Miracle-dz/UniFAR-FTUs huggingface dataset:
The Hepatotoxicity of Valproic Acid and Its Metabolites in Rats. I. Toxicologic, Biochemical and Histopathologic Studies

Valproic acid (VPA), its unsaturated metabolites and pent‐4‐enoate (4‐PA) were studied for potential hepatotoxicity in rats. 4‐PA, 4‐en‐VPA and 2,4‐dien‐VPA were potent inducers of microvesicular steatosis in young rats. Microvesicular steatosis induced by the 4‐en‐VPA was accompanied by ultrastructural changes characterized by myeloid bodies, lipid vacuoles and mitochondrial abnormalities. Myeloid bodies and lipid vacuoles were seen to a lesser extent in 2,4‐dien‐VPA and 4‐PA‐treated rats. VPA failed to induce discernible liver lesions in young rats even at near lethal doses of 700 mg per kg per day. The drug did, however, induce hepatic lipid accumulation in mature rats and in young rats dosed concomitantly with phenobarbital. β‐oxidation inhibition and several other biochemical alterations were observed in rats dosed with VPA, its unsaturated metabolites and 4‐PA. It was suggested that β‐oxidation inhibition observed in both VPA and en‐metabolite‐treated rats occurred by different mechanisms. VPA inhibits by a transient sequestering of CoA while the CoA esters of some en‐V,PA‐metabolites, particularly 4‐en‐VPA, inhibit specific enzyme(s) in the β‐oxidation sequences.
Assessment of patient‐reported outcomes in clinical trials: the example of health‐related quality of life

As the patient is the primary recipient of treatment, there is a need to recognize and value the patient's perception of change in response to treatment in clinical trials. A new outcomes classification, patient‐reported outcomes (PROs), has been proposed by regulators. The PROs are used as an umbrella term and include, for example measures of subjective symptoms, health‐related quality of life (HRQL) and treatment satisfaction. In this sense, the PROs are unique and complementary indicators of disease activity as well as of treatment efficacy. Frequently, pharmaceutical companies desire to include PRO benefits in the product label in order to reach a broad range of customers, including prescribers as well as patients. Therefore such information must be based on results that are scientifically valid. The measurement strategy, i.e. the thinking about and decision‐making related to PRO and HRQL evaluations, needs to be explicit for clinical trials. First of all it is necessary to specify and provide the rationale for measuring the PROs. Similarly, the reason for selecting particular instruments should be stated and, for the selected instruments, the psychometric evidence should be summarized. The key PRO domains must be prespecified and evidence of their importance to patients should be provided. The research question under study and potential claims need to be clearly delineated. Hence, instrument selection is a key initial step for planning successful and scientifically adequate clinical trials intended to support labelling and promotional claims of PRO benefits to patients. The scientific criteria and design issues of clinical trials are the same for clinical and PRO endpoints. However, important issues of particular relevance to PRO assessments, such as missing values, multiple outcomes, and the statistical analysis, require careful attention. The thinking and planning involved in developing the PRO component of the clinical trial need to be articulated. Successful evaluation of PROs in clinical trials relies on careful planning provided the treatment shows sufficient effectiveness.
Ca2+‐Dependence of Conoid Extrusion in Toxoplasma gondii Tachyzoites

The role of Ca2+ in conoid extrusion was investigated in isolated Toxoplasma gondii tachyzoites by treatment with Ca2+‐ionophores, Ca2+‐chelating agents and an inhibitor of the Ca2+‐ATPase at the endoplasmic reticulum. The results were evaluated by light phase‐contrast microscopy and electron microscopy. lonomycin (0.5‐1 μM) caused an immediate and sustained extrusion of the conoid in up to 80% of the tachyzoites, depending on the concentrations of ionophore and Ca2+ in the medium. However, over 50% of the tachyzoites extruded the conoid when treated with ionomycin in Ca2+‐free saline complemented with EGTA. The effect of ionomycin was reversible and could be induced a second time in about half of the responsive population. Similar results were obtained with A23187. Conoid extrusion induced by ionomycin in Ca2+‐free medium was almost completely abolished when the tachyzoites were previously loaded with a permeable compound known to chelate intracellular Ca2+ (BAPTA/AM; 25μM). On the other hand, exposure of tachyzoites to the Ca2+‐ATPase inhibitor thapsigargin (0.5‐1μM) produced significant extrusion of the conoid. Tachyzoites loaded with BAPTA/AM as well as those treated with ionomycin, i.e. with conoids paralyzed in opposite positions, had a diminished capacity to invade cultured epithelial cells. A substantial reduction in the response to stimulation by ionomycin was found also in parasites treated with cytochalasin‐D, a drug that depolymerizes actin‐filaments. The results suggest that Ca2+‐release from internal stores may act as a key signal to activate a mechanism of conoid extrusion probably mediated, at least in part, by actin‐filaments.
Le traité de Nice : déconstruction ou refondation de l'Union ?

