Amniotic fluid content in children with kidney and urinary tract anomalies determines pre- and postnatal development.

BACKGROUND: Renal oligohydramnios (ROH) describes an abnormally low volume of amniotic fluid (AF) during pregnancy. ROH is mostly caused by congenital fetal kidney anomalies. The ROH diagnosis frequently implies an increased risk of peri- and postnatal fetal mortality and morbidity. The present study aimed to evaluate the impact of ROH on pre-and postnatal development in children with congenital kidney anomalies. METHODS: This retrospective study included 168 fetuses with anomalies in the kidney and urinary tract. Based on the amount of AF measured by ultrasound, patients were divided into three groups: normal amniotic fluid (NAF), amniotic fluid in the lower normal range (LAF), and ROH. These groups were compared with respect to prenatal sonographic parameters, perinatal outcomes, and postnatal outcomes. RESULTS: Among the 168 patients with congenital kidney anomalies, 26 (15%) had ROH, 132 (79%) had NAF, and 10 (6%) had LAF. Of the 26 families affected by ROH, 14 (54%) decided to terminate pregnancy. Of 10 live-born children in the ROH group, 6 (60%) survived the observation time; of these, 5/6 presented with chronic kidney disease, stages I-III, at their last examination. The main differences in postnatal development between the ROH group and the NAF and LAF groups were: restricted height and weight gain, respiratory issues, complicated feeding, and the presence of extrarenal malformations. CONCLUSIONS: ROH is not a mandatory indicator of severe postnatal kidney function impairment. However, children with ROH have complicated peri-and postnatal periods, due to the presence of concomitant malformations, which must be considered in prenatal care. A higher resolution version of the Graphical abstract is available as Supplementary information.

Reversible Glutamate Coordination to High-Valent Nickel Protects the Active Site of a [NiFe] Hydrogenase from Oxygen.

NAD+-reducing [NiFe] hydrogenases are valuable biocatalysts for H2-based energy conversion and the regeneration of nucleotide cofactors. While most hydrogenases are sensitive toward O2 and elevated temperatures, the soluble NAD+-reducing [NiFe] hydrogenase from Hydrogenophilus thermoluteolus (HtSH) is O2-tolerant and thermostable. Thus, it represents a promising candidate for biotechnological applications. Here, we have investigated the catalytic activity and active-site structure of native HtSH and variants in which a glutamate residue in the active-site cavity was replaced by glutamine, alanine, and aspartate. Our biochemical, spectroscopic, and theoretical studies reveal that at least two active-site states of oxidized HtSH feature an unusual architecture in which the glutamate acts as a terminal ligand of the active-site nickel. This observation demonstrates that crystallographically observed glutamate coordination represents a native feature of the enzyme. One of these states is diamagnetic and characterized by a very high stretching frequency of an iron-bound active-site CO ligand. Supported by density-functional-theory calculations, we identify this state as a high-valent species with a biologically unprecedented formal Ni(IV) ground state. Detailed insights into its structure and dynamics were obtained by ultrafast and two-dimensional infrared spectroscopy, demonstrating that it represents a conformationally strained state with unusual bond properties. Our data further show that this state is selectively and reversibly formed under oxic conditions, especially upon rapid exposure to high O2 levels. We conclude that the kinetically controlled formation of this six-coordinate high-valent state represents a specific and precisely orchestrated stereoelectronic response toward O2 that could protect the enzyme from oxidative damage.

Efficacy and tolerability of brivaracetam monotherapy in childhood and juvenile absence epilepsy: An innovative adaptive trial design.

