Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug–drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.
Sperm DNA fragmentation: the evolution of guidelines for patient testing and management

Sperm DNA fragmentation (SDF) represents a perplexing biological phenomenon that can, at an elevated level, interfere with either initiating and/or maintaining pregnancy. Although we are in our third decade of studying this problem, few investigators have attempted to assess the value of the various available assays for SDF with the specific aim of amalgamating them into practice guidelines for managing SDF. Agarwal, in collaboration with urological experts from North and South America, has done just that, employing a number of clinical scenarios involving SDF to produce some evidence-based, practical guidelines for patient management (1). But if in our third decade of investigation, why are management guidelines so difficult to come by for patients with elevated SDF? First, it should be emphasized that SDF is an exceedingly complex process involving not one, but a number of causative mechanisms that can generate a variety of insults to the integrity of sperm DNA. Sakkas and Alvarez (2) have described six main mechanisms that can damage both sperm nuclear as well as mitochondrial DNA. Included in this list are testicular apoptotic processes during spermatogenesis, aberrations during the events of chromatin re-modeling, induction by exogenous caspases and nucleases plus damage by chemo- and radiotherapy as well as environmental toxicants. Perhaps the most robust events occur in the epididymis in response to insult by reactive oxygen species. That epididymal and ejaculated sperm have higher amounts of DNA fragmentation than testicular sperm is now well documented (3-5). What is not known are the testicular events that render sperm labile to chemical radicals traversing the epididymis. Secondly, the insults can produce single-stranded breaks, double-stranded breaks and/or nucleotide damage. Not all are detected by the same tests, the different types of damage are repaired to different degrees by processes resident in the oocyte and thus, do not have the same prognosis. Likely though, it is the tests used to detect and measure SDF, along with their varying levels of complexity, that introduce the bulk of the conflicting data and conclusions common in the SDF literature.
P-glycoprotein and chiral antidepressant drugs : Pharmacokinetic , pharmacogenetic and toxicological aspects

9 POPULÄRVETENSKAPLIG SAMMANFATTNING . 11 ABBREVIATIONS . 13 INTRODUCTION . 15 PSYCHOPHARMACOLOGY. 15 TOXICOLOGY . 19 CHIRALITY . 20 CHIRAL ANTIDEPRESSANT DRUGS . 22 Venlafaxine . 22 Citalopram and Escitalopram . 25 BLOOD-BRAIN BARRIER . 27 ABC transport proteins . 29 P-GLYCOPROTEIN . 31 In vitro and in vivo P-gp studies . 33 AIMS OF THE THESIS . 35 MATERIALS AND METHODS . 37 ANIMAL STUDIES (PAPERS I-III) . 37 Animals . 37 Drug administration and sample collection . 37 Acute administration . 37 Chronic administration . 38 Chiral determination of drugs . 38 Venlafaxine and metabolites . 38 Citalopram and metabolites . 39 Open-field behavior (Paper II) . 40 Statistics . 41 Ethics committee permission . 41 FORENSIC STUDY (PAPER IV). 42 Case selection. 42 Genotyping . 42 Statistics . 43 Ethics committee permission . 43 RESULTS AND DISCUSSION . 45 ANIMAL STUDIES (PAPERS I-III) . 45 Pharmacokinetics . 45 Pharmacodynamics . 51 FORENSIC STUDY (PAPER IV). 53 CONCLUSIONS . 59 ANIMAL STUDIES (PAPERS I-III) . 59 FORENSIC STUDY (PAPER IV). 60 FUTURE ASPECTS . 61 ACKNOWLEDGEMENTS . 63 REFERENCES . 67 APPENDIX (PAPERS I-IV) . 89
Ribosomal Protection Proteins and Their Mechanism of Tetracycline Resistance