Quel bilan peut-on faire du traite de Nice ? En tout etat de cause, un tel bilan ne peut etre dresse qu'a l'aune de l'objectif poursuivi : assurer le fonctionnement d'une Union passant de 15 a 27 membres — ou plus. A cet egard les reformes institutionnelles decidees a Nice ne paraissent guere ameliorer la capacite de gouvernance d'une Union elargie. Mais, parallelement, les roles du Parlement et du president de la Commission ont ete sensiblement renforces. Et l'Union a progresse en matiere de respect des droits fondamentaux, de politique de securite et de defense, et de cooperation renforcee. Au-dela de ces acquis immediats, le traite de Nice aura eu surtout le merite de preparer l'« apres-Nice », en prevoyant d'ouvrir un nouveau chantier institutionnel et de definir une nouvelle methode de revision des traites qui associe davantage les citoyens a l'avenir de l'Europe.
Ursodeoxycholic acid therapy in cystic fibrosis—associated liver disease: A dose‐response study

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose‐response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2‐mo periods in a replicated Latinsquare design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% ± 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile. Our data indicate a need for doses of ursodeoxycholic acid of 20 mg/kg body wt/day or greater to obtain optimal improvement in biochemical indices of liver function and biliary ursodeoxycholic acid enrichment in cystic fibrosis patients with associated liver disease. (HEPATOLOGY 1992;16:924–930.)
Clustering of genomic breakpoints at the MLL locus in therapy‐related acute leukemia with t(4;11)(q21;q23)

Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy‐related acute leukemias (t‐AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t‐AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t‐AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL‐AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130‐32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215‐17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non‐homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy‐related acute leukemia with MLL‐AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites. © 2013 Wiley Periodicals, Inc.
The biomechanics of interference screw fixation of patellar tendon anterior cruciate ligament grafts

Twenty-seven paired human cadaveric knee specimens were used to determine the effect of surgical technique and various interference screw parameters on the pullout strength of patellar tendon femoral bone blocks. The study compared the fixation strength of endoscop ically inserted and conventional "rear-entry" screws of different diameters and lengths. In all tests the most frequent mode of failure was bone block pullout from the interference screw. There was no significant differ ence in fixation strength between 9-mm diameter screws inserted through a conventional rear-entry tech nique and 7-mm diameter screws inserted through an endoscopic technique. There was no significant effect of screw length on fixation strength. The pullout force for 20-mm long screws increased on average 120% when 7-mm diameter screws were compared with 5.5- mm diameter screws. There was no significant effect of increased screw core diameter on fixation strength. There was a weak positive correlation (r2 = 0.45) between screw insertion torque and pullout force. Our measured mean pullout force for the 7-mm endoscopi cally inserted screws of 362 ± 198 N represents 20.1 % of the failure load of the normal young adult anterior cruciate ligament. Our data indicate that properly in serted 7-mm diameter endoscopic interference screws can provide fixation strengths of patellar tendon ante rior cruciate ligament grafts equivalent to those of con ventional 9-mm diameter rear-entry, outside-in screws.
Tomato and garlic can modulate azoxymethane-induced colon carcinogenesis in rats

