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.

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.

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.

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.

Effects of Acute Aerobic Exercise on Response Inhibition in Adult Patients with ADHD.

Previous studies suggest beneficial effects of aerobic exercise on executive functions, which are a core deficit in ADHD. The aim of the present fMRI study was to investigate acute effects of aerobic exercise on inhibitory control and related brain activation in adult patients with ADHD. 23 patients and 23 matched healthy controls performed on a Go/No-go task in an MRI scanner, following both, an exercise condition involving 30 min of cycling at moderate intensity, and a control condition. ADHD patients compared to healthy controls showed increased brain activation during successful inhibition in the exercise compared to the control condition in parietal, temporal, and occipital regions. Exercise did not improve behavioral performance in either group, but in ADHD patients, exercise-related increases in brain activation and behavioral task performance (i.e., correct inhibition rate) negatively correlated with correct inhibition rate in the control condition. Thus, patients with worse inhibition performance showed stronger exercise-related enhancements, indicating that the lack of improvements on the behavioral level for the whole patient group could be due to ceiling effects. Our findings might be an important step in understanding the neural basis of exercise effects and could, in the long term, help in developing alternative treatment approaches for ADHD.

Cells´ Flow and Immune Cell Priming under alternating g-forces in Parabolic Flight.

Gravitational stress in general and microgravity (µg) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating µg and hypergravity (hyper-g) on immune cells, the attachment of peripheral blood mononuclear cells (PBMCs) to adhesion molecules under flow conditions and the antigen-induced immune activation in whole blood were investigated in parabolic flight (PF). In contrast to hyper-g (1.8 g) and control conditions (1 g), flow and rolling speed of PBMCs were moderately accelerated during µg-periods which were accompanied by a clear reduction in rolling rate. Whole blood analyses revealed a "primed" state of monocytes after PF with potentiated antigen-induced pro-inflammatory cytokine responses. At the same time, concentrations of anti-inflammatory cytokines were increased and monocytes displayed a surface molecule pattern that indicated immunosuppression. The results suggest an immunologic counterbalance to avoid disproportionate immune responses. Understanding the interrelation of immune system impairing and enhancing effects under different gravitational conditions may support the design of countermeasures to mitigate immune deficiencies in space.

Ice-volume-forced erosion of the Chinese Loess Plateau global Quaternary stratotype site.

The International Commission on Stratigraphy (ICS) utilises benchmark chronostratigraphies to divide geologic time. The reliability of these records is fundamental to understand past global change. Here we use the most detailed luminescence dating age model yet published to show that the ICS chronology for the Quaternary terrestrial type section at Jingbian, desert marginal Chinese Loess Plateau, is inaccurate. There are large hiatuses and depositional changes expressed across a dynamic gully landform at the site, which demonstrates rapid environmental shifts at the East Asian desert margin. We propose a new independent age model and reconstruct monsoon climate and desert expansion/contraction for the last ~250 ka. Our record demonstrates the dominant influence of ice volume on desert expansion, dust dynamics and sediment preservation, and further shows that East Asian Summer Monsoon (EASM) variation closely matches that of ice volume, but lags insolation by ~5 ka. These observations show that the EASM at the monsoon margin does not respond directly to precessional forcing.

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.

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen-induced toxicity in humans.

Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP-induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice.

Treatment of a periorbital cyst in a dog by creation of a permanent drainage opening.

An inflammatory periorbital cyst with secondary pressure atrophy of the maxilla was treated by surgical creation of a drainage opening to the nasal cavity in a 4-year-old Yorkshire Terrier. Following treatment, clinical signs resolved and computed tomography 5 weeks after surgery confirmed the permanence of the drainage opening. Eight months later, the dog showed no clinical abnormalities. Therefore, the procedure described in this report may offer a suitable treatment option in cases where the cyst's size or localization prevents complete excision.

[Severe complications after non-intended usage of octenidine dihydrochloride. A case series with four dogs]. / Schwerwiegende Komplikationen nach nicht bestimmungsgemäßer Anwendung von Octenidindihydrochlorid. Eine Fallserie mit vier Hunden.

OBJECTIVE: Case series of four dogs in which extensive bite wounds had been treated using octenidine dihydrochloride (Octenivet® or Octenisept®) flushing. The dogs subsequently developed severe local complications. MATERIAL AND METHODS: Retrospective evaluation of clinical symptoms, diagnostics, therapy and course of the disease. RESULTS: In four dogs, severe necrosis and persistent edematous changes of the treated area developed after the application of octenidine dihydrochloride. The clinical course was comparable to complications described previously in human medicine. Therapy was protracted and complicated by secondary wound infection. CONCLUSION AND CLINICAL RELEVANCE: Irrigation of deep wounds, particularly bite wounds, using octenidine dihydrochloride without drainage may lead to persistent edematous changes, inflammatory reactions and necrosis. The inappropriate application of octenidine dihydrochloride for wound irrigation should be avoided in veterinary medicine.

