Burden and genotyping of rotavirus disease in the United Arab Emirates: a multicenter hospital-based surveillance.
Rotavirus (RV) is the most common etiological agent causing acute gastroenteritis (GE) in children aged <5 years. This cross-sectional, hospital-based surveillance study (NCT01201252) was designed to investigate RVGE disease burden. It was conducted from July 2009-July 2010 at 3 referral hospitals in the United Arab Emirates (UAE). Children who had been hospitalized for acute GE were enrolled with informed consent. Stool samples were tested for RV using enzyme immunoassay and RV-positive samples were further typed using reverse transcriptase-polymerase chain reaction and reverse hybridization to determine the G and P types. GE data were collected from medical charts and GE severity was assessed through clinical examination. Treatment and outcome were prospectively recorded. Among 6323 children hospitalized due to any reason, 771 (12.2%) presented acute GE and were enrolled, of whom 758 (98.3%) were included in the final analysis. Acute GE and RVGE accounted for 12.0% (758/6323) and 6.0% (381/6323) of all hospitalizations, respectively. RVGE accounted for 50.3% (381/758) of GE hospitalizations and predominantly affected, children younger than 2 years (66.1%; 252/381). The severity of GE before hospitalization was significantly associated with RV-positive status (P = 0.0031). The majority (>95%) of children received intravenous hydration during hospitalization. RVGE occurred throughout the year, with a subtle winter peak in February 2010 (63.6%; 56/88). G1WTP[8]WT was the most commonly detected RV strain (56.3%) in 268 analyzed samples. RV was a major cause of GE-hospitalizations in children under 5 years in the UAE; the highest number of RVGE cases was observed in children younger than 2 years.


A new perspective on the pathobiology of keratoconus: interplay of stromal wound healing and reactive species-associated processes.
Severe loss of vision manifests from the corneal protrusion, thinning and distortion that characterises keratoconus, which in its most severe form is still treated primarily by lamellar or penetrating keratoplasty. Unfortunately, alternative therapeutic options targeting the underlying pathobiology remain limited, attributable to an incomplete understanding of the biological mechanisms instigating stromal deterioration and other disease processes. We postulate that underlying abnormalities in stromal repair and reactive species-linked activities and the interaction between these phenomena are implicated in the development of keratoconus. This revised interpretation of the pathophysiology may, with further investigation, advance our knowledge and the clinical management of this prevalent ectatic disorder.


Mitochondrial perturbance and execution of apoptosis in platelet mitochondria of patients with amyotrophic lateral sclerosis.
Role of platelets have been evinced as a systemic tool in a variety of neurological disorders. Oxidative phosphorylation contributes approximately 80% of total adenosine-tri-phosphate (ATP) production in resting platelets suggesting potential dependence of platelets on modest mitochondrial functioning. Since mitochondria play a pivotal role in regulating metabolic and apoptotic pathways in various neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), we assessed mitochondrial membrane potential (MMP) associated alterations and apoptotic status of platelet mitochondria in ALS patients using case-control approach. Confocal microscopy reflected heterogeneous distribution of JC-1 aggregates and monomers indicating altered MMP in ALS platelets. Our flow cytometry results confirmed greater percentage of mitochondrial depolarization in ALS platelets. Greater exposure of phosphatidyl serine (PS) residue vindicated by annexin V binding and lesser accumulation of mitotracker red in mitochondrial matrix demonstrated initiation of apoptosis in ALS platelets. Our findings corroborate mitochondrial abnormalities such as perturbance of MMP, mitochondrial depolarization, and apoptosis in ALS platelet mitochondria. In conclusion, our study further evinces the involvement of mitochondrial dysfunction in the pathogenesis of ALS and suggests implication of cell death in peripheral tissues apart from motor neurons in ALS.


Intrauterine (extraamniotic) prostaglandins in the management of unsuccessful pregnancy.
Extraamniotic administration of prostaglandin E2 or prostaglandin F2alpha has been used in the treatment of 72 cases of unsuccessful pregnancy which included 50 of fetal death in utero, 13 of anencephaly and nine of hydatidiform mole. This management is highly effective in achieving abortion or delivery within 24 hours in almost all cases and results in few side effects. Pyrexia occurred during treatment in three patients, but in none was intrauterine infection observed. Blood loss greater than 250 ml occurred in only two patients, and none required transfusion. We advocate the use of extraamniotic prostaglandins as an active approach to the problem of unsuccessful pregnancy to relieve the patient of emotional distress and avoid the hazards of blood coagulopathy and intrauterine infection, both of which increase the longer a dead fetus is retained in utero.


Solid Solution Photocatalyst with Spontaneous Polarization Exhibiting Low Recombination Toward Efficient CO2 Photoreduction.
Decreasing the recombination of photogenerated carriers is a major challenge for efficiently converting solar energy into chemical energy by photocatalysis. Here, we have demonstrated that growth of a polar GaN:ZnO solid solution single crystal along its polarization axis is beneficial to efficient separation of photogenerated carriers, owing to the periodic potential barriers and wells generated from the periodically positive and negative atom arrangements in crystal structure. Local charge imbalance caused by replacing Ga(3+) with Zn(2+) leads to a polarization vector in the {0 0 0 1} planes of GaN:ZnO solid solution, thus forming a 1 D electron transport path along [2 1‾ 1‾ 0] in the {0 0 0 1} planes of GaN:ZnO solid solution to decrease recombination. Shorting the hole-transport distance by synthesizing porous nanoplates can further decrease recombination under the polarization field and improve the performance of polar photocatalyst in photoreduction of CO2 into CH4 .


Facile fabrication of diblock methoxy poly(ethylene glycol)-poly(tetramethylene carbonate) and its self-assembled micelles as drug carriers.
AB type diblock methoxy poly(ethylene glycol)-b-poly(tetramethylene carbonate) (mPEG-PTeMC) copolymers were designed for the first time and used as carriers for the sustained release of the hydrophobic drug ibuprofen. In this paper, we developed a facile ring-opening polymerization (ROP) method to prepare mPEG-PTeMC copolymers under the catalysis of Novozym-435 lipase. Attractively, the polymerization has been successfully performed at 30 degrees C, close to room temperature. The data show that the copolymer compositions agree well with the feed ratio of TeMC to mPEG, indicating the controllable feature of the polymerization. The copolymer structures were characterized by (1)H NMR, IR, SEC, and DSC measurements. mPEG-PTeMC exhibits no apparent in vitro cytotoxicity toward human embryonic kidney transformed 293T cells. Those amphiphilic copolymers can readily self-assemble into nanosized micelles (about 150 nm) in aqueous solution. Their critical micelle concentrations are in the range of (1.6-9.3) x 10(-7) mol/L, determined by fluorescence spectroscopy. The micelles present high stability in PBS solution, with no obvious change in micelle diameters over 5 days. Ibuprofen can be loaded effectively in mPEG-PTeMC micelles, and its sustained release behavior is observed. Transmission electron microscopy shows that the well-dispersed spherical micelles are around 25 nm in diameter, while the diameter is 30 nm after loading ibuprofen. The release rate increases when the chain length of the PTeMC block decreases. These properties show that the micelles self-assembled from mPEG-PTeMC copolymers would have great potential as carriers for the effective encapsulation as well as sustained release of hydrophobic drugs.


Synthesis and properties of sulfonated block copolymers having fluorenyl groups for fuel-cell applications.
A series of sulfonated poly(arylene ether sulfone)s (SPEs) block copolymers containing fluorenyl groups were synthesized. Bis(4-fluorophenyl)sulfone (FPS) and 2,2-bis(4-hydroxy-3,5-dimethylpheny)propane were used as comonomers for hydrophobic blocks, whereas FPS and 9,9-bis(4-hydroxyphenyl)fluorene were used as hydrophilic blocks. Sulfonation with chlorosulfonic acid gave sulfonated block copolymers with molecular weight (M(w)) higher than 150 kDa. Proton conductivity of the SPE block copolymer with the ion exchange capacity (IEC) = 2.20 mequiv/g was 0.14 S/cm [80% relative humidity (RH)] and 0.02 S/cm (40% RH) at 80 degrees C, which is higher or comparable to that of a perfluorinated ionomer (Nafion) membrane. The longer hydrophilic and hydrophobic blocks resulted in higher water uptake and higher proton conductivity. Scanning transmission electron microscopy observation revealed that phase separation of the SPE block copolymers was more pronounced than that of the SPE random copolymers. The SPE block copolymer membranes showed higher mechanical properties than those of the random ones. With these properties, the SPE block copolymer membranes seem promising for fuel-cell applications.


Photomechanical investigations on the stress-strain relationship in dentine macrostructure.
In this study photomechanical experiments were carried out to examine the relationship between macroscopic mechanical stress and strain gradients within the root dentine structure. Three-dimensional digital photoelasticity was used to study the stress distribution patterns in tooth models, while digital moire interferometry was used to study the strain gradients within the natural teeth. The stress analysis showed a distinct bending stress distribution, along faciolingual plane in the coronal and cervical regions of the tooth. There was a reduction in bending towards the apical third of the tooth model. The strain analysis displayed strain gradients in the axial (along the long axis of the tooth) and lateral (perpendicular to the long axis of the tooth) directions in dentine. There was a conspicuous reduction in strains from the cervical to the apical third of the root dentine. The root dentine displayed uniform distribution of normal strains. Although there was a steep increase in stresses from the inner core region to the outer surface of an isotropic tooth model, there were more uniform strain gradients in the natural dentine structure. It is apparent from these observations that complex organization of material properties facilitated distinct strain gradients in dentine structure during mechanical functions.