Tomato (Lycopersicon esculentum) and garlic (Allium cepa) are important constituents of the human diet. Compounds like diallyl sulfides, diallyl disulfides and quercetin, which are active components of garlic, have known anti-inflammatory, antimutagenic activities. Similarly, active components in tomato, such as kaempferol and chlorogenic acid, have antimutagenic activities and lycopene is the most active oxygen quencher with potential chemopreventive activities. In view of this, an endeavour was made to evaluate the anticarcinogenic effect, if any, of tomato and garlic consumption individually and in combination on azoxymethane-induced colonic precancerous lesion, the aberrant crypt foci in animal model. Sprague-Dawley rats (4–5 weeks old) were injected with azoxymethane (15 mg/kg b.w.) and orally administered with 2% (w/v) of tomato, garlic and a combination of both. After 12 weeks of first azoxymethane injection, colons were assessed for aberrant crypt foci and compared with the carcinogen control group. Lipid peroxidation level and glutathione-S-transferase (GST) activity were assessed in liver as well as in colon. Furthermore, in situ cell proliferation and apoptosis were estimated using the Brdu incorporation method and TUNEL method respectively. It was observed that aberrant crypt foci were reduced in all treated groups (by 32.11% in garlic, by 76.14% in tomato and by 55.96% in the combination group). Among treated groups, GST activity was found to be induced in both liver and colon, whereas considerable reduction in lipid peroxidation level was observed in liver as well as in colon with respect to the carcinogen control group. Significant reduction in Brdu labelling index and increase in apoptotic index in colon was noted in the treated groups. These results suggest that tomato and garlic suspensions have a protective effect on colon carcinogenesis, which is mediated by modulation of different biological pathways during carcinogenesis.
Decentralized school governance policy : a comparative study of general public schools and community-managed schools in Nepal

The literature reviewed for this study revealed that the movement toward decentralizing responsibility of school governance to communities has become a global policy in the contemporary world. With the aim of enhancing greater community participation and retaining students in public schools, the Government of Nepal introduced two different policies: the General Public School (GPS )Policy and the Community-Managed School (CMS) Policy; both guided by the Decentralized School Governance Policy. Since then, there has been a debate about whether centrally controlled but locally managed GPSs or community owned-locally governed CMSs are better. Policy documents in Nepal repeatedly claim that the CMS Policy achieves better results than the GPS Policy. The research reported on in this paper gathered evidence for examining claims concerning the performance of the policies. The research used mixed methods. Results indicate that there is no significant difference in the respective policy implementation performance between the two types of schools.
Characterization of human immunodeficiency virus type 1 gp120 binding to liposomes containing galactosylceramide

Human immunodeficiency virus type 1 (HIV-1) infects some cell types which lack CD4, demonstrating that one or more alternative viral receptors exist. One such receptor is galactosylceramide (GalCer), a glycosphingolipid distributed widely in the nervous system and in colonic epithelial cells. Using a liposome flotation assay, we found that the HIV-1 surface glycoprotein, gp120, quantitatively bound to liposomes containing GalCer but not to liposomes containing phospholipids and cholesterol alone. Binding was saturable and was inhibited by preincubating liposomes with anti-GalCer antibodies. We observed less efficient binding of gp120 to liposomes containing lactosylceramide, glucosylceramide, and galactosylsulfate, whereas no binding to liposomes containing mixed gangliosides, psychosine, or sphingomyelin was detected. Binding to GalCer was rapid, largely independent of temperature and pH, and stable to conditions which remove most peripheral membrane proteins. By contrast, gp120 bound to lactosylceramide could be removed by 2 M potassium chloride or 3 M potassium thiocyanate, demonstrating a less stable interaction. Removal of N-linked oligosaccharides on gp120 did not affect binding efficiency. However, as previously observed for CD4 binding, heat denaturation of gp120 prevented binding to GalCer. Finally, binding was critically dependent on the concentration of GalCer in the target membrane, suggesting that binding to glycolipid-rich domains occurs and that GalCer conformation may be important for gp120 recognition.
In vitro fertilization in a spontaneous cycle: a successful simple protocol.

