Direct Visualization of Distorted Twin Boundaries in Ce-Doped GdFeO3.

Utilizing advanced transmission electron microscopy (TEM), the structure at the (110)-type twin boundary (TB) of Ce-doped GdFeO3 (C-GFO) has been investigated with picometer precision. Such a TB is promising to generate local ferroelectricity within a paraelectric system, while precise knowledge about its structure is still largely missing. In this work, a direct measurement of the cation off-centering with respect to the neighboring oxygen is enabled by integrated differential phase contrast (iDPC) imaging, and up to 30 pm Gd off-centering is highly localized at the TB. Further electron energy loss spectroscopy (EELS) analysis demonstrates a slight accumulation of oxygen vacancies at the TB, a self-balanced behavior of Ce at the Gd sites, and a mixed occupation of Fe2+ and Fe3+ at the Fe sites. Our results provide an informative picture with atomic details at the TB of C-GFO, which is indispensable to further push the potential of grain boundary engineering.

Author Correction: CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

Discovery of a ZIP7 inhibitor from a Notch pathway screen.

The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.

A quantitative analysis of two-fold electrical conductivity relaxation behaviour in mixed proton-oxide-ion-electron conductors upon hydration.

Electrical conductivity relaxation experiments on oxides with three mobile charge carriers, H+, O2- and e-, yield in (de-)hydration experiments kinetic parameters (diffusion coefficients and surface reaction constants). In addition, three amplitude factors are obtained, but they have not been given further consideration because quantitative expressions for their forms are lacking. In this study, the forms of the amplitude factors are derived for a diffusion-limited and a surface-reaction-limited case and a mixed case. In order to demonstrate the benefits of the approach, the electrical conductivity relaxation behaviour of lanthanum tungstate (La5.4WO11.1, LaWO54) was investigated experimentally over the temperature range 923 ≤T/K ≤ 1223. A switch from two-fold non-monotonic relaxation behaviour at high temperatures to two-fold monotonic behaviour at low temperatures upon hydration was observed. The switch in sign of the fast kinetics' amplitude factor can be assigned to the electrochemical mobility of protons surpassing the electron-hole mobility with decreasing temperature.

Patient Selection in Surgical Centers of Expertise in the Treatment of Patients with Moderate to Severe Male Urinary Stress Incontinence.

OBJECTIVE: To analyze decision-making in patients with male urinary incontinence (SUI) in centers of expertise. The artificial urinary sphincter (AUS) remains the gold standard for male patients with moderate to severe SUI but adjustable male slings are a minimally invasive treatment option with good results, hence without a high level of evidence regarding the optimal patient selection. MATERIALS AND METHODS: In total, 220 patients (88 AUS; 132 adjustable slings) were investigated from the DOMINO database that underwent surgery between 2010 and 2012 in 5 urological departments that offer adjustable sling systems as well as AUS systems for patients with moderate to severe urinary incontinence. For statistical analysis, the Mann-Whitney U test was used to identify differences between both groups. RESULTS: Patients selected for an adjustable male sling were less likely to have a neurological disease (5.3 vs. 9.1%; p = 0.030), a prior urethral stricture (22.7 vs. 50.0%; p = 0.001), a prior incontinence surgery (24.4 vs. 45.5%; p = 0.01), or a prior radiation therapy (26.5 vs. 40.1%; p = 0.001). The severity of preoperative incontinence was higher in patients selected for an AUS with a mean pad usage per day of 7.60 versus 5.80 (p < 0.001). Mean postoperative pad usage and patients' subjective perception were comparable in both groups. CONCLUSION: In centers offering both options, the decision-making is mainly based upon presence of radiation therapy and previous failed incontinence surgery. Despite the more complex patient cohort selected for an AUS implantation with a possible impact on the postoperative outcome, the functional results seem to be comparable indicating a proper preoperative patient assessment and selection in this cohort.

[Can dental students and dental care providers in the Netherlands effectively and safely prescribe drugs?] / Serie: Onderwijs en de tandarts anno 2025. Kunnen tandheelkunde­studenten en mondzorgverleners in Nederland effectief en veilig geneesmiddelen voorschrijven?

