Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological actions of melatonin in acute and chronic inflammation.

A vast number of experimental and clinical studies implicates oxygen-derived free radicals (especially, superoxide and the hydroxyl radical) and high energy oxidants (such as peroxynitrite) as mediators of acute and chronic inflammation. The purpose of this review is to summarize the pharmacological actions of melatonin in acute and chronic inflammation. Reactive oxygen species can modulate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. Reactive oxygen species (e.g., superoxide, peroxynitrite, hydrogen peroxide and hydroxyl radical) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. These toxic reactions are likely to play a role in the pathophysiology of inflammation. Melatonin has been shown to possess both in vitro and in vivo important antioxidant activities as well as to inhibit the activation of poly (ADP ribose) synthetase. A large number of experimental studies have documented that melatonin exerts important anti-inflammatory actions.
Involvement of MMP-7 in invasion of pancreatic cancer cells through activation of the EGFR mediated MEK–ERK signal transduction pathway

Aims: To clarify the involvement of matrix metalloproteinase-7 (MMP-7) in cell dissociation and the subsequent invasion of pancreatic cancer cells. Methods: Western blotting, in vitro invasion assay, immunocytochemistry, and immunohistochemistry were performed in pancreatic cancer cell lines or pancreatic cancer tissue. Results: The active form of the MMP-7 protein was expressed exclusively in the conditioned medium of dissociated (PC-1.0 and AsPC-1) pancreatic cancer cells, whereas proMMP-7 protein was only detected in the conditioned medium of non-dissociated (PC-1 and Capan-2) cells. Both intracellular and conditioned medium localised MMP-7 was greatly reduced by treatment with the epidermal growth factor receptor (EGFR) inhibitor AG1478 and the mitogen activated protein kinase kinase (MEK) inhibitor U0126 in pancreatic cancer cells. MMP-7 treatment significantly induced the disruption of tight junction (TJ) structures and subsequent cell dissociation, and activation of the EGFR mediated MEK– ERK (extracellular signal regulated protein kinase) signalling pathway in the non-dissociated pancreatic cancer cells. Moreover, the strong in vitro invasiveness of dissociated cells was inhibited by AG1478 and U0126 treatment, whereas the weak invasiveness of non-dissociated cells was apparently induced by MMP-7 treatment. In addition, MMP-7 expression was stronger at the invasive front than at the centre of human pancreatic tumours. Conclusion: MMP-7 is involved in cell dissociation and the subsequent invasion of pancreatic cancer cells. It induces the disruption of TJ structures and forms a positive feedback loop with activation of the EGFR mediated MEK–ERK signalling pathway.
Evidence grade associating periodontitis to preterm birth and/or low birth weight: I. A systematic review of prospective cohort studies.

AIM The aims of this systematic review (SR) were to evaluate the association between maternal periodontitis and preterm birth (PB) and/or low birth weight (LBW), and the methodological quality of prospective cohort studies conducted for such a purpose. METHODS MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched up to and including October 2010 to identify prospective studies on the association of periodontitis with PB and/or LBW. Search was conducted by two independent reviewers. The methodological quality of the observational studies was assessed using a specially designed methodological tool. Random effects meta-analyses were conducted thoroughly. RESULTS Search strategy identified 1680 potentially eligible articles, of which 12 prospective studies were included. One cohort study had their data reported in two articles. Of the 11 studies, 10 showed a high methodological quality and one a medium methodological quality. Nine studies (81.8%) found an association between periodontitis and PB and/or LBW. Meta-analysis showed a significant risk of preterm delivery for pregnant women with periodontitis [risk ratio (RR): 1.70 (95% confidence interval (CI): 1.03, 2.81)] and a significant risk for LBW [RR: 2.11 (95% CI: 1.05, 4.23)] or PB/LBW [RR: 3.57 (95% CI: 1.87, 6.84)], as well as a high and unexplained degree of heterogeneity between studies. CONCLUSION Although this SR found a consistent association between periodontitis and PB and/or LBW, this finding should be treated with great caution until the sources of heterogeneity can be explained.
Laparoscopic Splenectomy: 3 Ports Are Enough

With advanced technologies and accumulating experience, a new consensus concerning the least invasive laparoscopic splenectomy should be addressed. We retrospectively analyzed 41 consecutive patients who underwent laparoscopic splenectomy from 1994 to 2007. We divided our patients into 3 groups according to the number of trocars used: group 1 (n=11, 5 trocars), group 2 (n=21, 4 trocars), and group 3 (n=9, 3 trocars). In each group, postural change was made for the operation: supine for group 1, semilateral for group 2, and true lateral for group 3. Except for the shorter operation time for group 3 compared with group 1 and group 2 (P<0.001), there were no differences in perioperative parameters. Considering the least invasive nature of laparoscopic operations, 3-port splenectomy seems to be very promising in this context. Additionally, proper modification of patient's posture is an essential part of the least invasive ever 3-port laparoscopic splenectomy.
Prostaglandin FP receptors do not contribute to 24-hour intraocular pressure variation in mice.

