Clinical features to distinguish meningitis among young infants at a rural Kenyan hospital.
Detection of meningitis is essential to optimise the duration and choice of antimicrobial agents to limit mortality and sequelae. In low and middle-income countries most health facilities lack laboratory capacity and rely on clinical features to empirically treat meningitis. We conducted a diagnostic validation study to investigate the performance of clinical features (fever, convulsions, irritability, bulging fontanel and temperature ≥39°C) and WHO-recommended signs (drowsiness, lethargy, unconsciousness, convulsions, bulging fontanel, irritability or a high-pitched cry) in discriminating meningitis in young infants. Retrospective cohort study. Kilifi County Hospital. Infants aged <60 days hospitalised between 2012 and 2016. Definite meningitis defined as positive cerebrospinal fluid (CSF) culture, microscopy or antigen test, or leucocytes ≥0.05 x 10∧9/L. Of 4809 infants aged <60 days included, 81 (1.7%) had definite meningitis. WHO-recommended signs had sensitivity of 58% (95% CI 47% to 69%) and specificity of 57% (95% CI 56% to 59%) for definite meningitis. Addition of history of fever improved sensitivity to 89% (95% CI 80% to 95%) but reduced specificity to 26% (95% CI 25% to 27%). Presence of ≥1 of 5 previously identified signs had sensitivity of 79% (95% CI 69% to 87%) and specificity of 51% (95% CI 50% to 53%). Despite a lower prevalence of definite meningitis, the performance of previously identified signs at admission in predicting meningitis was unchanged. Presence of history of fever improves the sensitivity of WHO-recommended signs but loses specificity. Careful evaluation, repeated assessment and capacity for lumbar puncture and CSF microscopy to exclude meningitis in most young infants with potential signs are essential to management in this age group.


Local Hotspots of Endemism or Artifacts of Incorrect Taxonomy? The Status of Microendemic Pill Millipede Species of the Genus Glomeris in Northern Italy (Diplopoda, Glomerida).
Local endemic species with their unique evolutionary history always stirred the interest of scientists. One such area especially rich in endemics is northern Italy. In case of pill millipedes of the genus Glomeris Latreille, 1803, only a single species is found in northern Europe, while 22 country-endemics alone are known from Italy. Many of these endemics, however, have not been studied in several decades; therefore we aimed to determine whether this diversity is the result of overlooked synonymies or natural processes. A focus was placed on the local endemics that are in some aspects morphologically similar to the widespread and variable G. klugii Brandt, 1833. The local endemics Glomeris larii Verhoeff, 1921, G. primordialis Verhoeff, 1930, G. oblongoguttata Verhoeff, 1894, G. oropensis Verhoeff, 1936, G. transalpina Koch, 1836, G. romana Verhoeff, 1900, G. ligurica Latzel, 1884 and G. apuana Verhoeff, 1911 were included in a molecular analysis incorporating ribosomal nuclear (28S) and mitochondrial (COI) genes. Individuals were sequenced and compared to 31 specimens from 18 localities of G. klugii. The final dataset included 657 base pairs for 56 terminals in the COI, and 14 terminals with 1068 base pairs in the combined 28S and COI analysis. Our analysis shows intraspecific distances of up to 5% in the COI gene in G. klugii that are not strictly correlated to geography or color pattern. G. larii is discovered to be genetically and morphologically identical to G. klugii and is synonymised with the latter. Interspecific distances in our dataset vary between 6.7 to 15.9%, with the lowest (6.7-9.0%) between G. primordialis and G. klugii. Our analysis confirms the species status of the local endemics G. primordialis, G. oblongoguttata, G. oropensis, G. transalpina, G. ligurica and G. apuana. We also confirm the synonymy of G. undulata Koch, 1844 under G. klugii. G. genuensis Latzel, 1886 is indistinguishable from G. ligurica.


NMR spectroscopy and imaging of the neonatal brain.
Magnetic resonance spectroscopy and imaging provide unique information about the brain to the biochemist and the clinician. In particular, the ability to image metabolites other than water and to get detailed information about dynamic cellular processes (such as blood flow, blood oxygenation and cell swelling) is leading to many new insights into brain function and dysfunction. This review describes the use of old and new NMR techniques which demonstrate that mitochondrial dysfunction plays an important role in the cell death that occurs following an hypoxic-ischaemic insult to the neonatal brain.


Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII.
A series of benzenesulfonamide derivatives, bearing benzimidazole moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CAs). Their binding affinities to recombinant human CA isozymes I, II, VII, XII and XIII were determined by the thermal shift assay. A group of compounds containing a benzimidazole substituent in the para position of the benzenesulfonamide ring was found to exhibit higher binding potency toward tested CAs than meta-substituted benzenesulfonamides. Some of these compounds exhibited nanomolar affinities and selectivity toward the CA isozymes tested.


Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress.
Asporin (ASPN), a small leucine-rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC-43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC-43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH-E1α, suggesting that ASPN reprograms HSC-43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC-44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN-/- mice revealed that growth of HSC-43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC-43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α-mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44-Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas.


Adult-type Diffuse Gliomas.
This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily practice of the general neurologist. The advances in molecular characterization of gliomas have translated into more accurate prognostication and tumor classification. Gliomas previously categorized by histological appearance solely as astrocytomas or oligodendrogliomas are now also defined by molecular features. Furthermore, ongoing clinical trials have incorporated these advances to tailor more effective treatments for specific glioma subtypes. Despite recent insights into the molecular aspects of gliomas, these tumors remain incurable. Care for patients with these complex tumors requires a multidisciplinary team in which the general neurologist has an important role. Efforts focus on translating the latest data into more effective therapies that can prolong survival.


Validation of Tuba1a as appropriate internal control for normalization of gene expression analysis during mouse lung development.
The expression ratio between the analysed gene and an internal control gene is the most widely used normalization method for quantitative RT-PCR (qRT-PCR) expression analysis. The ideal reference gene for a specific experiment is the one whose expression is not affected by the different experimental conditions tested. In this study, we validate the applicability of five commonly used reference genes during different stages of mouse lung development. The stability of expression of five different reference genes (Tuba1a, Actb Gapdh, Rn18S and Hist4h4) was calculated within five experimental groups using the statistical algorithm of geNorm software. Overall, Tuba1a showed the least variability in expression among the different stages of lung development, while Hist4h4 and Rn18S showed the maximum variability in their expression. Expression analysis of two lung specific markers, surfactant protein C (SftpC) and Clara cell-specific 10 kDA protein (Scgb1a1), normalized to each of the five reference genes tested here, confirmed our results and showed that incorrect reference gene choice can lead to artefacts. Moreover, a combination of two internal controls for normalization of expression analysis during lung development will increase the accuracy and reliability of results.


Fitts' Law in Tongue Movements of Repetitive Speech.
Fitts' law, perhaps the most celebrated law of human motor control, expresses a relation between the kinematic property of speed and the non-kinematic, task-specific property of accuracy. We aimed to assess whether speech movements obey this law using a metronome-driven speech elicitation paradigm with a systematic speech rate control. Specifically, using the paradigm of repetitive speech, we recorded via electromagnetic articulometry speech movement data in sequences of the form /CV…/ from 6 adult speakers. These sequences were spoken at 8 distinct rates ranging from extremely slow to extremely fast. Our results demonstrate, first, that the present paradigm of extensive metronome-driven manipulations satisfies the crucial prerequisites for evaluating Fitts' law in a subset of our elicited rates. Second, we uncover for the first time in speech evidence for Fitts' law at the faster rates and specifically beyond a participant-specific critical rate. We find no evidence for Fitts' law at the slowest metronome rates. Finally, we discuss implications of these results for models of speech.


CXCR5 polymorphisms in non-Hodgkin lymphoma risk and prognosis.
CXCR5 [chemokine (C-X-C motif) receptor 5; also known as Burkitt lymphoma receptor 1 (BCR1)] is expressed on mature B-cells, subsets of CD4+ and CD8+ T-cells, and skin-derived migratory dendritic cells. Together with its ligand, CXCL13, CXCR5 is involved in guiding B-cells into the B-cell zones of secondary lymphoid organs as well as T-cell migration. This study evaluated the role of common germline genetic variation in CXCR5 in the risk and prognosis of non-Hodgkin lymphoma (NHL) using a clinic-based study of 1,521 controls and 2,694 NHL cases including 710 chronic lymphocytic leukemia/small lymphocytic lymphoma, 586 diffuse large B-cell lymphoma (DLBCL), 588 follicular lymphoma (FL), 137 mantle cell lymphoma (MCL), 230 marginal zone lymphoma (MZL), and 158 peripheral T-cell lymphoma (PTCL). Of the ten CXCR5 tag SNPs in our study, five were associated with risk of NHL, with rs1790192 having the strongest association (OR 1.19, 95% CI 1.08-1.30; p = 0.0003). This SNP was most strongly associated with the risk of FL (OR 1.44, 95 % CI 1.25-1.66; p = 3.1 × 10(-7)), with a lower degree of association with DLBCL (OR 1.16, 95% CI 1.01-1.33; p = 0.04) and PTCL (OR 1.29, 95 % CI 1.02-1.64; p = 0.04) but no association with the risk of MCL or MZL. For FL patients that were observed as initial disease management, the number of minor alleles of rs1790192 was associated with better event-free survival (HR 0.64; 95% CI 0.47-0.87; p = 0.004). These results provide additional evidence for a role of host genetic variation in CXCR5 in lymphomagenesis, particularly for FL.


