Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes.

AIMS Our aim was to investigate associations between the single nucleotide polymorphisms (SNPs) in the SLCO1B1 (encoding OATP1B1) and ABCB1 (encoding P-glycoprotein) genes with the pharmacokinetics and efficacy of pravastatin in children with heterozygous familial hypercholesterolaemia (HeFH) and in paediatric cardiac transplant recipients. METHODS Twenty children with HeFH (aged 4.9-15.6 years) and 12 cardiac transplant recipients (aged 4.4-18.7 years and receiving triple immunosuppressive medication) who had participated in previous pharmacokinetic and pharmacodynamic studies with pravastatin were genotyped for the -11187G > A and 521T > C SNPs in the SLCO1B1 gene and for the 2677G > T/A and 3435C > T SNPs in the ABCB1 gene. RESULTS Two HeFH patients with the -11187GA genotype had a 81% lower peak plasma pravastatin concentration (Cmax) (difference in means -13.9 ng ml(-1), 95% CI -21.1, -6.7; P < 0.001) and a 74% smaller area under the plasma concentration-time curve (AUC0, infinity) (-25.3 ng ml(-1) h, 95% CI -35.6, -15.0; P < 0.0001) and significantly greater increase in high density lipoprotein (HDL) cholesterol after 2 months treatment with pravastatin than patients with the reference genotype. No significant differences were seen in the pharmacokinetics or effects of pravastatin between HeFH patients with the SLCO1B1 521TC and 521TT genotypes. The cardiac transplant recipients with the SLCO1B1 521TC genotype (n = 3) had a 46% lower Cmax (-67.7 ng ml(-1), 95% CI -135.7, 0.3; P = 0.055) and 62% lower AUC(0,24 h) (-228.5 ng ml(-1) h, 95% CI -402.7, -54.3; P = 0.016) and a shorter half-life (t1/2) (0.9 +/- 0.1 vs. 1.3 +/- 0.4 h, P = 0.015) of pravastatin than those with the reference genotype. Decreases in total and low-density lipoprotein cholesterol by pravastatin were significantly smaller, and the increase in HDL-cholesterol was greater in the transplant recipients with the 521TC genotype compared with patients with the 521TT reference genotype. CONCLUSIONS In children with HeFH and in paediatric cardiac transplant recipients receiving immunosuppressive medication, the -11187G > A and SLCO1B1 521T > C SNPs were associated with decreased plasma concentrations of pravastatin. These differences are opposite to those seen previously in healthy adults. The mechanisms underlying these phenomena are unclear and warrant further study.
Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis

Major etiologic factors associated with human hepatocellular carcinomas (HCCs) include infection with hepatitis C (HCV) and hepatitis B virus (HBV), excess alcohol intake and aflatoxin B1 exposure. While the G→T p53 mutation at codon 249 has been identified as a genetic hallmark of HCC caused by aflatoxin B1, the genetic profile associated with other etiologic factors appears to be less distinctive. In our study, we screened HCCs resulting from HCV infection (51 cases), HBV infection (26 cases) or excess alcohol intake (23 cases) for alterations in genes involved in the RB1 pathway (p16INK4a, p15INK4b, RB1, CDK4 and cyclin D1), the p53 pathway (p53, p14ARF and MDM2) and the Wnt pathway (β‐catenin, APC). Alterations of the RB1 pathway, mainly p16INK4a methylation, loss of RB1 expression and cyclin D1 amplification, were most common (69–100% of cases). There was a significant correlation between loss of RB1 expression and RB1 methylation. All 24 HCCs with RB1 promoter methylation lacked RB1 expression, while none of the 67 cases with RB1 expression exhibited RB1 methylation (p < 0.0001), suggesting that promoter methylation is a major mechanism of loss of RB1 expression in HCCs. Alterations of the p53 pathway consisted mostly of p53 mutations or p14ARF promoter methylation (20–48%). Mutations of the p53 gene were found at a similar frequency (13–15%) in all etiologic groups, without any consistent base change or hot spot. Mutations of β‐catenin were found in 13–31% of cases, while no APC mutations were detected in any of the HCCs analyzed. With the exception of only 3 of 39 cases (8%), cyclin D1 amplification and β‐catenin mutations were mutually exclusive, supporting the view that cyclin D1 is a target of the Wnt signaling pathway. Overall, the RB1, p53 and Wnt pathways were commonly affected in HCCs of different etiology, probably reflecting common pathogenetic mechanisms, i.e., chronic liver injury and cirrhosis, but tumors associated with alcoholism had more frequent alterations in the RB1 and p53 pathways than those caused by HCV infection. © 2003 Wiley‐Liss, Inc.
Timing of DNA integration, transgenic mosaicism, and pronuclear microinjection