Ribosomal protection represents an important tactic for promoting tetracycline resistance in both gram-positive and -negative species. Tet(O) and Tet(M) are the best studied of these determinants and were originally isolated from Campylobacter jejuni and Streptococcus spp. , respectively, although both are widely distributed (10). These are the only two ribosomal protection proteins (RPPs) that have been studied in detail, and therefore, they have been dealt with extensively in this review. It is assumed, however, that the other members of this class of RPPs [Tet(S), Tet(T), Tet(Q), TetB(P), Tet(W), and OtrA] function through similar mechanisms. The distribution of these determinants in the eubacteria has been extensively reviewed by Chopra and Roberts (10) and more recent information can also be found at http://faculty.washington. edu/marilynr/. Although this review focuses primarily on RPPs, it should be noted that a great variety of tetracycline resistance mechanisms exist (for a review, see reference 10). These determinants include (i) the efflux-based mechanisms found in gram-positive and gram-negative bacteria (10), (ii) the enzymatic degradation of tetracyclines found in Bacteroides (46), (iii) the rRNA mutations found in Propionibacterium acnes and Helicobacter pylori (19, 40, 55), and (iv) a host of undetermined mechanisms which bear little resemblance to the well-documented determinants mentioned above (10). In this review, we will survey recent advances in the study of the ribosome, tetracycline, and the RPPs that further the understanding of RPP activity. Earlier work dealing with Tet(M) and Tet(O) as well as the other RPPs has been reviewed previously (51, 52).
Evaluation of body composition and cartilage biomarkers in large-breed dogs fed two foods designed for growth.

OBJECTIVE To evaluate cartilage and bone biomarkers and body composition in growing large-breed dogs consuming a diet designed for growth. ANIMALS 43 large-breed 2 month-old-puppies. PROCEDURES Dogs were randomly assigned to receive 1 of 2 foods until 18 months of age. Dogs were evaluated at 2, 5, 12, and 18 months of age via dual energy x-ray absorptiometry (DEXA), CBC, serum biochemical profile, and concentrations or activities of taurine, vitamin E, fatty acids, glutathione peroxidase, C-propeptide of type II collagen (CPII), cartilage oligomeric matrix protein (COMP), carboxy-terminal cross-linked fragment of type II collagen (CTXII), bone specific alkaline phosphatase (BAP), osteocalcin, ghrelin, and growth hormone. RESULTS Blood components largely reflected the composition of the foods. Dogs fed the food with a higher concentration of protein, calcium, n-3 fatty acids, and antioxidants had a lower percentage of body fat and greater percentage of lean body mass at 5, 12, and 18 months of age, and higher CPII:CTXII ratio and lower COMP at 18 months of age. The BAP activity, osteocalcin concentration, and CTXII concentration declined with age, whereas COMP concentration and CPII concentration were similar at all time points for both foods. CONCLUSIONS AND CLINICAL RELEVANCE The BAP activity, osteocalcin concentration, and CTXII concentration were greater during growth than at 18 months of age. The food that was proportionately higher in protein, calcium, n-3 fatty acids, and antioxidants increased lean body mass and may have positively affected cartilage turnover as maturity was attained. Whether the rate of cartilage turnover during growth affects development of orthopedic disease or arthritis in adulthood has yet to be determined.
Impaired sodium excretion and increased blood pressure in mice with targeted deletion of renal epithelial insulin receptor

Renal tubule epithelial cells express the insulin receptor (IR); however, their value has not been firmly established. We generated mice with renal epithelial cell-specific knockout of the IR by Cre-recombinase-loxP recombination using a kidney-specific (Ksp) cadherin promoter. KO mice expressed significantly lower levels of IR mRNA and protein in kidney cortex (49–56% of the WT) and medulla (32–47%) homogenates. Immunofluorescence showed the greatest relative reduction in the thick ascending limb and collecting duct cell types. Body weight, kidney weight, and food and water intakes were not different from WT littermates. However, KO mice had significantly increased basal systolic blood pressure (BP, 15 mm Hg higher) as measured by radiotelemetry. In response to a volume load by gavage (20 ml/kg of body weight, 0.9% NaCl, 15% dextrose), KO mice had impaired natriuresis (37 ± 10 versus 99 ± 9 mmol of Na+ per 2 h in WT). Furthermore, volume load led to a sustained increase in BP in KO mice only. In contrast, insulin administration i.p. (0.5 units/kg of body weight) resulted in a significant fall in BP in WT, but not in KO mice. To test the role of reduced renal nitric oxide (NO) production in these responses, basal urinary nitrates plus nitrites excretion (UNOx) was measured and found to be 61% lower in KO vs. WT mice. Furthermore, acute insulin increased UNOx by 202% in the WT, relative to a significantly blunted rise (67%) in KO animals. These results illuminate a previously uncharacterized role for renal IR to reduce BP and facilitate sodium and water excretion, possibly via NO production.
Identification of Emerging Human-Pathogenic Pythium insidiosum by Serological and Molecular Assay-Based Methods