Tau isoform-specific stabilization of intermediate states during microtubule assembly and disassembly.
The microtubule (MT)-associated protein tau regulates the critical growing and shortening behaviors of MTs, and its normal activity is essential for neuronal development and maintenance. Accordingly, aberrant tau action is tightly associated with Alzheimer's disease and is genetically linked to several additional neurodegenerative diseases known as tauopathies. Although tau is known to promote net MT growth and stability, the precise mechanistic details governing its regulation of MT dynamics remain unclear. Here, we have used the slowly-hydrolyzable GTP analog, guanylyl-(α,β)-methylene-diphosphonate (GMPCPP), to examine the structural effects of tau at MT ends that may otherwise be too transient to observe. The addition of both four-repeat (4R) and three-repeat (3R) tau isoforms to pre-formed GMPCPP MTs resulted in the formation of extended, multiprotofilament-wide projections at MT ends. Furthermore, at temperatures too low for assembly of bona fide MTs, both tau isoforms promoted the formation of long spiral ribbons from GMPCPP tubulin heterodimers. In addition, GMPCPP MTs undergoing cold-induced disassembly in the presence of 4R tau (and to a much lesser extent 3R tau) also formed spirals. Finally, three pathological tau mutations known to cause neurodegeneration and dementia were differentially compromised in their abilities to stabilize MT disassembly intermediates. Taken together, we propose that tau promotes the formation/stabilization of intermediate states in MT assembly and disassembly by promoting both longitudinal and lateral tubulin-tubulin contacts. We hypothesize that these activities represent fundamental aspects of tau action that normally occur at the GTP-rich ends of GTP/GDP MTs and that may be compromised in neurodegeneration-causing tau variants.


Nectophore coordination and kinematics by physonect siphonophores.
Siphonophores are ubiquitous and often highly abundant members of pelagic ecosystems throughout the open ocean. They are unique among animal taxa in that many species use multiple jets for propulsion. Little is known about the kinematics of the individual jets produced by nectophores (the swimming bells of siphonophores) or whether the jets are coordinated during normal swimming behavior. Using remotely operated vehicles and SCUBA, we video recorded the swimming behavior of several physonect species in their natural environment. The pulsed kinematics of the individual nectophores that comprise the siphonophore nectosome were quantified and, based on these kinematics, we examined the coordination of adjacent nectophores. We found that, for the five species considered, nectophores located along the same side of the nectosomal axis (i.e. axially aligned) were coordinated and their timing was offset such that they pulsed metachronally. However, this level of coordination did not extend across the nectosome and no coordination was evident between nectophores on opposite sides of the nectosomal axis. For most species, the metachronal contraction waves of nectophores were initiated by the apical nectophores and traveled dorsally. However, the metachronal wave of Apolemia rubriversa traveled in the opposite direction. Although nectophore groups on opposite sides of the nectosome were not coordinated, they pulsed with similar frequencies. This enabled siphonophores to maintain relatively linear trajectories during swimming. The timing and characteristics of the metachronal coordination of pulsed jets affects how the jet wakes interact and may provide important insight into how interacting jets may be optimized for efficient propulsion.


A spontaneous ovarian teratoma in an FVB/n female mouse: Case report and literature review.
Teratomas are rare types of germ cell neoplasms composed of various differentiated or undifferentiated tissues. A 25-week-old female control FVB /n mouse in a 4-week toxicity study presented abdominal distension and poor body condition. It was euthanized, and the necropsy examination revealed a large mass connected to the tip of the right uterine horn, occupying the entire abdominal cavity. Microscopically, this mass showed areas of epidermal differentiation, with laminated keratin and sebaceous glands, differentiation into respiratory and digestive epithelium, cartilage, bone, and extensive areas of differentiation into the nervous tissue, being classified as an ovarian teratoma. As far as authors know, the occurrence of ovarian teratomas in the FVB/n mouse strain has never been previously described.


Cervical Range of Motion Assessment through Inertial Technology: A Validity and Reliability Study.
Inertial technology has spread widely for its comfortable use and adaptability to various motor tasks. The main objective of this study was to assess the validity of inertial measurements of the cervical spine range of motion (CROM) when compared to that of the optoelectronic system in a group of healthy individuals. A further aim of this study was to determine the optimal placement of the inertial sensor in terms of reliability of the measure, comparing measurements obtained from the same device placed at the second cervical vertebra (C2), the forehead (F) and the external occipital protuberance (EOP). Twenty healthy subjects were recruited and asked to perform flexion-extension, lateral bending, and axial rotation movements of the head. Outcome measurements of interest were CROM and mean angular velocities for each cervical movement. Results showed that inertial measurements have good reliability (0.75 < ICC < 0.9). Excellent reliability (ICC > 0.9) was found in both flexion and right lateral bending angles. All parameters extracted with EOP placement showed ICC > 0.62, while ICC < 0.5 was found in lateral bending mean angular velocities both for F and C2 placements. Therefore, the optimal sensor's positioning emerged to be EOP. These results suggest that inertial technology could be useful and reliable for the evaluation of the CROM.


Spheroid degeneration, keratopathy, pinguecula, and pterygium in Japan (Kyoto).
The prevalences of various possibly sunlight-induced degenerations of the exposed section of the eye have been studied in a series of 189 Japanese (Mongols) in Kyoto (subtropical climate, 35 degrees N. lat.). The results were compared with those of the author's examinations, using the same method and apparatus, in Jordan near the Red Sea (Arabs, N = 127) in Greenland (Eskimos, N = 659), and in Denmark (Caucasians, N = 810). In the Japanese series conjunctival spheroid degeneration was noticed in 31% and pinguecula in 60%, i.e. less frequently than in the sunny Jordan, but more frequently than in Greenland and Denmark. Climatokeratopathy was more rarely observed than in Greenland. This goes to show that the risk of corneal complications is lower in Japan despite the high prevalence of solar conjunctival degenerations. Pterygium was seen in a surprisingly small number of cases (1%), indicating that pterygium bears no relation to the conjunctival degenerations.


Twenty-four-hour intraocular pressure and blood pressure levels with bimatoprost versus latanoprost in patients with normal-tension glaucoma.
To evaluate 24 h intraocular pressure (IOP) and blood pressure (BP) with bimatoprost or latanoprost in patients with normal-tension glaucoma. Prospective, randomised, crossover, active-controlled, observer-masked study. After a 6-week medicine-free period, we randomised patients to either latanoprost or bimatoprost for 8 weeks and then to the opposite medicine for 8 weeks. At baseline, and at the end of each treatment period, we evaluated IOP and BP at 08:00 and then every 2 h over the 24 h day. Diastolic ocular perfusion pressure (DOPP) was calculated from the above parameters. Forty completed patients had a 24 h untreated baseline IOP of 15.5 (2.3) mm Hg, and a DOPP of 59.2 (6.1) mm Hg. Both treatments lowered IOP at each time point (p<0.006), and over the 24 h curve (p<0.001, both medicines 13.1 mm Hg, 16% decrease). No difference existed between treatments in absolute IOP, at each time point, and over the 24 h curve (p>or=0.26). Additionally, no differences were found between treated 24 h systolic (p>or=0.29) and diastolic BP (p>or=0.12). The mean 24 h DOPP for latanoprost was increased from baseline (3%, p = 0.031) but not for bimatoprost (2%, p = 0.21). However, no difference in DOPP existed between treatments at any time point or over the 24 h curve (p>or=0.17). No difference was observed between treatments for any adverse event (p>0.05). In patients with normal-tension glaucoma, both bimatoprost and latanoprost reduce the 24 h intraocular pressure from untreated baseline to a similar extent. Latanoprost is associated with slightly improved ocular diastolic perfusion pressure over 24 h but similar absolute perfusion levels to that of bimatoprost.


A case of congenital myopathy masquerading as paroxysmal dyskinesia.
Gastroesophageal reflux (GER) disease is a significant comorbidity of neuromuscular disorders. It may present as paroxysmal dyskinesia, an entity known as Sandifer syndrome. A 6-week-old neonate presented with very frequent paroxysms of generalized stiffening and opisthotonic posture since day 22 of life. These were initially diagnosed as seizures and he was started on multiple antiepileptics which did not show any response. After a normal video electroencephalogram (VEEG) was documented, possibility of dyskinesia was kept. However, when he did not respond to symptomatic therapy, Sandifer syndrome was thought of and GER scan was done, which revealed severe GER. After his symptoms got reduced to some extent, a detailed clinical examination revealed abnormal facies with flaccid quadriparesis. Muscle biopsy confirmed the diagnosis of a specific congenital myopathy. On antireflux measures, those episodic paroxysms reduced to some extent. Partial response to therapy in GER should prompt search for an underlying secondary etiology.


Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant.
Suvorexant (Belsomra®) is a dual orexin receptor antagonist approved for the treatment of insomnia. Because of its pharmacology within the central nervous system, intended therapeutic indication, and first-in-class status, an assessment of suvorexant abuse liability potential was required prior to marketing approval. The nonclinical abuse liability potential studies for suvorexant included: 1) rat drug-dependence model to assess physical dependence following abrupt cessation; 2) rat drug-discrimination model to examine the potential similarity of the interoceptive or subjective effects of suvorexant to those elicited by zolpidem and morphine; 3) self-administration model to assess the relative reinforcing efficacy of suvorexant in rhesus monkeys conditioned to self-administer methohexital. No significant signs of spontaneous drug withdrawal or 'discontinuation syndrome' were observed in rats following abrupt discontinuation of suvorexant. Suvorexant did not elicit complete cross-generalization to either a zolpidem or morphine training/reference stimuli in rats, and suvorexant was devoid of behavioral evidence of positive reinforcing efficacy in monkeys. These nonclinical findings suggested that suvorexant will have low abuse potential in humans. In the final regulatory risk assessment, suvorexant was placed into Schedule IV, likely due to its first-in-class status, its sedative properties, and the outcome of the clinical abuse potential assessment.