Selection of transgenic embryos prior to embryo transfer is a means to increase the efficiency of transgenic livestock production. Among transgenic reporters, cytoplasmic expression of green fluorescent protein (GFP) has features that make it ideal for transgenic embryo selection. The primary objective of this study was to assess cytoplasmic expression of a specially designed GFP reporter as a tool for transgenic bovine embryo selection. A second objective was to evaluate this reporter for studying transgenic mosaicism related to timing of integration of pronuclear microinjected DNA. Transgenic embryos produced by pronuclear injection showed a discrete pattern of GFP expression with clusters at 25, 50, and 100% of blastomeres expressing GFP. This pattern of mosaicism is interpreted to indicate that the integration of microinjected DNA occurred, not only at the pronuclear stage, but also in the subsequent cell divisions. Among the GFP‐positive transgenic embryos, only in 21% did all the blastomeres show the green fluorescence. Using the fraction of positive blastomeres within an embryo, the timing of integration of microinjected DNA was estimated. The frequency of nonmosaic embryos expressing GFP is consistent with published germline transmission success rates of transgenic cattle derived from pronuclear microinjected embryos. These results indicate the possible application of GFP as a marker of transgenic embryos and graphically illustrate underlying complexities in DNA integration in embryos subjected to pronuclear microinjection. Mol. Reprod. Dev. 52:406–413, 1999. © 1999 Wiley‐Liss, Inc.
Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain

The key enzyme in coronavirus polyprotein processing is the viral main proteinase, Mpro, a protein with extremely low sequence similarity to other viral and cellular proteinases. Here, the crystal structure of the 33.1 kDa transmissible gastroenteritis (corona)virus Mpro is reported. The structure was refined to 1.96 Å resolution and revealed three dimers in the asymmetric unit. The mutual arrangement of the protomers in each of the dimers suggests that Mpro self‐processing occurs in trans. The active site, comprised of Cys144 and His41, is part of a chymotrypsin‐like fold that is connected by a 16 residue loop to an extra domain featuring a novel α‐helical fold. Molecular modelling and mutagenesis data implicate the loop in substrate binding and elucidate S1 and S2 subsites suitable to accommodate the side chains of the P1 glutamine and P2 leucine residues of Mpro substrates. Interactions involving the N‐terminus and the α‐helical domain stabilize the loop in the orientation required for trans‐cleavage activity. The study illustrates that RNA viruses have evolved unprecedented variations of the classical chymotrypsin fold.
Lithium Increases Tyrosine Hydroxylase Levels Both In Vivo and In Vitro

Abstract: Lithium, a simple monovalent cation, is the mainstay in the treatment of manic‐depressive illness, but despite extensive research, its mechanism of action remains to be elucidated. Because lithium requires chronic administration for therapeutic efficacy and because its beneficial effects last well beyond its discontinuation, it has been postulated that lithium may exert major effects at the genomic level. We have previously shown that lithium, at therapeutically relevant concentrations, increases gene expression through the activator protein‐1 (AP‐1) transcription factor pathway in vitro. In the present study, we have sought to determine if lithium also increases the expression of endogenous genes known to be regulated by AP‐1 and have therefore investigated the effects of lithium on tyrosine hydroxylase (TH) levels. Male Wistar rats were treated with LiCI for 9 days (subacute) or 4 weeks (chronic), and TH levels were measured in frontal cortex, hippocampus, and striatum using immunoblotting. Chronic (but not subacute) lithium treatment resulted in significant increases in TH levels in rat frontal cortex, hippocampus, and striatum. Lithium (1 mM) also increased TH levels in human SH‐SY5Y neuroblastoma cells in vitro, indicating that lithium increases TH levels in both rodent and human tissues, likely via a direct cellular effect. These effects are compatible with (but likely not exclusively due to) an effect on the DNA binding of the 12‐O‐tetradecanoylphorbol 13‐acetate response element to the AP‐1 family of transcription factors.
Manganese speciation in exhaust particulates of automobiles using MMT-containing gasoline.

