Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils.

Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] α-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated α-syn (pS129 α-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target α-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other α-synucleinopathies.

The social, psychological, and physical impact of COVID-19 restrictions for institutionalized adults with intellectual and developmental disabilities.

During the COVID-19 pandemic, drastic measures to interrupt SARS-CoV-2 infection chains were implemented. In our study we investigated the consequences of pandemic related restrictions on the social, psychological, and physical well-being of institutionalized adults with intellectual and developmental disabilities. Methods: Online survey among professional caregivers in 71 residential groups, caring for 848 residents. Findings: (i.) A lack of participation concerning infection protection measures of the residents, their relatives, and their caregivers; (ii.) A 20% increase in doctor contacts during the pandemic; (iii.) A considerable deterioration in at least one item of the subdomains mood (49%), everyday skills (51%), social interaction (29%), exercise and coordination skills (12%), behavior (11%) and cognition and communication (7%); (iv.) A deterioration of the overall condition in 41%; Summery: Intensive attempts should be made to find individual and less categorical contra-infectious measures without questioning the basic everyday needs of people with intellectual and developmental disabilities.

Novel Nanotube Multiquantum Dot Devices.

Addressable quantum states well isolated from the environment are of considerable interest for quantum information science and technology. Carbon nanotubes are an appealing system, since a perfect crystal can be grown without any missing atoms and its cylindrical structure prevents ill-defined atomic arrangement at the surface. Here, we develop a reliable process to fabricate compact multielectrode circuits that can sustain the harsh conditions of the nanotube growth. Nanotubes are suspended over multiple gate electrodes, which are themselves structured over narrow dielectric ridges to reduce the effect of the charge fluctuators of the substrate. We measure high-quality double- and triple-quantum dot charge stability diagrams. Transport measurements through the triple-quantum dot indicate long-range tunneling of single electrons between the left and right quantum dots. This work paves the way to the realization of a new generation of condensed-matter devices in an ultraclean environment, including spin qubits, mechanical qubits, and quantum simulators.

Interrelation of Elasticity and Thermal Bath in Nanotube Cantilevers.

We report the first study on the thermal behavior of the stiffness of individual carbon nanotubes, which is achieved by measuring the resonance frequency of their fundamental mechanical bending modes. We observe a reduction of the Young's modulus over a large temperature range with a slope -(173±65) ppm/K in its relative shift. These findings are reproduced by two different theoretical models based on the thermal dynamics of the lattice. These results reveal how the measured fundamental bending modes depend on the phonons in the nanotube via the Young's modulus. An alternative description based on the coupling between the measured mechanical modes and the phonon thermal bath in the Akhiezer limit is discussed.

Modelling the biphasic growth of non-starter lactic acid bacteria on starter-lysate as a substrate.

Since cheese is poor in energy for bacterial growth, it is believed that non-starter lactic acid bacteria growth and flavour development are supported by the nutrients from lysis of the starter culture. This study was performed to investigate the dynamics of interaction between starter and non-starter strains from cheese. A starter culture lysate was prepared by enzymatic digestion and tested as a growth substrate for Lactobacillus sp. strains. The two starter culture strains of Lactococcus lactis were also tested on the starter-lysate. All seventeen strains were individually inoculated at the level of 5.0 log10 cfu mL-1 in M17 broth, with or without 10% starter-lysate, and incubated at 30 °C for 140 h. The optical density600 nm was modelled with the primary log-transformed Logistic model with delay and lag phase duration, maximum specific growth rate as well as maximum population density obtained. Biphasic growth was mainly observed when the strains were able to utilize the starter-lysate as an energy source. To deal with the lack-of-fit related to the biphasic growth, the observed data points of the curve were divided after graphic evaluation and according to deviation of the residuals from the range ±0.05. Modelling was then performed in two phases by applying the same primary Logistic model in each of the two parts of the growth curve. Values of root-mean-square error and graphic evaluation indicated the good fitting of the data with the suggested approach. The growth of the two Lactococcus lactis strains was not affected by the starter-lysate. However, thirteen of the non-starter strains had their growth rates increased. The increase was greatest for Lactobacillus rhamnosus KU-LbR1, which reached maximum optical densities of 0.23 and 0.58 in the absence and the presence of starter-lysate, respectively. No effect of the starter-lysate was shown for the growth of Lactobacillus curvatus strains. The extend of the growth of non-starter strains on the starter-lysate was shown to be species and strain dependent.