PURPOSE It is not known whether the prostaglandin FP receptor plays an important role in endogenous 24-hour regulation of intraocular pressure. The purpose of this study was to compare 24-hour intraocular pressure (IOP) in FP receptor-knockout mice with that of wild-type mice that have normal FP receptor expression. METHODS The 24-hour IOP profile was determined by rebound tonometry in FP-knockout and wild-type mice. Peak and trough IOP was then measured by microneedle cannulation of the anterior chamber in homozygous (FP(-/-); n = 8), heterozygous (FP(+/-); n = 14), and C57BL/6 background strain mice (FP(+/+); n = 11). To confirm any differences in baseline IOP between genotypes, midafternoon IOP was also measured in a larger, separate group of FP(-/-) mice (n = 20), FP(+/-) mice (n = 49), and FP(+/+) (n = 23) wild-type littermates. RESULTS Trough IOPs were measured between 10 AM and 12 PM, peak IOPs were measured between 8 and 10 PM. For FP(+/+), FP(+/-), and FP(-/-) mice trough IOP was 16.2, 15.3, and 15.1 mm Hg and peak IOPs were 18.2, 18.4, and 17.7 mm Hg, respectively. There was no significant difference among genotypes for mean peak or mean trough IOP or for peak-trough difference in IOP among genotypes (P > 0.05, ANOVA). In addition, there was no significant difference in midafternoon IOP between genotypes in a larger population (n = 92) of FP-knockout and wild-type mice. CONCLUSIONS An intact FP receptor does not appear to be critical for normal 24-hour IOP regulation in the mouse eye.
Rapid Diagnosis of Infected Ascitic Fluid Using Leukocyte Esterase Dipstick Testing

OBJECTIVES:Ascitic fluid infection is presumptively diagnosed when the fluid polymorphonuclear leukocyte (PMN) concentration equals or exceeds 250 cells/μl. The leukocyte esterase (LE) test has been shown to be a good predictor of the presence of PMNs and bacteria in urine and other body fluids. This study examines the value of the Multistix® 10 SG LE Dipstick test for the rapid diagnosis of infected ascitic fluid.METHODS:One hundred thirty-six ascitic fluid samples were evaluated by PMN count, culture, and LE Dipstick testing. LE dipstick values of “small” or greater were considered positive. For each sample, the LE test result was compared to the corresponding PMN count and culture result.RESULTS:Ten of the 11 LE-positive samples had PMN ≥250 cells/μl, while 10 of 12 samples with PMN ≥250 cells/μl were also LE-positive. Of the 125 LE-negative samples, 123 were also negative by PMN count. One hundred twenty-three of the 124 samples with PMN <250 cells/μl had negative LE tests. There was a less concordant relationship between the LE test and culture results. The sensitivity and specificity of the LE test for detecting ascitic fluid PMN ≥250 cells/μl were 83% and 99%, respectively, with a positive predictive value of 91% and a negative predictive value of 98%. CONCLUSIONS:The Multistix® leukocyte esterase test is useful for the prompt detection of an elevated ascitic fluid PMN count, and represents a convenient new method for the rapid diagnosis of infected ascitic fluid.
Handedness correlates with the dominant Parkinson side: A systematic review and meta‐analysis

Parkinson's disease (PD) characteristically presents with asymmetrical symptoms, contralateral to the side of the most extensive cerebral affection. This intriguing asymmetry, even included in the definition for diagnosing PD, however, is still part of a mystery. The relation with handedness as a common indicator of cerebral asymmetry might provide a clue in the search for causal factors of asymmetrical symptom onset in PD. This possible relationship, however, is still under debate. The objective of this study was to establish whether a relation between handedness and dominant PD side exists. We searched for cross‐sectional or cohort studies that registered handedness and onset side in PD patients in PubMed, EMBASE, and Web of Science from their first record until 14 February 2011. Data about handedness and dominant PD side was extracted. Authors who registered both but not described their relation were contacted for further information. Odds ratios (ORs) were analyzed with a fixed effect Mantel‐Haenszel model. Heterogeneity and indications of publication bias were limited. Our electronic search identified 10 studies involving 4405 asymmetric PD patients. Of the right‐handed patients, 2413 (59.5%) had right‐dominant and 1644 (40.5%) had left‐dominant PD symptoms. For the left‐handed patients this relation was reversed, with 142 (40.8%) right‐dominant and 206 (59.2%) left‐dominant PD symptoms. Overall OR was 2.13 (95% confidence interval [CI], 1.71–2.66). Handedness and symptom dominance in PD are firmly related with each other in such a way that the PD symptoms emerge more often on the dominant hand‐side. Possible causal factors are discussed. © 2011 Movement Disorder Society
Factors associated with the achievement of mucosal healing in Crohn’s disease: the benefit of endoscopic monitoring in treating to target