OBJECTIVE: Despite introduction of several antiseizure medications over the past two decades, treatment options for childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remain limited. We report the innovative adaptive design of an ongoing phase 2/3 trial to evaluate efficacy, safety, and tolerability of brivaracetam (BRV) monotherapy in patients 2-25 years of age with CAE or JAE. METHODS: N01269 (ClinicalTrials.gov: NCT04666610; start: July 2021; expected completion: 2024) is a randomized, dose-finding and confirmatory, double-blind, placebo-controlled, parallel-group, multicenter trial. The trial consists of a dose-selection and assessment for futility stage, followed by an optimal-dose stage after interim analysis. Both stages include an up to 2-week screening period, a 2-week placebo-controlled period, and an 11-week active treatment period (10 weeks of initial treatment followed by a 24-hour electroencephalogram [EEG] and an additional week of active treatment for 24-hour EEG assessment). Patients who are absence seizure-free will enter an up to 4-week randomized withdrawal period. Efficacy assessments will be based on 24-hour EEG and seizure diaries. SIGNIFICANCE: This two-stage adaptive trial design allows investigation of two potentially efficacious BRV doses, where one dose is dropped in favor of the other dose with a better benefit-risk profile. This allows for a combined phase 2 dose-finding and phase 3 confirmatory efficacy trial, which reduces the number of patients needed to be recruited and reduces trial duration. A randomized withdrawal period is included to evaluate sustainability of treatment effect over time and to allow for placebo control while minimizing placebo exposure. Use of EEG capture in addition to seizure diaries offers a robust mechanism of detecting seizure activity and measuring treatment effect. Positive efficacy and safety/tolerability data may support the use of BRV as monotherapy for CAE or JAE, providing another treatment option and representing long-delayed progress in the treatment of absence seizures in these populations.

Long-term safety, efficacy, and quality of life during adjunctive brivaracetam treatment in patients with uncontrolled epilepsy: An open-label follow-up trial.

OBJECTIVES: The primary objective of this long-term follow-up (LTFU) trial was to evaluate the long-term safety and tolerability of brivaracetam (BRV). The secondary objective was to evaluate the maintenance of efficacy of BRV (including quality of life) over time. METHODS: This open-label, multicenter, flexible-dose trial (N01379 [NCT01339559]) was conducted in adults (≥16 years) with focal or generalized-onset seizures, who had participated in a placebo (PBO)-controlled trial of adjunctive BRV (N01258: NCT01405508 or N01358: NCT01261325). RESULTS: Seven hundred and sixty-six patients received BRV in this LTFU trial (753 had focal seizures and 13 had generalized-onset seizures). Kaplan-Meier-estimated retention was 71.9% at 12 months, and 53.7% at 36 months. Treatment-emergent adverse events (TEAEs) were reported by 643 (83.9%) patients, most commonly headache (104 [13.6%] patients) and dizziness (100 [13.1%] patients). Two hundred and fifty-seven (33.6%) patients had drug-related TEAEs, most commonly somnolence (49 [6.4%] patients) and dizziness (41 [5.4%] patients). Permanent discontinuation of BRV due to TEAEs occurred in 91 (11.9%) patients. Patients with focal seizures had a median percentage reduction in focal seizure frequency of 52.0% and 51.7% were 50% responders (sustained over time); 26.0% were seizurefree for 6 months, and 17.9% were seizurefree for 12 months. 42.4% of patients at 12 months and 46.8% at 24 months had clinically meaningful improvements in Patient Weighted Quality of Life in Epilepsy Questionnaire 31 total score. CONCLUSIONS: In this select group of patients who entered the LTFU trial, BRV was generally safe and well tolerated. Results indicate the long-term efficacy of BRV in patients with focal seizures.

Long-term results following electrical stimulation of the peroneal nerve using the ActiGait® system in 33 patients with central drop foot.

OBJECTIVE: Direct electrical stimulation of the peroneal nerve, using the implantable ActiGait® system, enables a therapy of the centrally caused drop foot, to improve the gait of the patients. In this paper, we present long-term results at 36-month follow-up post implantation. METHOD: A total of 33 patients, 27 stroke and six multiple sclerosis (MS) patients, suffering from spastic drop foot were implanted in our center and assessed in terms of gait endurance, speed, risk of fall, and life quality at baseline and 36 months following implantation. RESULTS: The six min gait endurance test increased significantly from 202 ± 41 m without walking aids to 380 ± 30 m (p=0.038), while using the implant. Moreover, the time in the gait speed measured over 20 m decreased from 31.8 ± 10.2 s without to 18.5 ± 4.6 s by using the ActiGait® system (p=0.039). Similarly, gait steadiness, measured by the Timed Up and Go (TUG) test improved by 36.6%, with patients demonstrating a reduced time from 18.6 ± 5.5 to 11.2 ±  3.8 s (p=0.041) upon implant activation. Most importantly, 31 of 33 patients reported remarkable improvements of their quality of life following direct electrical nerve stimulation. CONCLUSION: Our findings confirm previously published efficacy data at 12 months after implantation and underline the long-lasting effect of the ActiGait® system.

Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: An open-label, long-term follow-up trial.

