Integrated understanding of the Critical Zone processes in a subtropical karst watershed (Qingmuguan, Southwestern China): Hydrochemical and isotopic constraints.
Improving the management and protection of karst groundwater resources and addressing karst-related environmental and ecological problems still face challenges raised from the limited knowledge on the entire karstic Critical Zone (K-CZ), including soil, epikarst, the vadose and saturated zones. Particularly, there is still a lack of integrated understanding of K-CZ properties and major CZ processes across space and time. In this study, we measured and analyzed the hydrochemical and multiple stable isotopic compositions of soil water, surface- and groundwaters from various compartments of the K-CZ in a typical subtropical karst watershed - Qingmuguan (QKW), Southwestern China, in order to explore the source and spatiotemporal variations of water and solutes (C, N, S) within the K-CZ; thereby elucidating the hydrological and biogeochemical processes and their affecting factors. The results show that (i) the K-CZ of QKW is characterized by high heterogeneity and permeability, with fast and strong hydrologic variations in response to rainfall variability; (ii) water-CO2‑carbonate interactions (i.e. carbonate weathering) are remarkably active in different zones and are significantly modulated by hydrologic dynamics and seasonal change in biological activities; (iii) efficient migration of nitrate and sulfate occurs across the surface toward the saturated aquifer zone, which is affected by the source availability, elemental transformation and flow transport processes; (iv) human activities have clearly influenced groundwater quality and the natural K-CZ processes, for example, exogenic acids of anthropogenic origin (e.g. acid precipitation and nitrogenous fertilizers from crop lands) have been proven to be involved in the carbonate weathering, with a contribution of ~20%-30%. Our study highlights the strong coupling of hydrological and various biogeochemical processes and the interactive connection among various layers of K-CZ. Thus, systematical monitoring along the CZ profile and a process-based dynamic approach to elucidating climatic and anthropogenic forcing are necessary to better understand the K-CZ properties and functions.


Fat and salt contents affect the in-mouth temporal sodium release and saltiness perception of chicken sausages.
In cooked meats, sodium chloride is involved in taste, texture and flavour release. So a reduction in the salt content may have an impact on overall perception and acceptability. The aim of this study was to evaluate the influence of composition on sodium release and saltiness intensity in chicken sausages. The rheological properties of the sausages differed according to composition. Temporal sodium release and temporal saltiness intensity were evaluated by four selected subjects when eating sausages. At each time point, the effect of the salt level in sausages on sodium release was positive and highly significant. The effect of lipids on sodium release was negative. Concerning perception, the amount of salt used had a positive effect on saltiness intensity, and lipids seemed to exert a masking effect. Generally, clear relationships between salt levels, sodium release and saltiness intensity were found but the masking effect of lipids on saltiness intensity probably also involved texture or fat perception mechanisms.


Does the exposure to salinity variations and water dispersible carbon nanotubes induce oxidative stress in Hediste diversicolor?
Salinity plays a fundamental role in naturally fluctuating environments such as estuaries influencing physiological and biochemical performance of inhabiting biota. Moreover salinity is considered one of the main factors influencing nanoparticles' stability. Thus, the aim of the present paper was to show the impacts induced by different salinities (control-28 and 21) on the chemical behavior of water dispersible multi-walled carbon nanotube (MWCNTs-COOH) and the consequent toxicity in the common ragworm Hediste diversicolor, after long term exposure. Results showed a concentration-dependent toxicity in terms of energy reserves and metabolism, oxidative status and neurotoxicity. In addition, under low salinity (21), the toxicity of the carbon NMs was similar to the impacts measured under control (28), although under salinity 28 the concentrations of MWCNTs-COOH used generated greater alterations in LPO levels and antioxidant enzymes (SOD and GPx). These results demonstrate that higher salinity caused the formation of large-size aggregates, which increased the chance of physical retention, such as gravitational sedimentation, interception and straining of f-MWCNTs generating higher cell injuries than the impacts induced in polychaetes sensitivity to these contaminates due to low salinity.


Evidence-based psychotherapies for preschool children with psychiatric disorders.
The field of child and adolescent psychiatry is increasingly aware of the existence of psychiatric disorders in preschool-aged children. Concomitantly, there has been a greater understanding of both the effects of parenting on development as well as how a child's brain is shaped by the environment. There has also been a strong trend toward the use of time-limited, evidence-based therapies in adults and school-aged children, but evidence has been limited regarding the use of interventions to treat psychiatric disorders in preschoolers. In recent years, multiple research groups have worked to create effective psychotherapies for use with preschool populations, and there are also novel applications of existing psychotherapies. This review examines the latest evidence-based psychotherapies that treat preschool children with psychiatric disorders.


C3435T polymorphism of the ABCB1 gene is associated with poor clopidogrel responsiveness in a Mexican population undergoing percutaneous coronary intervention.
Clopidogrel is a pro-drug and its intestinal absorption is limited by the P-glycoprotein encoded by the ABCB1 gene. It is metabolized hepatically by cytochrome P450 enzymes encoded by CYP genes to produce an active metabolite that antagonizes the P2Y12 platelet receptor. Some patients exhibit poor clopidogrel responsiveness due to polymorphisms, resulting in thrombotic events. The aim of this study was to determine the relationship between poor clopidogrel responsiveness and the ABCB1, CYP and P2RY12 gene polymorphisms among patients undergoing percutaneous coronary intervention (PCI). Two hundred seventy-six patients who underwent PCI were included in this study. Clopidogrel responsiveness was determined via optical aggregometry in platelet-rich plasma using 10 μM ADP. Patients exhibiting a platelet aggregation response higher than 70% were classified as poor responders. The genetic polymorphisms were analyzed via real-time PCR. Poor responsiveness to clopidogrel was noted in 22.1% of the patients. The TT genotype of the C3435T polymorphism of the ABCB1 gene and omeprazole usage were each associated with poor clopidogrel responsiveness (Exp (β) 2.73, p=0.009 and Exp (β) 3.86, p=0.04, respectively). Poor clopidogrel responsiveness is associated with the TT genotype of the C3435T polymorphism of the ABCB1 gene.


[Psychological support for patients in pain].
Whether acute or chronic, pain leads to a reorganization of the subject's psychic functioning, and thus to a different interpretation of his or her own painful experience. To transform the experience, pain must be addressed in all its biopsychosocial components, and through the use of various therapeutic devices, with the hope of overcoming it.


Leaves that walk and eggs that stick: comparative functional morphology and evolution of the adhesive system of leaf insect eggs (Phasmatodea: Phylliidae).
Phylliidae are herbivorous insects exhibiting impressive cryptic masquerade and are colloquially called "walking leaves". They imitate angiosperm leaves and their eggs often resemble plant seeds structurally and in some cases functionally. Despite overall morphological similarity of adult Phylliidae, their eggs reveal a significant diversity in overall shape and exochorionic surface features. Previous studies have shown that the eggs of most Phylliidae possess a specialised attachment mechanism with hierarchical exochorionic fan-like structures (pinnae), which are mantled by a film of an adhesive secretion (glue). The folded pinnae and glue respond to water contact, with the fibrous pinnae expanding and the glue being capable of reversible liquefaction. In general, the eggs of phylliids appear to exhibit varying structures that were suggested to represent specific adaptations to the different environments the eggs are deposited in. Here, we investigated the diversity of phylliid eggs and the functional morphology of their exochorionic structure. Based on the examination of all phylliid taxa for which the eggs are known, we were able to characterise eleven different morphological types. We explored the adhesiveness of these different egg morphotypes and experimentally compared the attachment performance on a broad range of substrates with different surface roughness, surface chemistry and tested whether the adhesion is replicable after detachment in multiple cycles. Furthermore, we used molecular phylogenetic methods to reconstruct the evolutionary history of different egg types and their adhesive systems within this lineage, based on 53 phylliid taxa. Our results suggest that the egg morphology is congruent with the phylogenetic relationships within Phylliidae. The morphological differences are likely caused by adaptations to the specific environmental requirements for the particular clades, as the egg morphology has an influence on the performance regarding the surface roughness. Furthermore, we show that different pinnae and the adhesive glue evolved convergently in different species. While the evolution of the Phylliidae in general appears to be non-adaptive judging on the strong similarity of the adults and nymphs of most species, the eggs represent a stage with complex and rather diverse functional adaptations including mechanisms for both fixation and dispersal of the eggs.


Galectin-3 expression and secretion by tumor-associated macrophages in hypoxia promotes breast cancer progression.
Tumor-associated macrophages (TAMs) have been shown to be associated with poor prognosis of cancer and are predominately localized in the hypoxia regions of tumor. We demonstrated in this study that hypoxia increases the synthesis and secretion of galectin-3 by TAMs. The increased expression of galectin-3 in TAMs was seen to be associated with nucleation of transcription factor NF-κB through generation and activation of ROS and promoted tumor growth and metastasis in vitro and in mice through multiple molecular mechanisms. It was found that the TAMs-mediated promotion of tumor growth and metastasis in hypoxia was inhibited by administration of macrophage-depletion agent clodronate liposomal (CL) or galectin-3 inhibitor modified citric pectin (MCP) in orthotopic syngeneic mammary adenocarcinoma model and metastasis model. Co-administration of anti-angiogenesis agent sorafenib or bevacizumab with CL and MCP showed to cause stronger inhibition of tumor growth and metastasis than administration of each agent alone. These results indicate that hypoxia-induced galectin-3 expression and secretion from TAMs promotes tumor growth and metastasis. Targeting the actions of galectin-3 in hypoxia may be a potential therapeutic strategy for cancer treatment.