ABSTRACT Pythium insidiosum is a pathogen that causes disease in both animals and humans. Human infection is rare; however, when it does occur, most patients, especially those having underlying hemoglobinopathy syndromes, such as thalassemia, exhibit a severe form. We identified four isolates of P. insidiosum. Two were recovered from tissue biopsy specimens from thalassemic and leukemic patients, one was derived from brain tissue from a thalassemic patient, and another was isolated from a corneal ulcer from a fourth patient. Western blotting and an enzyme-linked immunosorbent assay (ELISA) were performed with a serum sample derived from one thalassemic patient. The methods used to identify the P. insidiosum isolates were based on morphology, nucleic acid sequencing, and a PCR assay. To confirm the identification, portions of the 18S rRNA genes of these four isolates were sequenced. The sequences were shown to be homologous to previously described P. insidiosum DNA sequences. In addition, PCR amplification of the internal transcribed spacer region specific for P. insidiosum was positive for all four isolates. The ELISA with the serum sample from the thalassemic patient gave a positive result from a serum dilution of 1:800. Finally, Western immunoblotting with this serum sample showed positive immunoglobulin G recognition for proteins of 110, 73, 56, 42 to 35, 30 to 28, 26, and 23 kDa. The results of this study show that both molecularly based diagnostic and serodiagnostic techniques are useful for the rapid identification of human pythiosis. The predominant antigens recognized by Western blotting may be useful in the development of a more sensitive and specific diagnostic tool for this disease.
Interleukin 1 receptor antagonist gene polymorphism is associated with severe renal involvement and renal sequelae in Henoch-Schönlein purpura.

OBJECTIVE To assess the influence of interleukin 1 receptor antagonist gene polymorphism (IL1RN) in the incidence of Henoch-Schönlein purpura (HSP) and cutaneous leukocytoclastic angiitis (CLA) and to determine if implications exist with severe systemic complications of HSP, in particular with severe renal involvement and permanent renal dysfunction (renal sequelae). METHODS Patients from Northwest Spain with primary cutaneous vasculitis classified as HSP or hypersensitivity vasculitis (HV) according to proposed criteria were studied. Patients with HV were included if they had a biopsy proven small size blood vessel leukocytoclastic vasculitis limited to skin and also fulfilled the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis definitions for CLA. All patients were required to have had at least 2 years' followup. Patients and ethnically matched controls were genotyped for IL-1 receptor antagonist intron 2 VNTR polymorphism. RESULTS We examined 96 Caucasian patients (58 HSP and 38 CLA) and 109 controls. No allele or genotype differences between the whole group of HSP or CLA patients and controls were observed. We found a significant association between carriage of IL-1 receptor antagonist allele 2 (ILRN*2) and severe renal involvement, manifested as nephrotic syndrome and/or renal insufficiency (p = 0.016), and permanent renal involvement (renal sequelae) (p = 0.012). CONCLUSION In unselected patients with cutaneous vasculitis, carriage of ILRN*2 alleles influences disease severity rather than susceptibility.
Die Bedeutung Kataloniens für die spanische Volkswirtschaft

Die politische Auseinandersetzung uber den zukunftigen Status Kataloniens weckt die Be-furchtung, dass davon die wirtschaftliche Entwicklung in Spanien nicht unberuhrt bleibt. Die Analyse macht deutlich, dass Spanien in den letzten Jahren die akute Wirtschafts- und Finanz-krise hinter sich gelassen hat. Zusammen mit anderen wirtschaftsstarken Regionen Spaniens hat Katalonien zur Erholung der spanischen Volkswirtschaft beigetragen. Allerdings dominiert Katalonien keineswegs die spanischen Wirtschaftsstrukturen und hat wie andere Regionen weiterhin mit wirtschaftlichen Problemen, insbesondere auf dem Arbeitsmarkt, zu kampfen. Seine exportorientierte, industriell gepragte Wirtschaft profitiert zudem von Verflechtungen mit anderen Teilen Spaniens und dem Europaischen Binnenmarkt, was durch eine einseitige Unabhangigkeitserklarung zur Disposition stande. Um einen dauerhaften Interessenausgleich zu erreichen, sollten vielmehr die foderalen Strukturen Spaniens auf Basis eines fiskalfodera-listischen Ansatzes weiterentwickelt werden.
Twenty‐five years clinical trials of the German Hodgkin Study Group (GHSG)