Background: Mucosal healing (MH), the proposed treat to target in Crohn’s disease (CD), is associated with improved disease outcomes. There are still scant data on factors associated with achieving MH in clinical practice. We evaluated the probability of achieving MH and identified factors predictive of subsequent MH in patients with CD. Methods: This was a retrospective, observational cohort study. A total of 272 patients with CD with serial endoscopy assessment and subsequent therapeutic management were reviewed. The primary outcome was MH. The cumulative incidence of MH and endoscopic improvement was estimated using the Kaplan–Meier method. Factors independently associated with MH were identified using the Cox proportional hazards model. Results: Of the 272 patients, 126 (46.32%) achieved MH after a median follow-up period of 33 months (interquartile range: 27–38 months). Factors independently associated with MH by multivariate analysis were time between endoscopic procedures within 26 weeks (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.05–3.39), adjustment of medical therapy when MH was not achieved (HR: 2.07; 95% CI: 1.26–2.33), prior enteric fistula (HR: 0.22; 95% CI: 0.06–0.91), perianal disease at CD diagnosis (HR: 0.58; 95% CI: 0.35–0.95), and C-reactive protein normalization within 12 weeks (HR: 3.23; 95% CI: 1.82–5.88). Similar factors have also been identified for endoscopic improvement. Conclusions: Performing serial endoscopic procedures at a 26-week interval and subsequent adjustment in medical treatment are helpful in achieving MH. Endoscopic monitoring plays an important role in the treating to target of CD.
Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.
[Insulin requirement in patients with type 1 diabetes with reduced renal function: human insulin versus analogue insulin].

INTRODUCTION Insulin clearance and the degree of insulin resistance change in type 1 diabetes in patients with reduced kidney function and make it more difficult to achieve good metabolic control. For some years different analogue insulins have become available. Their pharmacological characteristics in renal failure have not as yet been investigated in detail. The aim of the present retrospective study was to determine the insulin dosage in relation to kidney function in patients with type 1 diabetes treated with human or analogue insulin. METHODS Insulin dosage of 68 patients treated with human insulin and 74 patients treated with analogue insulin was related to the creatinine clearance (calculated with the Cockcroft-Gault formula). In addition, diabetes-related laboratory parameters, the prevalence of hypertension and the kind of antihypertensive therapy were analysed in both groups. RESULTS Patients with type 1 diabetes treated with human or analogue insulin have different insulin demands if their renal function is decreased. In analogue-treated patients, insulin dosage significantly decreased with reduced creatinine clearance (r = 0,257; p = 0,026) in contrast to human insulin treated patients who did not show such a decrease (r = 0,159; p = 0,165). There were no significant differences between treatment groups with respect to demographic data, metabolic control or antihypertensive therapy. Linear regression analysis revealed kidney function as a significant factor influencing insulin dosage in the analogue group, while the corresponding factors in the human insulin group were metabolic control and age. CONCLUSION The results indicate that insulin clearance and/or the metabolic activity of human and analogue insulin differ if renal function is reduced. This may be due to different pharmacokinetic or pharmacodynamic characteristics of these insulins in renal failure, a finding which needs further investigation.
Decoding cis-Regulatory Systems in Ascidians

Abstract Ascidians, or sea squirts, are lower chordates, and share basic gene repertoires and many characteristics, both developmental and physiological, with vertebrates. Therefore, decoding cis-regulatory systems in ascidians will contribute toward elucidating the genetic regulatory systems underlying the developmental and physiological processes of vertebrates. cis-Regulatory DNAs can also be used for tissue-specific genetic manipulation, a powerful tool for studying ascidian development and physiology. Because the ascidian genome is compact compared with vertebrate genomes, both intergenic regions and introns are relatively small in ascidians. Short upstream intergenic regions contain a complete set of cis-regulatory elements for spatially regulated expression of a majority of ascidian genes. These features of the ascidian genome are a great advantage in identifying cis-regulatory sequences and in analyzing their functions. Function of cis-regulatory DNAs has been analyzed for a number of tissue-specific and developmentally regulated genes of ascidians by introducing promoter-reporter fusion constructs into ascidian embryos. The availability of the whole genome sequences of the two Ciona species, Ciona intestinalis and Ciona savignyi, facilitates comparative genomics approaches to identify cis-regulatory DNAs. Recent studies demonstrate that computational methods can help identify cis-regulatory elements in the ascidian genome. This review presents a comprehensive list of ascidian genes whose cis-regulatory regions have been subjected to functional analysis, and highlights the recent advances in bioinformatics and comparative genomics approaches to cis-regulatory systems in ascidians.
Identification of specificity and promiscuity of PDZ domain interactions through their dynamic behavior

