitor. In our research, we found MeCP2 reduced PTCH1 expression in AA FLSs; 5-azadc obstructed the loss of PTCH1 expression. 5-Azadc, treatment of AA FLSs, also blocks the release of inflammatory cytokines. In order to probe the potential molecular mechanism, we assumed the epigenetic participation in the regulation of PTCH1. Results demonstrated that PTCH1 hypermethylation is related to the persistent FLS activation and inflammation in AA rats. Knockdown of MeCP2 using small-interfering RNA technique added PTCH1 expression in AA FLSs. Our results indicate that DNA methylation may offer molecule mechanisms, and the reduced PTCH1 methylation level could regulate inflammation through knockdown of MeCP2.
Graphical Abstract
The objective of the study was to clarify whether controlling nutritional status (CONUT) is useful for predicting the long-term prognosis of patients hospitalized with heart failure (HF). A total of 482 (57.5%) HF patients from the Ibaraki Cardiovascular Assessment Study-HF (N = 838) were enrolled (298 men, 71.7 ± 13.6 years). At admission, blood samples were collected and nutritional status assessed using CONUT. CONUT scores were defined as follows: 0–1, normal; 2–4, light; 5–8, moderate; and 9–12, severe undernutrition. Accordingly, 352 (73%) patients had light-to-severe nutritional disturbances. In the follow-up period [median 541.5 (range 354–786) days], 109 deaths were observed. A Kaplan–Meier analysis revealed that all-cause deaths occurred more frequently in HF patients with nutritional disturbances [n = 93 (26.4%)] than in those with normal nutrition [n = 16 (12.3%); log-rank p < 0.001]. The Cox proportional hazard analyses revealed that a per point increase in the CONUT score was associated with an increased risk of all-cause death (hazard ratio 1.142; 95% confidence interval, 1.044–1.249) after controlling simultaneously for age, sex, previous history of HF hospitalization, log brain natriuretic peptide, and use of therapeutic agents at admission (tolvaptan and aldosterone antagonists). This study suggests that nutritional screening using CONUT scores is helpful in predicting the long-term prognosis of patients hospitalized with HF in a multicenter registry setting.
RNA degradation is a major problem in tissue banking. We explored the effect of thawing flash-frozen biospecimens on the quality and integrity of RNA for genetic testing as well as for other cancer research studies. The histological quality of the frozen tumor sections was evaluated by using hematoxylin and eosin staining. RNA extraction from 60 lung cancer tissue samples subjected to various freeze/thaw cycles was performed using the RNeasy Plus isolation kit. RNA integrity was assessed by using an Agilent bioanalyzer to obtain RNA integrity numbers (RIN). Furthermore, RNA from different groups was used for fluorescence Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene mutation to verify whether it can be used for research or clinical testing. Highly variable RIN values were observed among the samples, which showed no correlation with the number of freeze/thaw cycles conducted. However, after 3 freeze/thaw cycles (each thaw event lasted for 10 min), an increasing number of changes in peak intensity in RINs were observed. After 5 freeze/thaw cycles, RNA integrity decreased to approximately 35%. After 3 freeze/thaw cycles, the RNA could still be used for RT-PCR analysis of EML4-ALK fusion gene mutations; whereas those subjected to 5 freeze/thaw cycles could not. Limited (<3) freeze/thaw cycles did not adversely affect the quality of RNA extracted from tumor tissues and subsequent RT-PCR analysis. Our data could be utilized in the establishment of a standardized procedure for tissue biospecimen collection and storage.
The review discusses the role of omnipresent transcription factors of the NF1 family in the development, establishment and regulation of tissue-specific gene expression in multicellular organisms with a different degree of complexity. The molecular mechanisms underlying the effect of these transcription factors on the development of tissues in the evolutionary lineage of multicellular animals are analyzed.