This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht-Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures. Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for ≥12 months, 403 (47.2 %) for ≥36 months, and 223 (26.1 %) for ≥96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had ≥96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6- and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595). Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease, with improvements in focal seizure frequency maintained over time.

Brivaracetam substituting other antiepileptic treatments: Results of a retrospective study in German epilepsy centers.

OBJECTIVE: To evaluate the success of initiation of adjunctive brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam. METHODS: In this retrospective noninterventional study conducted in specialized epilepsy centers across Germany, patients initiated adjunctive brivaracetam between February 15, 2016, and August 31, 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months, and withdrew at least one AED either before or within 6 months after brivaracetam initiation. RESULTS: Five hundred and six patients had at least one brivaracetam dose and were included in the safety set (SS). Four hundred and seventy patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation, and were included in the full analysis set (FAS) for effectiveness analyses. At baseline, patients had a median of seven lifetime AEDs and a median of 3.8 seizures/28 days. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (49.4%). 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure-free. In the SS, 34.6% of patients reported treatment-emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug-related. Incidences of behavioral AEs before (3-month baseline) and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs). SIGNIFICANCE: Brivaracetam was effective and well-tolerated in patients who required a change in AED drug regimen and initiated adjunctive brivaracetam in German clinical practice.

Long-term safety and efficacy of brivaracetam in adults with focal seizures: Results from an open-label, multinational, follow-up trial.

BACKGROUND: This long-term follow-up (LTFU) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses (maximum of 200 mg/day) in patients with focal seizures. The secondary objective was to evaluate the efficacy of BRV over time. METHODS: Two Phase III, randomized, double-blind, historical-controlled conversion-to-monotherapy trials (N01276: NCT00698581; N01306: NCT00699283) were conducted in patients aged ≥16 years with uncontrolled focal seizures. Patients who completed either of these core trials or who met a protocol-defined exit criterion could enter this LTFU trial (N01315; NCT00761774). Patients entered LTFU at a recommended BRV dose of 100 mg/day, with flexible dosing of 50-200 mg/day, as monotherapy or adjunctive therapy; additional AEDs could be prescribed and adapted in dose if clinically indicated. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables included duration of continuous monotherapy, reduction in focal seizure frequency and seizure freedom. Safety and efficacy variables were assessed for all patients in the safety set or efficacy set, respectively, regardless of BRV treatment regimen. In addition, a post hoc subgroup analysis was conducted for patients who completed the BRV monotherapy period in either core trial, and entered the LTFU on BRV monotherapy. For this subgroup, TEAEs were summarized by 3-month time intervals over the first 12 months of LTFU. RESULTS: 108 patients were enrolled in the LTFU trial between November 2008 and February 2010. 79 (73.1 %) patients discontinued the LTFU trial, most commonly due to lack of efficacy [37 (34.3 %)] and adverse events [16 (14.8 %)]. At core trial baseline, patients had a median of 6.3 focal seizures/28 days and 53 (49.1 %) had failed ≥5 previous lifetime AEDs. During LTFU, 70 (64.8 %) patients had ≥12 months and 56 (51.9 %) patients had ≥24 months of BRV treatment. TEAEs were reported by 98 (90.7 %) patients; most commonly (≥15 % of patients) convulsion (17.6 %), nasopharyngitis (17.6 %), depression (16.7 %) and fatigue (15.7 %). Median percent reduction from baseline in focal seizure frequency/28 days was 56.8 %. Among 86 patients who completed at least 6 months of treatment, 29 (33.7 %) patients were seizure-free for ≥6 months and 22 (25.6 %) were seizure-free for ≥12 months. 50/108 patients were included in the BRV monotherapy subgroup; 33/50 (66.0 %) patients reported a TEAE in the core trials, while 26/50 (52.0 %), 15/37 (40.5 %), 14/33 (42.4 %) and 9/27 (33.3 %) patients reported any TEAE during LTFU months 1-3, 4-6, 7-9 and 10-12, respectively. In the BRV monotherapy subgroup, the most common TEAEs (≥5% of patients) during LTFU months 1-3 were fatigue [3/50 (6.0 %)] and dizziness [3/50 (6.0 %)]. INTERPRETATION: Results from the LTFU trial support the long-term safety of BRV at individualized doses of up to 200 mg/day as a well-tolerated, and effective treatment for patients with focal seizures. Efficacy analyses indicate that seizure reductions with brivaracetam were generally maintained over time.