[Weidiao-3 Mixture Improves the Clinical Efficacy of Immunotherapy for Advanced Gastric Cancer by Regulating Intestinal Flora].
Objective To investigate the effects of Weidiao-3(WD-3)Mixture on the clinical efficacy of immunotherapy for advanced gastric cancer and the intestinal flora.Methods Fifty-one patients with advanced gastric cancer treated in Wuxi Traditional Chinese Medicine Hospital from January 2020 to December 2021 were randomized into a WD-3 group(immunotherapy + WD-3 Mixture,one dose per day)(n=25)and a gastric cancer(GC) group(only immunotherapy)(n=26)according to the admission time.Ten healthy volunteers were included as the healthy control group.The Karnofsky score and the Quality of Life Questionnare-Core score were evaluated before and after treatment,and the clinical efficacy was compared after treatment.After treatment,the stool samples were collected for 16SrRNA gene high-throughput sequencing and targeted metabolomics.The α and β diversity and structure of the intestinal flora and the content of short-chain fatty acids were compared between groups.Results The quality of life in both groups improved after treatment and was better in the WD-3 group than in the GC group(P=0.035).The dry mouth(P=0.038)and altered taste(P=0.008)were mitigated in the WD-3 group after treatment,and the reflux(P=0.001)and dry mouth(P=0.022)were mitigated in the GC group after treatment.After treatment,the WD-3 group outperformed the GC group in terms of dysphagia(P=0.047)and dry mouth(P=0.045).The WD-3 group was superior to the GC group in terms of objective remission rate and disease control rate,with prolonged median progression-free survival and median overall survival(P=0.039,P=0.043).The α and β diversity indexes of the intestinal flora showed no significant differences between WD-3 and GC groups(all P>0.05).At the phylum level,WD-3 and GC groups had lower relative abundance of Firmicutes(P=0.038,P=0.042)and higher relative abundance of Proteobacteria(P=0.016,P=0.015)than the healthy control group.The relative abundance of Actinomycetes in the GC group was lower than that in the healthy control group(P=0.035)and the WD-3 group(P=0.046).At the genus level,the GC group had lower relative abundance of Bifidobacteria and Coprococcus than the healthy control group and the WD-3 group(all P<0.001).LEfSe revealed the differences in the relative abundance of 6 intestinal bacterial taxa between the WD-3 group and the GC group.At the genus level,Saccharopolyspora had higher relative abundance in the WD-3 group than in the healthy control group and only existed in the WD-3 group.The content of isobutyric acid and isovaleric acid in the WD-3 group was higher than that in the healthy control group(P=0.037,P=0.004).Conclusion WD-3 Mixture may increase the relative abundance of Bifidobacteria and Coprococcus and the content of isobutyric acid and isovaleric acid to alter the intestinal microecology,thereby improving the efficacy of immunotherapy for gastric cancer.


Effect of methomyl on sex steroid hormone and vitellogenin levels in serum of male tilapia (Oreochromis niloticus) and recovery pattern.
Tilapia were exposed to sub-lethal concentrations of 0, 0.2, 2, 20 or 200 μg/L for 30 days, then transferred to methomyl-free water for 18 days. E2 , T, 11-KTand VTG in serum were examined. There were no significant changes in all the parameters in serum of tilapia exposed to 0.2 μg/L and 2 μg/L methomyl compared to the control. However, 20 μg/L and 200 μg/L have the potential to disrupt the endocrine system of male tilapia, as shown by its ability to increase VTG and E2 and decrease T and 11-KT in serum. Thus it would appear the no observed adverse effect level for sexual steroid hormones of methomyl is lower than 2 μg/L. Recovery data showed that the effects produced by 20μg/L were reversible but not at 200μg/L. Furthermore, the sensitivity of above parameters to methomyl followed the order of VTG>E2 >11-KT>T>GSI, suggesting VTG being the better biomarkers.


Cross-sectional research conducted in the Netherlands to identify relationships among the actual level of patient-centred care, the care gap (ideal vs actual care delivery) and satisfaction with care.
This study aimed to identify relationships among the actual level of patient-centred care (PCC), the care gap (ideal level of PCC vs actual care delivery) and satisfaction with care. This study was a cross-sectional survey. This study was conducted at two locations of a Dutch hospital (Nieuwegein and Leidsche Rijn Utrecht). Patients visiting the outpatient clinics for heart failure, chronic obstructive pulmonary disease (COPD) and cancer in March-May 2017 were asked to fill in a questionnaire. Inclusion criteria were diagnosis with COPD, heart failure or cancer and clinic visitation for a regular appointment. A total of 186 patients filled in the questionnaire. Outcomes evaluated were the actual level of PCC, the care gap and satisfaction with care. About half (45%) of the respondents were female, 38% had low educational levels and 31% were single. Respondents' mean age was 67.83 ± 10.02 (range, 16-94) years. Patients' experiences with actual care delivery and their conceptualisation of the ideal type of care differed significantly, representing care gaps, in all PCC dimensions. After controlling for background characteristics, patients' experiences with actual delivery and the care gap were related significantly to patients' satisfaction with care (β = 0.17 and β = - 0.41, respectively). Patients' experiences with the actual level of PCC and the care gap are important for patients' satisfaction with care.


Integrating pathway data for systems pathology.
The HumanPSD database on the complete proteomes of human, mouse and rat has been integrated with the databases TRANSFAC on gene regulation and TRANSPATH on signal transduction to provide a comprehensive systems biological platform for these organisms. As a next step, integration with PathoDB and PathoSign on pathologically relevant mutations is planned together with an extension beyond the limits of the individual cell, towards intercellular networks, by integrating the database EndoNet on hormonal networks as well. The overall aim is to come up with a platform that is suitable to provide knowledge for systems pathology, i. e. a system-wide modeling of pathological states and their development.


X-ray surface dose measurements using TLD extrapolation.
Surface dose measurements in therapeutic x-ray beams are of importance in determining the dose to the skin of patients undergoing radiotherapy. Measurements were performed in the 6-MV beam of a medical linear accelerator with LiF thermoluminescence dosimeters (TLD) using a solid water phantom. TLD chips (surface area 3.17 x 3.17 cm2) of three different thicknesses (0.230, 0.099, and 0.038 g/cm2) were used to extrapolate dose readings to an infinitesimally thin layer of LiF. This surface dose was measured for field sizes ranging from 1 x 1 cm2 to 40 x 40 cm2. The surface dose relative to maximum dose was found to be 10.0% for a field size of 5 x 5 cm2, 16.3% for 10 x 10 cm2, and 26.9% for 20 x 20 cm2. Using a 6-mm Perspex block tray in the beam increased the surface dose in these fields to 10.7%, 17.7%, and 34.2% respectively. Due to the small size of the TLD chips, TLD extrapolation is applicable also for intracavity and exit dose determinations. The technique used for in vivo dosimetry could provide clinicians information about the build up of dose up to 1-mm depth in addition to an extrapolated surface dose measurement.


Hsp90 and metal-binding J-protein family chaperones are not critically involved in cellular iron-sulfur protein assembly and iron regulation in yeast.
Systematic studies have revealed interactions between components of the Hsp90 chaperone system and Fe/S protein biogenesis or iron regulation. In addition, two chloroplast-localized DnaJ-like proteins, DJA5 and DJA6, function as specific iron donors in plastidial Fe/S protein biogenesis. Here, we used Saccharomyces cerevisiae to study the impact of both the Hsp90 chaperone and the yeast DJA5-DJA6 homologs, the essential cytosolic Ydj1, and the mitochondrial Mdj1, on cellular iron-related processes. Despite severe phenotypes induced upon depletion of these crucial proteins, there was no critical in vivo impact on Fe/S protein biogenesis or iron regulation. Importantly, unlike the plant DJA5-DJA6 iron chaperones, Ydj1 and Mdj1 did not bind iron in vivo, suggesting that these proteins use zinc for function under normal physiological conditions.


A critical scientific evaluation of a purportedly negative data report - response to Seneviratne et al. 2022.
A core principle in the pursuit of scientific knowledge is that science is self-correcting and that important results should be replicable. Hypotheses need to be reinforced, adjusted, or rejected when novel results are obtained. Replication of results confirms hypotheses and enhances their integration into scientific practice. In contrast, publication of substantiated and replicated negative findings (i.e., non-significant or opposite findings) can be the basis to reject erroneous hypotheses or develop alternative strategies for investigation. Replication is a problem in all research fields. The Psychology Reproductivity Project reported that only 36% of 'highly influential' published research in highly ranked journals were reproduced. Similar to positive data, negative data can be flawed. Errors in a negative data set can be based on methodology, statistics, conceptual defects, and flawed peer review. The peer review process has received progressive scrutiny. A large-scale review of the peer review process of manuscripts submitted to the British Medical Journal group indicated that the process could be characterized as inconsistent, inaccurate, and biased. Further analysis indicated that the peer process is easily manipulated, indicative of a failed system, is a major factor behind the lack of replication in science (acceptance of flawed manuscripts), suppresses opposing scientific evidence and views, and causes gaps in and lack of growth of science. Complicating the integrity of scientific publication is the role of Editors/Researchers. Ethical guidelines exist for major publishing houses about editorial ethics, behavior, and practice.


Transcriptional Control in Marine Copiotrophic and Oligotrophic Bacteria with Streamlined Genomes.
Bacteria often respond to environmental stimuli using transcriptional control, but this may not be the case for marine bacteria such as "Candidatus Pelagibacter ubique," a cultivated representative of the SAR11 clade, the most abundant organism in the ocean. This bacterium has a small, streamlined genome and an unusually low number of transcriptional regulators, suggesting that transcriptional control is low in Pelagibacter and limits its response to environmental conditions. Transcriptome sequencing during batch culture growth revealed that only 0.1% of protein-encoding genes appear to be under transcriptional control in Pelagibacter and in another oligotroph (SAR92) whereas >10% of genes were under transcriptional control in the copiotrophs Polaribacter sp. strain MED152 and Ruegeria pomeroyi When growth levels changed, transcript levels remained steady in Pelagibacter and SAR92 but shifted in MED152 and R. pomeroyi Transcript abundances per cell, determined using an internal RNA sequencing standard, were low (<1 transcript per cell) for all but a few of the most highly transcribed genes in all four taxa, and there was no correlation between transcript abundances per cell and shifts in the levels of transcription. These results suggest that low transcriptional control contributes to the success of Pelagibacter and possibly other oligotrophic microbes that dominate microbial communities in the oceans. Diverse heterotrophic bacteria drive biogeochemical cycling in the ocean. The most abundant types of marine bacteria are oligotrophs with small, streamlined genomes. The metabolic controls that regulate the response of oligotrophic bacteria to environmental conditions remain unclear. Our results reveal that transcriptional control is lower in marine oligotrophic bacteria than in marine copiotrophic bacteria. Although responses of bacteria to environmental conditions are commonly regulated at the level of transcription, metabolism in the most abundant bacteria in the ocean appears to be regulated by other mechanisms.


Clinical syndromes of arteriovenous malformations of the transverse-sigmoid sinus.
Arteriovenous malformations or fistulae shunting arterial blood from branches of the external and internal carotid and vertebral arteries into the transverse-sigmoid sinus may produce different clinical syndromes. The literature is reviewed with 96 patients including six personal cases. Usually these malformations have a congenital origin and only in 4% of the series was there a previous history of a severe head injury. Clinical groups are defined and the role of angiography assessed. Direct surgical approach with occlusion or removal of the vascular malformation is the treatment of choice. Possible methods of treatment by selective embolization are discussed.