The spatial structure of the receptive field (RF) of a visually sensitive neuron, as defined by presentation of stationary visual stimuli, predetermines in most cases central processing of visual information concerning moving visual images. In our study, properties of a group of neurons in the extrastriate cortical area 21a (≈18% of the examined sampling) with extremely small RF sizes (≈1.5 deg2) determined by stationary visual stimuli were investigated. It was found that spatial dimensions of each neuronal RFs may undergo manifold expansions; the neuronal response profiles depended strongly on the size, shape, and contrast of the applied moving stimuli. As a result, a high degree of diversification of neuronal response patterns depending of the shapes and contrasts of applied moving stimuli was observed. These data confirm the suggestion that the RFs of neurons in the extrastriate area 21a undergo temporary dynamic changes due to activation of surrounding neuronal groups/networks by moving visual stimuli. Thus, it is evident that processing of visual information in the course of visual image recognition is realized by integrated activity of a complex of the corresponding cortical networks of visually sensitive neurons.
Parameters of saccades (latency, amplitude, duration, and velocity) were measured using a saccadometer in 32 nurses (30 women and 2 men) before and after a night shift. The mean latency of saccades was found to significantly increase after this period (209.6 ± 6.84 vs. 188.6 ± 6.08 msec, P = 0.002); the same was found with respect to the saccade duration (55.0 ± 0.97 vs. 54.2 ± 1.23 msec, P < 0.05). Thus, stress and sleep deprivation noticeably influence the parameters of saccades; the latter, nonetheless, remain within a physiological range. Considering that a number of brain structures are involved in the control of saccade parameters, the above-described modulations of saccades can be potentially used as generalized indices characterizing the level of brain tiredness.
Decision making is one of the most complicated and controversial topics in neuroscience. Today, there are important classes of chemicals that increase cognitive performance; in particular these are psychostimulants (e.g., methylphenidate, MPH). However, the long-term effects of MPH on cost-benefit decision making in healthy animals remain unknown. Therefore, we aimed to compare the short- and long-term effects of MPH in adult healthy male rats on the decision making in two distinct T-maze tasks and the ability of the animals to adjust the height of the obstacle in a T-maze or to process information on the reward amount. We found that short-term effects of MPH (2 weeks) played a significant role in making the correct decision in T-maze tasks, while the respective effects of long-term administration (12 weeks) were much weaker. These data suggest that chronic application of MPH has short- but not long-term effects on cost-benefit decision making in healthy adult animals.
In rats anesthetized with urethane (1.7 g/kg, i. p.), we investigated the effects of stereotaxic microinjections of baclofen into the medullary nuclei involved in the neural control of cardiovascular activity (nuclei paramedianus, ambiguus, and reticularis lateralis). Changes in the hemodynamic parameters (systolic and diastolic blood pressure and heart rate) were measured. Injections of the above GABAB receptor agonist (10–7, 10–6, or 10–5 M, 0.1 μl) into the medullary cardiovascular nuclei was accompanied by changes in the blood pressure, the magnitude and direction of which depended not only on the baclofen concentration but also on the site of injection (into one nucleus or another). Injections of the agent into the nucl. ambiguus at a 10–7 M concentration resulted in an increase in the blood pressure, but a 10–5 M concentration provided significant reduction of the systolic and diastolic blood pressure. If baclofen was injected into the nucl. reticularis lat., the blood pressure also increased or decreased but the concentration dependence was opposite to the above described. Injections of the agent into the nucl. paramedianus were always accompanied by significant increases in the blood pressure. Changes in the heart rate following baclofen injections into the nuclei under study were insignificant. The specificities of the baclofen-induced effects are probably related to peculiarities of the functioning of GABAB receptors, the activation of which may mediate the effects of multiple neuronal mechanisms.
One of the causes of autoimmune diseases is the production of antibodies to extracellular loops of hormonal receptors coupled with heterotrimeric G-proteins (GPCR) and to ectodomains of receptors with tyrosine kinase activity. In recent years, the range of these diseases has considerably extended, raising interest to the mechanisms of their genesis and actualizing the search for effective ways of their prevention and treatment. The antibodies against extracellular regions of α1-, β1- and β2-adrenergic receptors and m2-muscarinic acetylcholine receptors (m2-MAChR) were found in patients with various forms of cardiomyopathy and other pathologies of the cardiovascular system; the antibodies against m3-MAChR were detected in Sjögren's syndrome and biliary cirrhosis; the antibodies against angiotensin receptors type 2 were found in pregnant women with pre-eclampsia and in different forms of hypertension; the antibodies to thyroid-stimulating hormone receptor were detected in Graves' disease and other autoimmune thyroid pathologies. The role of antibodies specific to the ectodomain of muscle specific receptor tyrosine kinase in the development of generalized myasthenia and those against the extracellular domain of platelet-derived growth factor receptor in the development of systemic sclerosis and other fibroses was shown. In the present review, we systematize and analyze the data on the molecular mechanisms that underlie the production of antibodies to GPCR and receptor tyrosine kinases and determine the development of autoimmune diseases they induce. Possible approaches toward their prevention and correction are also discussed.