Manganese speciation in exhaust particulates of automobiles using MMT-containing gasoline monochromator, 50% detuned, was used. Multiple scans varying from 4 sweeps for XANES and 8 sweeps for EXAFS were performed to yield optimal S/N ratios. All spectra were collected in the QEXAFS mode (Frahm, 1988). A manganese metal standard foil located in front of a reference ion chamber was measured simultaneously with each sample for in-situ energy calibration.
Accepted for publication in the Journal of Higher Education Policy and Management – October 2006 Who Do They Think they Are ? The Changing Identities of Professional Administrators and Managers in UK Higher Education

Contemporary universities, serving mass higher education markets, find themselves delivering complex, broadly based projects such as student support and welfare, human resource development, and business enterprise. Established concepts of academic administration and devolved management have been overlaid by more fluid institutional structures and cultures, with a softening of internal and external boundaries (Whitchurch 2004; 2005). These developments have caused major shifts in the identities of professional administrators and managers, as they adopt more projectoriented roles crossing functional and organisational boundaries. This paper considers the dynamics of these changes, in terms that move beyond conventional assumptions about ‘administration’ and ‘management’. While identities have been defined traditionally via structured domains such as professional knowledges, institutional boundaries, and the policy requirements of the higher education sector, an emergent ‘project’ domain has fostered the development of an increasingly multi-professional grouping of staff, with implications for career futures.
Characteristics of Color Development in Seeds of Brown- and Yellow-Seeded Heading Chinese Cabbage and Molecular Analysis of Brsc, the Candidate Gene Controlling Seed Coat Color

The proanthocyanidin (PA) is the main flavonoids which affect the seed coat color in Brassica species. In this paper, characteristics of color development and accumulation of flavonoids were analyzed in the seeds of brown-seeded (B147) and yellow-seeded (B80) heading Chinese cabbage (Brassica rapa L. ssp. Pekinensis). It is found that the content of phenolic compounds in B147 were significantly more than that of B80 by using dimethylaminocinnamaldehyde (DMACA) staining and toluidine blue O (TBO) staining. In previous studies, the locus associated with seed coat color has been mapped. The results of whole genome re-sequencing showed that there are large fragment deletions variation in the mapping region between the brown-seeded parent ‘92S105’ and the yellow-seeded parent ‘91-125. ’ Based on the B. rapa genome annotation information, the TRANSPARENT TESTA GLABRA 1 (TTG1), is likely to be the candidate gene controlling seed coat color. A 94-base deletion was found in the 96th base downstream of the initiation codon in the TTG1 of yellow seed, thus, the termination codon TGA was occurred in the 297th base which makes the full length of TTG1 of yellow seed is 300 bp. Based on the differential sequences of TTG1 of brown and yellow seed, a functional marker, Brsc-yettg1, was developed to detect the variation of TTG1. Quantitative real-time PCR analysis of BrTTG1 in different tissues showed that expression levels of BrTTG1 was not tissue-specific. During the whole seed development period, the expression of BrTTG1 in B147 was higher than that of B80. The expression levels of four structural genes, BrDFR, BrANS, BrANR1, and BrANR2 in B147 were also higher than those in B80. The co-segregation molecular markers obtained in this report and TTG1 related information provide a basis for further understanding of the molecular mechanism of seed coat color in heading Chinese cabbage.
Simultaneous Input and State Estimation for Linear Time-Varying Continuous-Time Stochastic Systems