Comparison of a combined nontreponemal (VDRL) and treponemal immunoblot to traditional nontreponemal and treponemal assays.
Serology is the mainstay for the diagnosis and management of patients with syphilis. Newer technologies such as immunoblotting are now available for the diagnosis of syphilis. A commercial IgM/IgG immunoblot assay that detects both nontreponemal (VDRL-Venereal Disease Research Laboratory) and treponemal antibodies was compared with standard nontreponemal and treponemal assays. The immunoblot and T. pallidum particle agglutination assay (TP-PA) were performed on 198 samples. Ninety-seven samples were Rapid plasma reagin (RPR)-positive and one hundred one were RPR-negative. Positive RPR samples were titered by VDRL. The agreement, sensitivity, and specificity of the IgM/IgG VDRL results of the immunoblot compared to RPR were 74.2% (95% CI: 67.2-80.2), 77.3% (95% CI: 70.2-83.4), and 71.3% (95% CI: 64.4-77.1), respectively. The agreement, sensitivity, and specificity of the IgM/IgG treponemal immunoblot compared to TP-PA were 100% for all parameters, if the ten equivocal results were not used in the calculation. The treponemal portion of the ViraBlot IgM/IgG immunoblot compared well with the treponemal confirmation assay and could be a useful supplemental method to fluorescent treponemal antibody or TP-PA for the confirmation of syphilis. The addition of the detection of nontreponemal antibodies to the immunoblot assay, however, may not be of added benefit to the overall assay, due to decreased sensitivity and specificity compared to standard assays.


Infectious keratitis related to overnight orthokeratology.
To report the microbial culture results, clinical course, and visual outcomes for infectious keratitis related to overnight orthokeratology. The records of patients with infectious keratitis related to overnight orthokeratology who presented to a tertiary referral center from April 2000 to March 2003 were retrospectively reviewed. Twenty patients (21 eyes) were included; 1 patient had bilateral infections. The average age of the patients was 14 years. The average period between the time the patient started the overnight orthokeratology program and the onset of infectious keratitis was 23 months. Thirteen of the 21 eyes were culture positive. Organisms cultured were Pseudomonas aeruginosa (n = 9), coagulase-negative Staphylococcus species (n = 2), Serratia marcescens (n = 1), and Acathamoeba species (n = 1). All patients responded well to medical antimicrobial treatment. Final best spectacle-corrected visual acuity ranged from 20/20 to 20/100. Infectious keratitis is a potential complication of overnight orthokeratology that may cause significant visual impairment. Parents of children who consider overnight orthokeratology should evaluate the benefit of temporary myopia reduction and the risk of infection.


Interplay of Composition, pH, and Temperature on the Conformation of Multi-stimulus-responsive Copolymer Brushes: Comparison of Experiment and Theory.
Poly(2-(2-methoxyethoxy)ethyl methacrylate) (PMEO2MA), a thermoresponsive polymer with a lower critical solution temperature of ∼28 °C, and poly(2-(diethylamino)ethyl methacrylate) (PDEA), a weak polybase with an apparent pKa of ∼7.5, have been statistically copolymerized using activators continuously regenerated via electron transfer atom transfer radical polymerization to form multi-stimulus-responsive polymer brushes. The stimulus-responsive behavior of these brushes has been investigated with ellipsometry and numerical self-consistent field (nSCF) theory. The pH- and thermoresponsive behaviors of a PDEA homopolymer brush were investigated experimentally in order to benchmark the nSCF theory calculations. nSCF theory was able to reproduce the responsive behavior of PDEA and PMEO2MA homopolymer brushes. Three copolymer compositions (90:10, 70:30, and 50:50 mol % MEO2MA:DEA) were investigated experimentally with pH ramps performed at low and high temperatures and temperature ramps performed at low and high pH. A broader range of compositions were investigated with nSCF theory and compared to the experimental results, with the nSCF calculations able to capture the general behavior of the homopolymer and copolymer brushes. The responsive behavior of each brush to a given stimulus (temperature or pH) was dependent on both the polymer composition and environment (temperature or pH). The influence of pH on the brush increased with higher DEA mol % with a copolymer brush response transitioning from temperature-dominant to pH-dominant. The temperature response of PMEO2MA was completely masked at low and high pH values by the presence of at least 30 mol % polybase in the copolymer.


X-ray line polarization of He-like Si satellite spectra in plasmas driven by high-intensity ultrashort pulsed lasers.
We present a modeling study of x-ray line polarization in plasmas driven by high-intensity, ultrashort duration pulsed lasers. Electron kinetics simulations of these transient and nonequilibrium plasmas predict non-Maxwellian and anisotropic electron distribution functions. Under these conditions, the magnetic sublevels within fine structure levels can be unequally populated which leads to the emission of polarized lines. We have developed a time-dependent, collisional-radiative atomic kinetics model of magnetic sublevels to understand the underlying processes and mechanisms leading to the formation of polarized x-ray line emission in plasmas with anisotropic electron distribution functions. The electron distribution function consists of a thermal component extracted from hydrodynamic calculations and a beam component determined by PIC simulations of the laser-plasma interaction. We focus on the polarization properties of the He-like Si satellites of the L y(alpha) line, discuss the time evolution of polarized satellite spectra, and identify suitable polarization markers that are sensitive to the anisotropy of the electron distribution function and can be used for diagnostic applications.


[Structure of Response and Dynamics of Preferred Orientation in Cat's V1 Neurons].
Preferred orientation of V1 neurons was changed during the respons time course. In order to reveal mechanisms of such changes, spike trains of single neurons to flashed bars of different orientations were studied by means of principal component and frequency-domain analysis of the spike density functions. There was found out that: 1. contribution of each of the components was dependent on the stimulus orientation. 2. the principal components of V1 neurons responses contain different kinds of transient and sustained parts and rhythmic oscillations in the theta/alpha and beta-bands. 3. There was no correlation between transient parts as well as between rhythmic oscillations within the same frequency band in different components. Taken together, the data obtained allow us to suggest that during generation of response there is a shift of dominance of the components with different orientations which determines the dynamics of the preferred orientations of V1 neurons.


Primary-care observational database study of the efficacy of GLP-1 receptor agonists and insulin in the UK.
We investigated use and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in UK practice. People starting a GLP-1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose-lowering agents were identified from The Health Information Network observational primary care database (2007-2011). Mean change in HbA1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics. Baseline characteristics of GLP-1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP-1 receptor agonist cohort was younger, had shorter diabetes duration and follow-up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose-lowering agents. Lower HbA1c reduction on GLP-1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference -1.4 (95% CI -4.1, 1.2) mmol/mol], except in the highest HbA1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference -17.8 (-28.6, -7.0) mmol/mol]. GLP-1 receptor agonist users lost weight [-4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6-month target reduction for GLP-1 receptor agonists of 11 mmol/mol (1.0%) HbA1c and 3% weight was reached by 24.9% of those continuing treatment. Those starting GLP-1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA1c reduction unless baseline HbA1c is very high. The UK 6-month GLP-1 receptor agonist target is usually not reached.


Autonomous Molecular Structure Imaging with High-Resolution Atomic Force Microscopy for Molecular Mixture Discovery.
Due to its single-molecule sensitivity, high-resolution atomic force microscopy (HR-AFM) has proved to be a valuable and uniquely advantageous tool to study complex molecular mixtures, which hold promise for developing clean energy and achieving environmental sustainability. However, significant challenges remain to achieve the full potential of the sophisticated and time-consuming experiments. Automation combined with machine learning (ML) and artificial intelligence (AI) is key to overcoming these challenges. Here we present Auto-HR-AFM, an AI tool to automatically collect HR-AFM images of petroleum-based mixtures. We trained an instance segmentation model to teach Auto-HR-AFM how to recognize features in HR-AFM images. Auto-HR-AFM then uses that information to optimize the imaging by adjusting the probe-molecule distance for each molecule in the run. Auto-HR-AFM is the initial tool that will lead to fully automated scanning probe microscopy (SPM) experiments, from start to finish. This automation will allow SPM to become a mainstream characterization technique for complex mixtures, an otherwise unattainable target.


Effect of partitioning the nonfiber carbohydrate fraction and neutral detergent fiber method on digestibility of carbohydrates by dairy cows.
Many nutrition models rely on summative equations to estimate feed and diet energy concentrations. These models partition feed into nutrient fractions and multiply the fractions by their estimated true digestibility, and the digestible mass provided by each fraction is then summed and converted to an energy value. Nonfiber carbohydrate (NFC) is used in many models. Although it behaves as a nutritionally uniform fraction, it is a heterogeneous mixture of components. To reduce the heterogeneity, we partitioned NFC into starch and residual organic matter (ROM), which is calculated as 100 - CP - LCFA - ash - starch - NDF, where crude protein (CP), long-chain fatty acids (LCFA), ash, starch, and neutral detergent fiber (NDF) are a percentage of DM. However, the true digestibility of ROM is unknown, and because NDF is contaminated with both ash and CP, those components are subtracted twice. The effect of ash and CP contamination of NDF on in vivo digestibility of NDF and ROM was evaluated using data from 2 total-collection digestibility experiments using lactating dairy cows. Digestibility of NDF was greater when it was corrected for ash and CP than without correction. Conversely, ROM apparent digestibility decreased when NDF was corrected for contamination. Although correcting for contamination statistically increased NDF digestibility, the effect was small; the average increase was 3.4%. The decrease in ROM digestibility was 7.4%. True digestibility of ROM is needed to incorporate ROM into summative equations. Data from multiple digestibility experiments (38 diets) using dairy cows were collated, and ROM concentrations were regressed on concentration of digestible ROM (ROM was calculated without adjusting for ash and CP contamination). The estimated true digestibility coefficient of ROM was 0.96 (SE = 0.021), and metabolic fecal ROM was 3.43 g/100 g of dry matter intake (SE = 0.30). Using a smaller data set (7 diets), estimated true digestibility of ROM when calculated using NDF corrected for ash and CP contamination was 0.87 (SE = 0.025), and metabolic fecal ROM was 3.76 g/100 g (SE = 0.60). Regardless of NDF method, ROM exhibited nutritional uniformity. The ROM fraction also had lower errors associated with the estimated true digestibility and its metabolic fecal fraction than did NFC. Therefore, ROM may result in more accurate estimates of available energy if integrated into models.