This study addresses the influence of combinations of two encoded amino acids with opposite, memory-inhibiting and memory-enhancing, effects on short-term and long-term memory formation in the honeybee. Experimentation was based on the classical proboscis extension response conditioning by a single-trial exposure to clove odor with a sucrose solution reward. The presence of the acquired conditioned response was tested 1 min (short-term memory) and 180 min (long-term memory) after the learning trial. The data obtained suggest a stimulatory (memory-enhancing) effect of the combination of two amino acids, individual effects of which are opposite. The stimulatory amino acid was present in the mixture in all the trials (8 combinations) at a subthreshold concentration, i.e. it did not influence memory formation. In some trials, the stimulatory effect of an amino acid mixture (for example, stimulatory aspartic acid combined with inhibitory lysine or serine) significantly exceeded that of a single stimulatory amino acid applied at a threshold concentration. Interestingly, the effect of amino acid combinations on memory formation in honeybees resembles their effect on cell proliferation in rat tissue explants of various origin.
In psychrophilic and thermophilic fish, significant differences were revealed under an optimal body temperature in the heart rate, initial atrial activity duration and descending slope of the P II wave. Differences were also detected in atrial electric activity during the initial and final periods of depolarization, reflecting different localization of the initial excitation area and the movement of the depolarization front toward the atrioventricular border.
A comparative analysis of enzymological characteristics of cholinesterase (ChE) and monoamine oxydase (MAO) from the optic ganglia was performed in the Pacific squid Todarodes pacificus and Commander squid Berryteuthis magister caught in their four habitats across the Pacific Northwest. A substrate–inhibitor analysis revealed a homogeneity of T. pacificus and B. magister ChE preparations as well as homogeneity of T. pacificus vs. heterogeneity of B. magister MAO preparations. In case of thiocholine derivatives, the rate of hydrolysis induced by T. pacificus ChE was practically independent of the structure of the acyl group, whereas in case of B. magister ChE it was found to decrease in this substrate series. It is only T. pacificus MAO that was found to be able to deaminate also a diaminooxydase substrate histamine. ChE activity was higher in T. pacificus than in B. magister for the whole substrate series, while for MAO the same activity pattern was observed for tyramine, tryptamine and serotonin. In both squids, the sensitivity of ChE to organophosphorus inhibitors containing the dimethylbutyl group was by several orders of magnitude higher than that in mammals. The sensitivity of ChE to the siloxane reversible inhibitors was lower in T. pacificus ChE and much lower in B. magister than in mammals.
The effect of serotonin solutions on the locomotor activity of cercariae with different swimming patterns, Cryptocotyle lingua and Himasthla elongate, was investigated during their lifespan using motion track analysis and a frame-by-frame count of behavioral elements. Serotonin caused a noticeable alteration of several locomotion parameters in both species studied, while the activity per se decreased significantly with age. In intermittently swimming C. lingua cercariae, serotonin induced an increase in the frequency of active swimming phases (spurts) without significant changes in the duration and velocity of the spurts themselves. In continuously swimming H. elongata cercariae, serotonin increased the number of stops during the first hour after the emission from the host mollusk under a constant average swimming velocity. Immunocytochemical visualization of serotonin revealed a decline in its level with age (time after emission) and different dynamics of this process in neurons located in the tail and body of C. lingua cercariae. The data are interpreted in the light of the modulatory role of serotonin known for other animals.
