Miracle-dz/UniFAR-FTUs huggingface dataset:
Rapid assessment of quantitative T1, T2 and T2* in lower extremity muscles in response to maximal treadmill exercise

MRI provides a non‐invasive diagnostic platform to quantify the physical and physiological attributes of skeletal muscle at rest and in response to exercise. MR relaxation parameters (T1, T2 and T2*) are characteristic of tissue composition and metabolic properties. With the recent advent of quantitative techniques that allow rapid acquisition of T1, T2 and T2* maps, we posited that an integrated treadmill exercise–quantitative relaxometry paradigm can rapidly characterize exercise‐induced changes in skeletal muscle relaxation parameters. Accordingly, we investigated the rest/recovery kinetics of T1, T2 and T2* in response to treadmill exercise in the anterior tibialis, soleus and gastrocnemius muscles of healthy volunteers, and the relationship of these parameters to age and gender. Thirty healthy volunteers (50.3 ± 16.6 years) performed the Bruce treadmill exercise protocol to maximal exhaustion. Relaxometric maps were sequentially acquired at baseline and for approximately 44 minutes post‐exercise. Our results show that T1, T2 and T2* are significantly and differentially increased immediately post‐exercise among the leg muscle groups, and these values recover to near baseline within 30–44 minutes. Our results demonstrate the potential to characterize the kinetics of relaxation parameters with quantitative mapping and upright exercise, providing normative values and some clarity on the impact of age and gender. Copyright © 2015 John Wiley & Sons, Ltd.
Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies.

AIMS To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.
Immunocytochemical localization of TrkB in the central nervous system of the adult rat

The TrkB family of transmembrane proteins serve as receptors for brain‐derived neurotrophic factor (BDNF), neurotrophin (NT)‐4/5, and possibly NT‐3, three members of the neurotrophin family of neurotrophic factors. In order to understand the potential roles played by these receptors, we have examined the distribution of the TrkB receptor proteins in the adult rat brain by using immunohistochemistry. Several different antisera, directed against either synthetic peptides corresponding to different regions of TrkB or a recombinant fusion protein comprising part of the extracellular domain, were generated. Each of these antisera was directed to epitopes found on all known TrkB isoforms (both the tyrosine kinase‐possessing isoform and the truncated kinase‐lacking isoforms). In addition, a commercially available antibody to the intracellular domain of TrkB was also used. Widespread and distinct staining was observed on the surface of neuronal cell bodies, axons, and dendrites in many structures, including the cerebral cortex, hippocampus, dentate gyrus, striatum, septal nuclei, substantia nigra, cerebellar Purkinje cells, brainstem and spinal motor neurons, and brainstem sensory nuclei. Staining was also observed in the pia matter, on a subpopulation of ependymal cells lining the cerebral ventricle wall, and other nonneuronal cells. The expression pattern of TrkB receptor protein suggests that TrkB plays a broad role in the central nervous system. In addition, the detection of TrkB immunoreactivity on cell bodies and dendrites is consistent with recent models suggesting that neurotrophins may be derived from presynaptic and/or autocrine sources in addition to the classical postsynaptic target. J Comp Neurol 378:135–157, 1997. 1997 © Wiley‐Liss, Inc.
Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24

Mandibuloacral dysplasia (MAD) is an autosomal recessive disorder characterized by hypoplasia of the mandible and clavicles, acro‐osteolysis, and lipodystrophy due to mutations in LMNA or ZMPSTE24. Only six MAD patients are reported so far with ZMPSTE24 mutations and limited phenotypic data are available for them. Here, we report on two brothers (4 years and 9‐month old) with early onset MAD due to ZMPSTE24 mutations in whom thin skin was noted as early as 5 months of age. Both had micrognathia, mottled hyperpigmentation, and enlarged fontanelles but little evidence of lipodystrophy. There was no delay of mental development. The older brother had small pinched nose, short clavicles, acro‐osteolysis, stunted growth, joint stiffness, and repeated fractures. There was no evidence of renal disease. Both patients were compound heterozygotes harboring a previously reported missense ZMPSTE24 mutation, p.Pro248Leu, and a novel null mutation, p.Trp450stop. These patients and the review of literature reveal that compared to MAD patients with LMNA mutations, those with ZMPSTE24 mutations develop manifestations earlier in life. Other distinguishing features in MAD due to ZMPSTE24 mutations may include premature birth, renal disease, calcified skin nodules, and lack of acanthosis nigricans. We conclude that in patients with MAD due to ZMPSTE24 mutations, the onset of disease manifestations such as thin skin and micrognathia occurs as early as 5 months of age. In these patients, skeletal phenotype presents earlier whereas lipodystrophy and renal disease may occur later in life. © 2010 Wiley‐Liss, Inc.
Medicinal Plants for Management of Gastroesophageal Reflux Disease: A Review of Animal and Human Studies.