Dentists and dental specialists are qualified to prescribe drugs. In this study, we assessed and compared the pharmacotherapeutic knowledge and skills of final year dental students, dentists and dental specialists in the Netherlands. In 2017, a random sample of these three groups was invited to complete an assessment. The knowledge assessment comprised 40 multiple choice questions covering often prescribed drugs. The skills assessment comprised three patient cases for which participants had to write a treatment plan. For the knowledge assessment, the response rates were 26 (20%) dental students, 28 (8%) dentists and 19 (19%) dental specialists, and for the skills assessment the response rates were 14 (11%) dental students, eight (2%) dentists, and eight (8%) dental specialists. On average, all three groups had inadequate knowledge scores (smaller 80%) and only a small proportion (smaller 30%) of their treatment plans was assessed as correct. These results suggest that dental students, dentists and dental specialists lack prescribing competence, which could be caused by poor pharmacotherapy education during under- and postgraduate dental training.

Postmicturition Dribble: A Physiological Phenomenon?

BACKGROUND: Postmicturition dribble (PMD) is a common condition in the male population. OBJECTIVES: Despite its common occurrence, there are only a few studies on this topic so far. The aim of this study was to investigate possible physiological aspects of PMD. METHOD: Seventeen men complaining of PMD and 10 healthy subjects were assessed via uroflometry, IPSS questionnaire, IIEF-5 questionnaire, and an adapted visual analogue scale (VAS) for ejaculation force -(0-10) and the amount of bother concerning PMD (0-10) were completed. In addition to that, a retrograde urethrography at 40 and 60 cm water column as pressure unit to measure the width of the bulbar urethra was performed, and the amount of PMD was measured with an adjusted pad test. RESULTS: The PMD group showed a significantly worse IPSS score, a lower Qmax rate in uroflowmetry, a worse IIEF-5 score, and a worse VAS score concerning ejaculation force. In both groups, worse IPSS levels correlated with a low bulbar urethral diameter at 40 and 60 cm water column. -Another correlation was found between a high maximum urine flow rate and a larger bulbar urethral diameter at 40 and 60 cm. Both groups showed urine loss after micturition, with no bother (VAS 0) in the control group, whereas the PMD group showed a VAS of 6. CONCLUSIONS: PMD should be regarded as a physiological occurrence in men rather than a disease by itself. Suffering is only to be expected in combination with other lower urinary tract symptoms.

Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters.

Natural resistance-associated macrophage protein (Nramp) family transporters catalyze uptake of essential divalent transition metals like iron and manganese. To discriminate against abundant competitors, the Nramp metal-binding site should favor softer transition metals, which interact either covalently or ionically with coordinating molecules, over hard calcium and magnesium, which interact mainly ionically. The metal-binding site contains an unusual, but conserved, methionine, and its sulfur coordinates transition metal substrates, suggesting a vital role in their transport. Using a bacterial Nramp model system, we show that, surprisingly, this conserved methionine is dispensable for transport of the physiological manganese substrate and similar divalents iron and cobalt, with several small amino acid replacements still enabling robust uptake. Moreover, the methionine sulfur's presence makes the toxic metal cadmium a preferred substrate. However, a methionine-to-alanine substitution enables transport of calcium and magnesium. Thus, the putative evolutionary pressure to maintain the Nramp metal-binding methionine likely exists because it-more effectively than any other amino acid-increases selectivity for low-abundance transition metal transport in the presence of high-abundance divalents like calcium and magnesium.

Synthesis and Bioactivity of Reduced Chalcones Containing Sulfonamide Side Chains.

The effect on the bioactivity of antibacterial sulfonamide drugs against malaria and tuberculosis via an increase of the lipid solubility groups by condensation with a reduced chalcone was investigated. Sulfonamide derivatives (8a-8d) were obtained via a 1,3-diarylpropane scaffold, prepared by reduction of the relevant chalcones, followed by the addition of a sulfonamide moiety via the Mannich and the Mannich exchange reactions. The ClogP values indicated that the lipophilicities of 8a-8d and intermediate reduced chalcones and N-alkylated reduced chalcones (5a-7a) were much higher than those of the sulfonamides (1a-1c). The N-alkylated reduced chalcone derivatives 6 and 7 exhibited the highest antimalarial (Plasmodium falciparum (NF54 strain)) activity. Addition of the sulfonamide group weakened the activity, even though some ClogP values were higher, while 1a-1c showed no activity. The reduced chalcones 5a and 5 showed potent growth inhibition of Mycobacterium tuberculosis (H37Rv strain), but the sulfonamide derivatives 8a and 8d showed no or insignificant activity (0 and 14%, respectively) against M. tuberculosis, despite high ClogP values. Thus, the possible increase in bioactivity expected from an increase in ClogP values (lipophilicity) might be counteracted by the higher molecular weight of the studied analogues.

Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction.

Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals. Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links, fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23 (refs 4, 5). These two proteins are involved in inherited deafness and feature long extracellular domains that interact tip-to-tip in a Ca(2+)-dependent manner. However, the molecular architecture of this complex is unknown. Here we combine crystallography, molecular dynamics simulations and binding experiments to characterize the protocadherin 15-cadherin 23 bond. We find a unique cadherin interaction mechanism, in which the two most amino-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predict that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex is shown to become unstable in response to Ca(2+) removal owing to increased flexure of Ca(2+)-free cadherin repeats. Finally, we use structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function. Overall, our results shed light on the molecular mechanics of hair-cell sensory transduction and on new interaction mechanisms for cadherins, a large protein family implicated in tissue and organ morphogenesis, neural connectivity and cancer.

Adenosine-assisted clipping of intracranial aneurysms.

Temporary parent vessel clip occlusion in aneurysm surgery is not always practical or feasible. Adenosine-induced transient cardiac arrest may serve as an alternative. We retrospectively reviewed our clinical database between September 2011 and July 2014. All patients who underwent microsurgical clipping of intracranial aneurysms under adenosine-induced asystole were included. A total of 18 craniotomies were performed, and 18 aneurysms were clipped under adenosine-induced asystole (7 basilar arteries, 8 internal carotid arteries, 1 middle cerebral artery, and 1 anterior communicating artery) in 16 patients (10 females, 6 males). Nine cases were elective and seven after subarachnoid hemorrhage. Mean age was 54 years (range 39-70). The indications for adenosine use were proximal control in narrow surgical corridors in 13 cases and "aneurysm softening" in 4 cases. A single dose was used in 14 patients; 3 patients had multiple boluses. The median (range) total dose was 30 (18-135) mg. Adenosine induced a bradycardia with concomitant arterial hypotension in all patients, and the majority also had asystole for 5-15 sec. Transient cardiac arrhythmias were noted in one patient (AFib in need of electroconversion after two boluses). Nine clinical scenarios where adenosine-induced temporary cardiac arrest and deep hypotension was an effective adjunct to temporary clipping during microsurgical clipping of intracranial aneurysms were identified.

Effect of serum calcium status at calving on survival, health, and performance of postpartum Holstein cows and calves under certified organic management.

The study objective was to assess the effect of hypocalcemia (HYPO; ≤2.0 mmol/L) of the dam at calving on survival, health, and performance of lactating dairy cows and their calves under certified organic management. Prepartum dairy cows (primiparous, n = 445; multiparous, n = 328) from 1 dairy herd were monitored (prepartum pen) for imminent signs of parturition (appearance of amniotic sac outside the vulva) until birth. All calves were subject to the same newborn care, colostrum management, and failure of passive transfer assessment (serum total protein ≤5.5 mg/dL). Serum total calcium of cows was determined in samples taken within 2 h after calving. To define HYPO cows after calving, a cut-point of total serum Ca concentration with optimal sensitivity and specificity to predict metritis or calf diarrhea was established by using the receiver operator characteristic. The effect of HYPO on survival (died or culled within 60 DIM), health status, and pregnancy per artificial insemination (PAI) for first services of lactating cows were analyzed using the GLIMMIX procedure of SAS. Additionally, the effect of HYPO at calving on days in milk (DIM) at first service (DIMFS), milk yield (kg), milk components (percent fat and protein), and somatic cell count were analyzed for the first 3 Dairy Herd Improvement Association (DHIA) tests using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC). The effect of parity (primiparous and multiparous), body condition score at calving, and manure hygiene score at calving were also included in the statistical models. The effect of HYPO at calving on calf survival, serum total protein, and diarrhea within 10 d of age were assessed using GLIMMIX procedure of SAS. The overall prevalence of HYPO was 14.6% (2.7% for primiparous and 30.8% for multiparous cows). Cows experiencing HYPO at calving had greater proportion of metritis (25.1 vs. 14.7%) and culling within 60 DIM (15.9 vs. 6.8%) compared with non-HYPO cows, respectively. For the first 3 DHIA tests, milk yield and components did not differ between HYPO and non-HYPO cows. The DIMFS as well as proportion of cows with dystocia, births of twins, mastitis, and PAI at first service were not different between HYPO and non-HYPO cows. The proportion of stillbirth, weaned calves, and serum total protein did not differ between calves born from HYPO or non-HYPO cows. However, calves born from HYPO cows had greater incidence of diarrhea (49%) than calves born (33.3%) from non-HYPO cows. Findings from the present study showed that HYPO at calving had significant health implications for both dams and calves under certified organic management.