The tasks, methods and principles of the evolution of functions are overviewed at various levels of organization of physiological systems with the focus on the central problem of physiological evolution—the origin of life and formation of protocellular functions. This stage of evolution is associated with the emergence of the plasma membrane and ion asymmetry of the cell relative to the extracellular environment. For a long time, evolution proceeded in the sea, where extracellular sodium ions in tandem with the intracellular potassium dominance created conditions for the emergence of electrogenesis, polar cells and epithelia, as well as for the formation of the extracellular body fluid system, making up the internal environment of multicellular organisms. The features of the evolution of organs and functional systems are analyzed. During evolution, hormones, autakoids and incretins began to be involved in the regulation of functions alongside with the nervous system. Sodium-dependent processes in the plasma membrane stimulated the development of absorptive, digestive, excretory, respiratory and homeostatic functions. The substance and patterns of functional evolution are discussed.
Immunoreactivity for calcium-binding proteins parvalbumin (PV) and calbindin (CB) was studied in the pigeon (Columba livia) telencephalic auditory center. All its regions displayed overlapping distribution patterns of PV and CB immunoreactivity, although in the central (L2) vs. peripheral (L1, L3, CMM) layers they were dissimilar. L2 and the inner L1 sublayer (L1i) were distinguished by a higher immunoreactivity of neuropil for both proteins and the presence (in L2) of numerous small densely packed granular-type cells: heavily stained PV-ir and, as a rule, poorly stained CB-ir neurons. In Lli, the number of neurons and the density of neuropil immunoreactive to both proteins decreased. The outer L1 sublayer (L1e) as well as L3 and CMM were characterized by a generally lesser density and irregular distribution of immunoreactive neuropil and a heterogenous repertoire of PV-ir and CB-ir neurons referring to diverse morphological types, with an increased number of large multipolar cells. The differences in PV and CB immunoreactivity among different regions of the pigeon telencephalic auditory center revealed the similarity of the latter to the laminar auditory cortex in mammals.
We review the genetics of the autosomal dominant, multi-system disorder Alagille syndrome, and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion.
Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human-induced pluripotent stem cells provide new opportunities in which to study disease mechanisms and manifestations.
We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille syndrome patients.
Shepparton News |
Simple test could save lives
Shepparton News As well as the start of winter, today is also the start of Bowel Cancer Awareness Month, an initiative of Bowel Cancer Australia to put the uncomfortable topic on the tip of everyone's tongue. Although nearly everyone is already ''aware'' of bowel ... and more » |
Technical dichlorodiphenyltrichloroethane (DDT) has been used worldwide as a pesticide since the beginning of the 1940s. Due to its persistence, DDT residues are still ubiquitously distributed in the environment. Photochemical UV degradation has been shown to be a potent degradation path for DDT and most of the resulting photoproducts have been identified up to now. Nevertheless, in 2012, a new DDT metabolite, most likely formed photochemically from DDE, was detected in ray liver samples from Brazil, an area which is highly contaminated with DDT. This study includes photochemical generation, chemical synthesis and isolation of this compound which was verified to consist of both cis- and trans-2,4-dichloro-1-[2-chloro-1-(4-chlorophenyl)ethenyl]benzene. Both stereoisomers were resolved by gas chromatography on a polar capillary column and detected in more than 60 biotic (e.g. marine mammals, birds, human milk) and abiotic samples (fat deposits in kitchen hoods) from different areas all over the world. The stereoisomer distribution and concentrations (0.3–3.9% relative to corresponding 1,1-dichloro-2,2-bis(p-chlorophenyl) ethane (p,p′-DDE) levels) were determined by means of the synthesized analytical standard, indicating the widespread occurrence of this compound as an additional minor metabolite of DDT.
RNA degradation is a major problem in tissue banking. We explored the effect of thawing flash-frozen biospecimens on the quality and integrity of RNA for genetic testing as well as for other cancer research studies. The histological quality of the frozen tumor sections was evaluated by using hematoxylin and eosin staining. RNA extraction from 60 lung cancer tissue samples subjected to various freeze/thaw cycles was performed using the RNeasy Plus isolation kit. RNA integrity was assessed by using an Agilent bioanalyzer to obtain RNA integrity numbers (RIN). Furthermore, RNA from different groups was used for fluorescence Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene mutation to verify whether it can be used for research or clinical testing. Highly variable RIN values were observed among the samples, which showed no correlation with the number of freeze/thaw cycles conducted. However, after 3 freeze/thaw cycles (each thaw event lasted for 10 min), an increasing number of changes in peak intensity in RINs were observed. After 5 freeze/thaw cycles, RNA integrity decreased to approximately 35%. After 3 freeze/thaw cycles, the RNA could still be used for RT-PCR analysis of EML4-ALK fusion gene mutations; whereas those subjected to 5 freeze/thaw cycles could not. Limited (<3) freeze/thaw cycles did not adversely affect the quality of RNA extracted from tumor tissues and subsequent RT-PCR analysis. Our data could be utilized in the establishment of a standardized procedure for tissue biospecimen collection and storage.