Ecological determinants of life-history evolution.
Density-dependent natural selection has been studied, empirically with laboratory populations of Drosophila melanogaster. Populations kept at very high and low population density have become differentiated with respect to important fitness-related traits. There is now some understanding of the behavioural and physiological basis of these differences. These studies have identified larval competitive ability and efficiency of food utilization as traits that are negatively correlated with respect to effects on fitness. Theory that illuminates and motivates additional research with this experimental system has been lacking. Current research has focused on models that incorporate many details of Drosophila ecology in laboratory environments.


A neural explanation of fetal heart rate patterns: A test of the polyvagal theory.
The current study applies a neurophysiological model based on the Polyvagal Theory (Porges, 1995) to interpret fetal heart rate patterns. Beat-to-beat heart rate data from 7 fetuses monitored during the first and second stages of labor were analyzed. Transitory heart rate accelerations and reduced beat-to-beat variability reliably preceded heart rate decelerations. The data are interpreted within the context of the Polyvagal Theory, which provides a plausible explanation of the neurophysiological mechanisms that mediate fetal heart rate decelerations. Specifically, it is proposed that both the transitory heart rate accelerations and the depression of the respiratory rhythm in the beat-to-beat heart rate pattern reflect a withdrawal of the vagal tone determined by myelinated vagal pathways originating in the nucleus ambiguus. Functionally, withdrawal of vagal tone originating in the nucleus ambiguus results in the cardiac pacemaker becoming vulnerable to sympathetic influences and to the more-primitive unmyelinated vagal pathways originating in the dorsal motor nucleus of the vagus, which may contribute to clinically relevant bradycardia.


X-ray emission spectroscopy of bulk liquid water in "no-man's land".
The structure of bulk liquid water was recently probed by x-ray scattering below the temperature limit of homogeneous nucleation (TH) of ∼232 K [J. A. Sellberg et al., Nature 510, 381-384 (2014)]. Here, we utilize a similar approach to study the structure of bulk liquid water below TH using oxygen K-edge x-ray emission spectroscopy (XES). Based on previous XES experiments [T. Tokushima et al., Chem. Phys. Lett. 460, 387-400 (2008)] at higher temperatures, we expected the ratio of the 1b1' and 1b1″ peaks associated with the lone-pair orbital in water to change strongly upon deep supercooling as the coordination of the hydrogen (H-) bonds becomes tetrahedral. In contrast, we observed only minor changes in the lone-pair spectral region, challenging an interpretation in terms of two interconverting species. A number of alternative hypotheses to explain the results are put forward and discussed. Although the spectra can be explained by various contributions from these hypotheses, we here emphasize the interpretation that the line shape of each component changes dramatically when approaching lower temperatures, where, in particular, the peak assigned to the proposed disordered component would become more symmetrical as vibrational interference becomes more important.


Impaired glycosylation of GmPAP15a, a root-associated purple acid phosphatase, inhibits extracellular phytate-P utilization in soybean.
Phosphorus (P) is an essential nutrient, but easily fixed in soils. Therefore, most of soil P exists in the form of inaccessible organic phosphorus (Po), particularly phytate-P. Root-associated purple acid phosphatases (PAPs) are considered to play a crucial role in phosphate (Pi) scavenging in soils. However, evidence for regulating root-associated PAPs in utilization of extracellular phytate-P remain largely unknown in plants at both transcriptional and posttranslational levels. In this study, a Pi-starvation responsive GmPAP15a was identified in soybean (Glycine max). Overexpressing GmPAP15a led to significant increases in root-associated phytase activities, as well as total P content when phytate-P was supplied as the sole P resource in soybean hairy roots. Meanwhile, mass spectrometry (MS) analysis showed GmPAP15a was glycosylated at Asn144 and Asn502 , and its glycan structures of N-linked oligosaccharide chains exhibited microheterogeneity. Moreover, two homologues of AtPHR1, GmPHR9 and GmPHR32 were found to activate GmPAP15a transcription through luciferase activity analysis. Taken together, it is strongly suggested that GmPAP15a plays a vital role in phytate-P utilization in soybean, which might be regulated at both transcriptional and glycosylation modification levels. Our results highlight the GmPHR9/GmPHR32-GmPAP15a signalling pathway might present, and control phytate-P utilization in soybean.


Presenilin-1 Established ER-Ca2+ Leak: a Follow Up on Its Importance for the Initial Insulin Secretion in Pancreatic Islets and β-Cells upon Elevated Glucose.
In our recent work, the importance of GSK3β-mediated phosphorylation of presenilin-1 as crucial process to establish a Ca2+ leak in the endoplasmic reticulum and, subsequently, the pre-activation of resting mitochondrial activity in β-cells was demonstrated. The present work is a follow-up and reveals the importance of GSK3β-phosphorylated presenilin-1 for responsiveness of pancreatic islets and β-cells to elevated glucose in terms of cytosolic Ca2+ spiking and insulin secretion. Freshly isolated pancreatic islets and the two pancreatic β-cell lines INS-1 and MIN-6 were used. Cytosolic Ca2+ was fluorometrically monitored using Fura-2/AM and cellular insulin content and secretion were measured by ELISA. Our data strengthened our previous findings of the existence of a presenilin-1-mediated ER-Ca2+ leak in β-cells, since a reduction of presenilin-1 expression strongly counteracted the ER Ca2+ leak. Furthermore, our data revealed that cytosolic Ca2+ spiking upon administration of high D-glucose was delayed in onset time and strongly reduced in amplitude and frequency upon siRNA-mediated knock-down of presenilin-1 or the inhibition of GSK3β in the pancreatic β-cells. Moreover, glucose-triggered initial insulin secretion disappeared by depletion from presenilin-1 and inhibition of GSK3β in the pancreatic β-cells and isolated pancreatic islets, respectively. These data complement our previous work and demonstrate that the sensitivity of pancreatic islets and β-cells to glucose illustrated as glucose-triggered cytosolic Ca2+ spiking and initial but not long-lasting insulin secretion crucially depends on a strong ER Ca2+ leak that is due to the phosphorylation of presenilin-1 by GSK3β, a phenomenon that might be involved in the development of type 2 diabetes.


Nonuniform image motion estimation using the maximum a posteriori principle.
An iterative scheme for frame-to-frame motion estimation from a pair of noisy images is established. The algorithm is developed by assuming that the Karhunen-Loeve coefficients of the motion vector waveform are zero mean and Gaussian random variables. Following the derivation of the generalized maximum likelihood (GML) algorithm, and invoking the maximum a posteriori (MAP) criterion, an iterative motion estimator is developed. A linear analysis of the algorithm is presented, and the convergence of the algorithm is discussed. Simulation experiments are performed and comparisons are made with the GML algorithm the algorithm reported by A.N. Netravali and J.D. Robbins (1979), and the scheme developed by K.P.G. Horn and G.G. Schunck (1981).


Effect of type of dietary fat on plasma and tissue cholesterol of calves.
Two experiments were conducted to examine the effects of liquid milk diets with varying proportions of beef tallow (T) and soybean oil (SBO), with and without dry feed, on cholesterol concentrations in blood and other tissues of nonruminating calves. In experiment 1, 4--10-day-old male Holstein calves were fed for 15 weeks a reconstituted milk containing 9% ot 12% dried skim milk and 2% SBO, 2% T or 3.5% T. Plasma cholesterol and cholesterol content (% of dry matter) of muscle, liver, omental fat and perirenal fat were greater (P less than 0.05) for calves fed the 2% SBO diet. No significant differences were observed in cholesterol concentrations of the aorta, coronary arteries, brain or spleen. Experiment 2 used 4--10-day-old male Holstein calves to study the effect of 2% fat diets formulated in ratios of SBO 2/3:T 1/3 and SBO 1/3:T 2/3 and to observe the effect of dry feed added to 2% T and 2% SBO diets. Tallow and SBO fed in weighted combinations affected plasma and tissue cholesterol concentrations like the predominant fat fed alone. The greatest increases in plasma and tissue cholesterol concentrations occurred in calves fed SBO diets. Dry feed supplementation decreased body cholesterol concentrations of calves fed either fat. Body weight gain of calves fed SBO was less in both experiments.


Horses do not exhibit motor bias when their balance is challenged.
In many equestrian pursuits such as dressage and show-jumping, it is important that the horse exhibits the same level of balance when ridden to the left as when ridden to the right in canter - that is, to show no motor bias. It is a long-held belief within such disciplines that to reduce bias that exists in horses and thus to enhance symmetry of performance to the left and right, the horse needs to be worked equally in both directions, although there is a lack of scientific evidence of this influencing bias. There also is little compelling evidence for either the existence or absence of motor bias in unridden (and therefore younger) or ridden (and therefore older) horses. In this study, we tested whether there was a difference in motor bias between unridden (n = 15) and ridden (n = 15) horses when their balance was challenged by cantering them in circles both to the left and to the right on the lunge. As indicators of a difference in balance between the left and right and thus as indicators of motor bias, we conducted three lunging tests - time spent in canter, whether the horse cantered on the correct lead and whether it became disunited. A grazing stance test, where the extended foreleg during grazing was recorded as the preferred forelimb, was also used to compare responses in a test where balance was not actively challenged, to the three lunging tests where balance was actively challenged. No bias was found in either the unridden or ridden groups when their balance was challenged, but ridden horses exhibited a motor bias in grazing stance - when their balance was not challenged. There was also a correlation between the responses in all three lunging tests, but none between the grazing stance test and any of the three lunging tests. We therefore conclude that neither ridden nor unridden horses are biased when their balance is challenged; thus it cannot be concluded that ambidextrous training affects an inherent bias, and that estimation of motor bias in horses is affected by the test conditions. Finally, if ridden horses are truly unbiased, strong human motor bias might be responsible for the common perception amongst riders that horses are biased.