PDZ domains (PDZs), the most common interaction domain proteins, play critical roles in many cellular processes. PDZs perform their job by binding specific protein partners. However, they are very promiscuous, binding to more than one protein, yet selective at the same time. We examined the binding related dynamics of various PDZs to have insight about their specificity and promiscuity. We used full atomic normal mode analysis and a modified coarse‐grained elastic network model to compute the binding related dynamics. In the latter model, we introduced specificity for each single parameter constant and included the solvation effect implicitly. The modified model, referred to as specific‐Gaussian Network Model (s‐GNM), highlights some interesting differences in the conformational changes of PDZs upon binding to Class I or Class II type peptides. By clustering the residue fluctuation profiles of PDZs, we have shown: (i) binding selectivities can be discriminated from their dynamics, and (ii) the dynamics of different structural regions play critical roles for Class I and Class II specificity. s‐GNM is further tested on a dual‐specific PDZ which showed only Class I specificity when a point mutation exists on the βA‐βB loop. We observe that the binding dynamics change consistently in the mutated and wild type structures. In addition, we found that the binding induced fluctuation profiles can be used to discriminate the binding selectivity of homolog structures. These results indicate that s‐GNM can be a powerful method to study the changes in binding selectivities for mutant or homolog PDZs. Proteins 2009. © 2009 Wiley‐Liss, Inc.
Turtle Nest-Site Choice, Anthropogenic Challenges, and Evolutionary Potential for Adaptation

Oviparous animals, such as turtles, lay eggs whose success or demise depends on environmental conditions that influence offspring phenotype (morphology, physiology, and in many reptiles, also sex determination), growth, and survival, while in the nest and post-hatching. Consequently, because turtles display little parental care, maternal provisioning of the eggs and female nesting behavior are under strong selection. But the consequences of when and where nests are laid are affected by anthropogenic habitat disturbances that alter suitable nesting areas, expose eggs to contaminants in the wild, and modify the thermal and hydric environment experienced by developing embryos, thus impacting hatchling survival and the sexual fate of taxa with temperature-dependent sex determination (TSD) and genotypic sex determination (GSD). Indeed, global and local environmental change influences air, water, and soil temperature and moisture, which impact basking behavior, egg development, and conditions within the nest, potentially rendering current nesting strategies maladaptive as offspring mortality increases and TSD sex ratios become drastically skewed. Endocrine disruptors can sex reverse TSD and GSD embryos alike. Adapting to these challenges depends on genetic variation, and little to no heritability has been detected for nest-site behavior. However, modest heritability in threshold temperature (above and below which females or males develop in TSD taxa, respectively) exists in the wild, as well as interpopulation differences in the reaction norm of sex ratio to temperature, and potentially also in the expression of gene regulators of sexual development. If this variation reflects additive genetic components, some adaptation might be expected, provided that the pace of environmental change does not exceed the rate of evolution. Research remains urgently needed to fill current gaps in our understanding of the ecology and evolution of nest-site choice and its adaptive potential, integrating across multiple levels of organization.
The Attenuated Genotype of Varicella-Zoster Virus Includes an ORF0 Transitional Stop Codon Mutation

ABSTRACT Varicella-zoster virus (VZV) is the first of the human herpesviruses to be attenuated and subsequently approved as a live vaccine to prevent varicella and herpes zoster. Both the attenuated VZV vaccine, called vaccine Oka or vOka, and the parental strain pOka have been completely sequenced. Yet the specific determinants of attenuation are uncertain. The open reading frame (ORF) with the most single nucleotide polymorphisms (SNPs), ORF62, encodes the regulatory protein IE62, but IE62 studies have failed to define a specific SNP associated with attenuation. We have completed next-generation sequencing of the VZV Ellen genome, a strain known to be highly attenuated by its very limited replication in human skin xenografts in the SCID mouse model of VZV pathogenesis. A comparative analysis of the Ellen sequence with all other complete VZV sequences was extremely informative. In particular, an unexpected finding was a stop codon mutation in Ellen ORF0 (herpes simplex virus UL56 homolog) identical to one found in vOka, combined with the absence of polymorphisms in most Ellen ORFs that were known to be mutated in vOka. The mutated ORF0 protein was also imaged in both two dimensions and three dimensions by confocal microscopy. The probability of two VZV strains not connected by a recent common ancestor having an identical ORF0 SNP by chance would be 1 × 10−8, in other words, extremely unlikely. Taken together, these bioinformatics analyses strongly suggest that the stop codon ORF0 SNP is one of the determinants of the attenuation genotype of live VZV vaccines.