Efficacy and safety of exogenous beta-hydroxybutyrate for preventive treatment in episodic migraine: A single-centred, randomised, placebo-controlled, double-blind crossover trial.

BACKGROUND: Several studies propose that brain energy deficit might be partially involved in the pathophysiology of migraine. Previously, studies demonstrated that ketogenic diet causes a substantial reduction in migraine frequency. Since the ketogenic diet is restricting and its adherence is difficult, we proposed to supplement ketone bodies exogenously to provide a prophylactic effect in migraineurs. AIM: To evaluate the prophylactic effect of exogenous DL-beta-hydroxybutyrate supplementation in episodic migraineurs. METHODS: A double-blind, placebo-controlled, randomised crossover trial was conducted, involving 41 patients with episodic migraine. Patients were randomised 1:1 into placebo or beta-hydroxybutyrate group before entering the first treatment period. Each treatment period was 12 weeks long, followed by four weeks of washout phase and four weeks of run-in phase before entering into the corresponding second treatment period. The primary endpoint was the number of migraine days in the last four weeks of treatment, adjusted for baseline. RESULTS: We observed no clinically significant amelioration of migraine frequency or intensity under DL-beta-hydroxybutyrate treatment as compared to placebo regarding number of migraine days (mean difference [95% CI]: -1.1[-5.07, 2.85]), migraine intensity (0-10 VAS: 1.5[-0.8, 3.7]). CONCLUSION: The selected dose of supplemented exogenous DL-beta-hydroxybutyrate did not demonstrate efficacy in episodic migraineurs.ClinicalTrials.gov Identifier: NCT03132233.

Spinal cord gray matter atrophy is associated with functional decline in post-polio syndrome.

OBJECTIVE: To determine if patients with post-polio syndrome (PPS) show spinal cord gray matter (SCGM) atrophy and to assess associations between SCGM atrophy, muscle strength and patient-reported functional decline. METHODS: Twenty patients diagnosed with PPS (March of Dimes criteria) and 20 age- and sex-matched healthy controls (HC) underwent 3T axial 2D-rAMIRA magnetic resonance imaging at the intervertebral disc levels C2/C3-C6/C7, T9/T10 and the lumbar enlargement level (Tmax ) (0.5 × 0.5 mm2 in-plane resolution). SCGM areas were segmented manually by two independent raters. Muscle strength, self-reported fatigue, depression and pain measures were assessed. RESULTS: Post-polio syndrome patients showed significantly and preferentially reduced SCGM areas at C2/C3 (p = 0.048), C3/C4 (p = 0.001), C4/C5 (p < 0.001), C5/C6 (p = 0.004) and Tmax (p = 0.041) compared to HC. SCGM areas were significantly associated with muscle strength in corresponding myotomes even after adjustment for fatigue, pain and depression. SCGM areaTmax together with age and sex explained 68% of ankle dorsiflexion strength variance. No associations were found with age at or time since infection. Patients reporting PPS-related decline in arm function showed significant cervical SCGM atrophy compared to stable patients adjusted for initial disease severity. CONCLUSIONS: Patients with PPS show significant SCGM atrophy that correlates with muscle strength and is associated with PPS-related functional decline. Our findings suggest a secondary neurodegenerative process underlying SCGM atrophy in PPS that is not explained by aging or residua of the initial infection alone. Confirmation by longitudinal studies is needed. The described imaging methodology is promising for developing novel imaging surrogates for SCGM diseases.

One-year outcome of brain injured patients undergoing early neurological rehabilitation: a prospective observational study.