A case report of an adjustable gastric band erosion and migration into the jejunum resulting in biliary obstruction.
Laparoscopic adjustable gastric band is a bariatric operation which has lost popularity due to its high rate of reoperation and complications such as band erosion. Erosion may be partial or complete with intragastric migration of the band. Once in the stomach lumen, the band has the potential to migrate into the small bowel. A 43-year-old male with history of morbid obesity and laparoscopic adjustable gastric band placement presented with abdominal pain secondary to biliary obstruction. Endoscopic retrograde cholangiopancreatography revealed eroded gastric band tubing into the lumen of the stomach and duodenum with resultant distortion of the ampulla. Upon surgical exploration, the band was found to have migrated into the jejunum and was removed through an enterotomy. The patient did well and was discharged home on postoperative day 8. Once completely eroded into the gastric lumen, a gastric band can migrate into the small bowel with the distance traveled being limited by the length of the connecting tube. The stretched tubing can result in distortion of the ampulla leading to biliary obstruction. Band erosion should be managed with band removal which can be completed using endoscopic, laparoscopic, or open approach. Band migration should be suspected in patients with a history of gastric band placement presenting with bowel or biliary obstruction. Its management depends on the location of the band as well as the expertise of the surgical team.


Everything you wanted to know about Markov State Models but were afraid to ask.
Simulating protein folding has been a challenging problem for decades due to the long timescales involved (compared with what is possible to simulate) and the challenges of gaining insight from the complex nature of the resulting simulation data. Markov State Models (MSMs) present a means to tackle both of these challenges, yielding simulations on experimentally relevant timescales, statistical significance, and coarse grained representations that are readily humanly understandable. Here, we review this method with the intended audience of non-experts, in order to introduce the method to a broader audience. We review the motivations, methods, and caveats of MSMs, as well as some recent highlights of applications of the method. We conclude by discussing how this approach is part of a paradigm shift in how one uses simulations, away from anecdotal single-trajectory approaches to a more comprehensive statistical approach.


The effects of ACE inhibitors on exercise capacity in the treatment of congestive heart failure.
In a double-blind, placebo-controlled, randomized, multicenter study, 225 patients with mild to moderate congestive heart failure (CHF) due to arterial hypertension and ischemic heart disease received quinapril, a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, in addition to maintenance therapy with digitalis and/or diuretics. The patients were randomized into four groups: (a) placebo; (b) quinapril, 5 mg twice daily (b.i.d.); (c) quinapril, 10 mg b.i.d.; and (d) quinapril, 20 mg b.i.d. All four groups were treated for 12 weeks. Patients receiving quinapril showed significant improvement in exercise time and NYHA functional class compared with those receiving placebo. A subset of 26 patients who received neither digitalis nor diuretics showed the same beneficial response after quinapril administration that was shown by patients who received maintenance therapy. After the double-blind trial, 189 patients entered a 1-year, open-label study in which the quinapril dosage could be titrated to a maximum of 40 mg/day (20 mg b.i.d.). The beneficial effect of quinapril was maintained over 12 months even when most patients received lower doses than in the double-blind trial.


Motor Control System for Adaptation of Healthy Individuals and Recovery of Poststroke Patients: A Case Study on Muscle Synergies.
Understanding the complex neuromuscular strategies underlying behavioral adaptation in healthy individuals and motor recovery after brain damage is essential for gaining fundamental knowledge on the motor control system. Relying on the concept of muscle synergy, which indicates the number of coordinated muscles needed to accomplish specific movements, we investigated behavioral adaptation in nine healthy participants who were introduced to a familiar environment and unfamiliar environment. We then compared the resulting computed muscle synergies with those observed in 10 moderate-stroke survivors throughout an 11-week motor recovery period. Our results revealed that computed muscle synergy characteristics changed after healthy participants were introduced to the unfamiliar environment, compared with those initially observed in the familiar environment, and exhibited an increased neural response to unpredictable inputs. The altered neural activities dramatically adjusted through behavior training to suit the unfamiliar environment requirements. Interestingly, we observed similar neuromuscular behaviors in patients with moderate stroke during the follow-up period of their motor recovery. This similarity suggests that the underlying neuromuscular strategies for adapting to an unfamiliar environment are comparable to those used for the recovery of motor function after stroke. Both mechanisms can be considered as a recall of neural pathways derived from preexisting muscle synergies, already encoded by the brain's internal model. Our results provide further insight on the fundamental principles of motor control and thus can guide the future development of poststroke therapies.


Moving Through COVID-19: Perspectives of Older Adults in the Getting Older Adults Outdoors Study.
Safety guidelines resulting from the coronavirus disease 2019 pandemic may reduce physical activity participation of older adults, particularly prefrail and frail individuals. The objective was to explore older adults' experiences with physical activity during the coronavirus disease 2019 pandemic. Using a qualitative descriptive approach, interviews were conducted with 16 older adults. Data were analyzed thematically. Two themes emerged: (a) coming to a standstill and (b) small steps. Participants described that imposed provincial and federal recommendations caused them to reduce their physical activity with negative consequences. As time progressed, participants used emerging public health knowledge about coronavirus disease 2019 to safely increase physical activity. Many participants developed strategies to remain active during the pandemic (e.g., wearing a pedometer, walking outdoors at particular times of day). Findings from this study can better inform the development of programs, clinical practice, and policy for physical activity promotion in older adults during periods of physical distancing and isolation.


Stenotrophomonas maltophilia produces an EntC-dependent catecholate siderophore that is distinct from enterobactin.
Stenotrophomonas maltophilia, a Gram-negative, multi-drug-resistant bacterium, is increasingly recognized as a key opportunistic pathogen. Thus, we embarked upon an investigation of S. maltophilia iron acquisition. To begin, we determined that the genome of strain K279a is predicted to encode a complete siderophore system, including a biosynthesis pathway, an outer-membrane receptor for ferrisiderophore, and other import and export machinery. Compatible with these data, K279a and other clinical isolates of S. maltophilia secreted a siderophore-like activity when grown at 25-37 °C in low-iron media, as demonstrated by a chrome azurol S assay, which detects iron chelation, and Arnow and Rioux assays, which detect catecholate structures. Importantly, these supernatants rescued the growth of iron-starved S. maltophilia, documenting the presence of a biologically active siderophore. A mutation in one of the predicted biosynthesis genes (entC) abolished production of the siderophore and impaired bacterial growth in low-iron conditions. Inactivation of the putative receptor gene (fepA) prevented the utilization of siderophore-containing supernatants for growth in low-iron conditions. Although the biosynthesis and import loci showed some similarity to those of enterobactin, a well-known catecholate made by enteric bacteria, the siderophore of K279a was unable to rescue the growth of an enterobactin-utilizing indicator strain, and conversely iron-starved S. maltophilia could not use purified enterobactin. Furthermore, the S. maltophilia siderophore displayed patterns of solubility in organic compounds and mobility upon thin-layer chromatography that were distinct from those of enterobactin and its derivative, salmochelin. Together, these data demonstrate that S. maltophilia secretes a novel catecholate siderophore.


Clinical aspects of xerostomia.
The physiology of saliva flow and hyposalivation is discussed. Drug-induced hyposalivation results in a higher incidence of dental caries, causes discomfort for denture wearers, and increases the risk of oral infections. Guidelines for preventing and treating drug-induced xerostomia are offered.


Characteristics of meropenem heteroresistance in Klebsiella pneumoniae carbapenemase (KPC)-producing clinical isolates of K. pneumoniae.
Meropenem heteroresistance was investigated in six apparently meropenem-susceptible, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) clinical isolates, compared with that in carbapenemase-negative, meropenem-susceptible controls. In population analyses, the KPC-KP isolates grew at meropenem concentrations of 64 to 256 microg/ml. Heteroresistant colonies had significantly elevated expression of the bla(KPC) gene compared with the native populations but did not retain heteroresistance when subcultured in drug-free media. Time-kill assays indicated that meropenem alone was not bactericidal against KPC-KP but efficiently killed the control strains.


Sodium retention in rats with liver cirrhosis is associated with increased renal abundance of NaCl cotransporter (NCC).
Liver cirrhosis is associated with enhanced renal tubular sodium retention, the mechanism of which is still debated. We hypothesized that liver cirrhosis is associated with increased expression of renal epithelial sodium transporter(s). Liver cirrhosis was induced by bile duct ligation (BDL) in rats. Steady state mRNA of ENaC subunits alpha, beta, gamma serum and glucocorticoid inducible kinase (Sgk1) were measured by TaqMan PCR in kidney homogenates at week 1, 2, 3 and 4 after BDL. Renal protein content of ENaC subunits, ubiquitin-protein-ligase Nedd4-2 and NaCl cotransporter (NCC) were assessed by western blot. Subcellular localization of ENaC subunits and NCC were analysed by immunohistochemistry. Steady state mRNA of ENaC alpha, beta and gamma were unchanged during the 4 weeks investigated, while ENaC protein decreased most prominently at week 2 (control vs BDL; alpha, -46%; beta, -81%; and gamma, -63%; n = 6). Subcellular localization of ENaC subunits was not altered at week 2. Sgk1 mRNA did not change, whereas Nedd4-2 protein was reduced by >50% 2-4 weeks after BDL. NCC protein significantly increased at week 1 (control vs BDL: +66%, n = 6, P<0.05) and decreased at week 3 (control vs BDL: -85%, n = 6, P<0.0005). Enhanced abundance of NCC was observed in the initial stage after BDL, followed by a marked decrease. ENaC transcription, translation or cell surface abundance was not increased after BDL.