Growth of Children with Food Allergy .
The prevalence of food allergy in children is increasing worldwide. Strict avoidance of identified allergens from the diet is still the cornerstone of the management of food allergies. There are widespread concerns that food allergy and elimination diet may predispose children to nutrient deficiencies and growth failure. The aim of this paper was to review the current evidence on growth of children suffering from food allergy. Summarised is literature on the effects of the number and type of offending allergens, the child's age and affected organ system, as well as the importance of supervision by a dietician/nutritionist. Children suffering from food allergy are stunted at the time of diagnosis and during the elimination diets, irrespective whether or not their nutritional requirements were fulfilled, and/or were under the control of a dietician. This underscores the need for further studies to obtain more precise insight into and better understanding of the mechanisms contributing to growth failure in children suffering from food allergy. .


Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing appendectomy and non-operative management with antibiotics.
Acute appendicitis is the most common surgical diagnosis in young patients, with lifetime prevalence of about 7%. Debate remains on whether uncomplicated AA should be operated or not. Aim of this meta-analysis of randomized controlled trials was to assess current evidence on antibiotic treatment for uncomplicated AA compared to standard surgical treatment. Systematic literature search was performed using PubMed, EMBASE, Medline, Google Scholar and Cochrane Central Register of Controlled Trials databases for randomized controlled trials comparing antibiotic therapy (AT) and surgical therapy-appendectomy (ST) for uncomplicated AA. Trials were reviewed for primary outcome measures: treatment efficacy based on 1 year follow-up, recurrence at 1 year follow-up, complicated appendicitis with peritonitis identified at the time of surgical operation and post-intervention complications. Secondary outcomes were length of hospital stay and period of sick leave. Five RCTs comparing AT and ST qualified for inclusion in meta-analysis, with 1.351 patients included: 632 in AT group and 719 in ST group. Higher rate of treatment efficacy based on 1 year follow-up was found in ST group (98.3% vs 75.9%, P < 0.0001), recurrence at 1 year was reported in 22.5% of patients treated with antibiotics. Rate of complicated appendicitis with peritonitis identified at time of surgical operation was higher in AT group (19.9% vs 8.5%, P = 0.02). No statistically significant differences were found when comparing AT and ST groups for the outcomes of overall post-intervention complications (4.3% vs 10.9%, P = 0.32), post-intervention complications based on the number of patients who underwent appendectomy (15.8% vs 10.9%, P = 0.35), length of hospital stay (3.24 ± 0.40 vs 2.88 ± 0.39, P = 0.13) and period of sick leave (8.91 ± 1.28 vs 10.27 ± 0.24, P = 0.06). With significantly higher efficacy and low complication rates, appendectomy remains the most effective treatment for patients with uncomplicated AA. The subgroups of patients with uncomplicated AA where antibiotics can be more effective, should be accurately identified.


Multi-frequency bioelectrical impedance for the prediction of body water compartments: validation in different ethnic groups.
Body weight, body height and impedance at 1 kHz and at 100 kHz were measured in the fasting state in groups of healthy adult males and females from Ethiopia, China, Italy and The Netherlands. Total body water (TBW) and extracellular water (ECW) were determined by deuterium oxide and bromide dilution respectively. TBW/height and ECW/height were calculated as a measure of body build. The relation between TBW and ECW as measured by dilution technique and impedance index (height2/impedance) at 100 kHz and 1 kHz respectively was not different between the four populations. When a prediction formula for TBW and ECW from impedance index, developed in another (Dutch) population was applied to the four country groups, TBW was slightly overestimated, varying from 0.1 ± 1.8kg in the Italian group to 0.6 ± 1.8kg in the Dutch group. Also ECW was slightly but significantly overestimated, varying from 0.3 ± 0.9kg in the Dutch group to 1.1 ± 0.9kg in the Italian group. The bias for TBW was correlated with TBW/height in all country groups (correlation coefficients ranging from 0.33 to 0.56, all p<0.05) and the bias for ECW was correlated with ECW/height in all country groups (correlation coefficients ranging from 0.52 to 0.63, all p<0.05) except in the Ethiopians (r=0.23, p<0.1). Moreover, the bias for TBW and ECW was, in two of the four country groups, correlated with body water distribution (ECW/TBW). When the differences between measur 1000 ed and predicted TBW and ECW were corrected for differences in TBW/height and ECW/height and for differences in body water distribution, the bias significantly decreased and was not different from zero any more. It is concluded that multi-frequency bioelectrical impedance is an appropriate technique to predict body water compartments in populations. Difference between (ethnic) groups can be partly attributed to differences in body build.


Low-Frequency Oscillations and Control of the Motor Output.
A less precise force output impairs our ability to perform movements, learn new motor tasks, and use tools. Here we show that low-frequency oscillations in force are detrimental to force precision. We summarize the recent evidence that low-frequency oscillations in force output represent oscillations of the spinal motor neuron pool from the voluntary drive, and can be modulated by shifting power to higher frequencies. Further, force oscillations below 0.5 Hz impair force precision with increased voluntary drive, aging, and neurological disease. We argue that the low-frequency oscillations are (1) embedded in the descending drive as shown by the activation of multiple spinal motor neurons, (2) are altered with force intensity and brain pathology, and (3) can be modulated by visual feedback and motor training to enhance force precision. Thus, low-frequency oscillations in force provide insight into how the human brain regulates force precision.


Biofilm formation enhances the oxygen tolerance and invasiveness of Fusobacterium nucleatum in an oral mucosa culture model.
The present study evaluates the survival capability of Fusobacterium nucleatum strains in an aerobic environment and compares the invasive capability of F. nucleatum in biofilm and planktonic forms in an organotypic cell culture (OCC) model. Biofilms of F. nucleatum American Type Culture Collection (ATCC) 25586 or Anaerobe Helsinki Negative (AHN) 9508 were produced by culturing on semipermeable membranes on brucella agar plates. The oxygen tolerance of the F. nucleatum strains was examined by incubating 3-day-old anaerobically grown biofilms in an aerobic environment (CO(2) [5% in air] incubator) for an additional 48 hours. The OCC model was constructed by seeding keratinocytes on a fibroblast-containing collagen gel. In invasion assays, a 3-day-old anaerobically grown biofilm (and planktonic bacteria in solution as the control) was placed upside down on the top of OCC and incubated under 5% CO(2) for 24 hours. Invasion of the bacteria and morphologic changes in OCC were assessed using hematoxylin and eosin, Ki-67, and periodic acid-Schiff stainings. In biofilms, both F. nucleatum strains continuously increased their cell numbers in an aerobic environment for 48 hours. After incubating the bacterial biofilm in contact with the OCC model, F. nucleatum AHN 9508 was able to pass through the epithelial/basement membrane barrier and invade the collagen matrix. The invasiveness of biofilm F. nucleatum ATCC 25586 was limited to the epithelium. Cytotoxic effects and invasiveness of F. nucleatum on the OCC were much stronger when the bacteria were in biofilms than in the planktonic form. Biofilm formation regulates the survival and invasiveness of F. nucleatum in an aerobic environment.


Improved hidden Markov model for nosocomial infections.
We propose a novel hidden Markov model (HMM) for parameter estimation in hospital transmission models, and show that commonly made simplifying assumptions can lead to severe model misspecification and poor parameter estimates. A standard HMM that embodies two commonly made simplifying assumptions, namely a fixed patient count and binomially distributed detections is compared with a new alternative HMM that does not require these simplifying assumptions. Using simulated data, we demonstrate how each of the simplifying assumptions used by the standard model leads to model misspecification, whereas the alternative model results in accurate parameter estimates.


Modeling the sequence-dependent diffusion coefficients of short DNA molecules.
A boundary element model for the computation of sequence-dependent hydrodynamic properties of short DNA molecules is introduced. The hydrated surface is modeled as a curved tube of uniform radius with ends capped by hemispheres, and the axis of the tube is a general space curve whose length and curvature are determined locally by the sequence using a rigid basepair model of double-helical DNA with parameters based on x-ray crystallography. Diffusion coefficients for families of random and periodic DNA sequences are computed and compared with theories for straight tubes and experimental data. Our results indicate that sequence-dependent curvature can have a measurable impact on both the translational and rotational diffusion coefficients, even for relatively short fragments of lengths less than about 150 basepairs, and that previous estimates of the hydrated radius of DNA are likely to be underestimates. Moreover, our results suggest a possible method for refining the rigid basepair model parameters for DNA in solution as well as the hydrated radius.


Validation of Active Surveillance Testing for Clostridium difficile Colonization Using the cobas Cdiff Test.
Clostridium difficile infection (CDI) is not declining in the United States. Nucleic acid amplification tests (NAAT) are used as part of active surveillance testing programs to prevent health care-associated infection. The objective of this study was to validate the cobas Cdiff Test on the cobas 4800 System (cobas) within a four-hospital system using prospectively collected perirectal swabs from asymptomatic patients at admission and during monthly intensive care unit (ICU) screening in an infection control CDI reduction program. Performance of the cobas was compared to that of toxigenic culture. Each positive cobas sample and the next following negative patient swab were cultured. The study design gave 273 samples processed by both cobas (137 positive and 136 negative) and culture (one negative swab was not cultured). Discrepant analysis was performed using a second NAAT, the Xpert C. difficile Epi test (Xpert). This strategy was compared to a medical record review for antibiotic receipt that would inhibit growth of C. difficile in colonic stool. None of the cobas-negative samples were culture positive. The cobas positive predictive value was 75.2% (95% confidence interval [CI], 66.9% to 82%) and positive percent agreement was 100% (95% CI, 96.0% to 100%). Overall agreement between cobas and direct toxigenic culture was 87.6% (95% CI, 83.1% to 91%). For the cobas-positive/culture-negative (discrepant) samples, 7 Xpert-positive samples were from patients receiving inhibitory antimicrobials; only 4 of 23 Xpert-negative samples received these agents (P = 0.00006). Our results support use of the cobas as a reliable assay for an active surveillance testing program to detect asymptomatic carriers of toxigenic C. difficile.


