Metabolic adaptation of human skin fibroblasts to ER stress caused by glycosylation defect in PMM2-CDG.

PMM2-CDG is the most prevalent type of congenital disorders of glycosylation (CDG). It is caused by pathogenic variants in the gene encoding phosphomannomutase 2 (PMM2), which converts mannose-6-phosphate to mannose-1-phosphate and thus activates this saccharide for further glycosylation processes. Defective glycosylation can lead to an abnormal accumulation of unfolded proteins in endoplasmic reticulum (ER) and cause its stress. The ER is a key compartment for glycosylation, and its connection and communication with mitochondria has been described extensively in literature. Their crosstalk is important for cell proliferation, calcium homeostasis, apoptosis, mitochondrial fission regulation, bioenergetics, autophagy, lipid metabolism, inflammasome formation and unfolded protein response. Therefore, in the present study we posed a question, whether defective glycosylation leads to bioenergetic disruption. Our data reveal possible chronic stress in ER and activated unfolded protein response via PERK pathway in PMM2-CDG fibroblasts. Presumably, it leads to bioenergetic reorganization and increased assembly of respiratory chain complexes into supercomplexes together with suppressed glycolysis in PMM2-CDG patient cells. These changes cause alterations in Krebs cycle, which is tightly connected to electron transport system in mitochondria. In summary, we present data showing metabolic adaptation of cells to glycosylation defect caused by various pathogenic variants in PMM2.

Can auditory cues improve visuo-spatial neglect? Results of two pilot studies.

Although neglect is known to be a multimodal deficit, current interventions often address the visual modality only. Experimental studies, however, found that neglect patients can partially overcome their spatial inattention temporarily when being exposed to auditory cues that move towards the neglected side of space. Two pilot studies investigated the impact of dynamic auditory cueing on egocentric neglect severity in a clinical-therapeutic setting. In both studies, the patient groups received 15 sessions of intervention. Study 1, designed as double-blinded trial with a historical control group, targeted severely impaired early-acute patients who listened to music or audio books which were presented as moving dynamically from right to left. Results showed a reduction in egocentric neglect severity that persisted after therapy termination in the intervention but not in the historical control group. In study 2, based on the comparison with reported effect sizes of previous studies, dynamic meaningful auditory cues and optokinetic stimulation were combined in a computer-based training. Both studies found a significant reduction of neglect severity. Results provide evidence for the reduction of egocentric neglect severity after repetitive auditory cueing therapy in both severely and moderately impaired patients. Our promising findings should be verified thoroughly in randomized-controlled trials.

Successful treatment of peritoneal nocardiosis caused by Nocardia paucivorans in a dog.

CASE HISTORY: A 7-year-old neutered female Labrador Retriever from Hesse (Germany) was referred for evaluation of peritoneal nodular masses identified by the referring veterinarian during an investigation for a 2-month history of lethargy. CLINICAL FINDINGS AND TREATMENT: Ultrasonographic examination of the abdomen showed multiple cavernous nodules in the intra-abdominal fat and greater omentum surrounded by free fluid. These findings were suspicious of steatitis and fatty tissue necrosis in the cranial abdomen. Cytologic and microbiological analysis of fine-needle aspirates of the fatty tissue and abdominal fluid revealed septic pyogranulomatous inflammation caused by Nocardia paucivorans. The septic abdomen indicated surgical management was appropriate and a celiotomy was performed, which revealed an inflammed mass attached by fibrous tissue to the spleen, stomach and liver. All abnormal tissue including parts of the greater omentum and the spleen, were removed and samples taken for histopathology and microbial culture. Following surgery, the dog was treated with amoxicillin/clavulanic acid. After initially improving, the dog's condition deteriorated 3 months later. Based on ultrasonographic and cytologic findings, and bacterial culture, recurrence of peritoneal nocardiosis was confirmed. In a second celiotomy, multiple inflammatory mass lesions inflammed masses in the remaining greater omentum were removed. After surgery, antimicrobial therapy was changed to trimethoprim/sulfamethoxazole for a 10-month period. No recurrence of clinical signs was reported 6, 12 and 27 months after the initial surgery. DIAGNOSIS: Peritonitis caused by Nocardia paucivorans. CLINICAL RELEVANCE: To our knowledge, this is the first published report of canine infection with Nocardia paucivorans and the first case of peritoneal nocardiosis successfully treated in a dog. This report indicates that reducing the microbial burden by surgical debridement of affected tissues and peritoneal lavage followed by long-term treatment with a suitable antimicrobial may be an effective treatment for peritoneal nocardiosis in dogs.