Five years of experience with the FiLaC™ laser for fistula-in-ano management: long-term follow-up from a single institution.

BACKGROUND: There are limited data available concerning endofistular therapies for fistula-in-ano, with our group reporting the first preliminary outcomes of the use of the radial fibre Fistula laser Closing (FiLaC ™) device. METHODS: The aim of this study was to assess a cohort of anal fistulae managed with laser ablation plus definitive flap closure of the internal fistula opening over a long-term follow-up. Factors governing primary healing success and secondary healing success (i.e. success after one or two operations) were determined. RESULTS: The study analysed 117 patients over a median follow-up period of 25.4 months (range 6-60 months) with 13 patients (11.1%) having Crohn's-related fistulae. No incontinence to solid and liquid stool was reported. Minor incontinence to mucus and gas was observed in two cases (1.7%), and a late abscess treated in one case (0.8%). The primary healing rate was 75/117 (64.1%) overall, and 63.5% for cryptoglandular fistulae versus 69.2% for Crohn's fistulae, respectively. Of the 42 patients who failed FiLaC™ 31 underwent a second operation ("Re-FiLaC™", fistulectomy with sphincter reconstruction or fistulotomy). The secondary healing rate, defined as healing of the fistula at the end of the study period, was 103/117 (88.0%) overall and 85.5% for cryptoglandular fistulae versus 92.3% for Crohn's fistulae. A significantly higher primary success rate was observed for intersphincteric-type fistulae with primary and secondary outcome unaffected by age, gender, presence of Crohn's disease, number of prior surgeries and the type of flap designed to close the internal fistula opening. CONCLUSIONS: There is a moderate primary success rate using first-up FiLaC™ treatment. If FiLaC™ fails, secondary success with repeat FiLaC™ or other approaches was high. The minimally invasive FiLaC™ approach may therefore represent a sensible first-line treatment option for anal fistula repair.

Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction.

The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6.SLE123 mouse, we determined that CD4 T follicular helper and germinal center B cells were significantly expanded compared with healthy controls. We traced this expansion to resistance of effector CD4 T and B cells in B6.SLE123 mice to regulation by either CD4 T regulatory cells (CD4Tregs) or CD8 T regulatory cells (CD8Tregs), despite demonstrating normal function by Tregs in this strain. Finally, we determined that B6.SLE123 mice resist anti-CD45RB-mediated tolerance induction to foreign islet allografts, even in the absence of islet autoimmunity. Overall, B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction, which provides a new model of failed tolerance in autoimmunity that may elucidate barriers to clinical transplantation in lupus through further cellular and genetic dissection.

TAM receptor tyrosine kinase function and the immunopathology of liver disease.

Tyro3, Axl, MERTK (TAM) receptor tyrosine kinases are implicated in the regulation of the innate immune response through clearance of apoptotic cellular debris and control of cytokine signaling cascades. As a result they are pivotal in regulating the inflammatory response to tissue injury. Within the liver, immune regulatory signaling is employed to prevent the overactivation of innate immunity in response to continual antigenic challenge from the gastrointestinal tract. In this review we appraise current understanding of the role of TAM receptor function in the regulation of both innate and adaptive immunity, with a focus on its impact upon hepatic inflammatory pathology.

Chemical analysis and risk assessment of prohibited colouring agents in face paint with special regard to CI 15585 (D&C Red No. 9, Pigment Red 53:1).