Histamine forming behaviour of bacterial isolates from aged cheese.

This study was performed to investigate the presence of histamine forming bacteria in commercially available cheeses as well as to evaluate the histamine forming potential using in vitro models. Five long-time-ripened cheeses made from different milk types were analysed for histamine producing bacterial isolates. The ability of the isolates to produce histamine was tested by incubation at 37 °C for five days in a restricted media with a pH indicator. Changes in the amino-compound profile were investigated using ultra performance liquid chromatography. Only eight of 106 isolates were able to produce compounds raising the pH and seven of those were confirmed to be histamine producers. Despite the fact that all isolates were obtained from the same vintage Danish Gouda cheese, made from raw cow milk, the amino-compound profile as well as the response to different environmental conditions diverged between the isolates. Rep-PCR and 16S rRNA gene sequencing was used to further characterize the isolates. Pediococcus pentosaceus was for the first time reported to be a histamine producer in cheese. The presence of the histidine decarboxylase gene (hdcA) was confirmed by PCR amplification of the histidine decarboxylase gene in four of the isolates. The results indicate that evaluating the presence and concentration of histamine is not only a relevant parameter to evaluate quality and safety, but is also an important tool to classify histamine producers in cheese.

Propofol sedation in Drug Induced Sedation Endoscopy without an anaesthesiologist â€" a study of safety and feasibility.

BACKGROUND: Propofol sedation in Drug Induced Sedation Endoscopy (DISE) of the upper airway of patients with obstructive sleep apnea (OSA) without the presence of anesthesiologist has not been done before. Propofol sedation is normally administered by an anesthesiologist. This is the first study of this new method. METHODOLOGY: Based on the positive experience with Nurse-administered Propofol Sedation (NAPS) for endoscopic procedures in the departments of gastroenterology we wanted to test the set-up as method of propofol sedation for DISE procedures in our Otorhinolaryngology (ORL) department. The ORL specialists and staff nurses that carry out DISE procedures all underwent a formalized education in Nurse-administered Propofol Sedation before the study. We included 200 patients with severe snoring and / or obstructive sleep apnea. They were referred for DISE examination prior to possible targeted surgery based on the findings. RESULTS: In our study the aforementioned ORL team successfully cared out propofol sedation without the presence of an anesthesiologist. All examinations were carried out according to plan. There were no adverse events during the procedures or in the following observational period. CONCLUSIONS: The NAPS method of sedation for DISE seems safe and feasible when performed by trained staff in a hospital setting.

Author Correction: High-temperature operation of electrical injection type-II (GaIn)As/Ga(AsSb)/(GaIn)As "W"-quantum well lasers emitting at 1.3 µm.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

High-temperature operation of electrical injection type-II (GaIn)As/Ga(AsSb)/(GaIn)As "W"-quantum well lasers emitting at 1.3 µm.

Electrical injection lasers emitting in the 1.3 µm wavelength regime based on (GaIn)As/Ga(AsSb)/(GaIn)As type-II double "W"-quantum well heterostructures grown on GaAs substrate are demonstrated. The structure is designed by applying a fully microscopic theory and fabricated using metal organic vapor phase epitaxy. Temperature-dependent electroluminescence measurements as well as broad-area edge-emitting laser studies are carried out in order to characterize the resulting devices. Laser emission based on the fundamental type-II transition is demonstrated for a 975 µm long laser bar in the temperature range between 10 °C and 100 °C. The device exhibits a differential efficiency of 41 % and a threshold current density of 1.0 kA/cm2 at room temperature. Temperature-dependent laser studies reveal characteristic temperatures of T0 = (132 ± 3) K over the whole temperature range and T1 = (159 ± 13) K between 10 °C and 70 °C and T1 = (40 ± 1) K between 80 °C and 100 °C.