Cation permeation through connexin 43 hemichannels is cooperative, competitive and saturable with parameters depending on the permeant species.
Kinetics of permeation through connexin 43-EGFP hemichannels (Cx43-EGFP HCs) were evaluated in divalent cation-free solutions, which enhance HC open probability and thus, allow measurements during initial velocity. Three cations that become fluorescent upon binding to intracellular nucleic acids [ethidium (Etd), propidium (Prd) and 4',6-diamidino-2-phenylindole (DAPI)] and Cx43-EGFP or Cx43 wild type HeLa cell transfectants (Cx43-EGFP- and Cx43-WT-HeLa cells, respectively) were used. Levels of Cx43-EGFP at the cell periphery and rate of dye uptake were directly related. The rate of uptake of each dye reached saturation consistent with a facilitated transport mechanism. Before saturation, the relation between rate of uptake and concentration of each dye was sigmoidal with Hill coefficients >1, indicating positive cooperativity of transport at low concentrations. The maximal rate of Etd uptake was not affected by the presence of DAPI and vice versa, but under each condition the apparent affinity constant of the main permeant molecule increased significantly consistent with competitive inhibition or competition for binding sites within the channel. Moreover, Cx43-EGFP and Cx43-WT HCs had similar permeability properties, indicating that EGFP bound to the C-terminal of Cx43 does not significantly alter the permeability of Cx43 HCs to positively charged molecules. Thus, competitive inhibition of permeation through hemichannels might contribute to cellular retention of essential molecules and/or uptake inhibition of toxic compounds.


The duo-drama.
A model of psychotherapy based on a 'dramatic look' is presented. It is an aspect developed from the demotorization of psycho-drama reduced to two actors Dialogue - in the sense of Plato and Buber - is looked at as action and dealt with accordingly. A pre-step of interpretation: confrontaion is used 'in flagranti' within the framework of here and now. The patient is continuously confronted with his 'action'.


BIOCHIP mosaic for the diagnosis of autoimmune bullous diseases in Chinese patients.
Autoimmune blistering diseases (AIBDs) are a group of fatal diseases with specific autoantibodies. BIOCHIP mosaic is a novel and all-in-one measure used for the rapid diagnosis of AIBDs. To evaluate the diagnostic accuracy based on BIOCHIP mosaic (FA1501-1005-60) in Chinese patients with AIBDs. Seventy-seven patients with AIBDs and 20 controls were enrolled. The BIOCHIP mosaic was performed using both serum and plasma samples. Based on BIOCHIP mosaic, the data from paired plasma and serum samples demonstrated a high degree of concordance (Cohen's kappa = 0.896-1.000) for autoantibodies against Dsg1, Dsg3, BP180-NC16A-4X, BP230gC, prickle-cell desmosomes, and pemphigoid antigens. Moreover, BIOCHIP mosaic also demonstrated a high degree of consistency for the detection rate of anti-Dsg1, Dsg3, plakins, BP180-NC16A-4X and non-collagenous domain of type VII collagen autoantibodies for the diagnosis of pemphigus foliaceus (77.3%), pemphigus vulgaris (88.6%), paraneoplastic pemphigus (100.0%), bullous pemphigoid (92.8%) and epidermolysis bullosa acquisita (99.0%), respectively. Using BIOCHIP mosaic, serum and plasma samples may be used interchangeably at 1/10 dilution. Overall, the BIOCHIP mosaic was shown to be a useful and accurate tool for the diagnosis of AIBDs.


Antigenic open reading frames from HHV-8 are present in multiple myeloma patients and normal individuals at similar frequency.
It has been proposed that the absence of a humoral response to human herpes virus 8 (HHV-8) in patients with multiple myeloma (MM) reflects strain variation or the mutation, or absence, of the antigenic regions of HHV-8 recognized in ELISA screening tests. We therefore assessed DNA sequence of three antigenic regions (ORF65, ORF73 and ORFK8.1) and the transforming hypervariable K1 ORF of HHV-8 in fresh bone marrow cells, bone marrow derived dendritic cells (DCs) and bone marrow stromal cells (BMSCs) from 12 patients with MM and 8 normal individuals. HHV-8 ORFs were detectable by nested PCR in MM patients (ORF65: 67% ORF73: 22% and K8.1: 58%), but were also surprisingly frequent in normal individuals (ORF65: 37%, ORF73: 12.5% and K8.1: 62%). HHV-8 sequences were more frequently detected in cells from BMSC and DC culture than from fresh bone marrow in MM. In contrast no HHV-8 sequences were detected in BMSC from normal individuals. Sequence analysis of ORF65 failed to demonstrate productive mutations in any MM sample. K1 genomic sequences were detected in 42% of MM and 37% of normals and exhibited 98% homology with the K1-A1 HHV-8 strain. In conclusion, our data do not support the presence of a K1-C3 strain of HHV-8 with ORF65 expression deficiency in MM patients. HHV-8 infection appears to be common in the general population when sensitive PCR is employed and multiple samples are analyzed.


Review of five paradigm papers on economic, biomedical, community, sociocultural and political perspectives in improving use of medicines.
This paper presents a review of five paradigm presentations at the first International Conference on Improving Use of Medicines (ICIUM) in Chiang Mai, Thailand, April 1-4, 1997. The paradigm papers covered economic, biomedical, community, socio-cultural and political approaches in improving the use of medicines. Salient points on problems examined by each of the paradigms, limitations of each paradigm, and challenges to be tackled are highlighted in the review from the view point of a health care provider. Some common features of the five paradigms relating to problems in medicine use have been reviewed. These features could provide bases for reaching consensus in finding solutions to some of the burning issues in the area of medicine use. It is becoming increasingly clear that there is growing concern about the way medicines are used: is it rational and in the best interest of the patients?


Taking biological rhythms into account: From study design to results reporting.
Numerous physiological and behavioral processes in living organisms exhibit strong rhythmicity and are regulated within a 24-hour cycle. These include locomotor activity and sleep patterns, feeding-fasting cycles, hormone synthesis, body temperature, and even mood and cognitive abilities, all of which are segregated into different phases throughout the day. These processes are governed by the internal timing system, a hierarchical multi-oscillator structure conserved across all organisms, from bacteria to humans. Circadian rhythms have been seen across multiple taxonomic kingdoms. In mammals, a hierarchical internal timing system is comprised of so-called central and periphereal clocks. Although these rhythms are intrinsic, they are under environmental influences, such as seasonal temperature changes, photoperiod variations, and day-night cycles. Recognizing the existence of biological rhythms and their primary external influences is crucial when designing and reporting experiments. Neglecting these physiological variations may result in inconsistent findings and misinterpretations. Thus, here we propose to incorporate biological rhythms into all stages of human and animal research, including experiment design, analysis, and reporting of findings. We also provide a flowchart to support decision-making during the design process, considering biological rhythmicity, along with a checklist outlining key factors that should be considered and documented throughout the study. This comprehensive approach not only benefits the field of chronobiology but also holds value for various other research disciplines. The insights gained from this study have the potential to enhance the validity, reproducibility, and overall quality of scientific investigations, providing valuable guidance for planning, developing, and communicating scientific studies.


Neurofilament light as an immune target for pathogenic antibodies.
Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunization with neuronal antigens such as neurofilament light (NF-L), a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, although antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.


Subepineurial injection in ultrasound-guided interscalene needle tip placement.
The neural elements of the brachial plexus between the anterior and middle scalene muscles are readily visible by ultrasound. However, the epineurium of these nerve structures is difficult to discern on ultrasound imaging because of the proximity of the scalene muscles to the nerve elements, and this may lead to unintentional subepineurial injection (SEI). To evaluate whether typical needle tip placement under ultrasound guidance results in SEI, as opposed to extraneural injection, we undertook this cadaver study. Six nonpreserved cadavers served as subjects for 10 injections. After imaging revealed the hypoechoic fascicles of the brachial plexus at the interscalene level, the tip of a 22-gauge, 5-cm short-bevel needle was inserted into a position adjacent to one of the fascicles by ultrasound guidance. At this point, 0.1 to 0.2 mL of india ink solution was injected. The brachial plexus at this level was then dissected and removed. The nerve elements discolored by the ink were removed, fixed, and stained for histologic analysis and were then examined for evidence of subepineurial ink deposition. Four nerve segments, which were unaffected by the injected ink, served as controls. These were subjected to topical india ink application for a 60-min period and were then washed, fixed, and stained for histologic analysis. In all 10 interscalene sites, ultrasonography revealed multiple hypoechoic nodules that could be traced proximally to the spine, as in live subjects. On gross analysis after dissection, the superficial nerve elements of the brachial plexus appeared to be stained by the ink. On histologic examination, 5 of 10 nerve specimens revealed ink within the epineurium (subepineurial), whereas in the other 5, it had not penetrated this barrier. The india ink did not penetrate the perineurium in any of the specimens. Among control specimens, none had evidence of subepineurial ink. In a cadaver model of needle tip placement for ultrasound-guided interscalene block, we found that SEI occurred more frequently than expected.


Introduction: glutamate transport, metabolism, and physiological responses.
The material covered in this set of articles was originally presented at Experimental Biology '98, in San Francisco, CA, on April 20, 1998. Here, the participants recount important elements of current research on the role of glutamate transporter activity in cellular signaling, metabolism, and organ function. W. A. Fairman and S. G. Amara discuss the five subtypes of human excitatory amino acid transporters, with emphasis on the EAAT4 subtype. M. A. Hediger discusses the expression and action of EAAC1 subtype of the human excitatory amino acid transporter. I. Nissim provides an overview of the significant role of pH in regulating Gln/Glu metabolism in the kidney, liver, and brain. J. D. McGivan and B. Nicholson describe some characteristics of glutamate transport regulation with regard to a specific experimental model of the bovine renal epithelial cell line NBL-1. Finally, T. C. Welbourne and J. C. Matthews introduce the "functional unit" concept of glutamate transport and how this relates to both glutamine metabolism and paracellular permeability.


