Tolerability, safety, and efficacy of adjunctive brivaracetam for focal seizures in older patients: A pooled analysis from three phase III studies

Introduction: This analysis was conducted to assess the tolerability, safety, and efficacy of brivaracetam (BRV) for adjunctive treatment of focal (partial-onset) seizures in patients aged ≥65 years. Methods: Safety/tolerability and efficacy data for patients aged ≥65 years were pooled from three randomized, double-blind, placebo-controlled, fixed-dose Phase III studies (NCT00490035, NCT00464269, and NCT01261325). Data were pooled by treatment group: placebo or the proposed therapeutic dose range of 50–200 mg/day: BRV 50, 100, 200 mg/day. Results: Thirty-two patients aged ≥65 years were randomized to placebo or BRV 50–200 mg/day. Of these, 30 patients (93.8%) completed their respective study. In the safety population (n = 32), 87.5% placebo- vs 73.3% BRV-treated patients reported treatment-emergent adverse events (TEAEs) during the treatment period; most commonly, headache (25.0% vs 12.5%), paresthesia (0% vs 12.5%), and somnolence (50.0% vs 12.5%) for placebo- vs BRV-treated patients, respectively. During the treatment period, drug-related TEAEs were reported by 62.5% of placebo- vs 53.3% of BRV-treated patients, and serious TEAEs (SAEs) were reported by 0% of placebo- and 4.2% of BRV-treated patients; there were no drug-related SAEs and no deaths. Three SAEs (placebo 1/8; BRV 2/24) and two deaths (placebo 1/8; BRV 1/24) occurred in the post-treatment period. In the efficacy population (n = 31), median percent reduction from baseline in focal seizure frequency/28 days was 14.0% for placebo vs 25.5%, 49.6%, and 74.9% for BRV 50, 100, and 200 mg/day, respectively. The ≥50% responder rate was 14.3% for placebo vs 25.0%, 50.0%, and 66.7% for BRV 50, 100, and 200 mg/day, respectively. Conclusions: Safety/tolerability and efficacy findings in this small subgroup of older patients treated with adjunctive BRV are consistent with those observed in the much larger overall pooled population. BRV may be a suitable adjunctive treatment for older patients with uncontrolled focal seizures. Further larger studies in this population are warranted

Response to combination therapy with interferon alfa-2a and ribavirin in chronic hepatitis C according to a TNF-alpha promoter polymorphism

Background. Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of chronic active hepatitis C. Polymorphisms in the promoter region of the TNF-alpha gene can alter the TNF-alpha expression and modify the host immune response. The present study aimed at the correlation of the G308A TNF-alpha polymorphism with the response to antiviral combination therapy in chronic hepatitis C. Patients and Methods: 62 patients with HCV and 119 healthy unrelated controls were genotyped for the G308A TNF-alpha promoter polymorphism. The patients received 3 x 3 million units of interferon alfa-2a and 1,0001,200 mg ribavirin daily according to their body weight. A response was defined as absence of HCV-RNA and normalization of S-ALT after 6 months of combination therapy. Results:With respect to the allele and genotype frequency, a significant difference was not observed between controls and patients with chronic hepatitis C. Furthermore, such a difference was also not observed if responders and non-responders to antiviral therapy were compared. Conclusions: The promoter polymorphism of the TNF-alpha gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin. Copyright (C) 2003 S. Karger AG, Basel

Anti-A/B antibody depletion by semiselective versus ABO blood group-specific immunoadsorption