BACKGROUND: The present study intended to analyze the outcome of patients with severe brain injury one-year after discharge from early rehabilitation. METHODS: Early neurological rehabilitation patients admitted to intensive or intermediate care units and discharged between June 2018 and May 2020 were screened for eligibility. The level of consciousness was evaluated using the Coma Recovery Scale-Revised (CRS-R) upon admission and at discharge. At one-year follow-up, the outcome was assessed with the Glasgow Outcome Scale-extended (GOSE). Demographical and clinical data collected during inpatient rehabilitation were used to predict the outcome 1 year after discharge. RESULTS: Two hundred sixty-four patients (174 males, 90 females) with a median age of 62 years (IQR = 51-75) and a median duration of their disease of 18 days (IQR = 12-28) were included in the study. At follow-up, the mortality rate was 27% (n = 71). Age and discharge CRS-R total score were independent predictors in a Cox proportional hazards model with death (yes/no) as the dependent variable. According to the GOSE interviews, most patients were either dead (n = 71; 27%), in a vegetative state (n = 28; 11%) or had a severe disability (n = 124; 47%), whereas only a few patients showed a moderate disability (n = 18; 7%) or a good recovery (n = 23; 9%) 1 year after discharge. Age, non-traumatic etiology, discharge CRS-R total score and length of stay independently predicted whether the outcome was good or poor at follow-up. CONCLUSION: Age was an important predictor for outcome at one-year follow-up, which might be due to altered brain plasticity and more comorbidities in elderly subjects. In addition, the present study demonstrated that the CRS-R total score at discharge might be more important for the prediction of one-year outcome than the initial assessment upon admission.

Validity of the Early Functional Ability scale (EFA) among critically ill patients undergoing early neurological rehabilitation.

BACKGROUND: A reliable assessment of the functional abilities of patients after severe brain damage is crucial for valid prognostication and treatment decisions, but most clinical scales are of limited use among this specific group of patients. AIM: The present study investigates the usefulness of the Early Functional Ability (EFA) scale, which determines the functional abilities of severely impaired patients. METHODS: Critically ill patients consecutively admitted to early neurological rehabilitation were screened for eligibility. We assessed the correlation between the EFA scale and (i) the Early Rehabilitation Barthel Index (ERBI), and (ii) the Coma Recovery Scale-Revised (CRS-R). The 1-year outcome on the Glasgow Outcome Scale-extended (GOSE) was used to examine the predictive validity. Demographical and medical variables were entered into univariate and multivariate binary regression models to identify independent predictors of 1-year outcome. RESULTS: Two hundred fifty-seven patients (168 men) with a median age of 62 years (IQR = 51-75) were enrolled. The correlation of the EFA scale with the CRS-R was high but low with the ERBI upon admission. Multivariate regression analysis yielded the vegetative subscale of the EFA scale as the only independent predictor for the 1-year outcome of patients admitted to early neurological rehabilitation. CONCLUSIONS: This study shows a high correlation of the EFA scale with the CRS-R but a weak correlation with the ERBI in patients with low functional abilities. With improving patient abilities, these correlations were partly reversed. Thus, the EFA scale is a useful tool to assess the functional abilities and the prognosis of critically ill patients adequately and may be more feasible than other scales.

Evaluation of the predictive validity of the Hessisch Oldendorf Risk of Falling Scale (HOSS).

OBJECTIVE: This study aims to further validate the Hessisch Oldendorf Risk of Falling Scale (HOSS) for neurological rehabilitation patients. DESIGN: The overall scale performance and fall rate was calculated in a retrospective data analysis. SETTING: The study was performed in a subacute care facility during inpatient neurological rehabilitation. SUBJECTS: The study population (n = 512) included neurological and neurosurgical patients with heterogeneous levels of disability. MAIN MEASURES: The HOSS total score and the suspected risk of falling were compared with the number of falls. Characteristics of fallers and non-fallers were compared using non-parametric group comparisons. Overall scale performance was assessed by calculating the area under the receiver operating characteristic curve of the HOSS as well as by calculating the sensitivity and specificity. RESULTS: A total of 82 (16%) patients experienced at least one fall. Fallers were characterized by an older age, a longer length of stay, a more severe impairment in the activities of daily living upon admission, a hemiparesis, an orientation disorder, a need of a walking aid device and an urinary incontinence. The number of falls was associated with the HOSS total score. Sixty-four fallers and two hundred seventy-four non-fallers were correctly categorized leading to a sensitivity of 78.0% and a specificity of 63.7%. The area under the receiver operating characteristic curve of the HOSS was 0.778 ± 0.25 (CI = 0.729-0.828, P < 0.001). CONCLUSION: The scale performance of the HOSS showed a good sensitivity and an adequate specificity to identify neurological patients who are at high risk of falling during inpatient rehabilitation.