Properties of a Rare-Earth-Ion-Doped Waveguide at Sub-Kelvin Temperatures for Quantum Signal Processing.

We characterize the 795 nm ^{3}H_{6} to ^{3}H_{4} transition of Tm^{3+} in a Ti^{4+}:LiNbO_{3} waveguide at temperatures as low as 800 mK. Coherence and hyperfine population lifetimes-up to 117 µs and 2.5 h, respectively-exceed those at 3 K at least tenfold, and are equivalent to those observed in a bulk Tm^{3+}:LiNbO_{3} crystal under similar conditions. We also find a transition dipole moment that is equivalent to that of the bulk. Finally, we prepare a 0.5 GHz-bandwidth atomic frequency comb of finesse >2 on a vanishing background. These results demonstrate the suitability of rare-earth-ion-doped waveguides created using industry-standard Ti indiffusion in LiNbO_{3} for on-chip quantum applications.

Tm 3+ Tm 3+ : Y3Ga5O12 materials for spectrally multiplexed quantum memories.

We investigate the relevant spectroscopic properties of the 795 nm (3)H(6)↔(3)H(4) transition in 1% Tm(3+):Y(3)Ga(5)O(12) at temperatures as low as 1.2 K for optical quantum memories based on persistent spectral tailoring of narrow absorption features. Our measurements reveal that this transition has uniform coherence properties over a 56 GHz bandwidth, and a simple hyperfine structure split by ± 44 MHz/T with lifetimes of up to hours. Furthermore, we find a (3)F(4) population lifetime of 64 ms-one of the longest lifetimes observed for an electronic level in a solid--and an exceptionally long coherence lifetime of 490 µs--the longest ever observed for optical transitions of Tm(3+) ions in a crystal. Our results suggest that this material allows realizing broadband quantum memories that enable spectrally multiplexed quantum repeaters.

Changes in exercise capacity, quality of life and fatigue in cancer patients during an intervention.

The study explored the interdependence of changes in oxygen uptake, quality of life and cancer-related side-effect fatigue during a 4-month exercise intervention. Participants were during adjuvant (curative) or palliative therapy and post-adjuvant therapy (finished within the previous 12 months). Aerobic exercise capacity (VO2 peak), quality of life and fatigue symptom (EORTC QLQ-C30) were obtained in 101 cancer patients (30-77 years). After initial examination, patients participated in supervised and/or home-based training interventions. Patients were re-examined after 16-20 weeks and stratified into 3 subgroups (terciles) with respect to the absolute change in VO2 peak. The ANCOVA, with significant covariate effect for pretest fatigue score (F(5,101) = 8.150, P < 0.001), indicated significant differences between groups in outcome measures (P < 0.001). Based on the absolute change of VO2 peak (1.9 ± 1.7; 1.8 ± 0.8; 5.7 ± 2.8 ml/kg/min) there were significant differences in the quality of life improvement (17.2 ± 15.1 vs. 4.8 ± 22.0 points, P < 0.05) and cancer-related fatigue reduction (-6.1 ± 30.7; -11.5 ± 20.9; -21.2 ± 21.4 points) between upper and lower tercile. The findings point towards a relationship of exercise capacity enhancement, quality of life improvement and fatigue symptom reduction during and shortly after cancer treatment.

How much oxidative stress exists without the liver?