Herpes zoster and meningitis due to reactivation of varicella vaccine virus in an immunocompetent child.
Neurologic complications from varicella zoster virus (VZV) reactivation are rare. In this article, we describe a previously immunized child who developed herpes zoster with meningitis. Vaccine strain of VZV was recovered from a skin swab and the cerebrospinal fluid. Reactivation of the vaccine strain of VZV should be recognized as a potential cause of meningitis in children.


A review of corporate sustainability reporting tools (SRTs).
Sustainability reporting has been increasingly adopted by corporations worldwide given the demand of stakeholders for greater transparency on both environmental and social issues. The popularity of such reporting is evidenced by the development of a range of tools in the last two decades - Global Reporting Initiative (GRI), AA1000 and Carbon Disclosure Project (CDP) inter alia. These tools, referred to collectively as corporate sustainability reporting tools (SRTs) are important as they serve to inform the progress of corporations towards achieving sustainability goals. However, the rapid growth of corporate SRTs, with different criteria and methodology has created major complications for stakeholders. This paper makes a genuine contribution by providing a review of some of these major tools, spanning across a wide spectrum - framework, standards, ratings and indices. A critique of SRTs is also given. Institutional investors, governments, practitioners and individuals may find this review useful in terms of understanding the nature of different corporate SRTs. As well, it can serve as a useful reference for the development of the next generation of corporate SRTs.


Are the Associations of Cardiac Acceleration and Deceleration Capacities With Fine Metal Particulate in Welders Mediated by Inflammation?
The aim of this study was to investigate whether associations of acceleration capacity (AC) and deceleration capacity (DC) with metal-PM2.5 are mediated by inflammation. We obtained PM2.5, C-reactive protein, interleukin (IL)-6, 8, and 10, and electrocardiograms to compute AC and DC, from 45 male welders. Mediation analyses were performed using linear mixed models to assess associations between PM2.5 exposure, inflammatory mediator, and AC or DC, controlling for covariates. The proportion of total effect of PM2.5 on AC or DC (indirect effect) mediated through IL-6 on AC was 4% at most. Controlling for IL-6 (direct effect), a 1 mg/m increase of PM2.5 was associated with a decrease of 2.16 (95% confidence interval -0.36 to 4.69) msec in AC and a decrease of 2.51 (95% confidence interval -0.90 to 5.93) msec in DC. IL-6 may be mediating the effect of metal particulates on AC.


Leishmania amazonensis: involvement of cysteine proteinases in the killing of isolated amastigotes by L-leucine methyl ester.
L-leucine-methyl ester (Leu-OMe) kills Leishmania mexicana amazonensis amastigotes by a mechanism which requires proteolytic cleavage of the ester. N-Benzyloxycarbonyl-phenylalanyl-alanyl diazomethane (Z-Phe-AlaCHN2), a specific and irreversible inhibitor of cysteine proteinases, was used to characterize the enzymes involved in parasite destruction. It was shown that (1) amastigotes preincubated with micromolar concentrations of Z-Phe-AlaCHN2 survived challenge with Leu-OMe concentrations lethal to control parasites; (2) the proteolytic activity of 25- to 33-kDa cysteine proteinases in parasite lysates subjected to electrophoresis in gelatin-containing acrylamide gels was selectively inhibited in parasites pretreated with Z-Phe-AlaCHN2 and chased in inhibitor-free medium; and (3) cysteine proteinase activity was also inhibited in gels incubated with amino acid and dipeptide esters, possibly because the compounds were acting either as substrates (e.g., Leu-Leu-OMe) or as inhibitors (e.g., Ile-OMe) of the enzyme. The results support the involvement of low molecular weight cysteine proteinases in the destruction of amastigotes by Leu-OMe. Characterization of the structure and substrate specificity of the enzymes may permit the rational development of more selectively leishmanicidal amino acid derivatives.


Synthesis of hyocholic acid and its derivatization with sodium periodate to distinguish it from cholic acid by mass spectrometry.
Low concentrations of hyocholic acid in human serum has been linked to diabetes. Due to its important role in human health, we were interested in synthesizing hyocholic acid to explore potential biochemical properties of this bile acid. Here, a synthesis of hyocholic acid is reported from chenodeoxycholic acid. The key step was a Rubottom oxidation of a silyl enol ether intermediate to directly incorporate the oxygen at C6. Furthermore, the synthesized hyocholic acid product was treated with NaIO4 to cleave the C6-C7 bond to yield a hemiacetal at C6. This CC bond cleavage reaction using NaIO4 was used to develop an ultra-performance liquid chromatography mass spectrometry method to distinguish between a 1 to 1 mixture of hyocholic acid and cholic acid (a 12α-hydroxylated bile acid), two bile acid regioisomers with identical masses. Upon treatment of the mixture with NaIO4, hyocholic acid was selectively cleaved in the B ring (C6-C7 bond) to yield the hemiacetal that formed between the C3-hydroxy and the C6-aldehyde moiety with an m/z 405 while cholic acid remained intact with an m/z 407 in the negative electrospray ionization mode. Subsequently, a commercially available ox bile extract was treated with NaIO4 to detect bile acid derivatives by mass spectrometry. Two possible hyocholic acid derivatives conjugated to serine and gamma-glutamic semialdehyde were detected in electrospray ionization positive mode, which oxidatively cleaved with NaIO4 (m/z 496 and 522 to m/z 494 and 520, respectively).


Chronic imipramine, L-sulpiride and mianserin decrease corticotropin releasing factor levels in the rat brain.
Among clinically effective antidepressant drugs, the action mechanism of mianserin has recently been related to variations in corticotropin releasing factor (CRF) levels in the rat locus coeruleus. We describe a specific effect on CRF levels after chronic treatment with different antidepressants: mianserin (10 mg/kg), imipramine (20 mg/kg), both for 21 days, or L-sulpiride (1 mg/kg) for 15 days. While all antidepressants used greatly decreased CRF concentrations in the hypothalamus, only mianserin decreased CRF concentrations by 40% in extrahypothalamic sites. Acute treatments failed to modify CRF levels. Chronic treatment with mianserin did not affect CRF density either in the hypothalamus or the extrahypothalamic areas. This new finding may add another facet to the therapeutic action of certain antidepressants and in particular to the atypical profile of mianserin.


Riché-Cannieu Anastomosis: Structure, Function, and Clinical Significance.
Objective To define the anatomy pattern and the incidence of Riché-Cannieu anastomosis, that is, median and ulnar communication in the palmar aspect of the hand. Materials Methods A total of 80 anatomical dissections were performed on 60 hands of 30 cadavers from 1979 to 1982, and on 20 hands from 2012 to 2015. All of these procedures were performed at the Department of Anatomy of our institution. The incidence of Riché-Cannieu anastomosis and the innervation of the thenar muscles were studied. Results Riché-Cannieu anastomosis was identified in every dissected hand (100%). The extramuscular Riché-Cannieu anastomosis was recorded in 57 hands, and the intramuscular, in 19 hands. The association of extra- and intramuscular Riché-Cannieu anastomoses occurred in four hands. The ulnar component always originated from the deep branch. The anastomotic branch arising from the median nerve originated from the motor thenar branch (recurrent branch) of the median nerve in most of the observations. The median-ulnar double innervation only to the deep head of the flexor pollicis brevis was identified in 29 of 80 hands. The double innervation only of the superficial head of the flexor pollicis brevis was found in 13 hands. In 12 hands, the deep head of the flexor pollicis brevis was absent. The double innervation of the superficial and deep heads of the flexor pollicis brevis occurred in 14 hands. The oblique head of the adductor pollicis received double innervation in 12 hands. The deep head of the flexor pollicis brevis and the oblique head of adductor pollicis were doubly-innervated in nine hands. The transverse head of the adductor pollicis received double innervation in two hands. Double innervation of the deep head of the flexor pollicis brevis and the transverse head of the adductor pollicis were found in one hand. Conclusion According to the present study, Riché-Cannieu anastomosis should be considered a normal anatomical neural connection, not an anatomical variation. Knowledge of this anastomosis is essential because the presence of such neural communication may result in confusing clinical, surgical, and electromyographic findings in cases of median or ulnar damage or entrapment.


Retroviral DNA integration: lessons for transposon shuffling.
Phylogenetic comparisons of retroviral IN (integrase) protein sequences have revealed homologies that extend to the retrotransposon and bacterial transposase families and have provided evidence for at least two functional domains. The N-terminal region is characterized by a Zn-finger-like array which is conserved in retrotransposons. The central region is defined by a D,D(35)E amino acid constellation which is conserved through the retrotransposons and several bacterial IS element transposases. Mutagenesis studies and biochemical analysis of the isolated central D,D(35)E domain support our original suggestion that this region contains the catalytic center of these proteins which must all share a similar enzymatic mechanism. These, and other recent findings suggest unexpected relationships between diverse pathways of nucleic acid metabolism in eukaryotes and prokaryotes.