OBJECTIVES Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disease that causes troublesome symptoms and/or complications. The major therapeutic strategy for GERD focuses mainly on symptom alleviation using proton pump inhibitors (PPIs), which does not produce a perfect response in all patients. An approach with new therapeutic agents for GERD seems to be essential. The aim of this study was to review animal and human studies investigating the effect of medicinal plants in GERD as well as mechanisms underlying their therapeutic effects. METHODS Medline, Scopus, and Cochrane Central Register of Controlled Trials were searched for animal or human studies. The data collected covered January 1966-October 2015. RESULTS A total of 22 studies were included in this review, of which nine were animal studies and 13 were human studies. Ceratonia siliqua as a medicinal plant and rikkunshito as a multicomponent herbal preparation were the most frequently studied herbal medicines in GERD. Antioxidant and anti-inflammatory activities were the main mechanisms demonstrated in animal studies for ameliorating the effects of medicinal plants in GERD. Other mechanisms include downregulation of genes encoding inflammatory proteins, improvement of barrier function and gastric mucus, a decrease in gastric acid, and induction of tonic contractions of the lower esophageal sphincter. All herbal preparations used in human studies have led to the alleviation of symptoms related to GERD. Myrtus communis and Cydonia oblonga showed marked reduction in GERD symptoms comparable to omeprazole. The therapeutic effect of Cydonia oblonga persisted after discontinuation of the drug. Tongjlang and rikkunshito showed therapeutic effects for non-erosive reflux disease (NERD) where PPIs failed to show a promising effect. Studies on Ceratonia siliqua have been solely focused on regurgitation in infants, and a remarkable decrease in the number of regurgitations was demonstrated. CONCLUSION The multiple mechanisms of action of medicinal plants in GERD other than anti-secretory properties appear to provide more efficient treatment and helped to manage the histopathological changes associated with this disorder. Further studies are needed to understand the effects of medicinal plants on GERD better.
Comparative biodistribution of meta‐Tetra (Hydroxyphenyl) chlorin in multiple species: Clinical implications for photodynamic therapy

To optimize photodynamic therapy, it is necessary to know the distribution of photosensitizer in normal tissue as well as tumors and to know how well animal models match human. This study measured the biodistribution of meta‐Tetra(Hydroxyphenyl) Chlorin (mTHPC) in three species of animals and in humans.
Piscirickettsia salmonis induces apoptosis in macrophages and monocyte‐like cells from rainbow trout

Piscirickettsia salmonis is the etiologic agent of the salmonid rickettsial septicemia (SRS) which causes significant losses in salmon production in Chile and other and in other regions in the southern hemisphere. As the killing of phagocytes is an important pathogenic mechanism for other bacteria to establish infections in vertebrates, we investigated whether P. salmonis kills trout macrophages by apoptosis. Apoptosis in infected macrophages was demonstrated by techniques based on morphological changes and host cell DNA fragmentation. Transmission electron microcopy showed classic apoptotic characteristics and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling showed fragmented DNA. Programmed cell death type I was further confirmed by increased binding of annexin V to externalized phosphatidylserine in infected macrophages. Moreover, significant increases of caspase 3 activation were detected in infected cells and treatment with caspase inhibitor caused a decrease in levels of apoptosis. This is the first evidence that P. salmonis induces cell death in trout macrophages. This could lead to bacterial survival and evasion of the host immune response and play an important role in the establishment of infection in the host. J. Cell. Biochem. 110: 468–476, 2010. © 2010 Wiley‐Liss, Inc.
Minimal genome: Worthwhile or worthless efforts toward being smaller?