BACKGROUND: Oxidative stress (OS) represents an important pathogenetic factor of acute liver failure and chronic liver diseases. To elucidate whether the liver itself is a major source of OS, the present study was performed to assess OS and antioxidant status in an anhepatic porcine model. METHODS: Six pigs underwent a total hepatectomy, five pigs were sham operated. OS and antioxidant status were evaluated by measuring plasma concentrations of malondialdehyde (MDA), xanthine oxidase (XO), superoxide dismutase (SOD) and the ferric reducing ability of plasma (FRAP). They were sampled at the start of the experiment, immediately after surgery, and then at 8 and 16 hours post hepatectomy. RESULTS: Increased concentrations of MDA were observed in anhepatic pigs postoperatively (p < 0.02) and 8 hours after hepatectomy (p < 0.003) compared to controls. XO activity increased soon after hepatectomy (22.6 ±â€Š5.4 mU/L versus 3.3 ±â€Š2.1 mU/L in sham animals, p < 0.03) but returned to normal values in the further course. SOD levels did not change during the observational period in both groups. FRAP values rose significantly in the anhepatic animals compared to control (p < 0.015). A significant positive correlation was observed between MDA levels and FRAP levels (Spearman's ρ = 0.62; p < 0.0001). CONCLUSIONS: These findings show that hepatectomy does not completely prevent the occurrence of OS because the production and regulation of OS are also located outside the liver.

Validity of the six-minute walk test in cancer patients.

The present study evaluated the validity of the six-minute walk test (6MWT) in cancer patients. 50 subjects (36 f, 14 m; 57.4±10.2 years; during (56%) or off (44%) cancer treatment) performed a 6MWT and a spiroergometry on a cycle ergo-meter (0+25 W, 3 min) to evaluate maximum exercise capacity (VO2peak). A subsample (n=30) completed a retest of the 6MWT within 2-7 days. Patients covered a distance of 594±81 m during 6MWT at an average intensity of 86.3±9.6% of HRmax and achieved a VO2peak of 21.2±4.86 ml · kg - 1 · min - 1 during cycle ergometry. The distance walked correlated significantly (p<0.001) with VO2peak (r=0.67) and perceived physical function (EORTC QLQ-C30 physical function subscale) (r=0.55). Concerning reliability the intraclass correlation coefficient was r=0.93 (95%CI: +0.86;+0.97; p<0.001) and the coefficient of variation 3%. During retest participants walked 3.1% (95%CI: +1.1; +5.2) farther and achieved a higher RPE (+1.0; 95%CI: +0.3;+1.8). Limits of agreement were between - 43.1 and 76.4 m. In cancer patients the 6MWT seems to be as valid and reliable as in healthy elderly, cardiac and pulmonary patients. Thus, it can be recommended for use in cancer patients.

Exercise effects on HRV in cancer patients.

The present study evaluated the effects of physical exercise on heart rate variability (HRV) in cancer patients. 3 matched groups of each 15 tumour patients (60.4±8.9 years, 27 male, 18 female) were recruited: Physical exercise group 1 (acute treatment), Physical exercise group 2 (post treatment) and non-intervention group (acute treatment, no exercise). Exercise group patients received counselling for exercise and participated in a Nordic-Walking program. Short-term HRV-recordings, assessments of fatigue and quality of life (QoL) were performed prior to and 16 weeks after the exercise program initiation. MANCOVA revealed group × time differences in total power frequency domain of HRV and QoL (p<0.05). TP follow-up scores [logms(2)] differed significantly between non-intervention and intervention post treatment (2.0±0.5 vs. 2.6±0.5), but not between non-intervention and intervention during acute treatment. QoL follow-up scores differed significantly between non-intervention and intervention during acute treatment (47±15 vs. 64±18) and post treatment (47±15 vs. 69±19). Exercise enhances cardiac autonomic regulation of tumour patients during and after acute treatment. Because of the association of higher HRV-parameters and prolonged survival in cancer patients, improvement in autonomic control may be an important goal of exercise.

[Activity trails, risk of falling, and health-related quality of life. Effects of a 12-week guided intervention]. / Bewegungsparcours, Sturzrisiko und gesundheitsbezogene Lebensqualität : Effekte einer 3-monatigen Bewegungsintervention.