The effects of rearing condition on methamphetamine self-administration and cue-induced drug seeking.
Little is known about the effect of different rearing conditions on the effects of methamphetamine and whether the introduction of enriched rearing conditions at different stages of development could produce different behavioral outcomes. In Experiment 1, rats were reared in either enriched (EE) or isolated environments (IE) from PND 21 to 60. In Experiment 2, two groups of animals were handled in the same fashion as those in Experiment 1. Additional two groups were housed in IE during the first 20 or 30 days and then housed under EE for the remaining 20 or 10 days respectively. Locomotor activity and Morris Water Maze were tested. The effects of rearing conditions on methamphetamine (METH) self-administration were investigated. IE animals exhibited higher levels of locomotion than EE animals, but EE animals showed enhanced Morris water maze performance. Animals reared in IE for 30 and 40 days more readily acquired METH self-administration, compared to those reared in IE for 20 and in EE for 40 days respectively. However, the effect of rearing conditions was only seen at the lowest dose tested under FR schedule and breakpoints obtained from PR schedule were not significantly affected. Those reared in IE for 20 and EE for 40 days animals produced significantly fewer responses during the extinction and cue-induced reinstatement of METH self-administration, compared with animals reared in IE for 30 and 40 days, respectively. Rearing condition plays a significant role in locomotor activity, spatial memory and behavioral effects of METH.


From model system to clinical medicine: pathophysiologic links of common proteinopathies.
Recent clinical evidence suggests that Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB), though distinct neurological disorders, have some common pathological features that may have an impact on the clinical characteristics of these diseases. However, the question of whether these disorders have a common pathophysiology remains. Clinton and colleagues recently reported a mouse model that exhibits the combined pathologies of AD, PD, and DLB, a finding that may shed some light on this issue. Using this mouse model, the authors demonstrate that the pathogenic proteins amyloid beta, tau, and alpha-synuclein interact synergistically to enhance the accumulation of one another and accelerate cognitive decline. These data indicate shared pathogenic mechanisms and suggest the possibility that therapeutic interventions successfully targeting one of these pathogenic proteins have implications for a number of related neurodegenerative disorders.


Anxiety and sleep quality in a sample of Lebanese healthcare workers during the COVID-19 outbreak.
A cross-sectional, survey based study was conducted in order to assess mental health outcomes among healthcare workers in a private university hospital involved in the COVID-19 response in Lebanon. The main objective was to quantify symptoms of anxiety and sleep quality using self-rating scales (the State-Trait Anxiety Inventory (STAI) and Pittsburgh Sleep Quality Index (PSQI) respectively), while identifying factors that might affect those symptoms. A total of 628 healthcare workers completed the survey; 409 (66.2%) were younger than 40 years, and 441 (71.4%) were women. Of all participants, 503 (81.4%) were nurses, 52 (8.4%) were physicians and 63 (10.2%) were residents. Registered nurses, residents, women, and younger participants presented higher scores on both scales than other categories of participants. Among factors related with COVID-19, those associated with higher scores were having relatives affected by the virus (22.2%), being excessively exposed to media (12.9%), and increasing the consumption of substances/alcohol (31.2%) during this period. Factors associated with higher risk of anxiety symptoms after multivariable logistic regression analysis were: female sex, young age, poor sleep quality, and living with elderly. Our findings contribute to the understanding of the psychological wellbeing of health care workers involved in the acute COVID-19 outbreak in Lebanon.


Role of Moesin in Advanced Glycation End Products-Induced Angiogenesis of Human Umbilical Vein Endothelial Cells.
Disorders of angiogenesis are related to microangiopathies during the development of diabetic vascular complications, but the effect of advanced glycation end products (AGEs) on angiogenesis and the mechanism has not been completely unveiled. We previous demonstrated that moesin belonging to the ezrin-radixin-moesin (ERM) protein family protein played a critical role in AGE-induced hyper-permeability in human umbilical vein endothelial cells (HUVECs). Here, we investigated the impact of moesin on AGE-induced HUVEC proliferation, migration, and tubulogenesis. Silencing of moesin decreased cell motility and tube formation but not cell proliferation. It also attenuated cellular F-actin reassembly. Further, phosphorylation of threonine at the 558 amino acid residue (Thr 558) in moesin suppressed AGE-induced HUVEC proliferation, migration, and tube formation, while the activating mutation of moesin at Thr 558 enhanced HUVEC angiogenesis. Further, the inhibition of either RhoA activity by adenovirus or ROCK activation with inhibitor Y27632 decreased AGE-induced moesin phosphorylation and subsequently suppressed HUVEC angiogenesis. These results indicate that the Thr 558 phosphorylation in moesin mediates endothelial angiogenesis. AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/ROCK pathway.


Journey of change and back: a case study of a reconstituted social work service.
As a result of Total Quality Management and Reengineering principles during the VA's "Journey of Change" in the mid-1990s many hospital social work departments were re-organized under umbrella-care lines. Outcome studies of this movement have focused primarily on patient services. This study focused on the service providers' (including social workers) point of view and their satisfaction with the change in service structure. Data gathering consisted of a master thesis project by one of the co-authors, an administrative in-house survey of staff satisfaction, a qualitative presentation of staff concerns, and the perspective of the administrator who took the decision.


A method for improving the estimation of extreme air temperature by satellite.
Air temperature (Ta) data obtained from meteorological stations were spatially discontinuous. Some satellite data have complete spatial coverage and strong relationships with Ta (e.g., elevation and land surface temperature). Therefore, Ta can be mapped using in situ Ta and satellite data. However, this method may have a large bias when estimating the extreme Ta. In this study, the error prediction and correction (EPC) method, incorporating Cubist machine learning algorithm, was proposed to improve the estimation of extreme Ta. The accuracy of the EPC method was compared with that of the widely used method in previous studies in east China from 2003 to 2012. The mean absolute errors (MAEs) of the estimated daily Ta using the EPC method ranged from 0.75-1.01 °C, which were 0.57-0.96 °C lower than that of the method in the literature. The biases of the estimated Ta obtained using the two methods were close to zero. However, the biases can be as high as 7.10 °C when Ta is extremely low and as low as -3.09 °C when Ta is extremely high. Compared with the method in the literature, the EPC method can reduce the MAE by 1.41 °C, root mean square error by 1.49 °C, and bias by 1.61 °C of the estimated extreme Ta. Additionally, the EPC method produced satisfactory accuracy (MAEs <0.9 °C) of the estimated heat and cold wave magnitudes. Finally, a 1 km resolution daily Ta map in east China from 2003 to 2012 was developed, which will be useful data in multiple research fields.


Characteristics of falls and recurrent falls in residents of an aging in place community: A case-control study.
Falls and fall-related injuries remain an ongoing and serious health problem in older adults. Many clinical and environmental factors have been implicated in falls and recurrent falls, including sleep disturbances, sensory deficits, balance problems, incontinence, comorbid conditions, and certain categories of medications. We undertook this study to determine if there was an association between these factors and falls or recurrent falls in older adult residents of an aging in place community. Our retrospective case-control study compared residents who did and did not fall in an aging in place community, as well as those who experienced recurrent versus single falls in a single year. A total of 50 residents met the criteria for inclusion in this study, with 30 participants (60%) having experienced one or more falls during the observation period. Of the 30 participants who fell, 21 (70%) experienced more than one fall in a single year. Variables associated with falls included marital status and bowel incontinence; variables associated with recurrent falls included self-reported sleep difficulty, balance with sitting to standing and surface-to-surface transfer, use of a walker, and use of antidepressant medications. Our study supports the existing nursing research that falls, and recurrent falls are the result of multiple, interrelated factors. Further research is needed into preventative measures for both falls and recurrent falls, particularly in the context of aging in place.


Can naloxone inhibit the cardiovascular effect of acupuncture?
Forty dogs were studied during MAC-1 halothane anesthesia with a chronically implanted electromagnetic flow probe on the ascending aorta. Cardiac output, stroke volume, heart rate, mean arterial pressure, pulse pressure, central venous pressure and total peripheral resistance were determined in addition to Pao2, pH, Paco2 and base deficit. Acupuncture moxibustion with electrocautery at Jen Chung (Go-26) produced a significant (five per cent level) increase in the cardiac output, stroke volume, heart rate, mean arterial pressure and pulse pressure and a significant decrease in total peripheral resistance during a 120-minute period of observation in dogs under halothane anaesthesia. Acupuncture moxibustion at Go-26 following pretreatment with the narcotic antagonist naloxone (1 mg.kg-1) produced a significant increase in cardiac output, heart rate, mean arterial pressure. It is concluded that naloxone, which inhibits the analgesic effects of acupuncture, does not inhibit the symphathomimetic effect of acupuncture or moxibustion at Jen Chung (Go-26) in dogs under light MAC-1 halothane anaesthesia.


Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches.
The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.


Concentrations of foliar quercetin in natural populations of white birch (Betula pubescens) increase with latitude.
We investigated latitudinal and regional variations in the composition and concentrations of foliar flavonoids and condensed tannins in wild populations of white birch (Betula pubescens EHRH) in a large climatic transect in Finland. Concentrations of quercetin derivatives were correlated positively with latitude. By contrast, the concentrations of apigenin and naringenin derivatives were correlated negatively with latitude. These compound-specific latitudinal gradients compensated each other, resulting in no changes in the concentration of total flavonoids. Our results thus demonstrate a qualitative, but not quantitative, latitude-associated gradient in the foliar flavonoids in white birch. Due to higher antioxidant capacity of the quercetin derivatives in relation to other flavonoids, the qualitative change can reflect higher adaptation to light in the north than south. An investigation on a regional scale in the northern boreal zone showed that the temperature sum was correlated positively and soil P concentration was correlated negatively with the concentrations of foliar flavonoid, while the concentration of condensed tannins was correlated with slope. The variation in concentrations of flavonoids at large-scale geographical patterns is in line with the conjecture that foliar flavonoids are synthesized for protection against photooxidative stress.