In this technical note, we consider the problem of optimal filtering for linear time-varying continuous-time stochastic systems with unknown inputs. We first show that the unknown inputs cannot be estimated without additional assumptions. Then, we discuss some conditions under which meaningful estimation is possible and propose an optimal filter that simultaneously estimates the states and unknown inputs in an unbiased minimum-variance sense. Conditions for uniform asymptotic stability, and the existence of a steady-state solution, as well as the convergence rate of the state and input estimate biases are given. Moreover, we show that a principle of separation of estimation and control holds and that the unknown inputs may be rejected. A nonlinear vehicle reentry example is given to illustrate that our filter is applicable even when some strong assumptions do not hold.
Transient erythroblastopenia due to human parvovirus B19 infection: A case report of a boy suffering from purpura

Transient erythroblastopenia of childhood (TEC) was observed in a boy infected by human parvovirus B19 (B19) before the manifestation of the typical clinical picture of erythema infectiosum (EI). He did not have any apparent symptoms of anemia, and spontaneous resolution of erythroblastopenia was observed before the manifestation of the symptoms of EI. The difference between primary B19 infection and classical TEC is discussed.
Hypermobility and Dance: A Review

Joint hypermobility is defined as an excessive range of motion. Although the dance profession has often promoted hypermobility for aesthetic reasons, there is a belief amongst health professionals that potential risks associated with the condition may have been overlooked. The aims of this review were to examine the epidemiology of joint hypermobility in dancers; the effects on fatigue and bone health; the injury profile of hypermobile dancers; and the use of the Beighton score as a diagnostic tool. Depending on the criteria used, epidemiological studies suggest that hypermobility among dancers can be as high as 44%, especially in students. As hypermobility has been linked to fatigue in the general population, the hypermobile dancer should be careful given the association between fatigue and aetiology of injury in dance. Similarly, in light of research encouraging dancers to become fitter, this recommendation may not be appropriate for hypermobile dancers. In addition, the Beighton score used in most dance related studies may not be an appropriate measure of hypermobility in these populations. More research is necessary into this area to ascertain the reasons for the attrition rate from student to soloist/principal level and whether it is linked to dance health and injury issues.
Critical Paracrine Interactions Between TNF-α and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E2 Production1

Increased production of PGs by gestational membranes is believed to be a principal initiator of term and preterm labor. Intrauterine infection is associated with an inflammatory response in the choriodecidua characterized by elevated production of cytokines and PGs. The precise physiological significance of enhanced choriodecidual cytokine production in the mechanism of preterm labor remains uncertain. These studies were undertaken to dissect the roles and regulation of endogenous cytokines in regulating PG production by human choriodecidua. We used LPS treatment of human choriodecidual explants as our model system. In choriodecidual explant cultures, LPS (5 μg/ml) induced a rapid increase in TNF-α production, peaking at 4 h. In contrast, IL-10, IL-1β, and PGE2 production rates peaked 8, 12, and 24 h, respectively, after LPS stimulation. Immunoneutralization studies indicated that TNF-α was a primary regulator of IL-1β, IL-10, and PGE2 production, while IL-1β stimulated only PGE2 production. Neutralization of endogenous IL-10 resulted in increased TNF-α and PGE2 production. IL-10 treatment markedly decreased TNF-α and IL-1β production, but had no effect on PGE2 production. Taken together, these results demonstrate that the effects of LPS on choriodecidual cytokine and PG production are modulated by both positive and negative feedback loops. In the setting of an infection of the intrauterine, TNF-α may be a potential target for treatment intervention; IL-10 could be one such therapeutic.
Factors associated with survival following blunt chest trauma in older patients: results from a large regional trauma cooperative.