The Sentinel |
College finds possible correlation between TMI partial meltdown ...
The Sentinel Penn State College of Medicine Wednesday reported that its researchers are showing, for the first time, a possible correlation between the partial meltdown at ... Researchers study correlation between TMI, thyroid cancerWGAL Lancaster all 8 news articles » |
Precision Tevatron and Linear Hadron Collider measurements at Fermilab and CERN have revealed the numerically accurate mass equality W + Z = t. This equality between two gauge bosons (gb) and the top quark t is only valid if reinterpreted as an energy equality, where E = mc 2, since energy is a shared property of particles and quarks. The experimental data indicate that the LHC particle excitation energy is quantized in the form of gauge boson energy packets E gb , which are created by factor-of-137 proton-quark energy increases denoted as α-boosts, where α ~ 1/137 is the fine structure constant. These α-boosts occur during the rare head-on quark–quark collisions in the proton beams. The α-boost energy quantization mechanism also occurs in low-energy electron–positron boson and fermion particle production channels, where it generates E b and E f energy packets. These α-boost energy channels link together coherently, as demonstrated by the accurate top quark energy equation E top = (18/α2) E electron. Particle production energy equations are derived which combine to create an overall energy pattern that accurately reproduces the energies of the (u,d), s, c, b, t fermion constituent quarks, the µ and τ leptons, and the proton.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan–Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (P = 0.023, P = 0.042, P = 0.028, and P = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2 = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (P < 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32–3.37, P = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31–2.93, P = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.
Our study aims to investigate the prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma. Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for overall survival (OS) in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.
The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods.
The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures.
Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85.
The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature.
This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures.
While the impact of interpersonal discrimination on mental health is well established, its effects on physical health outcomes have not been fully elucidated. This study systematically reviewed the literature on the prospective association between interpersonal discrimination and markers of adiposity. Medline, Web of Science, Scopus, PsycInfo, SciELO, LILACS, Google Scholar, Capes/Brazil and ProQuest databases were used to retrieve relevant information in November 2016. The results from the 10 studies that met the inclusion criteria support an association between interpersonal self-reported discrimination and the outcomes. In general, the most consistent findings were for weight and body mass index (BMI) among women, i.e. high levels of self-reported discrimination were related to increased weight and BMI. Waist circumference (WC) showed a similar pattern of association with discrimination, in a positive direction, but an inverted U-shaped association was also found. Despite a few inverse associations between discrimination and markers of adiposity, none of the associations were statistically significant. Overall, markers of adiposity were consistently associated with discrimination, mainly through direct and nonlinear associations. This review provides evidence that self-reported discrimination can play an important role in weight, BMI and WC changes.
The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068–2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410–9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299–2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.
Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty-seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (N = 30) and in age-matched controls (N = 20). Only YKL-40 levels were found to be significantly higher in PIBO patients with exacerbation compared with that in bronchiolitis patients and showed a positive correlation with the severity of disease before diagnosis of PIBO.
Conclusion: Our results suggest that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.
What is Known:
• The children with post-infectious BO (PIBO) usually have recurrent wheezing and need frequent hospitalization due to acute exacerbation during the first disease years.
• Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment.
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What is New:
• Measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.