OBJECTIVES: Face painting in the colours of the national flags has become a mass phenomenon during international mega sporting events. Face paints, belonging to the group of lipophilic decorative cosmetics, pose an analytical challenge, especially in the sample preparation steps to obtain sample extracts of the colouring agents of low solubility. METHODS: In the context of official cosmetics control, a sample of German flag-coloured face paints (n = 42) offered during the soccer world cup 2014 was analysed. Sample-clean-up of hydroalcoholic and dichloromethane sample extracts was conducted using preparative thin-layer chromatography (TLC). For identification, analytical TLC, spectrophotometry considering bathochromic effects, and high-performance liquid chromatography (LC) with diode array detector were applied. Nuclear magnetic resonance (NMR) spectroscopy and LC-tandem mass spectrometry (LC-MS/MS) were used in positive cases for confirmatory analysis. NMR spectroscopy was also applied to determine the identity and purity of reference substances. Risk assessment was provided using the margin of exposure (MOE) methodology. RESULTS: The prohibited red colouring agent CI 15585 (D&C Red No. 9, Pigment Red 53:1), which is carcinogenic in animals, was positively identified in 40% of the analysed samples. Per face painting event, about 0.04 mg kg(-1) bw (adult) or 0.11 mg kg(-1) bw (child) of CI 15585 is systemically absorbed. Assuming an annual use of five times (adult) or 20 times (child), the exposure would be 5.8E-04 mg kg(-1) bw per day (adult) or 5.8E-03 mg kg(-1) bw per day (child). The MOE in these worst-case scenarios would be 6871 (adult) and 695 (child). Because the mechanism of CI 15585 is non-genotoxic and the MOE is higher than a safety factor of 100, CI 15585 does not pose a serious health risk to the consumer, but should be avoided for reasons of precautionary public health protection. CONCLUSION: An analytical strategy to determine colouring agents in face paints was developed and non-compliance with the European Union (EU) cosmetic products regulation in a considerable number of products was detected. An increased control frequency especially at the points of entry into the EU is recommended.

Michigan Dentists' Attitudes toward Medicaid and an Alternative Public Dental Insurance System for Children.

PURPOSE: Healthy Kids Dental (HKD) was created as a pilot program of the Michigan State Medicaid program to increase access to care for Medicaid-eligible children. The purpose of this study was to evaluate dentists' attitudes toward Healthy Kids Dental and Medicaid in Michigan. METHODS: An online survey was sent to practitioners with an email address registered with the Michigan Dental Association (n=4,285). RESULTS: Surveys were returned from 965 practitioners (~23 percent). Although practitioners were not fully satisfied with HKD, their satisfaction with the program was significantly higher than their satisfaction with the traditional Medicaid program (P<.001). Sixty-four percent of providers that accept Medicaid limit the number of children seen in some manner, while 28 percent of providers that accept HKD limit the number of children seen. Families with traditional Medicaid who contact an office are significantly less likely to receive treatment for their child than families with HKD insurance who contact the same office (P<.001). CONCLUSIONS: Practitioners were more satisfied with programmatic and patient-related factors of the Healthy Kids Dental program than they were with Medicaid. Dentists were more likely to treat children with HKD than children with Medicaid when the parent contacts a dentist in Michigan.

Enzymatic blockade of the ubiquitin-proteasome pathway.

Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrates, a treatment less toxic than the use of proteasome inhibitors. Recognition of misfolded proteins in the ER lumen, their dislocation to the cytosol, and degradation are usually tightly coupled but can be uncoupled by the EBV-DUB: a misfolded glycoprotein that originates in the ER accumulates in association with cytosolic chaperones as a deglycosylated intermediate. Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity.

Effect of oral contraceptives on lamotrigine levels depends on comedication.

OBJECTIVES: To evaluate prospectively the influence of cyclic oral contraceptive (OC) use on lamotrigine (LTG) serum levels when used in combination therapy. METHODS: Women with epilepsy using LTG in combination with valproate (VPA; n=7), carbamazepine (CBZ; n=3) or oxcarbazepine (OXC; n=1) were evaluated during two periods of 28 days cyclic OC use, monitoring antiepileptic drug (AED) levels every other day with the dried blood spot sampling method. Results were compared with women on LTG monotherapy and OCs (n=12). Pharmacokinetic analysis was performed using NONMEM software. RESULTS: Mean study population value of LTG clearance estimated by the final model was 3.17 l/h. Introduction of covariates for comedication (VPA, CBZ, OXC and OC) significantly reduced the between-subject variability. A significant influence of OC comedication on LTG clearance was seen in both LTG monotherapy (clearance with OC 4.02±0.38 l/h, OC-free week 3.03±0.39 l/h) and in LTG-CBZ combination (clearance with OC 4.95±0.15 l/h, OC-free week 4.15±0.26 l/h). No influence of OC was found in LTG-VPA combination (clearance with OC 0.99±0.16 l/h, OC-free week 0.90±0.15 l/h). CONCLUSIONS: Adding OCs to LTG monotherapy or the combination LTG-CBZ significantly increased the LTG clearance and thus reduced LTG serum levels. In the combination LTG-CBZ, OCs had a non-significant effect on CBZ clearance. No significant influence of cyclic OC use on LTG or VPA clearance was found when these AEDs were used in combination.