Donor Smoking and Older Age Increases Morbidity and Mortality After Lung Transplantation.

BACKGROUND: The lack of lung transplant donors has necessitated the use of donors with a smoking history and donors of older age. We have evaluated the effects of donor smoking history and age on recipient morbidity and mortality with baseline values of pulmonary function and survival free of chronic lung allograft dysfunction (CLAD) as morbidity variables. METHODS: This is a retrospective analysis of 588 consecutive lung transplant recipients and their corresponding 454 donors. Donors were divided into three groups: group 1 included smokers, group 2 nonsmokers, and group 3 had unknown smoking status; these were further divided into three age groups: group A: 0 to 39 years; group B: 40 to 54 years; and group C: ≥55 years. RESULTS: One hundred fifty-one donors were former or actual smokers, 175 were nonsmokers, and 128 had unknown smoking histories. Baseline forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of carbon monoxide were lowest in the groups who received lungs from a smoking donor. CLAD-free survival was identical in all smoking groups, and overall survival was better both for lungs from nonsmoking donors and donors with unknown smoking status compared to lungs from smoking donors. One hundred sixty-nine donors were in age group A, 203 in B, and 82 in C. Baseline forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of carbon monoxide were lowest in the groups who received lungs from donors older than 55 years. Overall survival as well as CLAD-free survival was significantly lower with donors ≥55 years. CONCLUSIONS: Donor smoking history and older donor age impact lung function, mortality, and CLAD-free survival after transplantation. Because of a shortage of organs, extended donor criteria may be considered while taking waiting list mortality into account.

Autoimmune encephalitis associated with voltage-gated potassium channels-complex and leucine-rich glioma-inactivated 1 antibodies - a national cohort study.

BACKGROUND AND PURPOSE: The aim of this study was to describe clinical and paraclinical characteristics of all Danish patients who tested positive for anti-voltage-gated potassium channels (VGKC)-complex, anti-leucine-rich glioma-inactivated 1 (LGI1) and anti-contactin-associated protein-2 antibodies in the serum/cerebrospinal fluid between 2009 and 2013 with follow-up interviews in 2015 and 2016. METHODS: We evaluated antibody status, symptoms leading to testing, course of disease, suspected diagnosis and time of admission as well as diagnosis and treatment. All magnetic resonance imaging, electroencephalography and 18 F-fluorodeoxyglucose positron emission tomography scans were re-evaluated by experts in the field. RESULTS: A total of 28/192 patients tested positive for VGKC-complex antibodies by radioimmunoassay and indirect immunofluorescence; 17 had antibodies to LGI1 and 6/7 of the available cerebrospinal fluids from these patients were seropositive. These 17 patients all had a clinical phenotype appropriate to LGI1 antibodies. The remaining 11 were LGI1 negative (n = 4) or not tested (n = 7). Of these, two had a phenotype consistent with limbic encephalitis. The remaining phenotypes were Guillain-Barré syndrome, Creutzfeldt-Jakob disease, neuromyotonia and anti-N-methyl-D-aspartate receptor encephalitis. Magnetic resonance imaging abnormalities were demonstrated in 69% of the LGI1-positive patients. Two patients with normal magnetic resonance imaging demonstrated temporal lobe hypermetabolism using 18 F-fluorodeoxyglucose positron emission tomography. Abnormal electroencephalography recordings were found in 86% of the patients. Upon follow-up (median 3.2 years), the median modified Rankin Scale score of anti-LGI1-positive patients was 2 and only two patients reported seizures in the past year. CONCLUSIONS: Patients diagnosed with anti-LGI1 autoimmune encephalitis increased significantly from 2009 to 2014, probably due to increased awareness. In contrast to seropositive anti-VGKC-complex patients, all anti-LGI1-positive patients presented with a classical limbic encephalitis. The majority of patients recovered well.