Identification of specific PP2A complexes involved in human cell transformation.
The SV40 small t antigen (ST) interacts with the serine-threonine protein phosphatase 2A (PP2A). To investigate the role of this interaction in transformation, we suppressed the expression of the PP2A B56gamma subunit in human embryonic kidney (HEK) epithelial cells expressing SV40 large T antigen, hTERT, and H-RAS. Suppression of PP2A B56gamma expression inhibited PP2A-specific phosphatase activity similar to that achieved by ST and conferred the ability to grow in an anchorage-independent fashion and to form tumors. Overexpression of PP2A B56gamma3 in tumorigenic HEK cells expressing ST or human lung cancer cell lines partially reversed the tumorigenicity of these cells. These observations identify specific PP2A complexes involved in human cell transformation.


Validation and quality control of protein microarray-based analytical methods.
The microarray has emerged as an important format for simultaneous analysis of tens of thousands of substances present in a sample. Successful adaptation of microarray assays to clinical diagnostics will require particular attention to issues of quality control and quality assurance. Results of an assay can be compromised by a number of preanalytical factors including the quality of the reagents (e.g., the microarray and the detection reagents) and the integrity of the sample. Similarly, numerous factors in the analytical phase of a microarray assay, including changes in the reaction conditions and calibration, can contribute to inaccuracy and imprecision. Furthermore, a microarray combines many reagents or samples in a single device and therefore presents additional issues not usually encountered in discrete testing of a single analyte in a single sample. Various strategies (e.g., replicate analysis, array orientation control features, on-array controls, normalization) have been implemented to control and assess analytical factors that might compromise data generated from a microarray. The current range of measures taken to ensure the analytical accuracy and quality of data generated from protein microarrays is reviewed in the context of the lessons learned from DNA microarrays. The special considerations for protein microarrays as they transition from research into routine clinical analysis and the resulting quality control of clinical test results generated using such devices are discussed.


Studies on deoxyribonucleases from Haemophilus influenzae on DNA agarose affinity chromatography. Two-step purification of ATP-dependent deoxyribonuclease.
In a first part of this report, purification and characterization of several nucleased from lysates of Haemophilus influenzae are described. The enzymes bind to DNA with agarose columns and are removed by elution with phosphate buffer. Among the considered enzymes, the exonucleases 1 and 3, and endonuclease, a DNA polymerase and a restriction enzyme were recovered mixed by raising the phosphate concentration from 0.1 to 0.3 M, while the ATP-dependent DNAase recovered well purified, by raising the phosphate concentration to 0.45 M. After a rechromatography, on a second DNA with agarose column, of the peak of the ATP-dependent DNAase, the specific activity tested with 3H-labeled DNA was 125 units/mg of protein, representing a 300-fold purification of the original crude extract. In a second part, we have investigated the inactivation, at various pH, of transforming DNA of Haemophilus influenzae wild strain Rd with the different eluted fractions of the column, in order to determine the importance of contamination with other enzymatic activities, and also in order to confirm the nature of theisolated enzymes with a biological method. Finally, with enzymatic extracts of mutant strain Rd com minus 56, a strain which integrates shorter than normal pieces of DNA and which is suspected to possess and "activated specific endonuclease" able to recognize even small conformational modifications in paired structures, we tried to detect this activity on artificially constructed heteroduplex regions in DNA.


Effect of Paternal Age on Reproductive Outcomes of In Vitro Fertilization.
Although the adverse effects of maternal aging on reproductive outcomes have been investigated widely, there is no consensus on the impact of paternal age. Therefore, we investigated the effect of paternal age on reproductive outcomes in a retrospective analysis of 9,991 in vitro fertilization (IVF) cycles performed at the Reproductive Medicine Center of the Third Affiliated Hospital of Guangzhou Medical University (China) between January 2007 and October 2013. Samples were grouped according to maternal age [<30 (3,327 cycles), 30-34 (4,587 cycles), and 35-38 (2,077 cycles)] and then subgrouped according to paternal age (<30, 30-32, 33-35, 36-38, 39-41, and ≥42). The groups did not differ in terms of fertilization rate, numbers of viable and high-quality embryos and miscarriage rate when controlling maternal age (P >0.05). Chi-squared analysis revealed that there were no differences in implantation and pregnancy rates among the different paternal age groups when maternal age was <30 and 35-38 years (P >0.05). However, implantation and pregnancy rates decreased with paternal age in the 31-34 y maternal age group (P <0.05). Our study indicates that paternal age has no impact on fertilization rate, embryo quality at the cleavage stage and miscarriage rate. For the 30-34 y maternal age group, the implantation rate decreased with increased paternal age, with the pregnancy rate in this group being significantly higher in the paternal <30 y and 30-32 y age groups, compared with those in the 36-38 y and 39-41 y groups.


Prospective associations between depressive symptoms and cognitive functions in middle-aged and elderly Chinese adults.
To examine prospective associations of clinically relevant depressive symptoms with cognitive functions and rates of cognitive decline among Chinese adults aged 45 years and older. Data was from the China Health and Retirement Longitudinal Study (CHARLS) with a follow-up of 4 years. Based on the Chinese version of 10-item Center for Epidemiologic Studies Depression Scale (CESD-10), clinically relevant depressive symptoms were defined with a CESD-10 score≥10 points. Cognitive functions were measured in three domains: episodic memory, mental status and global cognition. Linear mixed models were used to assess the associations between clinically relevant depressive symptoms and cognitive functions. A total of 7335 participants (50.10% men; mean age: 57.47) were included in analyses. Participants with clinically relevant depressive symptoms showed poorer episodic memory (β=-0.35; 95% CI:-0.41, -0.29), mental status (β=-0.48; 95% CI: -0.57, -0.39), and global cognition (β=-0.82; 95% CI: -0.94, -0.70) during the follow-up. Compared with counterparts, rates of decline in episodic memory, mental status, and global cognition increased by 0.04 (β=0.04; 95% CI: 0.02, 0.06), 0.06 (β=0.06; 95% CI: 0.02, 0.09) and 0.11 (β=0.11; 95% CI: 0.06, 0.15) units per year in participants with clinically relevant depressive symptoms. A major limitation is that clinically relevant depressive symptoms were assessed by a screening tool and the follow-up was short. More severe clinically relevant depressive symptoms were associated with poorer cognitive functions and moderately faster cognitive decline in episodic memory, mental status and global cognition in middle-aged and elderly Chinese adults.


Septic pulmonary embolism secondary to prosthetic conduit fungal endocarditis in a child.
An 11 year-old boy underwent pulmonary vegetectomy and right ventricle-to-pulmonary artery conduit replacement for septic pulmonary embolism secondary to prosthetic conduit fungal endocarditis. He had previous surgical history of Senning/Rastelli procedure for corrected transposition of the great arteries at 5 years old. He was diagnosed with prosthetic fungal endocarditis caused by Candida parapsilosis, and suffered from growing vegetation and progressive septic pulmonary embolism despite fungal treatment. At emergent operation, pulmonary vegetectomy was performed under intermittent moderate hypothermic circulatory arrest, and infected conduit with vegetation was replaced. Approximately 2 years after the operation, he is well under anti-fungal medication.


Influence of prednisolone on gastric alkaline response in rat stomach. A possible explanation for steroid-induced gastric lesion.
Exposure of the rat stomach for 10 min to 1 M NaCl produced an increase of luminal pH (alkaline response) with a concomitant reduction of the transmucosal potential difference (PD) and an increased generation of mucosal prostaglandins of E2 and 6-keto F1 alpha. Prednisolone (3-50 mg/kg), given subcutaneously 4 hr before exposure to 1 M NaCl, dose-dependently inhibited alkaline response without affecting the PD reduction, and at 50 mg/kg completely prevented the increased production of mucosal prostaglandins after exposure to 1 M NaCl. The inhibitory effect of prednisolone on alkaline response was significantly antagonized by pretreatment with 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) (3 micrograms/kg) or cycloheximide (1.5 mg/kg). A repeated administration of prednisolone (3-50 mg/kg), once daily for 4 days, produced gastric lesions dose-dependently. At 50 mg/kg, gastric lesions appeared after administration of this drug for more than 2 days, and the inhibition of alkaline response caused by 1 M NaCl became more potent as the days of treatment increased. Either 16,16-dmPGE2 (10-100 micrograms/kg) or cycloheximide (1 or 3 mg/kg), given daily in two divided doses for 4 days, dose-dependently inhibited formation of gastric lesions in response to prednisolone (50 mg/kg). These results indicate that prednisolone inhibits gastric alkaline response caused by 1 M NaCl by reducing generation of endogenous prostaglandins. The weakened self-defense mechanisms caused by prednisolone may be involved in the pathogenesis of steroid-induced gastric lesions.


SARS vaccine: progress and challenge.
Severe acute respiratory syndrome (SARS) emerged in 2002 as a severe and highly contagious infectious disease that rapidly spread to a number of different countries. The collaborative efforts of the global scientific community have provided, within a short period of time, substantial insights into the molecular biology and immunology of SARS-CoV. Although the outbreak has been contained, there is continuous concern that the virus may resurface into the human population through seasonal changes, animal reservoirs or laboratory accidents. The severe morbidity and mortality associated with SARS make it imperative that an effective vaccine be developed to prevent reemergence and epidemics in the future.