Long-term safety, efficacy, and quality of life outcomes with adjunctive brivaracetam treatment at individualized doses in patients with epilepsy: An up to 11-year, open-label, follow-up trial.

OBJECTIVE: To evaluate long-term safety/tolerability of brivaracetam at individualized doses ≤200 mg/d (primary) and maintenance of efficacy over time (secondary) in adults with focal seizures or primary generalized seizures (PGS) enrolled in phase 3, open-label, long-term follow-up trial N01199 (NCT00150800). METHODS: Patients ≥16 years of age who had completed double-blind, placebo-controlled adjunctive brivaracetam trials NCT00175825, NCT00490035, NCT00464269, or NCT00504881 were eligible. Outcomes included safety, efficacy, and quality of life. RESULTS: The safety set included 667 patients (focal seizures, 97.8%; PGS, 2.2%); the efficacy set included 648 patients with focal seizures and 15 patients with PGS. Overall, 49.2% of patients had ≥48 months of exposure. Treatment-emergent adverse events (TEAEs) occurred in 91.2% of all patients (91.3% of focal seizures group), brivaracetam discontinuation due to TEAEs in 14.8%, drug-related TEAEs in 56.7%, and serious TEAEs in 22.8%. The most common TEAEs in the focal seizures group (≥15%) were headache (25.3%) and dizziness (21.9%). Mean changes from baseline in Hospital Anxiety and Depression Scale scores at last value during 2-year evaluation were -0.7 (standard deviation [SD] = 4.3) and -0.2 (SD = 4.4) overall. In the focal seizures group, median reduction from baseline in focal seizure frequency/28 days was 57.3%, 50% responder rate was 55.6%, and 6-month and 12-month seizure freedom rates were 30.3% and 20.3%, respectively. Efficacy outcomes improved by exposure duration cohort and then stabilized through the 108-month cohort. Mean improvement from baseline in Patient-Weighted Quality of Life in Epilepsy Inventory total score (efficacy set) was 5.7 (SD = 16.1, Cohen's d = 0.35) at month 12 and 6.5 (SD = 18.0, Cohen's d = 0.36) at month 24. SIGNIFICANCE: Adjunctive brivaracetam was well tolerated, with a good safety profile in long-term use in adults with epilepsy at individualized doses. Approximately half of the patients remained in the trial at 4 years. Brivaracetam reduced focal seizure frequency versus baseline. Efficacy improved with increasing exposure duration and remained stable through the 9-year cohort.

Formyltetrahydrofolate Decarbonylase Synthesizes the Active Site CO Ligand of O2-Tolerant [NiFe] Hydrogenase.

[NiFe] hydrogenases catalyze the reversible oxidation of molecular hydrogen into two protons and two electrons. A key organometallic chemistry feature of the NiFe active site is that the iron atom is co-coordinated by two cyanides (CN-) and one carbon monoxide (CO) ligand. Biosynthesis of the NiFe(CN)2(CO) cofactor requires the activity of at least six maturation proteins, designated HypA-F. An additional maturase, HypX, is required for CO ligand synthesis under aerobic conditions, and preliminary in vivo data indicated that HypX releases CO using N10-formyltetrahydrofolate (N10-formyl-THF) as the substrate. HypX has a bipartite structure composed of an N-terminal module similar to N10-formyl-THF transferases and a C-terminal module homologous to enoyl-CoA hydratases/isomerases. This composition suggested that CO production takes place in two consecutive reactions. Here, we present in vitro evidence that purified HypX first transfers the formyl group of N10-formyl-THF to produce formyl-coenzyme A (formyl-CoA) as a central reaction intermediate. In a second step, formyl-CoA is decarbonylated, resulting in free CoA and carbon monoxide. Purified HypX proved to be metal-free, which makes it a unique catalyst among the group of CO-releasing enzymes.

[Intraprosthetic luxation of trapeziometacarpal joint prosthesis].

Total joint replacement is used for treating osteoarthritis of the trapeziometacarpal joint. The prosthesis is a ball and socket design resembling a total hip prosthesis and with the same risk of head luxation. To reduce this risk, dual mobility articulations have also been introduced in prosthesis of the thumb, and this is a case report of luxation of the polyethylene liner in a dual mobility prosthesis, illustrating that introducing new designs in prosthesis for the basal joint of the thumb may lead to similar complications as are seen in the hip joint.