HYPOTHESIS We hypothesized that patient factors, injury patterns, and therapeutic interventions influence outcomes among older patients incurring traumatic chest injuries. DESIGN Patients older than 50 years with at least 1 rib fracture (RF) were retrospectively studied, including institutional data, patient data, clinical interventions, and complications. Univariable and multivariable analyses were performed. SETTING Eight trauma centers. PATIENTS A total of 1621 patients. MAIN OUTCOME MEASURE Survival. RESULTS Patient data collected include the following: age (mean, 70.1 years), number of RFs (mean, 3.7), Abbreviated Injury Scale chest score (mean, 2.7), Injury Severity Score (mean, 11.7), and mortality (overall, 4.6%). On univariable analysis, increased mortality was associated with admission to high-volume trauma centers and level I centers, preexisting coronary artery disease or congestive heart failure, intubation or development of pneumonia, and increasing age, Injury Severity Score, and number of RFs. On multivariable analysis, strongest predictors of mortality were admission to high-volume trauma centers, preexisting congestive heart failure, intubation, and increasing age and Injury Severity Score. Using this predictive model, tracheostomy and patient-controlled analgesia had protective effects on survival. CONCLUSIONS In a large regional trauma cooperative, increasing age and Injury Severity Score were independent predictors of survival among older patients incurring traumatic RFs. Admission to high-volume trauma centers, preexisting congestive heart failure, and intubation added to mortality. Therapies associated with improved survival were patient-controlled analgesia and tracheostomy. Further regional cooperation should allow development of standard care practices for these challenging patients.
Clinical Outcomes of Tigecycline in the Treatment of Multidrug-Resistant Acinetobacter baumannii Infection

PURPOSE Acinetobacter baumannii (A. baumannii) has emerged as a major cause of nosocomial pneumonia and sepsis in seriously ill patients. Multidrug-resistant A. baumannii (MDRAB) is increasing in frequency, and the management of it's infections is consequently difficult. Therefore, tigecycline is considered to be the drug of choice for MDRAB treatment. The aim of our study was to evaluate the microbiological eradication and clinical effectiveness of tigecycline against MDRAB in seriously ill patients, including patients with ventilator-associated pneumonia (VAP). MATERIALS AND METHODS We conducted a retrospective study including patients with A. baumannii infections who were treated with tigecycline between April 1, 2009 and March 31, 2010. We treated 27 patients with tigecycline for MDRAB infections. RESULTS The mean age of patients was 66.2 years, and 20 (74.1%) patients were male. The median length of stay at hospital was 74.6 days. MDRAB was eradicated from the site of infection in 23 cases (85.2%), however, only 17 cases (63.0%) showed positive clinical responses. Overall, an in-hospital mortality rate of 51.9% was observed, and 4 cases of death were attributable to sepsis. The combination therapy showed better clinical and microbial success rates than the monotherapy without significant difference. CONCLUSION We observed the relatively low clinical success rate although the microbial eradication rate was high, probably due to superinfections in VAP and bacteremia. We suggest that clinicians should limit tigecycline monotherapy for MDRAB infection in critically ill patients, until large controlled clinical trials should be conducted.
Negative impact of cardiovascular risk factors on left atrial and left ventricular function related to aortic stiffness--new application of 2-dimensional speckle-tracking echocardiography.

BACKGROUND The aim of the present study was to detect earlier the negative effect of cardiovascular risk (CVR) factors on left atrial (LA) and left ventricular (LV) function related to abdominal aortic (AAO) stiffness using 2-dimensional speckle-tracking echocardiography (2DSTE) in asymptomatic patients. METHODS AND RESULTS One hundred and twelve patients with CVR factors and 56 healthy individuals were studied. 2DSTE data were acquired for determination of LA and LV myocardial and AAO wall deformations. LA volume index, LV mass index, ratio of early diastolic transmitral flow to mitral annular velocity (E/e')/peak systolic LA strain (S-LAs), and AAO stiffness were greater, and peak early diastolic LV longitudinal strain rate (SR-LVe) was lower in the patient group. Among the significantly correlated variables with AAO stiffness on univariate analysis, multivariate linear regression analysis identified SR-LVe and (E/e')/S-LAs in the patient group, and only age in the healthy group, as independent predictor of AAO stiffness. CONCLUSIONS Structural and functional changes in the LA and LV and AAO stiffening were accelerated with CVR factors, and higher AAO stiffness was associated with deteriorated LA compliance and impaired LV relaxation in asymptomatic patients with CVR factors. 2DSTE has a potential for earlier detection of abnormal LA and LV function related to increased AAO stiffness.