Framingham study data and "established wisdom" about cigarette smoking and coronary heart disease.
With the Framingham Heart Study widely recognized as the most comprehensive, sustained investigation of the precursors of coronary heart disease (CHD), an examination was made of its manifold published data on the relationship of cigarette smoking to CHD and the results were compared with the "conventional wisdom" about cigarette smoking and CHD as projected by the Surgeon General. The analysis of data in the Framingham Heart Study shows that its results are inconsistent with the Surgeon General's views about cigarette smoking and coronary heart disease. The inconsistencies refer to (1) the magnitude of the association between cigarette smoking and CHD; (2) the relative incidence of CHD in "heavy" smokers and nonsmokers; (3) the independent effect of cigarette smoking on CHD; (4) the increasing risk of developing CHD with duration of cigarette smoking; (5) the effect of smoking cessation; and (6) the association between cigarette smoking and CHD in women.


Pontomedullary reticular projections into the region of the ascending medial longitudinal fasciculus in cat.
The medial longitudinal fasciculus (MLF) and immediately adjacent reticular formation were stimulated electrically just caudal to the trochlear nucleus in the cat. In the pontomedullary reticular formation within 1.5 mm of the midline, antidromically excited neurons were detected in (1) the contralateral abducens nucleus, (2) the contralateral reticular formation just caudal and caudoventral to the abducens nucleus, and (3) the ipsilateral nucleus reticularis pontis caudalis beneath and rostral to the abducens nucleus. The possible involvement of these neurons in eye or body movements is discussed.


West Midlands regional quality control scheme for haematology.
A regional quality control scheme is described together with details of the organisation, preparation of material, and an evaluation of the results.


Using registry data to improve quality of care.
Patient registries provide clinicians, patients and families with the ability to track important health outcomes at a population, cystic fibrosis (CF) center, and patient level. International quality improvement (QI) work driven by registries has been effective at improving the health and the care delivered to the individual patient. In this review, we examine the role CF registries have played in the QI process over the years and discuss the inherent strengths and limitations that exist when using registry data for this purpose.


Enhancement of bone ingrowth into a porous hydroxylapatite-matrix using a resorbable polylactic membrane: an experimental pilot study.
The objective of this pilot study was to study bone ingrowth into porous hydroxylapatite (HA) blocks using a polylactic membrane for guided tissue regeneration. Porous HA blocks were placed on both sides of the mandible and of the ilium in five Göttingen minipigs. On one side a polylactic membrane was used to cover the blocks. After 5 months, the blocks with the membrane covering showed complete bony penetration of the HA matrix both in the mandible and the ilium. The blocks without the membrane covering showed substantially less and irregular bone ingrowth after placement on the mandible and poor ingrowth after placement on the ilium. The newly formed bone in the blocks from the ilium showed a cancellous structure while bone tissue inside the blocks from the mandible exhibited a dense cortical appearance. The polylactic membrane was nearly completely degraded at the time of investigation.


Point of care testing system via enzymatic method for the rapid, efficient assay of glycated albumin.
The ratio of glycated albumin to albumin concentration in serum is termed the glycated albumin (GA) value. The GA value provides a time-averaged index of the state of glycemic control for the previous 2 weeks. In this study, a dry chemistry system (GA monitor) via an enzymatic method was proposed in order to provide a GA value measurement for point of care testing (POCT). The GA monitor was made from three devices a set of test-tapes, a test-strip and an optical analyzer. A GA test-tape, a ketoamine test-tape and an albumin test-tape were enclosed in the fabricated test-strip. Time-course changes of the optical characteristics were evaluated using the test-strip. It was found that the three test tapes must be enclosed in the test-strip to create a dry chemistry system for small sample volumes (20 microl). A temperature control unit, which could hold the temperature of the GA test-tape at 45 degrees C and at 25 degrees C for the other two types of test-tape was incorporated into the optical analyzer. With the GA test-tape held separately and controlled at 45 degrees C, the analytical time decreased to one-third of the time taken for the three tapes at 25 degrees C. The analytical accuracy of the three types of test-tape showed favorable results, with R2 values of 0.96-0.98 and coefficients of variation (CV) of 2.4-6.8%. Compared with a commercially available liquid chemistry system, the analytical accuracy of the GA monitor exhibited a relatively favorable linearity of R=0.82. According to these results, a new GA value analytical system was realized, in which the GA value could be assayed within five minutes using only 20 microl of blood sample with a disposable test-strip. This system could potentially be used for clinical purposes as test equipment for rapid and efficient POCT.


Analyzing Ensembles of Amyloid Proteins Using Bayesian Statistics.
Intrinsically disordered proteins (IDPs) are notoriously difficult to study experimentally because they rapidly interconvert between many dissimilar conformations during their biological lifetime, and therefore cannot be described by a single structure. The importance of studying these systems, however, is underscored by the fact that they form toxic aggregates that play a role in the pathogenesis of many disorders. The first step towards a comprehensive understanding of the aggregation mechanism of these proteins involves a description of their thermally accessible states under physiologic conditions. The resulting conformational ensembles correspond to coarse-grained descriptions of their energy landscapes, where the number of structures in the ensemble is related to the resolution in which one views the free energy surface. Here, we provide step-by-step instructions on how to use experimental data to construct a conformational ensemble for an IDP using a Variational Bayesian Weighting (VBW) algorithm. We further discuss how to leverage this Bayesian approach to identify statistically significant ensemble-wide observations that can form the basis of further experimental studies.


Sleep, epilepsy and translational research: what can we learn from the laboratory bench?
The relationship between sleep and epilepsy has been known since ancient times, and the modulating effects of both on each other have been widely described in clinical studies. However, the mechanisms of this correlation remain unclear. Translational research is essential for filling the gaps in our knowledge, and for developing better therapeutic approaches to improve the quality of life of epileptic patients. Excellent animal models of epilepsy are available for the investigation of various aspects of epilepsy, such as epileptogenesis and hippocampal sclerosis. These models also show an association between sleep and epilepsy, suggesting that they are suitable for translational research on this relationship. While some knowledge has been obtained from preclinical studies, the topic remains relatively unexplored. In terms of the role of sleep in modulating seizure susceptibility in epilepsy, animal sleep research is a major tool. In this review, we focus on the intricate relationship between sleep and epilepsy in the preclinical setting, using a translational science approach.


Publisher Correction: CNspector: a web-based tool for visualisation and clinical diagnosis of copy number variation from next generation sequencing.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Renal failure following cardiac surgery in a 2.8-kg infant managed with continuous arteriovenous hemofiltration.
Renal failure occurred after repair of transposition of the great vessels with ventricular septal defect in a 2.8-kg infant and was managed successfully with continuous arteriovenous hemofiltration. The infant lost the weight that had been gained as extravascular water, thereby simplifying her fluid, electrolyte, and nutritional management. She ultimately died of cardiac failure.


Combining restricted access material (RAM) and turbulent flow for the rapid on-line extraction of the cyclooxygenase-2 inhibitor rofecoxib in plasma samples.
Restricted access material (RAM) has been used in the packing of a solid-phase extraction (SPE) column for on-line extractions under turbulent flow conditions. The bio-compatible RAM material works by the principle of size exclusion in addition to conventional reversed-phase chromatography, thereby allowing the extraction and preconcentration of small analyte molecules from biological samples such as plasma. Using small column dimensions (0.76 mm x 50 mm) and a consequently high linear velocity, turbulent flow was achieved during online sample extractions. The improved mass-transfer rate characteristic of turbulent flow allows fast sample cleanup without decreased extraction efficiency. The novel use of the RAM column, connected upstream to a C18 monolithic column, allowed the direct injection, extraction, separation, and MS/MS detection of plasma samples spiked with rofecoxib in a span of 5 min. Calibration curves obtained using this RAM turbulent flow coupled column method showed good linearity (R2 > 0.99) and reproducibility (%RSD < or = 7%). The lower limit of quantitation of rofecoxib in plasma samples was found to be 40 ng/ml. The extraction method showed good recovery of rofecoxib from a plasma matrix with minimal signal loss and robustness after more than 200 plasma injections.


Finger proteins and DNA-specific recognition: distinct patterns of conserved amino acids suggest different evolutionary modes.
Finger proteins, the first example of which was Xenopus TFIIIA, share Zn2+ finger-like folded domains capable of binding to nucleic acids. A large number of this type of protein have been characterised from diverse organisms, indicating a wide evolutionary spread of the DNA-binding fingers. At least two classes of finger proteins may be distinguished. Class I proteins contain variable numbers of the tandemly repeating TFIIIA-like finger motif, (Y/F-X-C-X2-4-C-X3-F-X5-L-X2-H-X3-H). Class II finger proteins display a single (C-X2-C-X13-C-X2-C) motif and a facultative second putative finger. The relation between the structure of finger proteins and their recognised DNA sequences is discussed.