[Relevance of the Clinical Ethics Committee (CEC) for Clinical Staff of a Specialized Neurological Clinic]. / Bedeutung des Klinischen Ethikkomitees (KEKs) für Klinikmitarbeiter einer neurologischen Fachklinik.

BACKGROUND: Clinical ethics committees (CECs) have been implemented in German clinics since the 1990s. Besides problems with the integration into clinical routines, CECs result in an enrichment and relief for employees and relatives. Investigating the current status of CECs in specialized neurological clinics is crucial because changes in therapy goals towards palliative care are often requested and the treatment team is sometimes overwhelmed with clarifying the presumed patient's wishes. So far, however, there have been no studies that have examined the work of the CEC and its importance for clinical staff in specialized neurological clinics. METHOD: In a single-center, prospective observational study, 161 clinic employees with contact to the patients and 10 members of the CEC were asked about their previous experiences and impressions with and in the CEC. At the same time, 31 patients were retrospectively identified for whom an ethical case consultation was carried out by the CEC in 2019. A qualitative evaluation was carried out for the protocols of the ethical case counseling. RESULTS: 56% of the clinic employees and 90% of the CEC members considered the CEC as enrichment for the clinic. Although more than a third of the clinic employees evaluated the CEC as a relief during difficult ethical decisions, the presence of the CEC in particular for relatives and employees is described as insufficient. In the majority, a reduction in the hierarchy by the CEC was confirmed by the members of the CEC (70%), whereas the majority of the clinic employees increasingly denied this (55%). The CEC recommendation was implemented in 94% of the cases. CONCLUSION: A central problem in working with and within a CEC is maybe the lack of presence and information for employees. Due to this lack of presence, the CEC is not sufficiently visible in everyday clinical practice.

The influence of the CRS-R score on functional outcome in patients with severe brain injury receiving early rehabilitation.

BACKGROUND: The aim of the study was to determine the role of the Coma Recovery Scale-Revised (CRS-R) in the prediction of functional status at the end of neurological early rehabilitative treatment. METHODS: Patients consecutively admitted to intensive or intermediate care units of a neurological rehabilitation center were enrolled in the study. Consciousness and functional status were assessed with the Coma Recovery Scale-Revised (CRS-R) and the Early Rehabilitation Barthel Index (ERBI), respectively. Both assessments were carried out weekly within the first month and at the end of early rehabilitation. Patient and clinical data were entered into a binary logistic regression model to predict functional status at discharge. RESULTS: 327 patients (112 females, 215 males) with a median age of 63 years (IQR = 53-75) and a median disease duration of 18 days (IQR = 12-28) were included. Most patients suffered from stroke (59 %), followed by traumatic brain injury (31 %), and hypoxic ischemic encephalopathy (10 %). Upon admission, 12 % were diagnosed as comatose, 31 % as unresponsive wakefulness syndrome (UWS), 35 % as minimally conscious state (MCS) and 22 % already emerged from MCS (eMCS). Of all patients undergoing complete early rehabilitative treatment (n = 180), 72 % showed improvements in level of consciousness (LOC). In this group, age, initial CRS-R score and gains in CRS-R score after four weeks independently predicted functional outcome at discharge. CONCLUSIONS: The study confirms the relevance of the CRS-R score for functional outcome prediction. High CRS-R scores and young age facilitate functional improvements and increase the probability to continue treatment in subsequent rehabilitation phases. Moreover, results indicate that recovery might occur over a period of time that extends beyond acute care.