Immunohistochemical localisation and effect of matrix metalloproteinases and their inhibitors on canine spontaneous periodontitis.

Periodontitis is commonly observed in dogs. In human medicine, it is well documented that matrix metalloproteinases (MMPs) are involved in the destruction of the periodontium. Therefore, the aim of this prospective study was to investigate the impact of MMPs and their inhibitors, the TIMPs (tissue inhibitors of metalloproteinases), on canine periodontitis. The oral cavities of 57 dogs were examined clinically and radiologically. Gingival biopsies were obtained from the examined dogs and histologically analysed via haematoxylin and eosin stained sections. Immunohistological detection of MMP-2, MMP-3, MMP-8 and MMP-9 as well as TIMP-1 and TIMP-2 was performed by the avidin-biotin peroxidase complex technique. All sections were evaluated by light microscopy. Statistically significant positive correlations were detected between the histologically verified degree of inflammation and the expression of MMP-2, MMP-3, MMP-8 and MMP-9 as well as between changes in collagen fibre content and the occurrence of MMP-2, MMP-8 and MMP-9. Concerning TIMP-1 and TIMP-2, non-significant, generally negative correlations were observed. In summary, in canine periodontitis, an increased expression of the above mentioned MMPs and a tendentially decreased expression of TIMPs are present. In conclusion, in canine periodontitis, a MMP-TIMP imbalance is suggestive of contributing to the destruction of the periodontium.

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.

[Sublumbar abscesses in the dog. Retrospective evaluation of 13 patients]. / Sublumbale Abszesse beim Hund. Retrospektive Auswertung der Daten von 13 Patienten.

OBJECTIVE: Presentation of sublumbar abscesses in the dog with regard to diagnostic and therapeutic options as well as prognosis. MATERIAL AND METHODS: Retrospective evaluation of the data of 13 dogs, which were presented with sublumbar abscesses between 2002 and 2012. RESULTS: Young to middle-aged and middle to large breed dogs were mainly affected. The time until presentation varied from 1 day to 2 years. Symptoms were generally nonspecific. Computed tomography and sonography were normally applied for diagnosis. All dogs underwent surgery and several wound examinations; only in two cases was a single surgical intervention sufficient. In addition, after being discharged, ambulant post-operative care was usually necessary for a considerable time. In two cases, plant foreign bodies could be identified as a cause of abscess formation, and in one case a prostatic abscess and a putative prostate carcinoma were present. After surgery, 12 of 13 dogs could be discharged. Nine of them showed an unremarkable healing process, one dog had a relapse followed by an unremarkable healing process, and one dog was euthanized at the request of the owners because of a putative relapse. One animal was lost to follow-up. One dog was euthanized after two surgical procedures. CONCLUSION AND CLINICAL RELEVANCE: Sublumbar abscesses are a rare, but a serious disease in veterinary medicine. Sectional imaging techniques and sonography are suitable for diagnosis. Treatment is often sophisticated and long-standing. However, with adequate treatment, the prognosis with regard to a complete convalescence is favorable. In most cases, the cause of abscess formation remains unclear.

[Cisterna chyli ablation in three cats with idiopathic chylothorax]. / Cisterna-chyli-Ablation bei drei Katzen mit idiopathischem Chylothorax.

OBJECTIVE: Presentation of three cats with chronic, idiopathic chylothorax treated with ablation of the cisterna chyli as an additional or a sole surgical treatment. MATERIAL AND METHODS: Results of clinical and diagnostic examination, therapy and course of disease in three cats as well as the surgical technique of ablation of the cisterna chyli in cats are described. RESULTS: There were no intraoperative or postoperative complications regarding cisterna chyli ablation. Intraoperative visualization of the cisterna chyli is easily achieved by administering a small portion of a fatty aliment preoperatively or by injection of diluted methylene blue into the lymphatic system intraoperatively. Ablation of the cisterna chyli was performed following an unsuccessful ligation of the thoracic duct, in combination with the ligation of the thoracic duct and subtotal pericardectomy or as a single surgical treatment. CLINICAL RELEVANCE: Cisterna chyli ablation can be performed without complications in cats. This technique should be considered in cases of previously failed surgical therapy or as an adjunct therapy used with other surgical options to decrease the risk of recurrence.

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.