Landscape-level approach to assess aquatic exposure via spray drift for pesticides: a case study in a Mediterranean area.
The development of methods to extract information from landscape analysis to refine risk assessment is becoming increasingly important. This paper presents results from a pesticide surface water exposure assessment at the watershed scale, based on a combination of edge of field studies, large-scale monitoring studies, and modeling activities with GIS-based landscape analysis methodologies covering an area of approximately 3200 ha surrounding the Simeto River in Sicily (Italy). The dynamic behavior of the pesticide chlorpyrifos-methyl was modeled in two different steps: calculation of the fraction of the application rate that is deposited beyond the field edge and simulation of the fate and persistence of the pesticide in the aquatic environment. Drift loads showed high spatial variability. Considering spray drift deposition as a fraction of the pesticide application rate, 60% of the results were < or = 0.02 (equal to 0.04 mg/m2). Only 8.5% of the results were above 0.5. The highly variability of the landscape factors was reflected in the results. More than 60% of the predicted pesticide concentrations were less than the limit of quantification (0.05 microg/L), affecting about 75% of the total length of the river tract analyzed. Predicted pesticide concentrations were higher than 0.1 microg/L in 23% of cases, but this corresponded to an insignificant portion of the river (1.2% of the total length). These results suggest that management options, such as increased no-spray zones, could provide further protection for surface water. These could be modeled to illustrate their overall impact. As an alternative, the introduction of a 20-m no-spray zone clearly reduced potential exposure, and 92% of the water body was protected. Estimated data are in agreement with data collected during a field monitoring study.


Conjugated Polymer-Based Photoelectrochemical Cytosensor with Turn-On Enable Signal for Sensitive Cell Detection.
In this work, a new photoelectrochemical (PEC) cytosensor was constructed by using cationic polyfluorene derivative, poly(9,9-bis(6'-(N,N,N,-trimethylammonium)hexyl)fluorene-co-alt-1,4-phenylene)bromide (PFP) as the photoelectric-responsive material for sensitive cell detection. Positive-charged PFP with high photoelectric conversion efficiency can generate robust photocurrent under light illumination. In the PEC cytosensor, 3-phosphonopropionic acid was linked to the indium tin oxide electrode, followed by modification with antiepithelial-cell-adhesion-molecule (EpCAM) antibody via amide condensation reaction. Thus, target SKBR-3 cells with overexpressed EpCAM antigen could be captured onto the electrode via the specific antibody-antigen interactions. Upon adding cationic PFP, a favorable electrostatic interaction between cationic PFP and negatively charged cell membrane led to a turn-on detection signal for target SKBR-3 cells. This new cytosensor not only exhibits good sensitivity because of the good photoelectric performance of conjugated polymers, but also offers decent selectivity to target cells by taking advantage of the specific antibody-antigen recognition.


Effect of lipid-based suspension of Epimedium koreanum Nakai extract on sexual behavior in rats.
Herba of Epimedium koreanum is used in traditional Chinese and Korean herbal medicine as a potent enhancer of erectile function. Icariin, the main active component of Epimedium koreanum, possesses many biological effects, such as improving cardiovascular function, hormone regulation, immunological function modulation, and anti-tumor activity. This study supports the traditional use of extracts from Epimedium species in erectile dysfunction. The Epimedium koreanum dry extract was suspended in wheat germ oil using lecithin and bee wax for oral administration. The effect of oral administration of two compositions (E-01 and E-02) standardized by their icariin content on the number of complete intromissions, the number of ejaculations, and the latent period of ejaculation (LPE) in rats were evaluated. E-01 and E-02 were administered orally for 10 days to the experimental animals. The control animals received olive oil for 10 days. On day 10, 0.5h after the dose was administered to male rats, one virgin female rat was placed with one male rat. The number of complete intromissions increased to 23.3+/-2.6 in the E-01 and E-02 group (dose 300 mg/kg body weight) (b.wt) and to 20.1+/-2.3 in the E-02 group (dose 750 mg/kg b.wt) compared with 15.2+/-2.4 in the control group of aged rats. The number of ejaculations increased from 1.1+/-0.3 in the control-aged group to 2.6+/-0.4 in the E-01 group. The LPE of male rats was 14.2+/-1.8 min in the control-aged group. The LPE of the aged group was reduced to 9.8+/-1.5 min, 9.8+/-1.6 min, and 11.4+/-1.8 min when treated with E-01 at a dose of 300 mg/kg b.wt, and E-02 at a dose of 300 mg/kg b.wt and 750 mg/kg b.wt, respectively. It was established that oral administration of lipid-based suspension of dry extract of Epimedium koreanum in wheat germ oil improved erectile function of aged rats.


Monaural speech intelligibility and detection in maskers with varying amounts of spectro-temporal speech features.
Speech intelligibility is strongly affected by the presence of maskers. Depending on the spectro-temporal structure of the masker and its similarity to the target speech, different masking aspects can occur which are typically referred to as energetic, amplitude modulation, and informational masking. In this study speech intelligibility and speech detection was measured in maskers that vary systematically in the time-frequency domain from steady-state noise to a single interfering talker. Male and female target speech was used in combination with maskers based on speech for the same or different gender. Observed data were compared to predictions of the speech intelligibility index, extended speech intelligibility index, multi-resolution speech-based envelope-power-spectrum model, and the short-time objective intelligibility measure. The different models served as analysis tool to help distinguish between the different masking aspects. Comparison shows that overall masking can to a large extent be explained by short-term energetic masking. However, the other masking aspects (amplitude modulation an informational masking) influence speech intelligibility as well. Additionally, it was obvious that all models showed considerable deviations from the data. Therefore, the current study provides a benchmark for further evaluation of speech prediction models.


Nematicidal activity of plant essential oils and components from coriander (Coriandrum sativum), Oriental sweetgum (Liquidambar orientalis), and valerian (Valeriana wallichii) essential oils against pine wood nematode (Bursaphelenchus xylophilus).
Commercial essential oils from 28 plant species were tested for their nematicidal activities against the pine wood nematode, Bursaphelenchus xylophilus. Good nematicidal activity against B. xylophilus was achieved with essential oils of coriander (Coriandrum sativum), Oriental sweetgum (Liquidambar orientalis), and valerian (Valeriana wallichii). Analysis by gas chromatography-mass spectrometry led to the identification of 26, 11, and 4 major compounds from coriander (Coriandrum sativum), Oriental sweetgum (Liquidambar orientalis), and valerian (Valeriana wallichii) oils, respectively. Compounds from each plant essential oil were tested individually for their nematicidal activities against the pine wood nematode. Among the compounds, benzaldehyde, trans-cinnamyl alcohol, cis-asarone, octanal, nonanal, decanal, trans-2-decenal, undecanal, dodecanal, decanol, and trans-2-decen-1-ol showed strong nematicidal activity. The essential oils described herein merit further study as potential nematicides against the pine wood nematode.


Large sessile adenomas are associated with a high prevalence of synchronous advanced adenomas.
The prevalence of synchronous neoplasia in patients with large sessile colorectal adenomas is uncertain. We conducted a retrospective single-center review of synchronous neoplastic findings in 190 consecutive patients with intact colons and single large sessile adenomas resected endoscopically. Synchronous polyps were those removed at the colonoscopy that discovered the large sessile adenoma or at any follow-up endoscopic examination within 12 months of discovery of the large sessile adenoma. Seventy-five percent of patients had at least 1 synchronous adenoma, and the 190 patients had a mean of 4 synchronous adenomas. Thirty percent of patients had > or =1 synchronous advanced adenoma (adenoma > or =1 cm in size or with high-grade dysplasia or villous elements). There were a total of 116 synchronous advanced adenomas, including 89 adenomas 10-19 mm in size and 8 that were > or =20 mm in size. Colonoscopists should be aware that patients with large sessile adenomas have a high prevalence of synchronous advanced neoplasia. Prospective study of this issue is warranted.


Economic regulation of next-generation sequencing.
Next-generation sequencing broadens the debate about appropriate regulatory oversight of genetic testing and may force scholars to move beyond familiar privacy and health and safety regulatory issues to address new problems with industry structure and economic regulation. The genetic testing industry is passing through a period of profound structural change in response to shifts in technology and in the legal environment. Making genetic testing safe and effective for consumers increasingly requires access to comprehensive genomic data infrastructures that can support accurate, state-of-the-art interpretation of genetic test results. At present, there are significant barriers to access and there is no sector-specific regulator with power to ensure appropriate data access. Without it, genetic testing will not be safe for consumers even when it is performed at CLIA-certified laboratories using tests that have been FDA-cleared or approved. This article explores the emerging structure of the genetic testing industry and describes its present economic regulatory vacuum. In view of this gap in regulation, the article explores whether generally applicable law, particularly antitrust law, may offer solutions to the industry's data access problems. It concludes that courts may have a useful role to play, particularly in Europe and other jurisdictions where the essential facilities doctrine enjoys continued vitality. After Verizon Communications v. Law Offices of Curtis V. Trinko, the role of U.S. federal courts is less certain. Congress has demonstrated willingness to address access issues as they emerged in other infrastructure industries in recent decades. This article expresses no preference between legislative and judicial solutions. Its aim is simply to highlight an emerging economic regulatory issue which, if left unresolved, presents real health and safety concerns for consumers who receive genetic tests.


Improved system for floor cleaning in health care facilities.
A new system has been developed for sanitizing floors in hospitals; this system replaces the traditional procedure of daily dusting and wet mopping with a disinfectant-detergent solution and periodic buffing . This new system relies on a sequence of procedures consisting of dust mopping using a chemically treated dust mop, machine buffing of a sprayed-on polymer treatment, and a second dust mopping . The effectiveness of the procedures was evaluated by means of surface sampling for bacterial contamination and air sampling for airborne bacteria and dust. The level of bacterial contamination on the floors was reduced by 93.6% by using the new system, compared with 79.8% by using the conventional process of dust mopping and wet mopping with a disinfectant solution. The levels of airborne bacteria during and after the individual procedures did not vary significantly from the initial level (123.6 CFU/per m3 of air). A survey of representative colonies from air samples revealed staphylococci, gram-positive bacilli, gram-positive diplococci, yeast cells, and infrequent gram-negative rods. The distribution at the conclusion of the sanitizing process was similar to that at the outset. Similarly, the levels of airborne dust measured during and after the individual procedures did not vary significantly from the initial level. When compared with the traditional method of cleaning by wet mopping , the new method was significantly more effective in removal of microbial contamination and required less labor.