Background. Recipient desensitization using blood group (BG)-specific immunoadsorption (ABO-IA) has proven to enable successful kidney transplantation across major ABO barriers. In this context, the efficiency of non-antigen-specific (semiselective) IA adsorbers has not yet been established. The objective of our study was to quantify anti-A/B antibody depletion by protein A-, peptide ligand- and anti-human immunoglobulin-based semiselective IA in comparison to ABO-IA. Methods. Eight ABO-IA-treated transplant candidates and 39 patients subjected to semiselective IA for a variety of different indications outside the context of ABO-incompatible transplantation were included. Antibody patterns (IgG, IgG1-4 subclasses, IgM, C4d-fixing reactivities) were analysed applying conventional agglutination testing and flow cytometry. Results. As assessed by sensitive flow cytometric antibody detection, ABO-IA-based desensitization led to a profound even though often incomplete reduction of anti-A/B reactivities. Persistent complement- or non-complement-fixing reactivities, however, were not associated with transplant rejection or capillary C4d deposition. Single sessions of semiselective IA turned out to be more effective than ABO-IA in decreasing levels of anti-A/B IgG [median reduction to 28 versus 59% (ABO-IA) of baseline values, P < 0.001). In contrast, BG-specific IgM (74 versus 30%, P < 0.001) and IgG3 (72 versus 42%, P < 0.05) were reduced to a lesser extent, without differences between tested adsorber types. Analysis of four consecutive IA sessions revealed that inferior efficiency could not be overcome by serial treatment. Conclusion. Our observation of limited adsorption capacities regarding distinct BG-specific Ig (sub)classes suggests caution in applying semiselective IA techniques in ABO-incompatible kidney transplantatio

Risk Factors Promoting Hypertensive Crises: Evidence From a Longitudinal Study

Background Current knowledge about risk factors promoting hypertensive crisis originates from retrospective data. Therefore, potential risk factors of hypertensive crisis were assessed in a prospective longitudinal study. Methods Eighty-nine patients of the medical outpatient unit at the University Hospital of Bern (Bern, Switzerland) with previously diagnosed hypertension participated in this study. At baseline, 33 potential risk factors were assessed. All patients were followed-up for the outcome of hypertensive crisis. Cox regression models were used to detect relationships between risk factors and hypertensive crisis (defined as acute rise of systolic blood pressure (BP) ≥200mmHg and/or diastolic BP ≥120mmHg). Results The mean duration of follow-up was 1.6 ± 0.3 years (range 1.0-2.4 years). Four patients (4.5%) were lost to follow-up. Thirteen patients (15.3%) experienced hypertensive crisis during follow-up. Several potential risk factors were significantly associated with hypertensive crisis: female sex, higher grades of obesity, the presence of a hypertensive or coronary heart disease, the presence of a somatoform disorder, a higher number of antihypertensive drugs, and nonadherence to medication. As measured by the hazard ratio, nonadherence was the most important factor associated with hypertensive crisis (hazard ratio 5.88, 95% confidence interval 1.59-21.77, P < 0.01). Conclusions This study identified several potential risk factors of hypertensive crisis. Results of this study are consistent with the hypothesis that improvement of medical adherence in antihypertensive therapy would help to prevent hypertensive crises. However, larger studies are needed to assess potential confounding, other risk factors and the possibility of interaction between predictor