Effectiveness of a community-based integrated service model for older adults living alone: A nonrandomized prospective study.
Older adults living alone face physical, emotional, and social health problems, and prefer to age in place (AIP) in their homes. A community-based integrated model for AIP is needed and few studies have identified its impact on older adults living alone. This was a non-randomized prospective study. Participants were 877 community-dwelling older adults living alone, aged above 65 years, in S* city in South Korea. The intervention group (n = 331) received a community-based integrated service (CBIS) model based on AIP for six months from October 2019 to April 2020. Scores on frailty (β = -0.377, p < .001), loneliness (β = -1.897, p = .018), and health-related quality of life (β = 4.299, p = .021) significantly improved in the intervention group. Among the intervention group, loneliness scores significantly improved among participants aged under 80 years than those aged over 80 years. The CBIS model improved frailty, loneliness, and quality of life in community-dwelling older adults living alone.


Soft liquid metal nanoparticles achieve reduced crystal nucleation and ultrarapid rewarming for human bone marrow stromal cell and blood vessel cryopreservation.
High warming rates during cryopreservation are crucial and essential for successful vitrification. However, realizing a faster warming rate in low-concentration cryoprotective agents appears to be challenging for conventional warming process through convective heat transfer. Herein, we developed a liquid metal (LM) nanosystem that can act as a spatial source to significantly enhance the warming rates with near-infrared laser irradiation during the warming process. The synthetic Pluronic F127-liquid metal nanoparticles (PLM NPs) displayed multiple performances with uniform particle size, superior photothermal conversion efficiency (52%), repeatable photothermal stability, and low cytotoxicity. Particularly, it is more difficult for the liquid PLM NPs with less surface free energy to form crystal nucleation than other solid NPs such as gold and Fe3O4, which is beneficial for the cooling process during cryopreservation. The viability of human bone marrow-derived mesenchymal stem cells postcryopreservation reached 78±3%, which is threefold higher than that obtained by the conventional warming method (25±6%). Additionally, the cells postcryopreservation maintained their normal attachment, proliferation, surface marker expression, and intact multilineage differentiation properties. Moreover, the results of mouse tails including blood vessel cryopreservation showed a relatively improved intact structure when using PLM NP rewarming compared with the results of conventional warming. The new LM nanosystem provides a universal platform for cryopreservation that is expected to have potential for widespread applications including bioengineering, cell-based medicine, and clinical translation. STATEMENT OF SIGNIFICANCE: In this study, we fabricated soft liquid metal nanoparticles with high photothermal conversion efficiency, repeatable photothermal stability, and low cytotoxicity. Particularly, soft liquid metal nanoparticles with less surface free energy and suppression effects of ice formation were first introduced to mediate cryopreservation. Superior ice-crystallization inhibition is achieved as a result of less crystal nucleation and ultrarapid rewarming during the freezing and warming processes of cryopreservation, respectively. Collectively, cryopreservation of human bone marrow stromal cells (HBMSCs) and mouse tails including blood vessels can be successfully performed using this new nanoplatform, showing great potential in the application of soft nanoparticles in cryopreservation.


CCR9 AND CCR7 are overexpressed in CD4- CD8- thymocytes of myasthenia gravis patients.
Chemokine CC motif receptors 9 and 7 (CCR9 and CCR7) play a major role in the migration of T-cell precursors to the thymus to initiate T thymopoiesis. However, their role in development of T-cells in myasthenia gravis (MG) patients has not been fully elucidated. Expression and distribution of CCR9+ and CCR7+ cells were detected by flow cytometry and immunofluorescence. Real-time polymerase chain reaction was used to check the adhesion molecules on CD4- CD8- double-negative (DN) thymocytes. CCR9 and CCR7 expression by DN thymocytes increased in the MG thymus; the levels of CCR9, CCR7, interleukin-7R mRNA increased, and CXCR4 levels decreased compared with levels in the non-MG thymus. More CCR7 and CCR9 double-positive (DP) thymocytes were gathered near the subcapsular region in MG thymus. Enhanced expression of CCR9 and CCR7 may complicate the differentiation of DP thymocytes from the DN stage in MG thymus. Muscle Nerve, 2016 Muscle Nerve 55: 84-90, 2017.


A Large Residual Vestibular Schwannoma Following Incomplete Resection: A Case Report With Literature Review.
Vestibular schwannomas (VSs), also known as acoustic neuromas, are benign, slow-growing tumors. If not detected early or treated appropriately, these tumors can lead to complications such as pressure on adjacent intracranial structures that can affect vital functions. The present report discusses a rare case of a residual VS in a 46-year-old female patient. The patient was a known case of left-sided VS who underwent partial excision of the tumor four years ago and had complete hearing loss on the left side since then. She reported to the clinic with progressive headaches and imbalance while walking. Magnetic resonance imaging of the brain revealed a large left residual VS compressing the brainstem and cerebellum, which was completely excised, and the patient did well postoperatively. Incomplete resection of VS carries a significant risk of tumor regrowth, necessitating the importance of complete resection with periodic follow-ups.


Striatal L-dopa metabolism studied in vivo in rats with nigrostriatal lesions.
We have used cerebral dialysis to monitor striatal metabolism of exogenously administered L-dopa (L-dihydroxyphenylalanine) in rats with unilateral lesions of the substantia nigra. The concentration of extracellular dopamine (DA) increased in both striata following L-dopa administration but the increase was markedly attenuated in the lesioned striatum. The formation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the major DA metabolites, was also reduced in the lesioned striata following L-dopa administration; however, the reduction was not as great as was that of DA formation. A significant metabolism of exogenous L-dopa to 3-O-methyldopa occurred in both striata. L-dopa administration transiently increased extracellular levels of 5-hydroxyindoleacetic acid (5 HIAA) in both the lesioned and intact striata. These results suggest that the striatum with a reduction in DA nerve terminals is deficient both in the capacity to synthesize DA and in the storage mechanisms necessary to protect the newly synthesized DA from oxidative metabolism.


Patients' attitude towards a sham-controlled trial on pulmonary vein isolation in atrial fibrillation.
The interpretation of recent trials on pulmonary vein ablation (PVI) for the treatment of atrial fibrillation (AF) is hampered by the lack of blinding and sham controls. The feasibility of a sham-controlled trial has been questioned. We aimed to assess the attitude of potential participants regarding a sham-controlled trial in a common AF-patient population planned for PVI. Patients in two tertiary care centres planned for PVI were asked for their current AF symptoms using the Atrial Fibrillation Effect on QualiTy of Life (AFEQT) questionnaire 1 day before catheter ablation. Subsequently, the study design of a hypothetical sham-controlled PVI-study was introduced, and patients were asked for their agreement in participation. Telephone follow-up of the AFEQT questionnaire was conducted 3 months after PVI. One hundred and ninety-six patients (mean age 64 ± 11 years, 63% male) were included. Seventy-nine (40%) patients expressed their agreement to participate in the hypothetical sham-controlled trial. An additional 7% agreed to participate if a cross-over option after three months was offered. Agreement rate was similar in patients with first and Redo-PVI and minimal, moderate or severe symptoms. Mean overall AFEQT at baseline was 55 ± 19 and improved by 25 ± 20 points after 3 months (p < 0.001 versus baseline). With a participation rate of 40% in potential study participants, a sham-controlled trial for pulmonary vein isolation seems feasible. Patient-reported symptom relief after pulmonary vein isolation is in accordance with previous randomized open studies. The benefit of PVI should be rigorously evaluated in a sham-controlled trial.


Experimental validation of the mechanism of stomatal development diversification.
Stomata are the structures responsible for gas exchange in plants. The established framework for stomatal development is based on the model plant Arabidopsis, but diverse patterns of stomatal development have been observed in other plant lineages and species. The molecular mechanisms behind these diversified patterns are still poorly understood. We recently proposed a model for the molecular mechanisms of the diversification of stomatal development based on the genus Callitriche (Plantaginaceae), according to which a temporal shift in the expression of key stomatal transcription factors SPEECHLESS and MUTE leads to changes in the behavior of meristemoids (stomatal precursor cells). In the present study, we genetically manipulated Arabidopsis to test this model. By altering the timing of MUTE expression, we successfully generated Arabidopsis plants with early differentiation or prolonged divisions of meristemoids, as predicted by the model. The epidermal morphology of the generated lines resembled that of species with prolonged or no meristemoid divisions. Thus, the evolutionary process can be reproduced by varying the SPEECHLESS to MUTE transition. We also observed unexpected phenotypes, which indicated the participation of additional factors in the evolution of the patterns observed in nature. This study provides novel experimental insights into the diversification of meristemoid behaviors.


Protons and how they are transported by proton pumps.
The very high mobility of protons in aqueous solutions demands special features of membrane proton transporters to sustain efficient yet regulated proton transport across biological membranes. By the use of the chemical energy of ATP, plasma-membrane-embedded ATPases extrude protons from cells of plants and fungi to generate electrochemical proton gradients. The recently published crystal structure of a plasma membrane H(+)-ATPase contributes to our knowledge about the mechanism of these essential enzymes. Taking the biochemical and structural data together, we are now able to describe the basic molecular components that allow the plasma membrane proton H(+)-ATPase to carry out proton transport against large membrane potentials. When divergent proton pumps such as the plasma membrane H(+)-ATPase, bacteriorhodopsin, and F(O)F(1) ATP synthase are compared, unifying mechanistic premises for biological proton pumps emerge. Most notably, the minimal pumping apparatus of all pumps consists of a central proton acceptor/donor, a positively charged residue to control pK(a) changes of the proton acceptor/donor, and bound water molecules to facilitate rapid proton transport along proton wires.