[Impact of occupational problems on employment status six months after inpatient neurological rehabilitation]. / Einfluss beruflicher Problemlagen auf den Beschäftigungsstatus sechs Monate nach stationärer neurologischer Rehabilitation.

BACKGROUND: By identifying occupational problems, job-related therapies may be included in rehabilitation at an early stage, increasing the return-to-work rate. The aim of the present study was to examine whether occupational problems that were identified were associated with the employment status six months after inpatient rehabilitation. METHODS: A total of 122 neurological patients undergoing neurological inpatient rehabilitation at the BDH-Clinic Hessisch Oldendorf were retrospectively analysed using clinical routine data from the database of the clinic. Occupational problems were identified with the help of a self-assessment (Wuerzburg Screening [WS]) and an ICF-compliant medical assessment (d850) at the beginning of neurological rehabilitation. In addition, data about the employment status six months after rehabilitation were collected. RESULTS: While the BPL identified in the WS was associated with the employment status at the time of follow-up (r=-0.288; p=.007), there was no relationship between the medical assessment of occupational impairment and the employment status. In binary logistic regression models for predicting the employment status, the duration of the incapacity to work, age, gender and an interdisciplinary assessment at the end of rehabilitation proved to be predictors for the employment status. CONCLUSION: Occupational problems are associated with occupational reintegration six months after discharge from neurological inpatient rehabilitation. Since occupational problems are taken into account in the treatment planning, the impact on the return to work rate may be underestimated in the current study.

Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease.

Previous studies demonstrated spontaneous type 2 airway inflammation with eosinophilia in juvenile Scnn1b (sodium channel, non-voltage-gated 1, ß-subunit)-transgenic (Scnn1b-Tg) mice with muco-obstructive lung disease. IL-1 receptor (IL-1R) signaling has been implicated in allergen-driven airway disease; however, its role in eosinophilic inflammation in muco-obstructive lung disease remains unknown. In this study, we examined the role of IL-1R signaling in the development of airway eosinophilia and type 2 inflammation in juvenile Scnn1b-Tg mice. We determined effects of genetic deletion of Il1r1 (IL-1 receptor type I) on eosinophil counts, transcript levels of key type 2 cytokines, markers of eosinophil activation and apoptosis, and tissue morphology in lungs of Scnn1b-Tg mice at different time points during neonatal development. Furthermore, we measured endothelial surface expression of intercellular adhesion molecule 1 (ICAM-1), an integrin involved in eosinophil transendothelial migration, and determined effects of eosinophil depletion using an anti-IL-5 antibody on lung morphology. Lack of IL-1R reduced airway eosinophilia and structural lung damage, but it did not reduce concentrations of type 2 cytokines and associated eosinophil activation in Scnn1b-Tg mice. Structural lung damage in Scnn1b-Tg mice was also reduced by eosinophil depletion. Lack of IL-1R was associated with reduced expression of ICAM-1 on lung endothelial cells and reduced eosinophil counts in lungs from Scnn1b-Tg mice. We conclude that IL-1R signaling is implicated in airway eosinophilia independent of type 2 cytokines in juvenile Scnn1b-Tg mice. Our data suggest that IL-1R signaling may be relevant in the pathogenesis of eosinophilic airway inflammation in muco-obstructive lung diseases, which may be mediated in part by ICAM-1-dependent transmigration of eosinophils into the lungs.

Longitudinal reliability of outcome measures in patients with Duchenne muscular dystrophy.