The battering of informed consent.
Autonomy has been hailed as the foremost principle of bioethics, and yet patients' decisions and research subjects' voluntary participation are being subjected to frequent restrictions. It has been argued that patient care is best served by a limited form of paternalism because the doctor is better qualified to take critical decisions than the patient, who is distracted by illness. The revival of paternalism is unwarranted on two grounds: firstly, because prejudging that the sick are not fully autonomous is a biased and unsubstantial view; secondly, because the technical knowledge of healthcare professionals does not include the ethical qualifications and prerogative to decide for others.Clinical research settings are even more prone to erode subjects' autonomy than clinical settings because of the tendency and temptation to resort to such practices as shading the truth when consent to participation is sought, or waiving consent altogether when research is done in emergency settings. Instead of supporting such dubious practices with unconvincing arguments, it would seem to be the task of bioethics to insist on reinforcing autonomy.


Using Combined Tabletop and Simulation Activities to Improve Nursing Students' Attitudes About Quality Improvement: A Feasibility Study.
Nursing students' attitudes about quality improvement (QI) reflect poor understanding of its importance. In a mixed-method interventional feasibility study, students received instruction about QI processes, plus information about factors contributing to central line-associated bloodstream infection (CLABSI) rates at a hypothetical hospital. Experimental group students observed a high-fidelity simulation bedside report for a CLABSI-affected patient. Both groups independently completed tabletop QI exercises to solve the CLABSI problem and had equivalent improvement in attitudes. Joint debriefing revealed how experimental group students developed greater understanding of interrelated, system-wide contributing factors. Hybrid learning activities with tabletop and simulation positively influence students' attitudes about QI.


Effect of gadolinium chloride on liver regeneration following thioacetamide-induced necrosis in rats.
Gadolinium chloride (GD) attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. The effect of GD was studied in reference to postnecrotic liver regeneration induced in rats by thioacetamide (TA). Rats, intravenously pretreated with a single dose of GD (0.1 mmol/Kg), were intraperitoneally injected with TA (6.6 mmol/Kg). Hepatocytes were isolated from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication, and samples of blood and liver were obtained. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the time course of DNA distribution and ploidy were assayed in isolated hepatocytes. The levels of circulating cytokine TNFα was assayed in serum samples. TNFα was also determined by RT-PCR in liver extracts. The results showed that GD significantly reduced the extent of necrosis. The effect of GD induced noticeable changes in the post-necrotic regeneration, causing an increased percentage of hepatocytes in S phase of the cell cycle. Hepatocytes increased their proliferation as a result of these changes. TNFα expression and serum level were diminished in rats pretreated with GD. Thus, GD pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. No evidence of TNFα implication in this enhancement of hepatocyte proliferation and liver regeneration was found. These results demonstrate that Kupffer cells are involved in TA-induced liver damage, as well as and also in the postnecrotic proliferative liver states.


Sonographic Estimation of Umbilical Cord Cross-section Area and its Reference Value in Normal Pregnancy.
The routine antenatal sonographic investigations of the umbilical cord are limited for assessment of number of umbilical vessels and doppler evaluation of umbilical blood flow. With the advancements of the sonographic techniques it is now possible to have more detailed evaluation of umbilical cord. There exist only few literatures on assessment of umbilical cord cross-sectional area during pregnancy to provide a baseline reference value. To establish the reference intervals of cross-sectional area of the umbilical cord during gestation and to find the correlation of umbilical cord cross-sectional area with the foetal anthropometric measurements. This study was conducted among 214 normal pregnant women who underwent a routine antenatal sonogram during gestational age ranging from 24-39 weeks in the Department of Radiodiagnosis. The umbilical cord cross-sectional area was calculated at a plane immediately close to the umbilical cord insertion to the foetal abdomen. The following foetal parameters were studied: Biparietal Diameters (BPD), Head Circumference (HC), Abdominal Circumference (AC), Femur Length (FL), and Estimated Foetal weight (EFW). The relationship between foetal anthropometric measurements and umbilical cord cross sectional area was assessed using spearman rank correlation. The 5th, 10th, 50th, 90th and 95th percentiles of umbilical cord cross-sectional area were calculated for each gestational groups using polynomial regression analysis. A statistically significant correlation was observed between cross-sectional area of umbilical cord with both gestational age and foetal anthropometric parameters. The mean age of study population was 25.08±3.5 years and the mean gestational age was 34.42±2.5 weeks. We observed a strong correlation between head circumference and umbilical cord cross-sectional area. The mean umbilical cord cross-section area increases steadily with gestational age for up to 34 weeks and then it declines. Umbilical cord cross-sectional area can be easily measured and hence it can be included in routine antenatal sonographic evaluations to predict the perinatal outcome. Careful monitoring of the pregnancy is needed in case of abnormal cross-sectional area measurements.


HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.
The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl(+) human leukemia cells, including those resistant to imatinib mesylate (IM). Bcr/Abl(+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model. Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph(+) ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34(+) cells from patients with CML, but not in normal CD34(+) cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K). HDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias.


Pancreatic transplantation: Brief review of the current evidence.
Kidney transplantation is the treatment of choice for management of end-stage renal disease. However, in diabetic patients, the underlying metabolic disturbance will persist and even may get worse after isolated kidney transplantation. Pancreatic transplantation in humans was first introduced in 1966. The initial outcome was disappointing. However, this was changed after the improvement of surgical techniques together with better patient selection and the availability of potent and better-tolerated immune-suppression like cyclosporine and induction antibodies. Combined kidney and pancreas transplantation will not only solve the problem of organ failure, but it will also stabilise or even reverse the metabolic complications of diabetes. Combined kidney and pancreas transplantation have the best long term outcome in diabetic cases with renal failure. Nevertheless, at the cost of an initial increase in morbidity and risk of mortality. Other transplantation options include pancreas after kidney transplantation and islet cell transplantation. We aim by this work to explore various options which can be offered to a diabetic patient with advanced chronic kidney disease. Our work will provide a simplified, yet up-to-date information regarding the different management options for those diabetic chronic kidney failure patients.


XRCC1 polymorphisms and cancer risk: a meta-analysis of 38 case-control studies.
Several potential functional polymorphisms (Arg194Trp, Arg280His, Arg399Gln) in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in cancer risk. Our meta-analysis on total of 11,957 cancer cases and 14,174 control subjects from 38 published case-control studies showed that the odds ratio (OR) for the variant genotypes (Trp/Trp + Arg/Trp) of the Arg194Trp polymorphism, compared with the wild-type homozygote (Arg/Arg), was 0.89 [95% confidence interval (95% CI), 0.81-0.98] for all tumor types without between-study heterogeneity. Similarly, the overall risk for the combined variant genotypes (His/His + Arg/His) of the Arg280His, compared with the wild homozygote (Arg/Arg), was 1.19 (95% CI, 1.00-1.42). However, there was no main effect in either recessive or dominant modeling for the Arg399Gln, and the variant Gln/Gln homozygote was not associated with overall cancer risk (OR, 1.01; 95% CI, 0.90-1.14). The analyses suggest that XRCC1 Arg194Trp, Arg280His polymorphisms may be biomarkers of cancer susceptibility and a single larger study with thousands of subjects and tissue-specific biochemical and biological characterization is warranted to further evaluate potential gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk.


Deployment risk factors and postdeployment health profiles associated with traumatic brain injury in heavy drinking veterans.
Along with post-traumatic stress disorder (PTSD), mild traumatic brain injury (mTBI) is considered one of the "signature wounds" of combat operations in Iraq (Operation Iraqi Freedom [OIF]) and Afghanistan (Operation Enduring Freedom [OEF]), but the role of mTBI in the clinical profiles of Veterans with other comorbid forms of post-deployment psychopathology is poorly understood. The current study explored the deployment risk and postdeployment health profiles of heavy drinking OIF and OEF Veterans as a function of mTBI. Sixty-nine heavy-drinking OIF/OEF Veterans were recruited through a Veterans' Affairs Medical Center and completed questionnaires and structured interviews assessing war-zone experiences, postdeployment drinking patterns, and PTSD symptoms. Veterans with positive mTBI screens and confirmed mTBI diagnoses endorsed higher rates of combat experiences, including direct and indirect killing, and met criteria for PTSD at a higher rate than Veterans without a history of mTBI. Both PTSD and combat experiences independently predicted screening positive for mTBI, whereas only combat experiences predicted receiving a confirmed mTBI diagnosis. mTBI was not associated with any dimension of alcohol use. These results support a growing body of literature linking mTBI with PTSD.


A qualitative analysis of provider barriers and solutions to HIV testing for substance users in a small, largely rural southern state.
Integrating HIV testing programs into substance use treatment is a promising avenue to help increase access to HIV testing for rural drug users. Yet few outpatient substance abuse treatment facilities in the United States provide HIV testing. The purpose of this study was to identify barriers to incorporating HIV testing with substance use treatment from the perspectives of treatment and testing providers in Arkansas. We used purposive sampling from state directories to recruit providers at state, organization, and individual levels to participate in this exploratory study. Using an interview guide, the first and second authors conducted semistructured individual interviews in each provider's office or by telephone. All interviews were recorded, transcribed verbatim, and entered into ATLAS.ti software (ATLAS.ti Scientific Software Development GmbH, Berlin, Germany). We used constant comparison and content analysis techniques to identify codes, categories, and primary patterns in the data. The sample consisted of 28 providers throughout the state, 18 from the substance use system and 10 from the public/ community health system. We identified 7 categories of barriers: environmental constraints, policy constraints, funding constraints, organizational structure, limited inter- and intra-agency communication, burden of responsibility, and client fragility. This study presents the practice-based realities of barriers to integrating HIV testing with substance use treatment in a small, largely rural state. Some system and/or organization leaders were either unaware of or not actively pursuing external funds available to them specifically for engaging substance users in HIV testing. However, funding does not address the system-level need for coordination of resources and services at the state level.