Momentary subjective responses to alcohol as predictors of continuing to drink during daily-life drinking episodes.
Subjective response to alcohol's stimulating and sedating effects is a person-level risk factor for heavy drinking and alcohol use disorder. Longitudinal and laboratory studies have demonstrated that at-risk individuals experience greater stimulation and lower sedation while drinking. While between-person subjective responses inform risk and etiology, in-the-moment assessments during daily-life drinking may elucidate the within-person processes by which stimulation and sedation may lead to heavier drinking. We aimed to characterize these momentary processes by testing momentary stimulation and sedation during drinking as predictors of subsequently continuing to drink during densely sampled, daily-life drinking episodes. 113 adults (54 with borderline personality disorder and 59 community participants; 77.9% female) completed ecological momentary assessment for 21 days, reporting momentary subjective stimulation and sedation throughout drinking episodes and momentary alcohol use after drink initiation (i.e., continued drinking). GLMMs demonstrated that greater day-level stimulation (OR=1.48, 95% CI=[1.20, 1.82], p<.001), greater person-level stimulation (OR=1.63, 95% CI=[1.05, 2.53], p=.031), and lower momentary sedation (OR=0.54, 95% CI=[0.41, 0.71], p<.001) predicted continued drinking. Although greater stimulation and lower sedation have been conceptualized as individual-level risk factors for heavy drinking, our findings suggest that these associations are accompanied by processes that operate within person. Our results suggest that greater stimulation may confer risk for heavy drinking at the level of the drinking episode, possibly acting as positive reinforcement that may contribute to heavier drinking during future episodes. In contrast, lower sedation may primarily confer in-the-moment risk by contributing to momentary decisions to keep drinking within an episode.


The use of pulmonary scintigraphy for endobronchial foreign bodies.
Pulmonary scintigraphy using 99mTc-MAA clearly demonstrated a perfusion defect in the entire left lung of an 11-month-old girl with endobronchial foreign body. Other initial examinations, including a chest roentgenogram, showed only minimal changes. Repeated pulmonary scintigraphy 24 hr after endoscopic removal of a peanut fragment from the left main stem bronchus demonstrated almost normal blood flow in the left lung. The well-known physiological explanation for diminished pulmonary blood flow due to endobronchial foreign bodies is as follows; alveolar hypoxia caused by hypoventilation due to bronchial check-valve obstruction leads to a pulmonary vasoconstriction with resultant diminution of the regional perfusion. Furthermore, the increase in alveolar pressure caused by bronchial check-valve obstruction may play a significant role in decreased pulmonary blood flow.


The influence of antituberculosis drugs on the plasma level of verapamil.
The influence of antituberculosis drugs on the plasma level of verapamil was studied after its oral and intravenous administration. Six patients who had been treated for at least 6 months with a combination of rifampicin, ethambutol and isoniazid received a single oral dose of 40 mg verapamil. As compared to untreated subjects, the antituberculosis drugs greatly reduced the bioavailability of the calcium antagonist. Studies in patients in whom treatment with ethambutol and isoniazid had been discontinued revealed that the effect was due to rifampicin. The drugs for tuberculosis had no influence on the plasma level of verapamil when it was given intravenously. The findings can be explained by the induction of verapamil metabolizing liver enzymes in patients treated with rifampicin.


Idiopathic Non-atherosclerotic Carotid Artery Disease.
The purpose of this review is to provide an overview of idiopathic non-atherosclerotic causes of carotid artery disease and its manifestations. Four major causes of non-atherosclerotic carotid artery disease including dissection, fibromuscular dysplasia, moyamoya disease, and inflammatory large vessel vasculitis are discussed. While there is a dearth of clinical trials involving some of the rarer conditions, recent data from clinical trials supporting antiplatelet over anticoagulation treatment of cervical artery dissection, recent consensus statements on the management of fibromuscular dysplasia, and guideline approaches to diagnosis and treatment of large vessel vasculitis are summarized. Idiopathic non-atherosclerotic causes of carotid artery disease are under appreciated and may lead to significant morbidity and mortality. While less common compared with atherosclerotic disease, non-atherosclerotic disease may affect younger patient populations and result in non-cerebrovascular arterial involvement and systemic organ damage. Therefore, prompt recognition of these disorders is key to their management.


Editor's Choice - Quality Assessment of European Society for Vascular Surgery Clinical Practice Guidelines.
An increasing number of clinical practice guidelines (CPGs) have emerged over recent years. To have clinical utility, they need to be rigorously developed and scientifically robust. Instruments have been developed to assess the quality of clinical guideline development and reporting. The aim of this study was to evaluate CPGs from the European Society for Vascular Surgery (ESVS) using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. CPGs published by the ESVS during the period January 2011 to January 2023 were included. Two independent reviewers assessed the guidelines after receiving training in the use and application of the AGREE II instrument. Inter-reviewer reliability was assessed with the intraclass correlation coefficient. Maximum scaled scores were 100. Statistical analysis was performed using SPSS Statistics v.26. Sixteen guidelines were included in the study. Good inter-reviewer score reliability was found on statistical analysis (> 0.9). The mean ± standard deviation domain scores were 68.1 ± 20.3% for scope and purpose, 57.1 ± 21.1% for stakeholder involvement, 67.8 ± 19.5% for rigour of development, 78.1 ± 20.6% for clarity of presentation, 50.3 ± 15.4% for applicability, 77.6 ± 17.6% for editorial independence, and 69.8 ± 20.1% for overall quality. Stakeholder involvement and applicability have improved in quality over time but are still the lowest scoring domains. Most ESVS clinical guidelines are of high quality and reporting. There is scope for improvement, specifically by addressing the domains of stakeholder involvement and clinical applicability.


Enhanced neutralization of La Crosse virus by the binding of specific pairs of monoclonal antibodies to the G1 glycoprotein.
Monoclonal antibodies specific for eight antigenic sites on the G1 glycoprotein of La Crosse virus were studied in a kinetics of neutralization assay. When examined at the same protein concentration, there were differences in the rates and degree of neutralization induced by these antibodies. The maximum amount of neutralization detected in antibody excess ranged from 1.5 to 3 logs. Another 2 to 3 logs of viral infectivity could be neutralized by the addition of polyclonal anti-G1 antibody or a second monoclonal antibody. However, only certain pairs of monoclonal antibodies enhanced the neutralization the additional 2 to 3 logs. The antibody pairs enhancing neutralization were those also found to be synergistic in a competition binding assay (L. Kingsford, L. D. Ishizawa, and D. W. Hill, 1983, Virology 129, 443-455) as well as any neutralizing antibody used in combination with antibodies to epitopes within one particular site on the glycoprotein. The data indicate that antibody binding to two different specific sites on G1 is needed to neutralize La Crosse virus to the same extent that is observed with polyclonal antibody.


Elevated lipoprotein(a) and lipoprotein-associated phospholipase A2 are associated with unfavorable functional outcomes in patients with ischemic stroke.
The association of lipoprotein(a) [Lp(a)] and stroke functional outcomes was conflicting. The aim of the study was to clarify whether high Lp(a) is associated with unfavorable functional outcomes in patients with ischemic stroke. A total of 9709 individuals from the third China National Stroke Registry cohort were recruited. Plasma level of Lp(a) at admission was measured with enzyme-linked immunosorbent assay. The cut-off was set at the median for Lp(a). Functional outcome was assessed using the modified Rankin scale (mRS) at 3 months and 1 year after ischemic stroke. The association between Lp(a) and functional outcomes was evaluated using a logistic regression model. The median age was 63.0 years, and 31.1% participants were women. Patients in higher Lp(a) group had higher incidences of unfavorable functional outcomes at 3 months. In logistic regression model, elevated Lp(a) levels were associated with unfavorable functional outcomes at 3 months (Q4 vs. Q1: odds ratio 1.33, 95% confidence interval 1.11-1.61). Subgroup analysis showed that in the lower Lp-PLA2 group, Lp(a) level was not associated with functional outcomes, but in the higher Lp-PLA2 group, Lp(a) level was significantly associated with functional outcomes. After grouped by different levels of Lp(a) and Lp-PLA2, the Lp(a) high/ Lp-PLA2 high group showed the highest incidence of unfavorable functional outcomes at 3 months and 1 year. Elevated Lp(a) level is associated with unfavorable functional outcomes in patients with ischemic stroke. The increment in both Lp(a) and Lp-PLA2 are associated with unfavorable functional outcomes at 3 months and 1 year after ischemic stroke.


Evaluation of the dietary inflammatory index in children and adolescents with type 1 diabetes mellitus and its relationship with nutritional status and metabolic control.
The aim of this study was to evaluate the association of the dietary inflammatory index (DII) with the nutritional status and metabolic control of children and adolescents with type 1 diabetes mellitus. This was a cross-sectional study that examined data of children and adolescents ages 7 to 16 y diagnosed with type 1 diabetes mellitus. Dietary intake was assessed using a 24-h dietary recall, from which the DII was calculated. The outcomes were body mass index, lipid profiles (low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol), and glycated hemoglobin. The DII was evaluated in tertiles and in a continuous way. Multiple linear regression was adopted in the analysis, with P < 0.05 considered significant. Overall, 120 children and adolescents with a mean age of 11.7 (± 2.8) y were included, 53.3% (n = 64) of whom were girls. Excess weight was present in 31.7% participants (n = 38). The average DII was +0.25, ranging from -1.11 to +2.67. Higher values of selenium (P = 0.011), zinc (P = 0.001), fiber (P < 0.001), and other micronutrients were observed in the first tertile of the DII (diet with more antiinflammatory potential). The DII appeared as a predictor of body mass index (P = 0.002; β = 0.23; 95% confidence interval [CI], 0.39-1.75) and non-high-density lipoprotein cholesterol (P = 0.034; β = 0.19; 95% CI, -13.5 to 0.55). There was a tendency for DII to be associated with glycemic control (P = 0.09; β = 0.19; 95% CI, -0.04 to 0.51). The inflammatory potential of the diet was associated with increased body mass index and aspects related to metabolic control in children and adolescents with type 1 diabetes mellitus.