OBJECTIVE To study the efficacy of a simple protocol of in vitro fertilization in the spontaneous natural cycle. METHOD A prospective study using in vitro fertilization in a natural cycle for the treatment of infertility due to tubal factor. RESULTS Fifty-eight patients were monitored by vaginal ultrasound and LH in urine for 229 cycles. In 49.8% of the cycles the pick-up was canceled because of the early LH rise or failure to visualize a dominant follicle. Ovum pick-up was performed in 112 cycles and oocyte retrieval rate was 87.5%. Embryo transfer was performed in 86 cycles, pregnancy rate per pick-up was 10.2%, and there was no pregnancy wastage. CONCLUSION IVF in a spontaneous cycle is a simple, low cost and safe treatment, which yields reasonable PR, for young regularly menstruating women with tubal factors of infertility.
Automated RNA tertiary structure prediction from secondary structure and low‐resolution restraints

A novel protocol for all‐atom RNA tertiary structure prediction is presented that uses restrained molecular mechanics and simulated annealing. The restraints are from secondary structure, covariation analysis, coaxial stacking predictions for helices in junctions, and, when available, cross‐linking data. Results are demonstrated on the Alu domain of the mammalian signal recognition particle RNA, the Saccharomyces cerevisiae phenylalanine tRNA, the hammerhead ribozyme, the hepatitis C virus internal ribosomal entry site, and the P4–P6 domain of the Tetrahymena thermophila group I intron. The predicted structure is selected from a pool of decoy structures with a score that maximizes radius of gyration and base–base contacts, which was empirically found to select higher quality decoys. This simple ab initio approach is sufficient to make good predictions of the structure of RNAs compared to current crystal structures using both root mean square deviation and the accuracy of base–base contacts. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Misconception of emergency contraception among tertiary school students in Akwa Ibom State, South-south, Nigeria.

OBJECTIVE To assess the degree of awareness and use of emergency contraception among tertiary school students inAkwa Ibom State, Nigeria. DESIGN A self-administered questionnaire survey. SETTING The Akwa Ibom State Polytechnic, Ikot Osurua, located on the outskirts of Ikot Ekpene local government area between 1stApril 2002 and 31st April 2002. SUBJECTS 1,000 randomly selected female students ofthe Akwa Ibom State polytechnic, Ikot Osurua RESULTS The students were aged between 16 and 43 years. Five hundred and eighty-nine (68.5%) of the respondents had heard of products that could be used as emergency contraceptives. However, only 49 (5.7%) of the respondents had practised some form of emergency contraception, which was most commonly practised by those between 16 and 25 years (71.4%). Menstrogen (30.6%), gynaecosid (24.5%), and quinine (14.3%) were the most common medications used for emergency contraception. Patent medicine dealers (40.9%) and friends/course mates (29.7%) were the most common sources of knowledge about emergency contraception. CONCLUSION This study shows that awareness and use of emergency contraception by our youths is low. Community enlightenment about emergency contraception using specifically designed programmes, the formation of reproductive health clubs in our tertiary institutions and training of peer group educators in all our communities are advocated. Patent medicine dealers in our communities should have basic training in modern contraceptive methods and periodic evaluation should be carried out to assess their knowledge and practice of emergency contraception.
History of falls in Parkinson disease is associated with reduced cholinergic activity

Objective: To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD). Background: There is a need to explore nondopaminergic mechanisms of gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system–mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function. Methods: In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I–III) without dementia and 15 control subjects underwent a clinical assessment and [11C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [11C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging. Results: Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (−12.3%) followed by the PD nonfallers (−6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (−11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers. Conclusions: Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD.
Further Characterization of Apolipoprotein B Genetic Variations in Taiwanese

Apolipoprotein B (apoB, protein; APOB, gene) is the main protein component of low-density lipoprotein (LDL) and plays an important role in blood lipid metabolism. Previously, we have reported four APOB coding regions, 5' signal peptide, and 3' repeat sequence polymorphisms in our population. In this report, we further characterize other APOB genetic variations. The results illustrate that the mutation frequencies for Arg3500Gln (1/846 alleles), Arg4019Trp (2/786 alleles), -265 C/T promoter region (0/264 alleles), and intron 2 A/G (0/450 alleles) are very low. Our population showed a frequency of 68.9% for the B4311 Ser allele. The B4311 Asn allele was associated with a higher apoB level than the Ser group (p < 0.05) in normal controls. In the normal controls, a higher B4311 Asn/Asn genotype frequency was found in the group with total cholesterol (TC) > 200 mg/dL and apoB concentration > 85 mg/dL than in the group with a TC < 200 mg/dL and apoB < 85 mg/dL (p = 0.03 for TC comparison).