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To assess risk factors for recurrent carbapenem-resistant Klebsiella pneumoniae bloodstream-infection (CR-KP BSI), we performed a prospective observational cohort study of all consecutive adult patients cured of a CR-KP BSI at our hospital over a six-year period (June 2010 to June 2016). Maximum follow-up per patient was 180 days from the index blood cultures (BCs). Recurrent CR-KP BSI was defined as new evidence of positive BCs in patients with documented clinical response after completing a course of anti-CR-KP therapy. Univariate and multivariate cause-specific Cox proportional hazards analysis were performed. During the study period 249 patients were diagnosed with a CR-KP BSI, 193 were deemed as cured within 14 days after index BCs and were analysed. Recurrence occurred in 32/193 patients (16.6%) within a median of 35 (IQR 25–45) days after index BCs. All but one of the recurrences occurred within 60 days after the index BCs. Comparison of recurrent and non-recurrent cases showed significant differences for colistin use (84.4% vs. 62.2%, p = 0.01), meropenem-colistin-tigecycline regimen (43.8% vs. 24.8%, p = 0.03) and length of therapy for the index BSI episode (median 18 vs. 14 days, p = 0.004). All-cause 180-day mortality (34.4% vs. 16.1%, p = 0.02) was higher in recurrent cases. In the multivariate analysis, the only independent variable was source control as a protective factor for recurrence. Recurrence is frequent among patients cured of a CR-KP BSI and is associated with higher long-term mortality. When feasible, source control is mandatory to avoid recurrence. The role of antibiotic treatment should be further investigated in large multicentre studies.
Free Press Journal |
Indore: Students' drawings send out strong message against tobacco use
Free Press Journal “Heart attacks, strokes, chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis), and cancer (particularly lung cancer, cancers of the larynx and mouth, and pancreatic cancer) are some of the common diseases,” Agrawal ... |
Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target-derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, NT4–/– mice were protected from allergen-induced mucus overproduction and changes along the nerve–PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in NT4–/– mice after early life allergen exposure. Together, our findings provide the first evidence for NT4-dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve–PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma.—Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus-Randall, V. E., Ai, X. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion.
Nickel–zinc ferrites with the general chemical formula, \(\hbox {Ni}_{0.3}\hbox {Zn}_{0.7-x}\hbox {Mg}_{x}\hbox {Fe}_{2}\hbox {O}_{4}\) with x varying from 0.00 to 0.25 in steps of 0.05, have been prepared by conventional solid-state method. Final sintering of the samples was carried out at \(1200{^{\circ }}\hbox {C}\) for 6 h in air to investigate their structural and magnetic properties. X-ray diffraction patterns of all the samples confirm the cubic spinel structure. Percent porosity and lattice constants of the samples are similar for all the samples except for the sample with \(x=0.05\) implying that the changes in magnetic properties could be solely attributed to the effects caused by substitutions only. The saturation magnetization has been observed to increase continuously with the substitution of \(\hbox {Mg}^{2+}\) ions in the place of \(\hbox {Zn}^{2+}\) ions. Curie temperature of the system was also found to increase from \(261{^{\circ }}\hbox {C}\) ( \(x=0.00\) ) to \(364{^{\circ }}\hbox {C}\) ( \(x=0.25\) ) with the increase in magnesium content. Smooth coercivity variation suggests better structural homogeneity. The results are discussed in the light of the distribution of the cations among octahedral and tetrahedral sites.
The Saha equations for the photoionization process of hydrogen atoms and the creation of electron–positron pairs at high temperature are investigated in a reference frame undergoing a uniform accelerated motion. It is known as the Rindler space.
A direct rational exponential scheme is introduced and applied to construct exact multisoliton solutions of the clannish random walker's parabolic and the Vakhnenko–Parkes equations. We discuss the nature of soliton solutions before and after their interactions, and present their fusion (non-elastic) and elastic collisions of the soliton solutions. These soliton solutions of the equations are connected to physical phenomena: weakly non-linear surface, internal waves in a rotating ocean and interacting population motions. In addition, some three-dimensional and contour plots of the soliton wave solutions are presented to visualize the dynamics of the models.
In order to further understand a self-exciting Faraday disc dynamo (Hide et al, in Proc. R. Soc. A 452, 1369 1996), showing chaotic attractors with very complicated topological structures, we present codimension one and two (degenerate) Hopf bifurcations and prove the existence of periodic solutions. In addition, numerical simulations are given for confirming the theoretical results.
The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods.
The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures.
Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85.
The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature.
This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures.