INTRODUCTION: The definition of reliable outcome measures is of increasing interest in patients with Duchenne muscular dystrophy (DMD). METHODS: In this retrospective study, we analyzed the longitudinal reliability of clinical and radiological endpoints in 29 ambulant patients with DMD. Clinical outcome measures included motor function measure (MFM) and timed function tests, while quantitative MRI data were mean fat fraction (MFF) and T2 relaxation time of thigh muscles. Statistical analysis was based on 3-, 6-, and 12-month follow-up data. RESULTS: Quantitative MRI using the MFF was the most sensitive and powerful marker of disease progression with a sample size of four at 1-year follow-up, followed by the D1 domain of MFM (standing and transfer function) with a sample size of 12. DISCUSSION: Our data support the longitudinal design of clinical trials over at least 12 months and the combinational use of clinical and radiological surrogate outcome measures.

Influence of paroxysmal sympathetic hyperactivity (PSH) on the functional outcome of neurological early rehabilitation patients: a case control study.

BACKGROUND: Paroxysmal Sympathetic Hyperactivity (PSH) is a frequently observed condition among critically ill patients on intensive care units. According to different studies, PSH is associated with worse recovery and increased mortality in acute-care facilities. In this monocentric, retrospective case-control study, we investigated whether this association also applies to post-acute neurological early rehabilitation. METHODS: The study included n = 387 patients, admitted to an intensive care or intermediate care unit within 1 year (2016). Among these, 97 patients showed clinical signs of PSH. For each patient with PSH, a patient without PSH was identified, controlling for age, gender, functional and respiratory status upon admission. However, for 25 patients with PSH, there was no suitable control patient fulfilling all defined matching criteria. Primary outcome was type of discharge, dichotomized into favorable (follow-up rehabilitation) and unfavorable outcome (all others). Secondary outcome measures were functional and respiratory status, number of secondary diagnoses, duration of treatment interruptions and length of stay at discharge. RESULTS: About 25% of neurological early rehabilitation patients showed clinical signs of PSH. A young age (OR = 0.94; CI = 0.91-0.97) and less severe PSH symptoms (OR = 0.79; CI = 0.69-0.90) were independent predictors of a favorable outcome. In addition, severity of PSH symptoms was associated with weaning duration, while the occurrence of PSH symptoms alone had no influence on most secondary outcome variables. The treatment on intermediate care units proved to be longer for patients with PSH symptoms, only. CONCLUSIONS: Patients with PSH represent a large group of neurological early rehabilitation patients. Overall, we did not find PSH-related differences in most of the examined outcome measures. However, severe PSH symptoms seem to be associated with poorer outcome and longer treatment on intermediate care units, in order to prevent possible complications.

Epidemiology and pathophysiology of autonomic seizures: a systematic review.

PURPOSE: To review the epidemiology and pathophysiology of autonomic symptoms and signs during epileptic seizures. METHODS: We performed a systematic literature search on the following autonomic symptoms and signs during epileptic seizures: cardiovascular changes, respiratory manifestations, gastrointestinal symptoms, cutaneous manifestations, sexual and genital manifestations, and urinary symptoms. RESULTS: Autonomic symptoms and signs can represent the predominant symptom at the onset of a focal seizure, which would then lead to the seizure being classified as a focal onset autonomic seizure. Conversely, clinically relevant autonomic symptoms and signs frequently accompany seizures of focal, generalized, and/or unknown onset, but the seizure is regardless classified according to other, more relevant features. Autonomic symptoms and signs do not represent mere reactions to motor activity or other behavioral seizure manifestations, but rather they are generated by epileptic discharges affecting the central autonomic network. We have reviewed the localizing and lateralizing information currently available on the seizure onset zone and on seizure propagation pathways as provided by systematic analysis of specific autonomic seizure symptoms and signs. We present data on how autonomic seizure symptoms and signs are useful for gaining a better understanding of the anatomical and functional organization of the central autonomic network. Finally, we discuss the differential diagnosis of focal autonomic seizures with autonomic symptoms and signs representing the sole seizure manifestation versus various non-epileptic conditions. CONCLUSIONS: Autonomic seizure symptoms and signs are relevant in clinical epileptology and open a unique window on the functional organization and pathophysiology of the central autonomic network.