Microbial cells are versatile hosts for the production of value‐added products due to the well‐established background knowledge, various genetic tools, and ease of manipulation. Despite those advantages, efficiency of newly incorporated synthetic pathways in microbial cells is frequently limited by innate metabolism, product toxicity, and growth‐mediated genetic instability. To overcome those obstacles, a minimal genome harboring only the essential set of genes was proposed, which is a fascinating concept with potential for use as a platform strain. Here, we review the currently available artificial reduced genomes and discuss the prospects for extending use of the genome‐reduced strains as programmable chasses. The genome‐reduced strains generally showed comparable growth to and higher productivity than their ancestral strains. In Escherichia coli, about 300 genes are estimated as the minimal number of genes under laboratory conditions. However, recent advances revealed that there are non‐essential components in essential genes, suggesting that the design principle of minimal genomes should be reconstructed. Current technology is not efficient enough to reduce large amount of interspaced genomic regions or to synthesize the genome. Furthermore, construction of minimal genome frequently has failed due to lack of genomic information. Technological breakthroughs and intense systematic studies on genomes remain tasks.
Adverse reaction with suvorexant for insomnia: acute worsening of depression with emergence of suicidal thoughts

A 59-year-old woman on daily peritoneal dialysis for end-stage renal failure received care at an outpatient psychiatric clinic for her diagnoses that include major depressive disorder, generalised anxiety disorder and insomnia disorder. Although there was partial improvement in the patient’s mood and anxiety symptoms with antidepressant treatment, insomnia remained a persistent complaint despite adequate trials of different sleep medications. The novel hypnotic, suvorexant (Belsomra, Merck & Co.) was then initiated at the recommended bedtime dose of 10 mg and was followed by a 15 mg dose the following night. Within an hour after taking her second suvorexant dose, the severity of patient’s depression symptoms worsened and was accompanied by new onset of suicidal thoughts.
Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome

Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10− 9) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10− 5). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10− 5) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10− 7) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10− 7) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.
Information Technology Revolution in the Republic of Korea: Socio Economic Development Issues and Policy Making Challenges

Abstract : The worldwide explosion of information and communication technologies profoundly affected economic growth and society in the Republic of Korea in the 1990s and early 2000s. Among developing countries, South Korea was hardly alone in pursuing strategies to capitalize on ICTs as a potential motor of economic growth and, whatever the strains caused by the present slowdown in ICT industries as a whole, the Republic of Korea can largely be considered a success as a developing country that has harnessed ICTs for economic growth and social transformation. Many other developing countries among them India, the Philippines, Jordan, Brazil, and Ghana have tried to become world or regional sources of ICT products and services with varying degrees of success. The Republic of Koreas experience can shed some light on the important factors in ICT-based national development strategies, as well as illustrate the multifaceted way in which ICTs interact with economic and social objectives. This chapter will help place the ongoing Digital Revolution in South Korea in perspective, drawing on the authors experience with ICT applications in a wide variety of international development contexts. It will then discuss some of the dominant features of ICTs in the ROKs economy. Next, it will turn to some of the economic governance issues related to ICTs in South Korea. Finally, it will look at some of the future developments and implications for both the ROK and other countries considering or engaged in ICT growth strategies.
Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cDNA.

Sulfation is an important pathway in the metabolism of many hormones and drugs. Human liver contains at least three well characterized sulfotransferase (ST) enzymes, i.e., dehydroepiandrosterone (DHEA) ST and two forms of phenol sulfotransferase (PST). Our goal was to purify, to obtain partial amino acid sequence for, and to clone and express cDNA for human liver DHEA ST. Polymerase chain reaction primers were designed on the basis of homology among rat liver hydroxysteroid ST, rat liver PST, and bovine estrogen ST. These primers amplified a unique sequence from human liver cDNA, and this polymerase chain reaction product was used to screen a human liver cDNA library. Two clones were isolated that contained identical open reading frames, of 855 nucleotides, that encoded a protein of 285 amino acids. The deduced amino acid sequence of the encoded protein included two separate 27- and 23-amino acid sequences that were identical to those obtained by microsequencing of proteolytic fragments from purified human liver DHEA ST. Translation, in a rabbit reticulocyte lysate system, of mRNA transcribed in vitro from the two cDNA clones resulted in a 35-kDa translation product that comigrated with purified human liver DHEA ST during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This translation product also catalyzed the sulfation of DHEA but not the sulfation of model substrates for the two forms of PST found in human liver. The two cDNA clones were also used to create expression constructs with the eukaryotic expression vector P91023(B), and these constructs were used to transfect COS-1 cells. The transfected cells expressed a high level of DHEA ST activity, and this enzyme activity displayed a pattern of inhibition by the ST inhibitor 2,6-dichloro-4-nitrophenol identical to that of human liver DHEA ST. Cloning of cDNA for this important human sulfate-conjugating enzyme will enhance understanding of the relationship between DHEA ST and other human liver STs, as well as ST enzymes in other species.
Effects of middle hepatic vein reconstruction on right liver graft regeneration