Evaluation of a cross contamination model describing transfer of Salmonella spp. and Listeria monocytogenes during grinding of pork and beef.

In a previous study, a model was developed to describe the transfer and survival of Salmonella during grinding of pork (Møller, C.O.A., Nauta, M.J., Christensen, B.B., Dalgaard, P., Hansen, T.B., 2012. Modelling transfer of Salmonella typhimurium DT104 during simulation of grinding of pork. Journal of Applied Microbiology 112 (1), 90-98). The robustness of this model is now evaluated by studying its performance for predicting the transfer and survival of Salmonella spp. and Listeria monocytogenes during grinding of different types of meat (pork and beef), using two different grinders, different sizes and different numbers of pieces of meats to be ground. A total of 19 grinding trials were collected. Acceptable Simulation Zone (ASZ), visual inspection of the data, Quantitative Microbiological Risk Assessment (QMRA), as well as the Total Transfer Potential (TTP) were used as approaches to evaluate model performance and to access the quality of the cross contamination model predictions. Using the ASZ approach and considering that 70% of the observed counts have to be inside a defined acceptable zone of ±0.5 log10CFU per portion, it was found that the cross contamination parameters suggested by Møller et al. (2012) were not able to describe all 19 trials. However, for each of the collected grinding trials, the transfer event was well described when fitted to the model structure proposed by Møller et al. (2012). Parameter estimates obtained by fitting observed trials performed at different conditions, such as size and number of pieces of meat to be ground, may not be applied to describe cross contamination of unlike processing. Nevertheless, the risk estimates, as well as the TTP, revealed that the risk of disease may be reduced when the grinding of meat is performed in a grinder made of stainless steel (for all surfaces in contact with the meat), using a well-sharpened knife and holding at room temperatures lower than 4°C.

Auditory function following post-dural puncture headache treated with epidural blood patch. A long-term follow-up.

BACKGROUND: Epidural analgesia is commonly used for pain management during labor. Sometimes, accidental dural puncture (ADP) occurs causing severely debilitating headache, which may be associated with transient hearing loss. We investigated if auditory function may be impaired several years after ADP treated with epidural blood patch (EBP). METHODS: Sixty women (ADP group) without documented hearing disability, who received EBP following ADP during labor between the years 2005-2011 were investigated in 2013 for auditory function using the following tests: otoscopic examination, tympanometry, pure tone audiometry, and transient-evoked otoacoustic emissions. Additionally, they responded to a questionnaire, the Speech, Spatial and Qualities (SSQ) of hearing, concerning perceived hearing impairment. The results were compared to a control group of 20 healthy, non-pregnant women in the same age group. RESULTS: The audiometric test battery was performed 5.2 (1.9) years after delivery. No significant differences were found between the ADP and the control groups in tympanometry or otoacoustic emissions. Pure tone audiometry revealed a significant but small (< 5 dB) difference between the ADP and control groups (P < 0.05). The ability to hear speech in noise as measured by SSQ was significantly reduced in the ADP group compared to the control group (P < 0.05). CONCLUSIONS: A minor hearing loss was detected in the ADP group compared to the control group in pure tone audiometry in some women and during speech-in-noise component several years after accidental dural puncture treated with an epidural blood patch. This small residual hearing loss has minor clinical significance.

Novel type-II material system for laser applications in the near-infrared regime.

The design and experimental realization of a type-II "W"-multiple quantum well heterostructure for emission in the λ > 1.2 µm range is presented. The experimental photoluminescence spectra for different excitation intensities are analyzed using microscopic quantum theory. On the basis of the good theory-experiment agreement, the gain properties of the system are computed using the semiconductor Bloch equations. Gain values comparable to those of type-I systems are obtained.