Start Spreading the News: A Comparative Experiment on the Effects of Populist Communication on Political Engagement in Sixteen European Countries.

Although populist communication has become pervasive throughout Europe, many important questions on its political consequences remain unanswered. First, previous research has neglected the differential effects of populist communication on the Left and Right. Second, internationally comparative studies are missing. Finally, previous research mostly studied attitudinal outcomes, neglecting behavioral effects. To address these key issues, this paper draws on a unique, extensive, and comparative experiment in sixteen European countries (N = 15,412) to test the effects of populist communication on political engagement. The findings show that anti-elitist populism has the strongest mobilizing effects, and anti-immigrant messages have the strongest demobilizing effects. Moreover, national conditions such as the level of unemployment and the electoral success of the populist Left and Right condition the impact of populist communication. These findings provide important insights into the persuasiveness of populist messages spread throughout the European continent.

Are adverse childhood experiences and depression associated with impaired glucose tolerance in females? An experimental study.

Adverse childhood experiences (ACE) enhance the risk for mental disorders, e.g. major depressive disorder (MDD). Increasing evidence suggests an association between ACE and impaired physical health, e.g. metabolic syndrome. The aim of this study was to assess several metabolic risk markers in healthy individuals with and without ACE and depressed patients with and without ACE. We examined glucose and insulin release in the oGTT in 33 women with MDD and ACE, 47 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 36 healthy women without either MDD or ACE. Several metabolic markers such as triglycerides, cholesterol, LDL, HDL, HbA1c, BMI and waist to hip ratio were assessed. The four groups did neither differ in insulin release and glucose concentrations in the oGTT nor with respect to other metabolic variables. Depressed patients with and without psychotropic medication did not differ in any outcome variable, but there was a trend towards higher glucose concentrations in the oGTT in patients with current psychotropic medication. In this physically healthy sample neither ACE nor MDD were associated with metabolic risk factors. Thus, metabolic alterations might not directly be linked to ACE and depression.

Neurovascular complications after supracondylar humerus fractures in children.

BACKGROUND: Supracondylar fractures of the humerus are a common injury in pediatric traumatology. The most common operative therapy is closed reduction and percutaneous pinning using K-wires. Common complications associated with this entity are neurovascular lesions, especially of the brachial artery and the median nerve. METHODS: We report two cases of patients treated in our trauma-center with supracondylar fracture of the humerus (AO IV°) and neurovascular complications. RESULTS: Both patients underwent open revision and recovered completely in their further course. CONCLUSION: We recommend detailed neurovascular examination initially and after reposition of the fracture. The threshold for open reduction in cases of irreducible fractures should be low. In the presence of neurovascular impairment an open revision is mandatory, even months after the initial Trauma.Level of evidence: Level V (case report).

ActiGait implantable drop foot stimulator in multiple sclerosis: a new indication.

OBJECTIVE Direct stimulation of the peroneal nerve by the ActiGait implantable drop foot stimulator is a potent therapy that was described previously for stroke-related drop foot. The authors report here successful long-term application of the ActiGait implantable drop foot stimulator in patients with multiple sclerosis (MS). METHODS Six patients with MS and 2 years of persisting central leg paresis received an implantable ActiGait drop foot stimulator after successful surface test stimulation. Ten weeks and 1 year after surgery, their gait speed, endurance, and safety were evaluated. Patient satisfaction was assessed with a questionnaire. RESULTS In the 20-m gait test, stimulation with the ActiGait stimulator significantly reduced the time needed, on average, by approximately 23.6% 10 weeks after surgery, and the time improved further by 36.3% after 1 year. The median distance covered by patients with the stimulator after 6 minutes of walking increased significantly from 217 m to 321 m and remained stable for 1 year; the distance covered by patients after surface stimulation was 264 m. Patients with an implanted ActiGait stimulator noticed pronounced improvement in their mobility, social participation, and quality of life. CONCLUSIONS The ActiGait implantable drop foot stimulator improved gait speed, endurance, and quality of life in all patients over a period of 1 year. It may serve as a new therapeutic option for patients with MS-related drop foot.

Restoration of ankle movements with the ActiGait implantable drop foot stimulator: a safe and reliable treatment option for permanent central leg palsy.