BACKGROUND: The purpose was to evaluate the interventional effects of activity trails (courses) on fall risk factors and health-related quality of life (hrQoL). MATERIALS AND METHODS: A total of 94 subjects (67.7 ± 5.7 years; 29 men, 65 women) completed the following measurements prior to and 12 weeks after the initiation of the activity trail intervention: maximum isometric leg extensors force (Fmax, m3 diagnoses©), gait velocity (GV), and static postural stability (STAB, Zebris FDM©), fall-associated self-efficacy (FALL, FES-I), and hrQoL (SF-36). RESULTS: During the 12-week intervention period, the participants increased Fmax (1.63 ± 0.6 vs. 1.70 ± 0.6 N•kg(-1)) and GV (1.06 ± 0.25 vs. 1.11 ± 0.18m•s(-1); p < 0.05). Neither FALL (19.44 ± 3.6 vs. 19.41 ± 4.3 points) nor STAB (84.3 ± 56.4 vs. 79.7 ± 63.1 mm(2)) changed. Additionally, significant improvements in hrQoL regarding vitality (56.3 ± 17.2 vs. 63.2 ± 18.3 points) and mental health (69.4 ± 18.7 vs. 75.5 ± 16.5 points; p < 0.05) were found. CONCLUSION: The improvements in fall-related risk factors and hrQoL may be expected to contribute to fall prevention and psychosocial quality of life.

Recurrent childhood wheezing and exercise induced asthma in later life.

AIM: Exercise induced asthma (EIA) common in endurance and other athletes limits physical activity. Although a correlation between recurrent childhood bronchitis and the development of asthma has been reported, its relation to EIA in adult athletes has not been assessed. The study evaluates the EIA risk after recurrent childhood wheezing (RCW) and its aggravating influence on the known risk factors outdoor and professional sports. METHODS: To evaluate the effect of RCW on EIA, 570 multiple choice questionnaires were evaluated, assessing the history of RCW and the EIA occurrence. The latter was defined either according to physician-derived diagnosis, by typical symptoms or by decrease of the 1-second forced expiratory volume after a 6-minute running test. Contingency tables and a logistic regression model were worked out to describe referring parameters of EIA incidence. RESULTS: Almost one quarter of the athletes with RCW were attributed positive for EIA. Contingency calculations revealed a 2.6 times higher chance of symptoms of EIA after RCW which further increased in outdoor sports on a professional level. The duration of sports participation, cold environment and self-limiting of symptoms are predicting factors of a higher risk of EIA, being responsible for 53% of the prevalence variance. CONCLUSION: The results point towards a facilitating effect of recurrent affections of the respiratory tract in young age in addition to generally accepted factors of EIA in adults. For safe sports participation, the athlete, as well as involved caregivers (parents, coach) should have an adequate knowledge of EIA and prevention/intervention strategies like warming up or the use of inhalers.

[Sports medical counseling to promote physical activity in unemployed]. / Sportmedizinische Bewegungsberatung bei Arbeitslosen.

Although strong evidence suggests that unemployment increases health risks and physical activity results in significant health benefits, the participation rate in prevention programs among unemployed men is still low. For this reason, a sports medical counseling service was implemented at regional job centers in 2006 to refer unemployed persons into local sports for health programs. The participation rate from 741 long-term unemployed persons was analyzed with respect to gender, health, and physical activity status. Women were more active than men (p = 0.038). Among men, physically active persons differed from non-active persons in BMI, activity status, and self-reported health status (p < 0.05). Especially men with lower fitness, health, and activity status could be motivated for more physical activity (p < 0.001). The odds ratio for program participation of men with lower fitness, health, and activity status is 2.8 (95% confidence interval 1.8-4.3) compared to persons with lower risk factors. Sports medical counseling at job centers seems to be a promising and feasible intervention approach.

Quantum interference and entanglement of photons that do not overlap in time.