There is conflicting evidence of the effectiveness of montelukast in preschool wheeze. A recent Cochrane review focused on its use in viral-induced wheeze; however, such subgroups are unlikely to exist in real life and change with time, recently highlighted in an international consensus report. We have therefore sought to investigate the effectiveness of montelukast in all children with preschool wheeze (viral-induced and multiple-trigger wheeze). The PubMed, Cochrane Library, Ovid Medline and Ovid EMBASE were screened for randomised controlled trials (RCTs), examining the efficacy of montelukast compared with placebo in children with the recurrent preschool wheeze. The primary endpoint examined was frequency of wheezing episodes. Five trials containing 3960 patients with a preschool wheezing disorder were analysed. Meta-analyses of studies of intermittent montelukast showed no benefit in preventing episodes of wheeze (mean difference (MD) 0.07, 95% confidence interval (CI) −0.14 to 0.29; mean for montelukast 2.68 vs placebo 2.54 (p = 0.5)), reducing unscheduled medical attendances (MD −0.13, 95% CI −0.33 to 0.07; mean for montelukast 1.62 vs placebo 1.78 (p = 0.21)) and reducing oral corticosteroids (MD −0.06, 95% CI −0.16 to 0.02; mean for montelukast 0.35 vs placebo 0.36 (p = 0.25)). The pooled results of the continuous regimen showed no significant difference in the number of wheezing episodes between the montelukast and placebo groups (MD −0.40, 95% CI −1.00 to 0.19; mean for montelukast 2.05 vs placebo 2.37 (p = 0.18)).
Conclusions: This review highlights that the currently available evidence does not support the use of montelukast in preschool children with recurrent wheeze. We recommend further studies to investigate if a ‘montelukast responder’ phenotype exists, and how these can be easily identified in the clinical setting.
What is Known:
• Current guidelines recommend montelukast use in preschool children with recurrent wheeze.
• A recent Cochrane review has found montelukast to be ineffective at reducing courses of oral corticosteroids for viral-induced wheeze.
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What is New:
• This meta-analysis has examined all children with preschool wheeze and found that montelukast was not effective at preventing wheezing episodes or reducing unscheduled medical attendances.
• A specific montelukast responder phenotype may exist, but such patients should be sought in larger multicentre RCTs.
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Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately 2-fold (highest versus lowest quintile), and the shape of the dose-response was linear (Ptrend =1.24x10−13 and 3.02x10−14 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (Pinteraction =0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (Ptrend =0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival. This article is protected by copyright. All rights reserved.
The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed.
Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG-1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge.
This study opens the door for the use of MG-1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. This article is protected by copyright. All rights reserved.
Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial. This article is protected by copyright. All rights reserved.
Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed pre-diagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin, and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988.
We conducted a nested case-control study including 127 non-cardia gastric adenocarcinoma (NCGA), 41 esophago-gastric junctional adenocarcinoma (EGJA), and 60 esophageal squamous cell carcinoma (ESCC) incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection, and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower pre-diagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7 to 12.6 for lowest compared to highest quartile, p-trend < 0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population.
As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen. This article is protected by copyright. All rights reserved.
The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5, and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n=244) or a control set (FIRE3-Bev, n=246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n=76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, P=0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, P=0.005, multivariate: HR 2.02, 95% CI: 1.14–3.55, P=0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients. This article is protected by copyright. All rights reserved.
USA TODAY |
Three Mile Island nuke accident linked to thyroid cancer
USA TODAY A new Penn State Medical Center study has found a link between the 1979 Three Mile Island nuclear accident and thyroid cancer cases in south-central Pennsylvania. The study marks the first time the partial meltdown of Unit 2's reactor can be connected ... Possible correlation shown between the partial meltdown at TMI and thyroid cancersScience Daily 'Possible' link between thyroid cancers and 1979 Three Mile Island nuclear accident reportedLancasterOnline Hershey researcher believes new study makes first connection between TMI and cancerPennLive.com York Daily Record/Sunday News -ABC27 all 8 news articles » |
MAJOR FINDINGS
Drugs used in cancer treatment exhibit varied temporal dynamics of absorption and clearance, summarized by their pharmacokinetic (PK) parameters. Typically these dynamics are neglected in evolutionary models of cancer progression under combination therapy. By developing a computational framework to incorporate PK and drug interaction effects, we showed that the complex interplay of dynamics of drugs and various cancer clones significantly affect dosing strategies. Applied to an ongoing phase-Ib clinical trial, our framework predicted efficacies of different dosing schedules and suggested new strategies to significantly improve cancer cell eradication and reduce associated toxicities.