Management of anterior spacing with orthodontics and prosthodontics.
Closing maxillary and mandibular diastemas is facilitated by a multidisciplinary approach involving orthodontics and prosthodontics. This case study demonstrates the management of a discrepancy in maxillary and mandibular anterior tooth widths. The problem is resolved by limited orthodontic treatment followed by porcelain laminate veneers. Anterior spacing is one of the major reasons adults seek esthetic treatment. Multidisciplinary treatment (periodontics, orthodontics and/or prosthodontics) is often indicated for an optimal result.


Association between the rs2910164 polymorphism in pre-Mir-146a sequence and thyroid carcinogenesis.
Rs2910164, a Single nucleotide polymorphism (SNP) located in the precursor microRNA sequence of miR-146a, is the only MicroRNA sequence SNP studied in papillary thyroid cancer (PTC). Association studies had been performed in US and UK-Northern European populations, but results were inconsistence. This study evaluated the association between rs2910164 and the risk of PTC as well as benign thyroid tumor (BN), and examined the clinicopathological characteristics of PTC and BN for different genotypes. This case-control study genotyped rs2910164 in 753 PTCs, 484 BNs and 760 controls in a Chinese Han population. Clinicopathological and genetic data were collected and compared. Multivariate logistic regression was performed to calculate adjusted odds ratios (ORs). There were no differences in rs2910164 genotype distributions between the three groups. PTC cases with three genotypes (CC, CG, GG) had similar clinicopathological characteristics except the existence of "para-cancer" BN (PTC/BN, P = 0.006). PTC/BN patients were older (P = 0.009), and had smaller cancer lesions (P<0.001), lower serum thyrotropin levels (1.82±1.42 vs. 2.21±1.74, P = 0.04), and lower rates of level VI lymph node metastasis (20.8% vs. 52.7%, P<0.001) and lateral neck lymph node metastasis (11.5% vs. 23.0%, P = 0.011) compared with PTC only. Then we supposed a possible progression from BN to PTC which may involve rs2910164 in and performed a multivariate logistic regression analysis of PTC/BN and BN cases to determine risk factors of this progression. Results showed that the rs2910164 GG homozygote (OR = 2.25, 95% CI 1.22-4.14, P = 0.01) was the only risk factor in this study. Rs2910164 was not associated with increased risk of PTC and BN in Chinese patients, but may play a latent role in the transformation from BN to PTC.


Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.
Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA.


Identification of microRNA biomarkers in the blood of breast cancer patients based on microRNA profiling.
Accumulating evidence indicates that human circulating microRNAs (miRNAs) could serve as diagnostic and prognostic biomarkers in various cancers. We aimed to explore novel miRNA biomarkers in the blood of breast cancer patients based on miRNA profiling. A miRCURY™ LNA Array was used to identify differentially altered miRNAs in the whole blood of breast cancer patients (n=6) and healthy controls (n=6). Levels of candidate miRNAs were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in whole blood specimens of 15 breast cancer patients and 13 age-matched healthy control individuals. The miRWalk database was used to predict miRNA targets and the DAVID tool was used to identify significant enrichment pathways. A total of 171 differentially expressed miRNAs were identified by microarray, including 169 upregulated and 2 downregulated miRNAs in breast cancer. Five upregulated miRNAs (miR-30b-5p, miR-96-5p, miR-182-5p, miR-374b-5p, and miR-942-5p) were confirmed by qRT-PCR. The areas under the receiver operating characteristic curve of miR-30b-5p, miR-96-5p, miR-182-5p, miR-374b-5p, and miR-942-5p were 0.9333, 0.7692, 0.7590, 0.8256, and 0.8128, respectively. Importantly, upregulation of these five miRNAs was observed even in patients with very early-stage breast cancer. A total of 855 genes were predicted to be targeted by the five miRNAs, and the one cut domain family member 2 gene (ONECUT2) was a shared target of the five miRNAs. Analysis of publicly available data revealed that these dysregulated miRNAs and the target genes were associated with the survival of breast cancer patients. Furthermore, the five miRNAs were significantly enriched in numerous cancer-related pathways, including "MicroRNAs in cancer", "Pathways in cancer", "FoxO signaling pathway", "Ras signaling pathway", "Rap1 signaling pathway", "MAPK signaling pathway", and "PI3K-Akt signaling pathway". Our data support the potential of the five identified miRNAs as novel biomarkers for the detection of breast cancer, and indicate that they may be involved in breast cancer development and progression.


New method ("SPAC ET") for free thyroxin in serum evaluated.
We analytically and clinically evaluated a new commercial method ("SPAC ET") for simultaneously determining total and free thyroxin in serum. We found the method to be rapid, simple, and precise. Results significantly correlated with those by "symmetric" dialysis and also agreed with the clinical data for patients with extremely low or high concentrations of thyroxin-binding globulin. On contrast, in those patients the most commonly used thyroid indexes (free thyroxin index or thyroxin:thyroxin-binding globulin ratio) failed to correctly reflect the true functional status of the thyroid.


Making clear and effective communication SOuND BETTeR for patients with communication barriers.
The consequences of ineffective communication between patients and clinicians in the ED range from frustration to significant adverse events. Unfortunately, scenarios where we are unable to understand what our patient is saying to us are common, due to a multitude of factors including acute illness, disability and patient diversity. Current communication aids can be difficult to access and use in the Emergency setting due to lack of physical resources, specific training and time. Our aim was to develop a communication tool which allowed for the rapid identification of urgent patient needs. In order to overcome current challenges, the tool had to be resource-light, quick to use and not reliant on additional staff training or patient education for its effective use. The SOuND BETTeR communication tool is a list of yes/no questions, formatted as a mnemonic, which aims to identify the most common and urgent needs of patients in the ED. As the list of potential needs is not exhaustive, the tool does not purport to replace formal communication aids in the medium and long term, but to bridge the gap often left in the ED where urgent needs must be met and more formal communication aids are not yet available. The tool can effectively and quickly identify important needs in patients with expressive communication barriers such as those with aphasia, facial trauma and on non-invasive ventilation. In addition, the tool can be modified for use in patients with non-English speaking backgrounds. At this stage the tool has not yet been prospectively validated.


A novel parameter for pulmonary blood flow during palliative procedures: velocity time integral of the pulmonary vein†.
The main goal of palliative procedures for congenital heart defects is adequate pulmonary blood flow (PBF), but precise intraoperative PBF evaluation is sometimes difficult. The purpose of this preliminary study was to investigate the usefulness of velocity time integral of the pulmonary vein (PV-VTI) measured by transoesophageal echocardiography (TOE) at the time of palliative procedure as a parameter for PBF. Case histories of 63 patients who underwent palliative procedures (bilateral pulmonary artery banding in 18 patients, main pulmonary artery banding in 22 patients and systemic-to-pulmonary artery shunt in 23 patients) and whose intraoperative PV-VTI was measured by TOE from 2011 to 2017 at our centre were retrospectively reviewed. Low-body-weight infants, cases in which cardiopulmonary bypass was used and cases that were anatomically difficult to measure were excluded. PV-VTIs measured at 4 orifices of the pulmonary veins were all significantly decreased in both the bilateral pulmonary artery banding and main pulmonary artery banding groups and increased in the systemic-to-pulmonary artery shunt group immediately after the procedure. There were significant correlations between the velocity time integrals of both right and left pulmonary veins and arterial oxygen saturation (r = 0.564 and 0.703). Nine patients (6 bilateral pulmonary artery banding and 3 systemic-to-pulmonary artery shunt) required unplanned early reoperation due to inadequate PBF; their PV-VTIs were significantly different from those of patients not requiring reoperation. No major complications related to TOE occurred postoperatively. The PV-VTI measured by TOE during palliative procedures reflected the change of PBF and could help identify patients at higher risk of early reoperation due to inadequate PBF. This parameter may be a useful additional tool for evaluating intraoperative PBF.


[Application of peloidotherapy at the early stage of rehabilitation after cerebral ischemic stroke].
The objective of the present study was to evaluate clinical efficiency of peloidotherapy in the early reconvalescence period following cerebral ischemic stroke. A rationale for the application of peloidotherapy is presented based on the results of follow-up of 60 patients (26 men and 34 women) aged from 43 to 70 years at the early stage of recovery (within 10 weeks and more after stroke). Special attention was given to clinical dynamics of the post-stroke condition and the influence of peloidotherapy on the mechanisms underlying formation of cerebral hemodynamic effects, adaptive changes in the functional systems of hemostasis and microcirculation, and development of pathophysiological cascade of metabolic processes in the brain. All therapeutic procedures were fairly well tolerated by the patients. Neither allergic reactions nor other adverse effects of the treatment were documented which testifies to the safety of peloidotherapy at the early stage of rehabilitation after cerebral ischemic stroke.


Clinical and molecular characterization of a family with autosomal recessive cornea plana.
Autosomal recessive cornea plana is characterized by a flattened corneal surface associated with hyperopia and various anterior segment abnormalities. Mutations have been detected in the keratocan gene (KERA), a member of the small leucine-rich proteoglycan family. To clinically and molecularly characterize a consanguineous family of Hispanic origin in which 3 individuals are affected with cornea plana. Clinical ophthalmic examination, including corneal topography and axial eye length measurement, was performed on 7 family members. Molecular analysis of KERA was performed on DNA from each family member who had been examined. All 3 affected individuals showed extreme flattening of the cornea (< 36 diopters [D]), normal axial eye lengths, and hyperopia greater than 6.25 D (spherical equivalent). Anterior segment abnormalities included scleralization of the cornea and central iris strands to the corneal endothelium. Affected individuals were homozygous for a novel mutation in KERA. The sequence change was found in exon 2, which results in an asparagine to aspartic acid change at codon 131. This amino acid change occurs within a highly conserved leucine-rich repeat of keratocan. The cause of disease in this family is likely to be a mutation in exon 2 of KERA. Other mutations in KERA known to cause cornea plana also fall within the region encoding the leucine-rich repeat motifs and are predicted to affect the tertiary structure of the protein. This is the first report of the identification of a mutation within KERA in a family of Hispanic origin with autosomal recessive cornea plana. Although the vast majority of cases of cornea plana are in individuals of Finnish descent, this report demonstrates the occurrence of the disease in other populations.