[Effects of Respiratory Muscle Training on the Incidence of Pneumonia in Neurological and Neurosurgical Early Rehabilitation: Results from a Matched-Pair Analysis]. / Einfluss der Atmungstherapie auf die Inzidenz von nosokomialen Pneumonien in der neurologisch-neurochirurgischen Frührehabilitation: Ergebnisse einer Fall-Kontroll-Analyse.

BACKGROUND: Most disorders in neurological and neurosurgical early rehabilitation (NNER) are associated with an increased pneumonia risk. Respiratory therapy aims to prevent respiratory complications. However, there are no studies showing an effect of respiratory muscle training on the incidence of pneumonia in NNER. METHOD: The study included 81 phase-B-patients receiving respiratory muscle training and 81 control patients. Routine data such as age, sex, diagnoses, and comorbidities, length of stay, information on ventilation and incidence of pneumonia were analyzed retrospectively. RESULTS: The development of pneumonia was associated with a longer duration of treatment, a higher number of ventilation hours, the presence of a tracheal canula, and a tendency to lower Early Rehabilitation Barthel-Index on admission. The incidence rate of nosocomial pneumonia was 20% in both study groups. The groups differed significantly in disease severity on admission, duration of treatment, number of dysphagia patients, and in therapy intensities of physio and speech therapy. CONCLUSION: A direct correlation between the respiratory muscle training and the incidence of pneumonia in the NNER could not be conclusively demonstrated due to the insufficient comparability of both study groups. Besides the duration of ventilation, the intensity of dysphagia therapy was the strongest factor influencing the pneumonia incidence.

Comparison of fall prediction by the Hessisch Oldendorf Fall Risk Scale and the Fall Risk Scale by Huhn in neurological rehabilitation: an observational study.

OBJECTIVE: To calculate scale performance of the newly developed Hessisch Oldendorf Fall Risk Scale (HOSS) for classifying fallers and non-fallers in comparison with the Risk of Falling Scale by Huhn (FSH), a frequently used assessment tool. DESIGN: A prospective observational trail was conducted. SETTING: The study was performed in a large specialized neurological rehabilitation facility. SUBJECTS: The study population ( n = 690) included neurological and neurosurgery patients during neurological rehabilitation with varying levels of disability. Around the half of the study patients were independent and dependent in the activities of daily living (ADL), respectively. INTERVENTIONS: Fall risk of each patient was assessed by HOSS and FSH within the first seven days after admission. MAIN MEASURES: Event of fall during rehabilitation was compared with HOSS and FSH scores as well as the according fall risk. Scale performance including sensitivity and specificity was calculated for both scales. RESULTS: A total of 107 (15.5%) patients experienced at least one fall. In general, fallers were characterized by an older age, a prolonged length of stay, and a lower Barthel Index (higher dependence in the ADL) on admission than non-fallers. The verification of fall prediction for both scales showed a sensitivity of 83% and a specificity of 64% for the HOSS scale, and a sensitivity of 98% with a specificity of 12% for the FSH scale, respectively. CONCLUSION: The HOSS shows an adequate sensitivity, a higher specificity and therefore a better scale performance than the FSH. Thus, the HOSS might be superior to existing assessments.

Impaired mucus clearance exacerbates allergen-induced type 2 airway inflammation in juvenile mice.