Background. A right liver graft without the middle hepatic vein (MHV) trunk is now commonly used in living-donor liver transplantation for adult patients. The significance of MHV reconstruction on regeneration or functional recovery of right liver grafts after living-donor liver transplantation, however, remains unclear. Methods. From 2000 to 2002 at the University of Tokyo Hospital in Tokyo, Japan, 56 adult patients received a right liver graft. The patients were divided into three groups by graft type: right liver graft without MHV trunk or MHV reconstruction (n=17); right liver graft without MHV trunk, but with MHV reconstruction (n=27); and extended right liver graft (n=12). Regeneration rate and postoperative liver function were compared among groups. Predictive factors associated with the graft regeneration were identified among clinical variables, including the graft type. Results. The regeneration rate of the right paramedian sector and the whole graft was lowest in the right liver grafts without the MHV trunk or MHV reconstruction. The regeneration rate of the lateral sector was highest in this type of graft, but the difference was not statistically significant. The factors that significantly correlated with the regeneration rate were preoperative graft volume and graft type. There was no significant difference among groups in any of the liver function parameters. Conclusions. In the present series, satisfactory outcome was independent of the type of graft used, which indicates that MHV reconstruction should not be omitted routinely but should be performed in selected patients.
Identification of the Mechanisms Regulating the Differential Activation of the MAPK Cascade by Epidermal Growth Factor and Nerve Growth Factor in PC12 Cells*

In PC12 cells, epidermal growth factor (EGF) transiently stimulates the mitogen-activated protein (MAP) kinases, ERK1 and ERK2, and provokes cellular proliferation. In contrast, nerve growth factor (NGF) stimulation leads to the sustained activation of the MAPKs and subsequently to neuronal differentiation. It has been shown that both the magnitude and longevity of MAPK activation governs the nature of the cellular response. The activations of MAPKs are dependent upon two distinct small G-proteins, Ras and Rap1, that link the growth factor receptors to the MAPK cascade by activating c-Raf and B-Raf, respectively. We found that Ras was transiently stimulated upon both EGF and NGF treatment of PC12 cells. However, EGF transiently activated Rap1, whereas NGF stimulated prolonged Rap1 activation. The activation of the ERKs was due almost exclusively (>90%) to the action of B-Raf. The transient activation of the MAPKs by EGF was a consequence of the formation of a short lived complex assembling on the EGF receptor itself, composed of Crk, C3G, Rap1, and B-Raf. In contrast, NGF stimulation of the cells resulted in the phosphorylation of FRS2. FRS2 scaffolded the assembly of a stable complex of Crk, C3G, Rap1, and B-Raf resulting in the prolonged activation of the MAPKs. Together, these data provide a signaling link between growth factor receptors and MAPK activation and a mechanistic explanation of the differential MAPK kinetics exhibited by these growth factors.
Meat, fat and risk of breast cancer: A case‐control study from Uruguay

To examine whether meat intake modifies breast‐cancer risk, a case‐control study was conducted in Uruguay. Dietary patterns were assessed in detail (for cases, before diagnosis or symptoms occurred) using a food frequency questionnaire involving 64 food items, which allowed total energy intake to be calculated. Nutrient residuals were calculated through regression analysis. After adjustment for potential confounders (which included family history of breast cancer, menopausal status, body‐mass index, total energy and total alcohol intake), an increased risk associated with consumption of total meat intake, red meat intake, total fat and saturated fat intake was observed. The strongest effect was observed for red meat intake (OR 4.2, 95% CL 2.3–7.7) for consumption in the upper quartile, after controlling for protein and fat intake. This suggests an independent effect for meat. Since experimental studies have shown a strong effect of heterocyclic amines in rat mammary carcinogenesis, further studies should be performed in human epidemiology, perhaps using biomarkers of heterocyclic amine exposure. © 1996 Wiley‐Liss, Inc.