[Personality factors as predictors of alcohol consumption by university students].
This study aimed to verify differences in personality factors between abstainers and drinkers and between individuals with higher versus lower levels of alcohol consumption in the previous three months, and to test the predictive power of factors for any lifetime alcohol consumption and for at least monthly alcohol consumption. A total of 169 university students participated, of whom 66.7% were women, with a mean age of 21.2 years. Lifetime alcohol consumption was 90.1%; 42.3% had consumed at least twice in the previous three months; and 57.7% consumed alcohol at least monthly. Participants with less frequent consumption in the previous three months showed higher mean scores for personality factors involving socialization and achievement, while those that consumed more frequently scored higher on extroversion. A predictive model showed that increments in extroversion contributed to increased odds of drinking alcohol, while increments in achievement decreased the odds of drinking. Personality characteristics were able to distinguish between different groups of drinkers and predict the frequency of alcohol consumption.


Immunoglobulin heavy chain constant regions regulate immunity and tolerance to idiotypes of antibody variable regions.
Particular syngeneic adjuvant-free monoclonal antibodies are immunogenic and elicit antibody responses against the variable region idiotypes (Ids). We here study how heavy-chain constant regions (C(H)) regulate immune responses to Ids of free, uncomplexed monoclonal antibodies. To this end, we selected two hybridomas, called Id(3) and Id(A.01), that produce immunogenic IgM(lambda)2 directed toward 2,4,6-trinitrophenyl, and subcloned rare IgG1, IgG3, IgE, or IgA class switch variants. The purified switch variants, which possessed the Ids of their IgM progenitors, were injected repeatedly without added adjuvant into BALB/c mice, and anti-Id IgG responses were determined. These repeated injections revealed that the immunogenicity of Ids was lost by switching to IgG1 and IgG3, restored when the Fc piece of IgG1 was removed, maintained by switching to IgE and monomeric IgA, and lost in polymeric IgA. Loss of immunogenicity was associated with acquisition of Id-specific tolerogenicity, as determined by immunization challenge with Id borne by IgM. An Id borne by IgG induced tolerance when injected at least 90 days before or 3-21 days after immunization with IgM Id was begun. Ids of IgG were also tolerogenic in mice deficient in Fc(gamma)RIIB or Fc(gamma)RI + III. The results suggest that Ids that have switched to IgG and pIgA negatively control immune responses to shared Ids, including the Ids of their IgM progenitors.


A Metabolic Imaging Study of Lexical and Phonological Naming Errors in Alzheimer Disease.
Patients with Alzheimer disease (AD) produce a variety of errors on confrontation naming that indicate multiple loci of impairment along the naming process in this disease. We correlated brain hypometabolism, measured with 18fluoro-deoxy-glucose positron emission tomography, with semantic and formal errors, as well as nonwords deriving from phonological errors produced in a picture-naming test by 63 patients with AD. Findings suggest that neurodegeneration leads to: (1) phonemic errors, by interfering with phonological short-term memory, or with control over retrieval of phonological or prearticulatory representations, within the left supramarginal gyrus; (2) semantic errors, by disrupting general semantic or visual-semantic representations at the level of the left posterior middle and inferior occipitotemporal cortex, respectively; (3) formal errors, by damaging the lexical-phonological output interface in the left mid-anterior segment of middle and superior temporal gyri. This topography of semantic-lexical-phonological steps of naming is in substantial agreement with dual-stream neurocognitive models of word generation.


Application of Different Sampling Methods Combined with Metagenomic Next-Generation Sequencing to Detect Pathogens in Children with Severe Pneumonia on Mechanical Ventilation.
The aim of this study was to explore the value of applying different sampling methods combined with metagenomic next-generation sequencing (mNGS) to detect pathogens in children with severe pneumonia on mechanical ventilation. Forty children with severe pneumonia on mechanical ventilation were selected, and routine endotracheal suctioning and bronchoalveolar lavage fluid (BALF) sampling methods were performed. The diagnostic efficacy of different sampling methods combined with mNGS versus traditional etiological pathogen detection strategies was compared. The positive rate of mNGS pathogen detection after routine endotracheal suctioning and BALF sampling was higher than that of traditional etiological detection strategies (P < 0.05). There was no significant difference in the positive rates of pathogen detection by routine endotracheal suctioning + mNGS and BALF + mNGS (P > 0.05). Compared with traditional etiological detection strategies, mNGS is more efficient for diagnosing pathogens. In clinical practice, an appropriate sampling method should be selected for mNGS-based detection according to the condition of the patient. These findings could be of great importance in the diagnosis and treatment of severe pneumonia.


[Telephone assistance for neurological diseases: a systematic review].
While part of the care for neurological patients is done by telephone, it is not well known what neurological diseases and which part of that care is provided by telephone. Our goal is to find it out through a bibliographic review. References on telephone care for neurological diseases accessible through the PubMed, Embase, and Cochrane platforms have been systematically reviewed, with an unspecified start date and up to March 2022. We found 618 references, and as 219 did not pass the exclusion criteria, 399 were finally included in the review. Dementia is the area of neurology with more publications about its telephone assistance. It is followed by stroke, head trauma, multiple sclerosis, Parkinson's disease and movement disorders, epilepsy, neuromuscular disorders, and others. Dementias are the diseases with more bibliographic references on their telephone assistance despite not being the most prevalent. The telephone is frequently used to administer diagnostic scales or support caregivers and is particularly useful in diseases that limit mobility and attending a medical practice.


In rheumatoid arthritis, changes in autoantibody levels reflect intensity of immunosuppression, not subsequent treatment response.
Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies like rheumatoid factor (RF), anti-cyclic citrullinated peptide-2 (anti-CCP2), and anti-carbamylated protein (anti-CarP) antibodies. It is currently unclear whether changes in autoantibody levels are associated with disease activity/treatment outcomes and whether they are modified by treatment intensity. Therefore, we determined longitudinal changes in RA-autoantibody levels, the association between these changes and activity score (DAS) and treatment outcomes, and the effect of intensity of immunosuppressive treatment on levels. In 381 seropositive RA patients from the IMPROVED study, we measured IgG, IgM, and IgA of anti-CCP2 and anti-CarP; IgM and IgA of RF; and IgG against four citrullinated and two acetylated peptides at 4-month intervals over the first year of treatment. Following initial prednisone and methotrexate (MTX), treatment was changed every 4 months aiming for DAS < 1.6. We investigated changes in autoantibody levels following treatment escalation versus tapering, and the association of levels with DAS over time, EULAR response, and drug-free remission (DFR) ≥ 1 year. For all 14 autoantibodies, levels decreased from 0 to 4 months and then rose until 12 months. Following treatment escalation, autoantibody levels dropped markedly, while they rose following tapering: RF IgM levels, a representative autoantibody, dropped 10% after restarting prednisone and rose 15% aU/mL after tapering MTX (p < 0.0001). There was no association between autoantibody levels and DAS over time or EULAR response. Greater relative changes between 0 and 12 months did not predict DFR (0-12-month relative change RF IgM, - 39% for no DFR (n = 126) and - 16% for DFR (n = 18)). Changes in RA-autoantibody levels are not associated with DAS or long-term treatment response, but reflect intensity of immunosuppression. This suggests that autoantibody levels are modifiable by current therapies, but that modifying levels is in itself of limited clinical relevance. ISRCTN11916566 . Registered on 7 November 2006.


Rigid thinking about deformables: do children sometimes overgeneralize the shape bias?
Young children learning English are biased to attend to the shape of solid rigid objects when learning novel names. This study seeks further understanding of the processes that support this behavior by examining a previous finding that three-year-old children are also biased to generalize novel names for objects made from deformable materials by shape, even after the materials are made salient. In two experiments, we examined the noun generalizations of 72 two-, three- and four-year-old children with rigid and deformable stimuli. Data reveal that three-year-old, but not two- or four-year-old, children generalize names for deformable things by shape, and that this behavior is not due to the syntactic context of the task. We suggest this behavior is an overgeneralization of three-year-old children's knowledge of how rigid things are named and discuss the implications of this finding for a developmental account of the origins of the shape bias.


Epigenetics of T lymphocytes in health and disease.
The risk of developing autoimmune diseases depends on both genetic and environmental factors, with epigenetic mechanisms of regulation potentially translating environmental cues into stable modifications in gene expression. Such stable memory of a functional state has been deciphered into a number of molecular mechanisms that collectively define the epigenetic status of a cell. In recent years, it has become increasingly clear that epigenetic modifications are highly dynamic and are able to adapt to the changing environment, with important impact on the onset and development of a number of diseases. Here, we describe some of the epigenetic mechanisms of regulation of cellular functional states in T lymphocytes, with a particular focus on DNA methylation. We will also discuss current knowledge on the role of epigenetics in autoimmunity and consider open questions in the field.


Fire and Water: Assessing Drinking Water Contamination After a Major Wildfire.
We investigated patterns of volatile organic compound (VOC) contamination in drinking water systems affected by the California 2018 Camp Fire. We performed spatial analysis of over 5000 water samples collected over a 17 month period by a local water utility, sampled tap water for VOCs in approximately 10% (N = 136) of standing homes, and conducted additional nontargeted chemical analysis of 10 samples. Benzene contamination was present in 29% of service connections to destroyed structures and 2% of service connections to standing homes. A spatial pattern was apparent. Tap water in standing homes 11 months after the fire contained low concentrations of benzene in 1% of samples, but methylene chloride was present in 19% of samples, including several above regulatory limits. Elevated methylene chloride was associated with greater distance from the water meter to the tap, longer stagnation time, and the presence of a destroyed structure on the service connection; it was inversely associated with certain trihalomethanes. Nontargeted analysis identified multiple combustion byproducts in the water at 2/10 homes. Our findings support the hypothesis that pyrolysis and smoke intrusion from depressurization contributed to the benzene contamination. Further research is needed to test the hypothesis that methylene chloride may be generated from the dehalogenation of disinfection byproducts stagnating in galvanized iron pipes.