Abstract: This review presents a short overview of 25‐years of clinical trials by the GHSG for the treatment of primary Hodgkin's Lymphoma. The trials HD1‐HD12 that have been conducted between 1978–2002 are reviewed and major results are discussed. Furthermore, the development of the strategies concerning chemo‐ and radiotherapy for the treatment of Hodgkin's Lymphoma is characterized.
Transient Response of Single or Coupled Wire Antennas Above Dielectric Half-space

New time domain integral equations of single and two identical coupled thin wire antennas located above real ground are presented, which can be converted into a simple form expressed only by vector potential. The influence of the lossy ground is taken into account via Fresnel space-time reflection coefficient, and the equations are solved efficiently by method of moments (MOM) combined with marching on in time (MOT) procedure. Results of instances are compared with data from references and the validation of the numerical solutions is verified.
Production of Tolerance in the Rat to Octamethyl Pyrophosphoramide (OMPA).∗

Summary The cumulative effect of OMPA in rats has been confirmed. It was possible to induce a tolerance to OMPA by gradually increasing the daily dose or by treating the animals daily with a sublethal dose for a prolonged period. Animals prepared in this manner were able to tolerate for several weeks, without symptoms, a daily dose which would normally kill all rats in a few days. No gross or microscopic pathological changes were seen in the organs of the rats examined in this study.
Neurogenetic Disorders and Treatment of Associated Seizures

Seizures are a frequent complication associated with several neurogenetic disorders. Antiepileptic medications remain the mainstay of treatment in these patients. We summarized the available data associated with various antiepileptic therapies used to treat patients with neurogenetic disorders who experienced recurrent seizures. A MEDLINE search was conducted to identify articles and abstracts describing the use of antiepileptic therapy for the treatment of various neurogenetic syndromes. Of all the neurogenetic syndromes, only autism spectrum disorders, Angelman syndrome, Rett syndrome, Dravet syndrome, and tuberous sclerosis complex were identified as having sufficient published information to evaluate therapy. Some efficacy trends were identified, including frequent successes with valproic acid with clonazepam for epilepsy with Angelman syndrome; valproic acid, stiripentol, and clobazam (triple combination therapy) for epilepsy with Dravet syndrome; and vigabatrin for infantile spasms associated with tuberous sclerosis complex. Due to a paucity of information regarding the mechanisms by which seizures are generated in the various disorders, approach to seizure control is primarily based on clinical experience and a limited amount of study data exploring patient outcomes. Although exposure of the developing brain to antiepileptic medications is of some concern, the control of epileptic activity is an important undertaking in these individuals, as the severity of eventual developmental delay often appears to correlate with the severity of seizures. As such, early aggressive therapy is warranted.
Eye-hand and eye-foot visual reaction times of young soccer players.

PURPOSE The aim of this study was to investigate the eye-hand and eye-foot visual reaction time among young soccer players and to compare those with non-soccer players in order to evaluate possible differences. METHODS A vision screening of 53 young male soccer players belonging to the Valencia Soccer Club was done. Soccer players were divided in three categories, with mean ages of 8.2 +/- 0.5 years (range, 8- to 9-year olds), 10.6 +/- 0.2 years (range, 10- to 11-year-olds), and 12.7 +/- 0.3 years (range, 12- to 13-year-olds). An age-matched sample of 60 young male non-soccer players served as a control population. Mean ages in this population were 8.3 +/- 0.6 years, 10.5 +/- 0.4 years, and 12.6 +/- 0.2 years for each category, respectively. Eye-hand and eye-foot visual reaction times were determined in players and non-players by means of a computer-controlled stimuli device. RESULTS We obtained a mean and standard deviation value (in seconds) of eye-hand reaction time in soccer players of 0.301 +/- 0.037, 0.256 +/- 0.040, and 0.207 +/- 0.031, respectively, for each category, and for non-soccer players of 0.382 +/- 0.061, 0.320 +/- 0.063, and 0.282 +/- 0.043, respectively. The values for eye-foot reaction time in players were: 0.412 +/- 0.062, 0.406 +/- 0.046, and 0.387 +/- 0.034, respectively, for each category, and for nonplayers of 0.496 +/- 0.081, 0.460 +/- 0.026, and 0.446 +/- 0.054, respectively. There are statistically significant differences between eye-hand and eye-foot reaction times between players and nonplayers (p < 0.05). There was no correlation between visual reaction times and age (p > 0.05). CONCLUSIONS Eye-hand and eye-foot visual reaction times were found to be different between the two populations evaluated. The results show differences between soccer and non-soccer players, with the soccer players demonstrating faster reaction times.
Differences in inhibition of chromosome separation and G2 arrest by DNA topoisomerase II inhibitors merbarone and VM-26.