Characterisation of machinable structural polymers in restorative dentistry

Objectives To characterise the mechanical properties of the machinable polymers Pekkton® (Cendres-Meteaux, Biel/Bienne, Switzerland), Lava Ultimate® (3MESPE, Seefeld, Germany), Vita Enamic® (Ivoclar Vivadent, Schaan, Liechtenstein) and the ceramic IPS e.Max Press® (Ivoclar Vivadent, Schaan, Liechtenstein). To determine the structural integrity of full coverage crowns fabricated from these materials. Methods The following tests were conducted: Biaxial flexural strength (BFS) using the piston on 3 balls jig (n = 10); Vickers Hardness (VH) 10 indentations per sample with 10 kg load & 20 s dwell time (n = 5); Hygroscopic Expansion Change (HEC) in artificial saliva over 68 days (n = 5). Structural Strength (SS) of teeth analogues (n = 20) restored with monolithic crowns from the four materials. Mean values and standard deviations for BFS, VH, HEC and SS tests were calculated and compared using one-way ANOVA with post-hoc Tukey’s test at a level of 5% significance. Results BFS: IPS e.Max Press® (317 MPa ± 37 MPa), Pekkton® (227 MPa ± 18 MPa), Lava Ultimate® (145 MPa ± 18 MPa) and Vita Enamic® (137 MPa ± 7 MPa) with a significance between groups of p < 0.0001. VH: IPS e.Max Press® (5064 MPa ± 131 MPa), Vita Enamic® (1976 MPa ± 12 MPa), Lava Ultimate® (924 MPa ± 27 MPa) and Pekkton® (445MPa ± 21 MPa) with a significance between groups of p < 0.0001. HEC (%vol change): Pekkton® (0.14% ± 0.14%), Vita Enamic® (0.38% ± 0.16%) and Lava Ultimate® (1.06% ± 0.17%). SS for full-coverage crowns: Pekkton® (2037 N ± 49 N no fracture), IPS e.Max Press® (1497 N ± 165 N), Lava Ultimate® (1476 N ± 142 N) and Vita Enamic® (1127 N ± 108 N). Significance The properties investigated suggest that full coverage monolithic PEKK crowns possess adequate mechanical and physical properties for use in the posterior region of the mouth. These results must be considered alongside other data including clinical studies

Effects of daily static stretch training over 6 weeks on maximal strength, muscle thickness, contraction properties, and flexibility

PurposeStatic stretch training (SST) with long stretching durations seems to be sufficient to increase flexibility, maximum strength (MSt) and muscle thickness (MTh). However, changes in contraction properties and effects on muscle damage remain unclear. Consequently, the objective of the study was to investigate the effects of a 6-week self-performed SST on MSt, MTh, contractile properties, flexibility, and acute response of creatine kinase (CK) 3 days after SST.MethodsForty-four participants were divided into a control (CG, n = 22) and an intervention group (IG, n = 22), who performed a daily SST for 5 min for the lower limb muscle group. While isometric MSt was measured in leg press, MTh was examined via sonography and flexibility by functional tests. Muscle stiffness and contraction time were measured by tensiomyography on the rectus femoris. Additionally, capillary blood samples were taken in the pretest and in the first 3 days after starting SST to measure CK.ResultsA significant increase was found for MSt (p &lt; 0.001, η2 = 0.195) and flexibility in all functional tests (p &lt; 0.001, η2 &gt; 0.310). Scheffé post hoc test did not show significant differences between the rectus femoris muscle inter- and intragroup comparisons for MTh nor for muscle stiffness and contraction time (p &gt; 0.05, η2 &lt; 0.100). Moreover, CK was not significantly different between IG and CG with p &gt; 0.05, η2 = 0.032.DiscussionIn conclusion, the increase in MSt cannot be exclusively explained by muscular hypertrophy or the increased CK-related repair mechanism after acute stretching. Rather, neuronal adaptations have to be considered. Furthermore, daily 5-min SST over 6 weeks does not seem sufficient to change muscle stiffness or contraction time. Increases in flexibility tests could be attributed to a stretch-induced change in the muscle–tendon complex

Base-specific spin-labeling of RNA for structure determination

To facilitate the measurement of intramolecular distances in solvated RNA systems, a combination of spin-labeling, electron paramagnetic resonance (EPR), and molecular dynamics (MD) simulation is presented. The fairly rigid spin label 2,2,5,5-tetramethyl-pyrrolin-1-yloxyl-3-acetylene (TPA) was base and site specifically introduced into RNA through a Sonogashira palladium catalyzed crosscoupling on column. For this purpose 5-iodouridine, 5-iodo-cytidine and 2-iodo-adenosine phosphoramidites were synthesized and incorporated into RNA-sequences. Application of the recently developed ACE (R) chemistry presented the main advantage to limit the reduction of the nitroxide to an amine during the oligonucleotide automated synthesis and thus to increase substantially the reliability of the synthesis and the yield of labeled oligonucleotides. 4-Pulse Electron Double Resonance (PELDOR) was then successfully used to measure the intramolecular spin–spin distances in six doubly labeled RNA-duplexes. Comparison of these results with our previous work on DNA showed that A- and B-Form can be differentiated. Using an all-atom force field with explicit solvent, MD simulations gave results in good agreement with the measured distances and indicated that the RNA A-Form was conserved despite a local destabilization effect of the nitroxide label. The applicability of the method to more complex biological systems is discussed