Valerenic acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish).
Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis. Our aims were to examine the anticonvulsant properties of valerenic acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs. All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, valerenic acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with valerenic acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p < 0.05 level of significance. All treatments were compared with the untreated animals and with the other pretreatments. After exposure to pentylenetetrazole, zebrafish exhibited a series of stereotypical behaviors prior to the appearance of clonic-like movements--convulsions. Both valerenic acid and valerian extracts (aqueous and ethanolic) significantly extended the latency period to the onset of seizure (convulsion) in adult zebrafish. The ethanolic valerian extract was a more potent anticonvulsant than the aqueous extract. Valerenic acid and both valerian extracts interacted synergistically with clonazepam to extended the latency period to the onset of seizure. Phenytoin showed interaction only with the ethanolic valerian extracts. Valerenic acid and valerian extracts have anticonvulsant properties in adult zebrafish. Valerian extracts markedly enhanced the anticonvulsant effect of both clonazepam and phenytoin, and could contribute to therapy of epileptic patients.


OBT analysis method using polyethylene beads for limited quantities of animal tissue.
This study presents a polyethylene beads method for OBT determination in animal tissues and animal products for cases where the amount of water recovered by combustion is limited by sample size or quantity. In the method, the amount of water recovered after combustion is enhanced by adding tritium-free polyethylene beads to the sample prior to combustion in an oxygen bomb. The method reduces process time by allowing the combustion water to be easily collected with a pipette. Sufficient water recovery was achieved using the polyethylene beads method when 2 g of dry animal tissue or animal product were combusted with 2 g of polyethylene beads. Correction factors, which account for the dilution due to the combustion water of the beads, are provided for beef, chicken, pork, fish and clams, as well as egg, milk and cheese. The method was tested by comparing its OBT results with those of the conventional method using animal samples collected on the Chalk River Laboratories (CRL) site. The results determined that the polyethylene beads method added no more than 25% uncertainty when appropriate correction factors are used.


Evidence for alteration of EZH2, BMI1, and KDM6A and epigenetic reprogramming in human papillomavirus type 16 E6/E7-expressing keratinocytes.
A number of epigenetic alterations occur in both the virus and host cellular genomes during human papillomavirus (HPV)-associated carcinogenesis, and investigations of such alterations, including changes in chromatin proteins and histone modifications, have the potential to lead to therapeutic epigenetic reversion. We report here that transformed HPV16 E6/E7-expressing primary human foreskin keratinocytes (HFKs) (E6/E7 cells) demonstrate increased expression of the PRC2 methyltransferase EZH2 at both the mRNA and protein levels but do not exhibit the expected increase in trimethylated H3K27 (H3K27me3) compared to normal keratinocytes. In contrast, these cells show a reduction in global H3K27me3 levels in vitro, as well as upregulation of the KDM6A demethylase. We further show for the first time that transformation with the HPV16 E6 and E7 oncogenes also results in an increase in phosphorylated EZH2 serine 21 (P-EZH2-Ser21), mediated by active Akt, and in a downregulation of the PRC1 protein BMI1 in these cells. High-grade squamous cervical intraepithelial lesions also showed a loss of H3K27me3 in the presence of increased expression of EZH2. Correlating with the loss of H3K27me3, E6/E7 cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. These results suggest that the observed reduction in H3K27me3 may be due to a combination of reduced activities/levels of specific polycomb proteins and increases in demethylases. The dysregulation of multiple chromatin proteins resulting in the loss of global H3K27me3 and the transcriptional reprogramming in HPV16 E6/E7-infected cells could provide an epigenetic signature associated with risk and/or progression of HPV16-associated cancers, as well as the potential for epigenetic reversion in the future.


Effect of a passive hip exoskeleton on walking distance in neurological patients.
Severe neurodegenerative diseases such as Parkinson's disease or multiple sclerosis and acute events like stroke, spinal cord injuries, or other related pathologies have been shown to negatively impact the central and peripheral nervous systems, thus causing severe impairments to mobility. The development and utilization of exoskeletons as rehabilitation devices have shown good potential for improving patients' gait function. Ten older adults (age: 68.9 ± 9.2 yrs; height: 1.65 ± 0.08 m; mass: 71.6 ± 11.0 kg) affected by neurological diseases impacting their gait function completed a 10-session gait training protocol where they walked for 10 minutes wearing a passive exoskeleton assisting hip flexion, namely, Exoband. Results showed that participants walked a significantly longer distance in the last session of training with respect to the first session (453.1 ± 178.8 m vs 392.4 ± 135.1 m, respectively). This study indicates the potential of Exoband as an effective tool for gait rehabilitation in patients with neurological diseases. Wearable, lightweight, and low-cost devices such as the one involved in this work have the potential to improve walking distance in patients.


[The decline in moderate alcohol consumption has been associated with a decrease in heavy drinkers in Spain in the 1987-1993 period].
To examine whether the decline in alcohol consumption among moderate drinkers, which has occurred in Spain in the period 1987-1993, has been associated with changes in the proportion of heavy drinkers and abstainers. The units of analysis have been the 17 administrative regions of Spain. Alcohol consumption data have been taken from the 1987 and 1993 National Health Interview Surveys. A decrease of 10 g/week in mean alcohol consumption among male moderate drinkers has been associated with a decrease of 1.2% (95% CI: 0.7-1.7%) in the proportion of heavy drinkers. The association was also observed among women, those over and below 45 years of age, and was stronger for wine than for other alcoholic beverages. The decrease in moderate consumption of alcohol has probably had a beneficial effect on the health of the Spanish population.


Reduced genetic variation and the success of an invasive species.
Despite the severe ecological and economic damage caused by introduced species, factors that allow invaders to become successful often remain elusive. Of invasive taxa, ants are among the most widespread and harmful. Highly invasive ants are often unicolonial, forming supercolonies in which workers and queens mix freely among physically separate nests. By reducing costs associated with territoriality, unicolonial species can attain high worker densities, allowing them to achieve interspecific dominance. Here we examine the behavior and population genetics of the invasive Argentine ant (Linepithema humile) in its native and introduced ranges, and we provide a mechanism to explain its success as an invader. Using microsatellite markers, we show that a population bottleneck has reduced the genetic diversity of introduced populations. This loss is associated with reduced intraspecific aggression among spatially separate nests, and leads to the formation of interspecifically dominant supercolonies. In contrast, native populations are more genetically variable and exhibit pronounced intraspecific aggression. Although reductions in genetic diversity are generally considered detrimental, these findings provide an example of how a genetic bottleneck can lead to widespread ecological success. In addition, these results provide insights into the origin and evolution of unicoloniality, which is often considered a challenge to kin selection theory.


The Therapeutic Effect of Laparoscopic Combined with Plasma Electric Cutting Knife on Patients with Rectal Cancer and its Impact on Serum Inflammatory Factors: A Retrospective Study.
This study investigated the therapeutic effect of laparoscopic surgery combined with the plasma electric cutting knife on patients diagnosed with rectal cancer and its impact on serum inflammatory factors in the bloodstream. The researchers examined the clinical data of 85 patients who underwent laparoscopic low anterior resection for rectal cancer in our hospital from April 2020 to December 2021. The patients comprised two groups: an observation group of 40 cases and a control group of 45 cases. The CD3+, CD4+, CD8+, and CD4+/CD8+ levels in both groups were detected using flow cytometry. The levels of relevant inflammatory factors in serum were measured using an automatic biochemical analyzer. The researchers then compared the perioperative outcomes between the two groups. The observation group demonstrated significantly shorter duration for the first time passing gas after surgery (P = .029) and hospital stays (P = .002) than the control group. Both groups experienced decreased levels of CD8+ cells following treatment, with the observation group exhibiting lower levels than the control group (P < .05). After three months of treatment, both groups showed reduced levels of relevant serum inflammatory factors, TNF-α, IL-1, IL-6, and IL-8; however, the observation group was significantly lower than the control group with statistical significance (P < .05). Similarly, after three months of treatment, both groups exhibited lower levels of relevant serum electrolytes K+, Na+, and Cl-, with the observation group having lower levels than the control group (P < .05). Throughout the 12-month follow-up period, the two groups had no significant differences (P > .05) in complications such as urinary tract infection, anastomotic leakage, or anastomotic bleeding. Using a combination of laparoscopic techniques and a plasma electric cutting knife proved a highly effective surgical approach in treating rectal cancer. The method has numerous advantages, such as enhanced safety and few complications. When considering perioperative complications, it was evident that laparoscopic combined with the plasma electric cutting knife surpassed other surgical methods in treating rectal cancer.