We discuss the possibility of quantum interferences and entanglement of photons that exist at different intervals of time, i.e., one photon being recorded before the other has been created. The corresponding two-photon correlation function is shown to violate Bell's inequalities.

A reproducible porcine model of acute liver failure induced by intrajejunal acetaminophen administration.

BACKGROUND AND AIMS: Severe intoxication following acetaminophen overdose is the most common cause of acute liver failure (ALF) in many Western European and North American countries. A reproducible large animal model of acetaminophen intoxication has not been successfully evaluated previously. METHODS: Eight male pigs underwent acetaminophen intoxication receiving an initial enteric bolus of 250 mg/kg body weight acetaminophen followed by an acetaminophen plasma level (300-450 mg/l) adapted enteric maintenance dose of 1,000-3,000 mg/h to the onset of ALF (prothrombin time value <30%). Vital and ventilation parameters were continuously recorded until death. Saline, hydroxyethyl starch, fresh frozen plasma and erythrocyte units were used for volume substitution, and norepinephrine to prevent severe hypotension. RESULTS: All animals developed ALF after 25 ± 3 h, which was confirmed by laboratory values, the clinical course and histological examinations. All animals died due to ALF after a further 21 ± 5 h, precipitated by cerebral edema. CONCLUSIONS: Using an initial enteric acetaminophen bolus, followed by body weight-adapted acetaminophen plasma level intoxication, it was possible to establish a reproducible, clinically relevant porcine model which may be used for the investigation of novel therapeutic approaches in this life-threatening condition.

Energy cost of youth obesity exercise modes.

The purpose of this study was to assess the energy expenditure (EE) of different exercise intervention modes commonly employed in youth obesity programs. Individual heart rate (HR) - EE relationships were obtained in 20 obese adolescents (13.6±1.4 years, BMI 31.8±4.1 kg·m(-2), peak VO(2) 30.1±4.9 ml·kg(-1)·min(-1)) attending inpatient comprehensive multidisciplinary intervention and EE was calculated from HR during different exercise therapy modes. Per week, a cumulative EE above baseline of 7 829±2 229 kJ·week(-1) was induced by 7.5 h of structured exercise intervention. EE [kJ·kg(-1)·h(-1)] of walking (14.0±2.9) differed significantly from swimming (19.9±5.9), water games (18.0±4.4), 65-85 W cycle ergometry (19.6±3.7), strength/stability circuit (18.9±3.7), small group games/relays (19.0±5.4) and team sports (20.6±7.0) (p<0.05). Since the energy cost of all exercise modes except walking was comparable, priority should be given to the adolescents' preferences to promote long-term activity behaviour change.

Reproducibility of muscle oxygen saturation.

The present study evaluated the reproducibility of tissue oxygenation in relation to oxygen consumption (VO2) across cycle exercise intensities in a test-retest design. 12 subjects (25.7±2.1 years; 24.7±1.9 kg · m(-2)) twice performed an incremental bicycle exercise protocol, while tissue oxygen saturation (StO2) in the vastus lateralis muscle was monitored by a commercially available NIRS unit and VO2 determined by an open-circuit indirect calorimetric system. Coefficients of variation across rest, workloads corresponding to 25, 50 and 75% of individual maximum capacity, and maximum load were 5.8, 4.6, 6.1, 8.0, 11.0% (StO2) and 7.6, 6.0, 3.7, 3.4, 3.1% (VO2), respectively. 95 % CI of relative test-retest differences ranged from -5.6 to +5.4% at 25% load to -17.2 to +7.5% at maximum load for StO2 and from -7.3 to +7.7% at rest to -3.3 to +3.2% at maximum load for VO2. With advancing exercise intensity, within-subject variability of StO2 was augmented, whereas VO2 variability slightly attenuated. NIRS measurements at higher workloads need to be interpreted with caution.

PCR detection of Anaplasma phagocytophilum in goat flocks in an area endemic for tick-borne fever in Switzerland.