BACKGROUND: Type 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. Recently, we demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile ß-epithelial Na+ channel (Scnn1b)-transgenic (Tg) mice. OBJECTIVE: We sought to determine the role of impaired mucus clearance in the pathogenesis of allergen-induced type 2 airway inflammation and identify cellular sources of the signature cytokine IL-13. METHODS: We challenged juvenile Scnn1b-Tg and wild-type mice with Aspergillus fumigatus and house dust mite allergen and compared the effects on airway eosinophilia, type 2 cytokine levels, goblet cell metaplasia, and airway hyperresponsiveness. Furthermore, we determined cellular sources of IL-13 and effects of genetic deletion of the key type 2 signal-transducing molecule signal transducer and activator of transcription 6 (STAT6) and evaluated the effects of therapeutic improvement of mucus clearance. RESULTS: Reduced mucociliary allergen clearance exacerbated Stat6-dependent secretion of type 2 cytokines, airway eosinophilia, and airway hyperresponsiveness in juvenile Scnn1b-Tg mice. IL-13 levels were increased in airway epithelial cells, macrophages, type 2 innate lymphoid cells, and TH2 cells along with increased Il33 expression in the airway epithelium of Scnn1b-Tg mice. Treatment with the epithelial Na+ channel blocker amiloride, improving airway surface hydration and mucus clearance, reduced allergen-induced inflammation in Scnn1b-Tg mice. CONCLUSION: Our data support that impaired clearance of inhaled allergens triggering IL-13 production by multiple cell types in the airways plays an important role in the pathogenesis of type 2 airway inflammation and suggests therapeutic improvement of mucociliary clearance as a novel treatment strategy for children with allergen-induced asthma.

Determination of enantiomeric excess of nipecotic acid as 1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl) derivatives.

For the enantiopure synthesis of novel chiral GABA uptake inhibitors, nipecotic acid (1) is an important key precursor. To characterize accurately the pharmacological activity of these interesting target compounds, the determination of the correct enantiomeric purity of nipecotic acid as the starting material is indispensable. In this report, a sensitive high-performance liquid chromatography (HPLC) based method for the separation and quantitation of both enantiomers of nipecotic acid as 1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl) derivatives (5) on a Chiralpak ID-3 column (Daicel, Illkirch, France) was established. UV/Vis-detection at 490 nm was chosen to ensure a selective determination of even highly enantioenriched samples. Reliability was demonstrated by validation of specificity, linearity, lower limit of quantification (LLOQ), accuracy, and precision. By spiking highly enantiopure samples with small amounts of racemic rac-5, it was proven that the established HPLC method is able to detect even slight changes in enantiomeric excess (ee) values. Thus, accurate determination of ee values up to 99.87% ee for (R)-5 and 99.86% ee for (S)-5 over a linear concentration range of 1-1500 µM for (R)-5 and of 1-1455 µM for (S)-5 could be demonstrated.

Critical illness polyneuropathy (CIP) in neurological early rehabilitation: clinical and neurophysiological features.

BACKGROUND: Critical illness polyneuropathy (CIP) is a complex disease affecting 30-70% of critically ill patients. METHODS: Clinical (Barthel index, length of stay (LOS), morbidity, duration of mechanical ventilation, routine lab results) and neurophysiological (neurography) data of 191 patients admitted to neurological early rehabilitation and diagnosed with CIP have been analyzed retrospectively. RESULTS: CIP diagnosis was correct in 159 cases (83%). In this study, systemic inflammation, sepsis, systemic inflammatory response syndrome (SIRS), multiple organic failure (MOF), chronic renal failure, liver dysfunction, mechanical ventilation, diabetes, dyslipidemia and impaired ion homeostasis (hypocalcaemia, hypokalemia) were associated with CIP. Neurography, in particular of the peroneal, sural, tibial and median nerves, helped to identify CIP patients. Compound muscle action potential amplitude (r = -0.324, p < 0.05), as well as sensory (r = -0.389, p < 0.05) and motor conduction velocity (r = -0.347, p < 0.05) of the median nerve correlated with LOS in neurological early rehabilitation but not with outcome measures. CONCLUSIONS: In most cases, diagnosis of CIP among neurological early rehabilitation patients seems to be correct. Neurography may help to verify the diagnosis and to learn more about CIP pathophysiology, but it does not allow outcome prediction. Further studies on CIP are strongly encouraged.