Merbarone, a novel DNA topoisomerase II (topo II) inhibitor, differs from teniposide (VM-26) in that it inhibits topo II activities without stabilizing topo II-DNA covalent complexes. Thus, while the cellular effects of VM-26 are the consequences of inhibition of topo II catalytic activities and generation of topo II-mediated DNA damage, those of merbarone may be due to inactivation of topo II catalytic function. To address the issues of mechanisms of cell cycle effects and pharmacological actions of these two topo II inhibitors in mammalian cells, we used synchronized cultures of HeLa cells to study the effects of these drugs on cell cycle processes where topo II is essential (e.g., chromosome separation) or possibly involved (e.g., G2 arrest, DNA replication). We found that both drugs inhibited chromosome separation and cell division without preventing cells from exiting mitosis. Both drugs caused S-phase retardation G2 arrest, and phase-specific cytotoxicity in that they are more toxic to S, M, and G2 cells than G0/G1 cells. However, merbarone produced the above effects in convergent dosages that were within one to five times its 90% inhibitory cytotoxic concentration, whereas the concentrations of VM-26 to cause quantitatively similar effects were quite divergent. VM-26 is 50-100-fold more efficient in causing G2 arrest than in inhibiting chromosome separation. Furthermore, at concentrations showing similar levels of S-phase suppression, VM-26 caused significant DNA breaks, while merbarone had no such effect. Our data suggest that the effects of merbarone and VM-26 during mitosis are most likely due to inhibition of topo II function. We conclude that while G2 arrest by VM-26 is related to topo II-mediated DNA damage and its sequelae, G2 arrest by merbarone likely results from different mechanisms.
Different distributions of hepatitis C virus genotypes among HIV‐infected patients with acute and chronic hepatitis C according to interleukin‐28B genotype

The C allele of the single nucleotide polymorphism rs12979860, located near the interleukin‐28B (IL‐28B) gene, has a strong impact on hepatitis C virus (HCV) treatment response, as well as on spontaneous viral clearance. In patients with chronic hepatitis C (CHC), genotype CC carriers harbour HCV genotype 3 more commonly than those with non‐CC genotypes. The aim of this study was to compare the HCV genotype distributions, according to IL‐28B genotype, in HIV‐infected patients with CHC and those with acute hepatitis C (AHC).
Fingerprint image super-resolution via ridge orientation-based clustered coupled sparse dictionaries

Abstract. The process of image quality improvement through super-resolution methods is still a gray area in the field of biometric identification. This paper proposes a scheme for fingerprint super-resolution using ridge orientation-based clustered coupled sparse dictionaries. The training image patches are clustered into groups based on dominant orientation and corresponding coupled subdictionaries are learned for each low- and high-resolution patch groups. While reconstructing the image, the minimum residue error criterion is used for choosing a subdictionary for a particular patch. In the final step, back projection is applied to eliminate the discrepancy in the estimate due to noise or inaccuracy in sparse representation. The performance evaluation of the proposed method is accomplished in terms of peak signal-to-noise ratio and structural similarity index. A filter bank-based fingerprint matcher is used for evaluating the performance of the proposed method in terms of matching accuracy. Our experimental results show that the new method achieves better results in comparison with other methods and will establish itself for improving performances of fingerprint-identification systems.