The 14-bp deletion polymorphism in the HLA-G gene displays significant differences between ulcerative colitis and Crohn's disease and is associated with ileocecal resection in Crohn's disease

HLA-G is a non-classical MHC class Ib molecule predominantly expressed in cytotrophoblasts and under pathological conditions also in chronically inflamed and in malignant tissues. Recently an increased expression of HLA-G was found in ulcerative colitis (UC), but not in Crohn's disease (CD). The HLA-G gene is located in IBD3, a linkage region for inflammatory bowel disease (IBD). A 14-bp deletion polymorphism (Del+/Del−) within exon 8 of the HLA-G gene might influence transcription activity and is therefore of potential functional relevance. To investigate whether the 14-bp deletion polymorphism is associated with IBD, 371 patients with CD, 257 patients with UC and 739 controls were genotyped. The heterozygous genotype (P = 0.031) and the Del+ phenotype (P = 0.038) were significantly increased, whereas the homozygous Del− phenotype (P = 0.038) was significantly decreased in UC when compared with CD. Thus, the 14-bp deletion polymorphism within the HLA-G gene displayed significant differences between UC and CD. Moreover, a significant increase of the Del+ allele (P = 0.002) and the Del+/Del+ genotype (P = 0.013) and a consecutive decrease of the Del−/− genotype (P = 0.024) were observed in those CD cases positive for ileocecal resection. Thus, a potential effect of the HLA-G gene in IBD may affect both UC and CD. Other polymorphisms linked to the 14-bp deletion polymorphism might also contribute to immunopathogenesis. As there are several partly functional polymorphisms within the promoter region potentially influencing HLA-G expression, further studies in IBD are necessary in the context of differential expression of HLA-G between UC and C

Anti-A/B antibody depletion by semiselective versus ABO blood group-specific immunoadsorption

Background. Recipient desensitization using blood group (BG)-specific immunoadsorption (ABO-IA) has proven to enable successful kidney transplantation across major ABO barriers. In this context, the efficiency of non-antigen-specific (semiselective) IA adsorbers has not yet been established. The objective of our study was to quantify anti-A/B antibody depletion by protein A-, peptide ligand- and anti-human immunoglobulin-based semiselective IA in comparison to ABO-IA. Methods. Eight ABO-IA-treated transplant candidates and 39 patients subjected to semiselective IA for a variety of different indications outside the context of ABO-incompatible transplantation were included. Antibody patterns (IgG, IgG1-4 subclasses, IgM, C4d-fixing reactivities) were analysed applying conventional agglutination testing and flow cytometry. Results. As assessed by sensitive flow cytometric antibody detection, ABO-IA-based desensitization led to a profound even though often incomplete reduction of anti-A/B reactivities. Persistent complement- or non-complement-fixing reactivities, however, were not associated with transplant rejection or capillary C4d deposition. Single sessions of semiselective IA turned out to be more effective than ABO-IA in decreasing levels of anti-A/B IgG [median reduction to 28 versus 59% (ABO-IA) of baseline values, P < 0.001). In contrast, BG-specific IgM (74 versus 30%, P < 0.001) and IgG3 (72 versus 42%, P < 0.05) were reduced to a lesser extent, without differences between tested adsorber types. Analysis of four consecutive IA sessions revealed that inferior efficiency could not be overcome by serial treatment. Conclusion. Our observation of limited adsorption capacities regarding distinct BG-specific Ig (sub)classes suggests caution in applying semiselective IA techniques in ABO-incompatible kidney transplantatio