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.

The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these antioxidant effects and the functional relevance of these properties remain unknown. Here, we show that endogenous and exogenous aPC prevents glomerular accumulation of oxidative stress markers and of the redox-regulating protein p66(Shc) in experimental diabetic nephropathy. These effects were predominately observed in podocytes. In vitro, aPC inhibited glucose-induced expression of p66(Shc) mRNA and protein in podocytes (via PAR-1 and PAR-3) and various endothelial cell lines, but not in glomerular endothelial cells. Treatment with aPC reversed glucose-induced hypomethylation and hyperacetylation of the p66(Shc) promoter in podocytes. The hyperacetylating agent sodium butyrate abolished the suppressive effect of aPC on p66(Shc) expression both in vitro and in vivo. Moreover, sodium butyrate abolished the beneficial effects of aPC in experimental diabetic nephropathy. Inhibition of p66(Shc) expression and mitochondrial translocation by aPC normalized mitochondrial ROS production and the mitochondrial membrane potential in glucose-treated podocytes. Genetic ablation of p66(Shc) compensated for the loss of protein C activation in vivo, normalizing markers of diabetic nephropathy and oxidative stress. These studies identify a unique mechanism underlying the cytoprotective effect of aPC. Activated PC epigenetically controls expression of the redox-regulating protein p66(Shc), thus linking the extracellular protease aPC to mitochondrial function in diabetic nephropathy.

Neonatal Mortality and Morbidity in Regional Provincial Hospitals in the People's Democratic Republic of Laos.

OBJECTIVE: The aim of this study was to identify the causes and incidences of neonatal diseases and deaths in five provincial hospitals in People's Democratic Republic of Laos retrospectively for the years 2010-12. METHODS: Data of neonatal patients were collected before a 3-year-training program for medical and nursing staff involved in the care of newborn infants in the provincial and associated district hospitals. RESULTS: In the years 2010-12, a total of 1673 neonatal patients were treated in the provincial hospitals. The reasons of treatment were as follows: 48% infections, 17% complications of prematurity, 14% intrapartum-related complications and 9% other, not categorized diseases. The average mortality rate in all hospitals was 6.5%. The main causes of death were complications because of prematurity, infectious diseases and asphyxia. CONCLUSION: These data could be the basis for any teaching program aimed at reducing neonatal mortality. Furthermore, they enable an evaluation of the ongoing teaching program.

Effect of omega-3 polyunsaturated fatty acids on the cytoskeleton: an open-label intervention study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) show beneficial effects on cardiovascular health and cognitive functions, but the underlying molecular mechanisms are not completely understood. Because of the fact that cytoskeleton dynamics affect almost every cellular process, the regulation of cytoskeletal dynamics could be a new pathway by which n-3 PUFAs exert their effects on cellular level. METHODS: A 12-week open-label intervention study with 12 healthy men was conducted to determine the effects of 2.7 g/d n-3 PUFA on changes in mRNA expression of cytoskeleton-associated genes by quantitative real-time PCR in whole blood. Furthermore, the actin content in red blood cells was analyzed by immunofluorescence imaging. RESULTS: N-3 PUFA supplementation resulted in a significant down-regulation of cytoskeleton-associated genes, in particular three GTPases (RAC1, RHOA, CDC42), three kinases (ROCK1, PAK2, LIMK), two Wiskott-Aldrich syndrome proteins (WASL, WASF2) as well as actin related protein 2/3 complex (ARPC2, ARPC3) and cofilin (CFL1). Variability in F-actin content between subjects was high; reduced actin content was only reduced within group evaluation. CONCLUSIONS: Reduced cytoskeleton-associated gene expression after n-3 PUFA supplementation suggests that regulation of cytoskeleton dynamics might be an additional way by which n-3 PUFAs exert their cellular effects. Concerning F-actin, this analysis did not reveal unmistakable results impeding a generalized conclusion.