Central Switzerland is a highly endemic region for tick-borne fever (TBF) in cattle, however, little is known about A. phagocytophilum in goats. In the present study, 72 animals from six goat flocks (373 EDTA blood-samples) in Central Switzerland were analysed for A. phagocytophilum DNA. A real-time PCR targeting the msp2 gene of A. phagocytophilum was performed and in positive samples the partial 165 rRNA, groEL and msp4 gene were amplified for sequence analysis. Four DNA extracts were positive. Different sequence types on basis of the amplified genes were found. For comparison, sequences of A. phagocytophilum from 12 cattle (originating from Switzerland and Southern Germany) were analysed. The 165 rRNA gene sequences from cattle were all identical amongst each other, but the groEL and msp4 gene differed depending on the origin of the cattle samples and differed from the variants from goats. This study clearly provides molecular evidence for the presence of different types of A. phagocytophilum in goat flocks in Switzerland, a fact which deserves more thorough attention in clinical studies.

Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1.

BACKGROUND: Psoriasis is a genetically complex, chronic inflammatory skin disease. The authors have previously identified a susceptibility locus on chromosome 19p13 (PSORS6). METHODS AND RESULTS: In a follow-up linkage disequilibrium (LD) study in an independent family based cohort, the authors found evidence for association to a newly discovered microsatellite at this locus (D19SPS21, p<5.3x10(-5)). An LD based association scan in 300 trios revealed association to several single, single nucleotide polymorphisms (SNPs) in one LD block. When the authors stratified this cohort for carrying the PSORS1 risk allele at the HLA-C locus, evidence for association became much stronger at single SNP and haplotype levels (p values between 1.0x10(-4) and 8.0x10(-4)). In a replication study of 1114 patients and 937 control individuals, evidence for association was also observed after stratification to the PSORS1 risk allele. In both study groups, logistic regression showed evidence for interaction between the risk alleles at PSORS1 and PSORS6. Best p values for rs12459358 in both study groups remained significant after correction for multiple testing. The associated LD block did not comprise any known genes. Interestingly, an adjacent gene, MUC16, coding for a large glycosylated protein expressed in epithelia and of unknown function, could be shown to be also expressed in tissues relevant for pathogenesis of psoriasis such as skin and thymus. Immunohistochemical analyses of skin revealed focal staining for MUC16 in suprabasal epidermal cells. Further functional studies are required to clarify its potential role in psoriasis and identify the causal variant(s) at this locus. CONCLUSION: The data establish PSORS6 as a confirmed psoriasis susceptibility locus showing interaction with PSORS1.

Hernia repair and simultaneous continuous ambulatory peritoneal dialysis (CAPD) catheter implantation: feasibility and outcome.

BACKGROUND: Occurrence of abdominal wall hernias during and before peritoneal dialysis constitutes a pivotal role in treatment discontinuation, failure, and exclusion from this dialysis method. We herein present a single-center experience regarding a one-stage surgical strategy, including hernia repair and simultaneous peritoneal dialysis catheter implantation. PATIENTS AND METHODS: Over a 4-year period, 123 patients underwent peritoneal dialysis catheter implantation and 23 patients (19%) had concomitant abdominal wall hernias and were enrolled in this monocentric prospective study. Data collection included recurrent and new-onset hernias, surgical site infection, 1-year and 2-year catheter survival. RESULTS: In 23 patients, 27 hernia repairs combined with peritoneal dialysis catheter implantation were performed. Median age was 52 years (range, 30-85 years) and 18/23 (78%) patients were male. There were no recurrent hernias and no early surgical site infections. Daily flushing was regularly started on the 1st to 3rd postoperative day. Five patients (22%) developed hernias on other anatomical sites, which required hernia repair and perioperative discontinuation of peritoneal dialysis. After a median follow-up of 37 months (range, 28-87 months), 96% of all implanted catheters were still working. CONCLUSION: Hernia repair and simultaneous peritoneal dialysis catheter implantation are associated with no recurrent hernias, an early start of peritoneal dialysis, a very low postoperative morbidity and very high 1-year and 2-year catheter survival.