OBJECT The ActiGait drop foot stimulator is a promising technique for restoration of lost ankle function by an implantable hybrid stimulation system. It allows ankle dorsiflexion by active peroneal nerve stimulation during the swing phase of gait. In this paper the authors report the outcome of the first prospective study on a large number of patients with stroke-related drop foot. METHODS Twenty-seven patients who experienced a stroke and with persisting spastic leg paresis received an implantable ActiGait drop foot stimulator for restoration of ankle movement after successful surface test stimulation. After 3 to 5 weeks, the stimulator was activated, and gait speed, gait endurance, and activation time of the system were evaluated and compared with preoperative gait tests. In addition, patient satisfaction was assessed using a questionnaire. RESULTS Postoperative gait speed significantly improved from 33.9 seconds per 20 meters to 17.9 seconds per 20 meters (p < 0.0001), gait endurance from 196 meters in 6 minutes to 401 meters in 6 minutes (p < 0.0001), and activation time from 20.5 seconds to 10.6 seconds on average (p < 0.0001). In 2 patients with nerve injury, surgical repositioning of the electrode cuff became necessary. One patient showed a delayed wound healing, and in another patient the system had to be removed because of a wound infection. Marked improvement in mobility, social participation, and quality of life was confirmed by 89% to 96% of patients. CONCLUSIONS The ActiGait implantable drop foot stimulator improves gait speed, endurance, and quality of life in patients with stroke-related drop foot. Regarding gait speed, the ActiGait system appears to be advantageous compared with foot orthosis or surface stimulation devices. Randomized trials with more patients and longer observation periods are needed to prove the long-term benefit of this device.

XacR - a novel transcriptional regulator of D-xylose and L-arabinose catabolism in the haloarchaeon Haloferax volcanii.

The haloarchaeon Haloferax volcanii degrades D-xylose and L-arabinose via oxidative pathways to α-ketoglutarate. The genes involved in these pathways are clustered and were transcriptionally upregulated by both D-xylose and L-arabinose suggesting a common regulator. Adjacent to the gene cluster, a putative IclR-like transcriptional regulator, HVO_B0040, was identified. It is shown that HVO_B0040, designated xacR, encodes an activator of both D-xylose and L-arabinose catabolism: in ΔxacR cells, transcripts of genes involved in pentose catabolism could not be detected; transcript formation could be recovered by complementation, indicating XacR dependent transcriptional activation. Upstream activation promoter regions and nucleotide sequences that were essential for XacR-mediated activation of pentose-specific genes were identified by in vivo deletion and scanning mutagenesis. Besides its activator function XacR acted as repressor of its own synthesis: xacR deletion resulted in an increase of xacR promoter activity. A palindromic sequence was identified at the operator site of xacR promoter, and mutation of this sequence also resulted in an increase and thus derepression of xacR promoter activity. It is concluded that the palindromic sequence represents the binding site of XacR as repressor. This is the first report of a transcriptional regulator of pentose catabolism in the domain of archaea.

Regulatory effects of a fermented food concentrate on immune function parameters in healthy volunteers.

OBJECTIVE: Nutrition is known to influence the immune system and can thereby modulate resistance to infection. The objective of this clinical trial was to assess the influence of a cascade-fermented food consisting of fruits, nuts, and vegetables rich in polyphenols (Regulat) on the immune system in healthy volunteers. METHODS: The clinical trial was double-blinded and placebo-controlled. In total, 48 healthy men 20-48 y of age with a body mass index of 20-28 kg/m(2) were enrolled in the clinical trial. The group was characterized according to lifestyle parameters and only men with regular low to moderate intake of fruit and vegetables were enrolled. The intervention lasted for a period of 4 wk. Volunteers received Regulat twice daily or a placebo product (essence of vinegar). RESULTS: The intake of Regulat significantly enhanced intracellular glutathione content in lymphocytes (P < 0.05), monocytes (P < 0.05), and natural killer cells (P < 0.01). Furthermore, activation of natural killer cell cytotoxicity in response to interleukin-2 stimulation (P < 0.05), a reduction of total lipid peroxidation, and a reduction of soluble vascular cell adhesion molecule-1 (P < 0.01) and soluble intercellular adhesion molecule-1 (P < 0.05) as inflammatory blood markers were found in the Regulat but not in the placebo group. CONCLUSION: In summary, the results from this intervention study demonstrate promising physiologic effects of immune regulation on the innate immune system and antioxidative and anti-inflammatory parameters after Regulat supplementation. However, these promising results need to be confirmed in more volunteers with a more prolonged application to ensure significant beneficial effects of Regulat in the general population.