Highly stabilized, polymer-lipid membranes prepared on silica microparticles as stationary phases for capillary chromatography.
The ability to rapidly screen complex libraries of pharmacological modulators is paramount to modern drug discovery efforts. This task is particularly challenging for agents that interact with lipid bilayers or membrane proteins due to the limited chemical, physical, and temporal stability of conventional lipid-based chromatographic stationary phases. Here, we describe the preparation and characterization of a novel stationary phase material composed of highly stable, polymeric-phospholipid bilayers self-assembled onto silica microparticles. Polymer-lipid membranes were prepared by photochemical or redox initiated polymerization of 1,2-bis[10-(2',4'-hexadieoyloxy)decanoyl]-sn-glycero-2-phosphocholine (bis-SorbPC), a synthetic, polymerizable lipid. The resulting polymerized bis-SorbPC (poly(bis-SorbPC)) stationary phases exhibited enhanced stability compared to particles coated with 1,2-dioleoyl-sn-glycero-phosphocholine (unpolymerized) phospholipid bilayers when exposed to chemical (50 mM triton X-100 or 50% acetonitrile) and physical (15 min sonication) insults after 30 days of storage. Further, poly(bis-SorbPC)-coated particles survived slurry packing into fused silica capillaries, compared to unpolymerized lipid membranes, where the lipid bilayer was destroyed during packing. Frontal chromatographic analyses of the lipophilic small molecules acetylsalicylic acid, benzoic acid, and salicylic acid showed >44% increase in retention times (P<0.0001) for all analytes on poly(bis-SorbPC)-functionalized stationary phase compared to bare silica microspheres, suggesting a lipophilic retention mechanism. Phospholipid membrane-functionalized stationary phases that withstand the chemical and physical rigors of capillary LC conditions can substantially increase the efficacy of lipid membrane affinity chromatography, and represents a key advance toward the development of robust membrane protein-functionalized chromatographic stationary phases.


Prosthetic replacement using titanium-based alloy artificial total femur incorporating its total hip and total knee joints with plasma-sprayed ceramic coating.
The authors developed a titanium-based alloy artificial total femur incorporating its total hip and total knee joints with plasma-sprayed ceramic coating 0.3 to 0.6 mm in thickness and a myriad of micropores of 50-200 microns in diameter. On the basis of reliable data obtained in the animal experiments and physical testing, the prosthesis was applied clinically with satisfactory results. This paper reports the results of two patients with a follow-up of 42-70 months.


Soluble receptor for advanced glycation end products (sRAGE) attenuates haemodynamic changes to chronic hypoxia in the mouse.
The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O2)-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentration-response curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.


Packaging of Mason-Pfizer monkey virus (MPMV) genomic RNA depends upon conserved long-range interactions (LRIs) between U5 and gag sequences.
MPMV has great potential for development as a vector for gene therapy. In this respect, precisely defining the sequences and structural motifs that are important for dimerization and packaging of its genomic RNA (gRNA) are of utmost importance. A distinguishing feature of the MPMV gRNA packaging signal is two phylogenetically conserved long-range interactions (LRIs) between U5 and gag complementary sequences, LRI-I and LRI-II. To test their biological significance in the MPMV life cycle, we introduced mutations into these structural motifs and tested their effects on MPMV gRNA packaging and propagation. Furthermore, we probed the structure of key mutants using SHAPE (selective 2'hydroxyl acylation analyzed by primer extension). Disrupting base-pairing of the LRIs affected gRNA packaging and propagation, demonstrating their significance to the MPMV life cycle. A double mutant restoring a heterologous LRI-I was fully functional, whereas a similar LRI-II mutant failed to restore gRNA packaging and propagation. These results demonstrate that while LRI-I acts at the structural level, maintaining base-pairing is not sufficient for LRI-II function. In addition, in vitro RNA dimerization assays indicated that the loss of RNA packaging in LRI mutants could not be attributed to the defects in dimerization. Our findings suggest that U5-gag LRIs play an important architectural role in maintaining the structure of the 5' region of the MPMV gRNA, expanding the crucial role of LRIs to the nonlentiviral group of retroviruses.


A Hierarchical Feature and Sample Selection Framework and Its Application for Alzheimer's Disease Diagnosis.
Classification is one of the most important tasks in machine learning. Due to feature redundancy or outliers in samples, using all available data for training a classifier may be suboptimal. For example, the Alzheimer's disease (AD) is correlated with certain brain regions or single nucleotide polymorphisms (SNPs), and identification of relevant features is critical for computer-aided diagnosis. Many existing methods first select features from structural magnetic resonance imaging (MRI) or SNPs and then use those features to build the classifier. However, with the presence of many redundant features, the most discriminative features are difficult to be identified in a single step. Thus, we formulate a hierarchical feature and sample selection framework to gradually select informative features and discard ambiguous samples in multiple steps for improved classifier learning. To positively guide the data manifold preservation process, we utilize both labeled and unlabeled data during training, making our method semi-supervised. For validation, we conduct experiments on AD diagnosis by selecting mutually informative features from both MRI and SNP, and using the most discriminative samples for training. The superior classification results demonstrate the effectiveness of our approach, as compared with the rivals.


ACE2-based capacitance sensor for rapid native SARS-CoV-2 detection in biological fluids and its correlation with real-time PCR.
The spread of the SARS-CoV-2 and its increasing threat to human health worldwide have necessitated the development of new technological tools to combat the virus. Particular emphasis is given to the development of diagnostic methods that monitor the spread of the virus rapidly and effectively. In this study, we report the development and testing of an antibody-free biosensor, based on the immobilization of ACE2 protein on the surface of gold interdigitated electrode. When the sensor was used in laboratory conditions for targeting the virus' structural spike protein, it showed a limit of detection [LOD] of 750 pg/μL/mm2. Thereafter, the response of the sensor to swab and saliva samples from hospitalized patients was examined. The virus presence in the samples was confirmed by electrical effective capacitance measurements executed on the biosensor, and correlated with real-time PCR results. We verified that the biosensor can distinguish samples that are positive for the virus from those that are negative in a total of 7 positive and 16 negative samples. In addition, the biosensor can be used for semi-quantitative measurement, since its measurements are divided into 3 areas, the negative samples, the weakly positive and the positive samples. Reproducibility of the experiments was demonstrated with at least 3 replicates and stability was tested by keeping the sensor standby for 7 days at 4 °C before repeating the experiment. This work presents a biosensor that can be used as a fast-screening test at point of care detection of SARS-CoV-2 since it needs less than 2 min to provide results and is of simple operation.


[Establishment of mechanical middle ear model and the study of the acoustic characteristics of different ossicular prostheses].
To design a tool for evaluating the sound transmission function of ossicular prosthesis and explore the impacts of ossicular prosthesis bead area and the effects of the mass of ossicular prosthesis on the sound transmission function in mechanical middle ear model. Two latex membranes were used to represent the tympanic membrane and oval window membrane. The ossicular prosthesis was fitted between the artificial tympanic membrane and oval window membrane during the test. Pure tune signals were used to stimulate the vibration of tympanic membrane. The vibration of oval window membrane was recorded by a laser Doppler vibrometer. The ossicular transmission function was evaluated by comparing the vibration velocities of oval window membrane. Two groups of titanium ossicular prosthesis with different head area and mass respectively were fitted into a mechanical middle ear model to evaluate their sound transmission functions. The feeling threshold curve of mechanical middle ear model (MMEM) was similar to the hearing threshold curve of normal person. The transmission function of the prosthesis with small head area was better than that of prostheses with large head area at frequencies 1500-4000 Hz. The small-massed prostheses functioned better at higher frequencies and the large-massed prostheses functioned better at lower frequencies. But small-massed prostheses functioned better as a whole. The MMEM was an idea tool to evaluate the transmission functions of different ossicular prostheses. Both the head area and prosthesis mass had an influence on the transmission function of ossicular prosthesis. So while designing the ossicular prosthesis or performing ossiculoplasty, both the head area and prosthesis mass should he taken into consideration.


How well can we identify the high-performing hospital?
Sharing lessons from high-performing hospitals facilitates quality improvement. High-performing hospitals have usually been identified using a small number of performance measures. The objective was to analyze how well 1,006 hospitals performed across a broader range of measures. Five measures were developed from publicly available data: adherence to processes of care, 30-day readmission rates, in-hospital mortality, efficiency, and patient satisfaction. For a subset of hospitals, the authors included two survey-based assessments of patient care quality, one by chief quality officers and one by frontline clinicians. In general, there was little correlation among the publicly available measures (r ≤ .10), though there was notable correlation between objective measures and survey-based measures (r = .23). Hospitals that performed well on a composite measure calculated from the publicly available measures were often not in the top quintile on most individual measures. This highlights the challenge in identifying high-performing hospitals to learn organizational-level best practices.


Needs of LMIC-based tobacco control advocates to counter tobacco industry policy interference: insights from semi-structured interviews.
Advocacy is vital for advancing tobacco control and there has been considerable investment in this area. While much is known about tobacco industry interference (TII), there is little research on advocates' efforts in countering TII and what they need to succeed. We sought to examine this and focused on low- and middle-income countries (LMICs) where adoption and implementation of the Framework Convention on Tobacco Control (FCTC) tend to remain slower and weaker. We interviewed 22 advocates from eight LMICs with recent progress in a tobacco control policy. We explored participants' experiences in countering TII, including the activities they undertake, challenges they encounter and how their efforts could be enhanced. We used Qualitative Description to analyse transcripts and validated findings through participant feedback. We identified four main areas of countering activities: (1) generating and compiling data and evidence, (2) accessing policymakers and restricting industry access, (3) working with media and (4) engaging in a national coalition. Each area was linked to challenges, including (1) lack of data, (2) no/weak implementation of FCTC Article 5.3, (3) industry ties with media professionals and (4) advocates' limited capacity. To address these challenges, participants suggested initiatives, including access to country-specific data, building advocates' skills in compiling and using such data in research and monitoring, and in coalition development; others aiming at training journalists to question and investigate TII; and finally, diverse interventions intended to advance a whole-of-government approach to tobacco control. Structural changes to tobacco control funding and coordination were suggested to facilitate the proposed measures. This research highlights that following years of investment in tobacco control in LMICs, there is growing confidence in addressing TII. We identify straightforward initiatives that could strengthen such efforts. This research also underscores that more structural changes to enhance tobacco control capacity building should be considered.