Arterial pressure during cardiopulmonary bypass is not associated with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is common and is associated with increased mortality. We wanted to investigate if the arterial pressure or the use of norepinephrine during cardiopulmonary bypass were associated with AKI. METHODS: A retrospective analysis of patients who underwent coronary artery bypass grafting with or without concomitant procedures was conducted. AKI was defined using the RIFLE criteria. Data on arterial pressure and use of norepinephrine during cardiopulmonary bypass were entered in a binary logistic regression model to control for possible perioperative confounders. RESULTS: A total of 623 patients were included. Mean age was 68.3 ± 9.7 years and 81% were males. AKI was observed in 198 patients (32%). Mean arterial pressure was 47 ± 6 mmHg and 45 ± 6 mmHg (P = 0.008) in the AKI and no-AKI group, respectively. Norepinephrine was used more frequently and in higher amounts, during cardiopulmonary bypass, in patients who developed AKI. These differences in arterial pressures and use of norepinephrine between the groups were not found to be significant when entered in the binary logistic regression model. CONCLUSION: No independent relationship between arterial pressure or use of norepinephrine and AKI was found.

A preclinical model of hyperalgesia following spinal stenosis/compression.

BACKGROUND: Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long-term evaluation of individual subjects because of the variability in effect over time for humans. METHODS: Rats were trained on an operant escape task that determined their preference for occupancy of a brightly lit compartment versus a dark compartment with a floor preheated to 10, 32 or 44.5 °C. Following determination of baseline preferences, the animals received extradural implantation of a small piece of polymer in the thoracic spinal canal. The polymer narrowed the spinal canal and compressed the spinal cord. Post-operative tests of escape preference were conducted over 23 weeks (experiments 1 and 2) and 62 weeks (experiment 3), permitting statistical evaluation of individual effects. RESULTS: Spinal stenosis/compression produced hyperalgesia for cold and/or heat stimulation (17 animals; 77%), no post-operative change in sensitivity (4 animals) or hypoalgesia for cold or heat (2 animals). When hyperalgesia occurred, it developed gradually over 4 months. Following removal of the polymer in experiment 3, heat sensitivity returned to baseline levels for four of four animals that had been hyperalgesic when the polymer was in place, but cold hyperalgesia was retained for four of five animals. Overall, post-operative changes in cold and heat sensitivity were not strongly related, indicating that different mechanisms were responsible for enhanced sensitivity to 10 and 44.5 °C. CONCLUSIONS: Histology revealed that hyperalgesia occurred when there was: (1) damage to spinal white matter; or (2) cystic cavitation; or (3) compression and distortion of the spinal cord without an obvious loss of grey or white matter.

Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non-human primates (Macaca mulatta).

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a metabolic regulator of glucose and lipid metabolism. The physiological role of FGF21 is not yet fully elucidated, however, administration of FGF21 lowers blood glucose in diabetic animals. Moreover, increased levels of FGF21 are found in obese and diabetic rodents and humans compared with lean/non-diabetic controls. METHODS: Adult male rhesus macaque monkeys were chronically maintained on a high-fat diet (HFD) or a standard diet (control, CTR). Plasma levels of FGF21, triglycerides and cholesterol were measured and body weight was record. Glucose-stimulated insulin secretion (GSIS) and glucose clearance was determined during an intravenous glucose tolerance test. Furthermore, expression of FGF21 and its receptors were determined in liver, pancreas, three white adipose tissues (WATs) and two skeletal muscles. RESULTS: A cohort of the high-fat fed monkeys responded to the HFD with increasing body weight, plasma lipids, total cholesterol, GSIS and decreased glucose tolerance. These monkeys were termed HFD sensitive. Another cohort of monkeys did not become obese and maintained normal insulin sensitivity. These animals were defined as HFD resistant. Plasma FGF21 levels were significantly increased in all HFD fed monkeys compared with the CTR group. The HFD-sensitive monkeys showed a significant increase in FGF21 mRNA expression in all examined tissues compared with CTR, whereas FGF21 expression in the HFD-resistant group was only increased in the liver, pancreas and the retroperitoneal WAT. In the WAT, the co-receptor ß-klotho was downregulated in the HFD-sensitive monkeys compared with the HFD-resistant group. CONCLUSION: This study demonstrates that HFD changes FGF21 and FGF21 receptor expression in a tissue-specific manner in rhesus monkeys; differential regulation is moreover observed between HFD-sensitive and -resistant monkeys. Monkeys that maintain normal levels of the FGF21 co-receptor ß-klotho in the WAT on HFD were protected toward development of dyslipidemia and hyperglycemia.