[Cytological studies in pulmonary pathology].
Cytological investigations of the bronchial secretion and sputum in particular have acquired in recent years a great practical significance in pulmonary pathology. It is recommended to use cytodiagnosis along with prophylactic X-ray examinations of the population to detect pulmonary pathology, in particular among individuals with a higher risk of developing cancer. A substantiated opinion is put forward that cytodiagnosis should precede examinations of patients with clinico-roentgenologically confirmed changes in the lungs.


Monitoring of dioxin-like, estrogenic and anti-androgenic activities in sediments of the Bizerta lagoon (Tunisia) by means of in vitro cell-based bioassays: contribution of low concentrations of polynuclear aromatic hydrocarbons (PAHs).
We used an array of in vitro cell-based bioassays to assess dioxin-like, estrogenic and (anti-)androgenic activities in organic extracts of sediments from the Bizerta lagoon, one of the largest Tunisian lagoons subjected to various anthropogenic and industrial pressures. The sediments were sampled both in winter and summer 2006 in 6 stations differently impacted and in one reference station located in the seawards entrance of Ghar el Melh lagoon. Chemical analyses of the 16 priority PAHs showed that the sediments were low to moderately contaminated (2-537 ng/g dry weight). By using the estrogen- (MELN) and androgen-responsive (MDA-kb2) reporter cell lines, significant estrogenic and anti-androgenic activities were detected only in the Menzel Bourguiba (MB) site, the most contaminated site, both in winter and summer. By using 7-ethoxyresorufin-O-deethylase (EROD) induction in the fish PLHC-1 cell line after both 4 and 24 h of cell exposure, dioxin-like activities were detected in all analysed samples. Dioxin-like activities were higher after 4 h exposure, and varied according to the sites and the sampling season. While highly significant correlation was observed between bioassay- and chemical analyses-derived toxic equivalents (TEQs), PAHs accounted for only a small part (up to 4%) of the detected biological activities, suggesting that other readily metabolised EROD-inducing compounds were present. This study argues for the use of short time exposure to assess biological TEQs in low contaminated samples and provides new induction equivalent factors (IEF(4h)) for 16 PAHs in the PLHC-1 cell line. Finally, our results stress the need to further characterise the nature of organic chemical contamination as well as its long-term impacts on aquatic wildlife in the Bizerta lagoon.


Residential Mobility and Reasons for Moving Among People Living With Spinal Cord Injury: Results of a Multisite Survey Study.
Residential mobility after spinal cord injury (SCI) has not been extensively examined despite a growing interest in investigating the relationship between neighborhood exposures and community living outcomes. This study explores residential mobility patterns, the annual move rate, and reasons for moving among a community-living sample of adults with SCI. A survey was conducted with 690 people at six SCI Model Systems centers in the United States between July 2017 and October 2020. The outcomes included move status in the past 12 months, move distance, and the primary reason for moving. A sample from the 2019 American Community Survey (ACS) 5-year pooled estimates was obtained for comparative analysis. Descriptive statistics were used to summarize the distributions of the outcomes and differences between the samples. The annual move rate for adults with SCI was 16.4%, and most moves were within the same county (56.6%). Recent movers were more likely to be young adults, be newly injured, and have low socioeconomic status. Housing quality, accessibility, and family were more frequently reported motivations for moving compared to employment. Young adults more commonly moved for family and accessibility, whereas middle-aged adults more commonly moved for housing quality. No notable difference was observed in the annual move rate between the SCI and the general population samples. These findings suggest an age-related pattern of residential relocation after SCI, which may be indicative an extended search for optimal living conditions that meet the housing and accessibility needs of this population.


Species- and size-related differences in dopamine-like immunoreactive clusters in the brain of Nasonia vitripennis and N. giraulti.
An extreme reduction in body size has been shown to negatively impact the memory retention level of the parasitic wasp Nasonia vitripennis. In addition, N. vitripennis and Nasonia giraulti, closely related parasitic wasps, differ markedly in the number of conditioning trials required to form long-term memory. These differences in memory dynamics may be associated with differences in the dopaminergic neurons in the Nasonia brains. Here, we used dopamine immunoreactivity to identify and count the number of cell bodies in dopaminergic clusters of normal- and small-sized N. vitripennis and normal-sized N. giraulti. We counted in total a maximum of approximately 160 dopaminergic neurons per brain. These neurons were present in 9 identifiable clusters (D1a, D1b, D2, D3, D4a, D4b, D5, D6 and D7). Our analysis revealed that N. giraulti had fewer cells in the D2 and D4a clusters but more in D4b, compared with normal-sized N. vitripennis. In addition, we found fewer cells in the D5 and D7 cluster of small-sized N. vitripennis compared to normal-sized N. vitripennis. A comparison of our findings with the literature on dopaminergic clusters in the fruit fly Drosophila melanogaster and the honey bee Apis mellifera indicates that clusters D2, D3 and D5 may play a role in memory formation in Nasonia wasps. The results from both the species comparison and the size comparison are therefore of high interest and importance for our understanding of the complex intricacies that underlie the memory dynamics of insects.


Increased expression of thymic stromal lymphopoietin and its receptor in Kimura's disease.
The objective of this study was to investigate the expression of thymic stromal lymphopoietin (TSLP) and TSLP receptor (TSLPR) in Kimura's disease (KD). Using parotid gland tissues from KD patients and control subjects, we quantified the expression levels of mRNA for TSLP, interleukin (IL)-25, IL-33, and their receptors by massively parallel sequencing. We also performed immunohistochemical analysis of TSLP and TSLPR, and counted cells immunoreactive for these proteins by the polymer immunocomplex and double immunofluorescence methods. The levels of mRNA for TSLP, TSLPR, and IL-25R, but not IL-25, IL-33, or IL-33R, were significantly elevated in parotid gland tissues from the KD group as compared to the control group. Immunohistochemical analysis revealed that TSLP- and TSLPR-positive cells were significantly increased in number in parotid gland tissues from KD patients. Double immunofluorescence staining showed that TSLP and TSLPR were localized mainly in CD68-positive macrophages and tryptase-positive mast cells, respectively. Overexpression of TSLP and TSLPR might contribute to the pathogenesis of KD through interactions between macrophages and mast cells. Regulation of TSLP/TSLPR signaling may be a potential therapeutic approach for KD.


Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents.
Second generation antipsychotics (SGAs) can increase weight gain and weight-induced insulin resistance. Recent studies have suggested weight-independent effects of certain SGAs on insulin resistance; however the magnitude of these effects and the relationship between BMI and insulin resistance in patients on SGAs are not established. To evaluate, the relationship between body mass index (BMI) and insulin resistance in 54 patients being stably treated with olanzapine (n=19), risperidone (n=16), or aripiprazole (n=19) was compared with data from a large reference population (n=201) not on SGAs. Insulin resistance was directly quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. The relationship between BMI and SSPG was similar between the SGA (r=0.58) and the reference population (r=0.50). When SSPG was standardized based on expected values for the reference population, patients on olanzapine had a higher degree of insulin resistance (mean z-score+/-SD, 0.68+/-0.9) than expected for level of BMI compared with those on aripiprazole (-0.25+/-1) and risperidone (-0.3+/-0.9), F(2,51)=6.28 (p=0.004). Thus, olanzapine group was 0.76 SD above the reference population or in the 78 percentile for insulin resistance. SSPG was correlated with fasting plasma insulin concentration (0.78 (0.64-0.87), p<0.001) but not fasting glucose concentration (0.15 (-0.13-0.40), p=0.29). In conclusion, BMI contributes a quarter to a third of the variance in insulin resistance in the SGA population similar to the reference population. Olanzapine also appears to have an independent effect on insulin resistance that is above and beyond obesity.


Prognostic impact of cancer/testis antigen expression in advanced stage multiple myeloma patients.
This study aims to analyze the expression of 14 cancer/testis (CT) antigens in multiple myeloma (MM) to identify possible prognostic markers and therapeutic targets. The expression of MAGEA1, MAGEA2, MAGEA3/6, MAGEA4, MAGEA10, MAGEA12, BAGE1, MAGEC1/CT7, the GAGE family, LAGE-1, PRAME, NY-ESO-1, SPA17 and SSX1 was studied by RT-PCR in 15 normal tissues, a pool of 10 normal bone marrow samples, 3 normal tonsils and bone marrow aspirates from 6 normal donors, 3 monoclonal gammopathies of undetermined significance (MGUS), 5 solitary plasmacytomas, 39 MM samples (95% advanced stage) and the MM cell line U266. MAGEC1/CT7 was expressed in bone marrow aspirates from one MGUS and one plasmacytoma. The frequencies at which CT antigen were found to be expressed in MM patients were MAGEC1/CT7 77%, LAGE-1 49%, MAGEA3/6 41%, MAGEA2 36%, GAGE family 33%, NY-ESO-1 33%, BAGE-1 28%, MAGEA1 26%, PRAME 23%, SSX-1 26%, MAGEA12 20.5%, MAGEA4 0%, and MAGEA10 0%. Cox's regression model showed that GAGE family expression and having >6 CT antigens expressed were independent prognostic factors when all patients were analyzed. However, MAGEC1/CT7 expression was the only independent prognostic factor when non-transplanted patients where analyzed. Based on our findings, MAGEC1/CT7, MAGEA3/6 and LAGE-1 are good candidates for immunotherapy, since together they cover 85% of our MM cases. Furthermore, expression of the GAGE family, >6 CT antigens and MAGEC1/CT7 seem to have impact on MM prognosis.