An ultrasound algorithm for identification of endometrial cancer.

OBJECTIVE: To propose a scoring system to predict endometrial cancer using different ultrasound image characteristics at gray-scale, with and without enhancement by gel infusion, and Doppler transvaginal sonography (TVS) and to evaluate intra- and interobserver variability in assessment of these characteristics. METHOD: Unenhanced TVS, Doppler examinations and gel infusion sonography (GIS) were performed prospectively in 174 consecutive postmenopausal women with endometrial thickness ≥ 5 mm. The reference standard in all women was hysteroscopy or hysterectomy with pathological evaluation of the malignancy. The presence of various ultrasound pattern characteristics indicative of endometrial malignancy and intra- and interobserver variability in their assessment were evaluated. Multivariate logistic regression was used to correlate image and clinical parameters to presence of endometrial cancer. RESULTS: A simple Doppler flow score (which considered only presence of vascularity and not presence of single/double dominant vessel, multiple vessels, large vessels, color splash or densely packed vessels) had an area under the receiver-operating characteristics curve (AUC) of 0.83 in the prediction of endometrial cancer. Models including endometrial thickness, Doppler score and interrupted endomyometrial junction on unenhanced TVS predicted endometrial cancer with an AUC of 0.95 (95% CI, 0.92-0.99) and, with addition of irregular surface on GIS, the AUC was 0.97 (95% CI, 0.94-0.99). A risk of endometrial cancer (REC) scoring system based on body mass index, Doppler score, endometrial thickness and interrupted endomyometrial junction on unenhanced TVS and irregular surface at GIS performed very well at identifying endometrial cancer; at a REC-score of ≥ 4 the sensitivity for detection of endometrial cancer was 91% and specificity was 94%. Observers agreed in 82.3% of cases (kappa, 0.63 (0.48-0.78)) when subjective parameters were analyzed in stored videoclips. CONCLUSION: Our observer-dependent proposed scoring system seems to perform well in the prediction of endometrial cancer and should be tested in future studies.

Differentiation of tannin-containing herbal drugs by HPLC fingerprints.

A new HPLC system coupled with multiple detectors - Diode array detector (DAD), fluorescence detector (FLD), electrochemical amperometric detector (ADC) and mass spectrometry detector (MSD) was developed for the characterization and differentiation of tannin-containing herbal drugs included in The European Pharmacopoeia. The HPLC separation system consisted of an Agilent ZORBAX Eclipse XDB C18 column and a gradient water and methanol as the mobile phase which was kept at a flow rate of 0.3 mL x min(-1). Four kinds of detectors were connected by a micro-splitter valve and simultaneously recorded the response of each analytical sample. Thirty-one samples from eight kinds of tannin-containing drugs were measured using this HPLC system and their signals from all detectors were comprehensively processed via principal component analysis (PCA). The statistic result demonstrates that thirty-one batches from different herbal drugs can be reasonably identified and systematically classified by their chemical fingerprints. The proposed multi-detector HPLC method aided by chemometrics not only offers a new pattern for the study of tannin-containing herbs, but also provides a useful foundation for quality control of herbal medicines.