Computerized gait analysis in Legg-Calvé-Perthes disease--analysis of the sagittal plane.
Current follow-up- and outcome-evaluations of Legg-Calvé-Perthes disease (LCPD) are based on subjective measures of function, clinical and radiological parameters. The objective of this study was to evaluate the sagittal plane kinematics and the effect on hip joint loading on the affected hip in children with LCPD. Computerized gait analysis was performed in 49 LCPD patients aged ≥ 5 years with unilateral hip involvement. Sagittal plane kinematics and kinetics were compared to a group of healthy children (n=30). Kinematics: a significantly increased anterior tilt and range of motion (ROM) of the pelvis combined with a marked reduction of the extension of the involved hip joint compared to the control group was observed. The increased ROM of the contralateral hip results from increased maximum flexion. Power generation: overall significantly decreased on the involved side during florid stage. Global hip function: significantly reduced hip flexor index of the involved hip; 46.2% of the patients in advanced stage, although having no significant changes in kinematics - except increased anterior pelvic tilt - had a pathologic HFI. Sagittal plane hip function is significantly impaired in florid and advanced LCPD. The results of this study will lead to further investigations into whether this development can be prevented by conservative or operative treatment thus improving function and long-term prognosis.


Modulation of the two promoters of the galactose operon of Escherichia coli.
The gal operon of Escherichia coli is controlled by two independent promotors--one is activated and the other inhibited by cyclic AMP and cyclic AMP receptor protein. The two promotors are modulated, however, by the same operator locus and receptor protein.


Potential effect of geometry on wall shear stress distribution across scaffold surfaces.
Bioreactors are used as cell culture systems for growth and maintenance of tissue-engineered scaffolds that serve as three-dimensional (3D) templates for initial cell attachment and subsequent tissue formation. The bioreactors' fluid dynamic environment is known to play a crucial role in the synthesis of cellular components via flow-mediated mechanical stimuli. Computational fluid dynamics (CFD) models in the slow turning lateral vessel (STLV Synthecon, Inc.) were simulated under Couette flow conditions. Systematic research of the wall shear stress (WSS) effects on the scaffold's geometry has been limited. Therefore, direct qualitative and quantitative correlations for WSS values were performed by analyzing and comparing WSS value distributions of two scaffold shapes. Under experimental flow conditions, the disc and prolate spheroid shapes exhibited dissimilar WSS distribution. Nonetheless, when compared to the disc models, the high pressure stagnation region of the spheroid was reduced between 60% and 95%. In the spheroid shape, approximately 40% increase in the shear stress surface exposure to flow ranged from 2 to 3 dyn/cm(2). These values suggest that WSSs are likely affected by scaffold shape and vary little with location within the Synthecon STLV. The proposed simulation studies evidenced the CFD model's flexibility to characterize and quantify forces affecting tissue-engineered scaffold design.


Drug residue formation from ronidazole, a 5-nitro-imidazole. IV. The role of the microflora.
When radioactive 1-methyl-5-nitroimidazole-2-methanol carbamate, ronidazole, labeled at the 4,5-ring positions was administered orally to germ-free and conventional rats, a much larger fraction of the radioactivity was excreted in the feces of the conventional animals. Determination of the total radioactive residues present in the carcass, blood, plasma, liver, fat and kidney 5 days after dosing indicated that the carcass of the germ-free animals contained a greater quantity of residue than that of conventional rats. On the other hand, the blood of the conventional animals contained a much higher level of radioactivity than that of the germ-free animals. These results show that while the microflora influence the distribution of the drug their presence is not obligating for the formation of persistent tissue residues in rats dosed with ronidazole.


Mechanisms of cigarette smoke toxicity: the inactivation of human alpha-1-proteinase inhibitor by nitric oxide/isoprene mixtures in air.
A mixture of nitric oxide (NO) and isoprene in air has been studied as a model for gas-phase cigarette smoke. We have shown that this model system duplicates many of the properties of cigarette smoke including the inactivation of human alpha-1-proteinase inhibitor (a1PI). In this study, buffered solutions of a1PI were exposed to puffs of air containing 300 ppm NO and 400 ppm isoprene. Bubbling of the NO/air/isoprene gas stream directly through buffered protein solutions causes a1PI to undergo a fast loss of inhibitory capacity. This fast inactivation is not observed when a1PI is exposed to aqueous extracts of the NO/air/isoprene mixture. Both direct exposure and exposure to aqueous extracts, however, cause a1PI to undergo a slow loss of activity that continues for several days as the protein is incubated in the buffer solutions. Gas-phase cigarette smoke has already been shown to cause this same two-phase inactivation of a1PI. The inactivation of a1PI by the model system is dependent on the presence of oxygen in the gas stream, suggesting that the oxidation of nitric oxide to nitrogen dioxide in air is involved in the formation of the inactivating species. The nature of these species remains to be determined; however, small alkoxyl or peroxyl radicals (such as are spin-trappable from gas-phase smoke as well as from the NO/air/isoprene system) do not appear to inactivate a1PI. One possibility is that the inactivating species are metastable compounds formed by radical processes in the gas phase of both cigarette smoke and our model system. Our data suggest that one possible class of species is peroxynitrates.


Effects of cervical rotatory manipulation on the cervical spinal cord: a finite element study.
Little information is available concerning the biomechanism involved in the spinal cord injury after cervical rotatory manipulation (CRM). The primary purpose of this study was to explore the biomechanical and kinematic effects of CRM on a healthy spinal cord. A finite element (FE) model of the basilaris cranii, C1-C7 vertebral bodies, nerve root complex and vertebral canal contents was constructed and validated against in vivo and in vitro published data. The FE model simulated CRM in the flexion, extension and neutral positions. The stress distribution, forma and relative position of the spinal cord were observed. Lower von Mises stress was observed on the spinal cord after CRM in the flexion position. The spinal cord in CRM in the flexion and neutral positions had a lower sagittal diameter and cross-sectional area. In addition, the spinal cord was anteriorly positioned after CRM in the flexion position, while the spinal cord was posteriorly positioned after CRM in the extension and neutral positions. CRM in the flexion position is less likely to injure the spinal cord, but caution is warranted when posterior vertebral osteophytes or disc herniations exist.


Histamine control affects the weal produced by the adjacent diluent control in skin prick tests.
The effect of histamine chloride control (10 mg/ml) on the weal reaction produced by the adjacent test solution (buffered glycerol-saline diluent control) in skin prick tests was studied among 270 peat workers and 214 lumberjacks. The diluent control was placed on the skin at two test sites: 3-4 cm and 18-19 cm from the site of the histamine control. Prick-test lancets (Dome/Hollister-Stier) were used to prick the skin. Weal areas of 6 mm2 or larger were considered to be positive reactions. In both populations the diluent control caused positive reactions nearly three times more often when the test site was 3-4 cm from the site of the histamine control than when it was 18-19 cm away from the control (P less than 0.001). Similar relationships might be found between histamine control and allergen solutions. This finding should be taken into account in histamine-based standardisation of the results of skin prick tests as well as in biological standardization of allergen solutions.


Purification and characterization of an endo-exonuclease from Podospora anserina mitochondria.
The senescence phenotype of Podospora anserina wild-type strains depends on mitochondrial (mt) genome stability. Characterization of activities implicated in the maintenance of the mt DNA is therefore essential for a better understanding of these degenerative processes. To address this question we looked for a nuclease activity in this fungal mitochondria. Here we describe the purification of an endo-exonuclease active on single-stranded, double-stranded and flap DNA. The Podospora nuclease also possesses an RNase H activity. Gel filtration chromatography showed a native molecular mass of 90 kDa for the P. anserina enzyme. The highly purified fraction shows a single polypeptide chain of 49 kDa on SDS-PAGE, indicating that the Podospora enzyme is probably active as a dimer. Purification and sequencing of the endolysine digestion peptides of the Podospora mt nuclease suggested that this enzyme could belong to the 5' structure-specific endo-exonuclease family. The possible involvement of this nuclease in mt DNA recombination during the senescence process is evoked.


International Survey Reveals Opportunities to Improve Tuberculous Meningitis Management and the Need for Standardized Guidelines.
Tuberculous meningitis (TBM) is a medical emergency, yet there are no standardized treatment guidelines for the medical or neurosurgical management of these patients and little data on neurocritical care. We conducted an international survey to understand current medical and neurosurgical TBM management and resource availability to provide baseline data needed for future multicenter trials addressing unanswered clinical research questions and the establishment of standardized guidelines. An online survey of 77 questions covering medical and neurosurgical TBM management aimed at clinicians/nurses treating TBM was distributed as an anonymous link through email invitation, international organizations' membership distribution, and direct links on organizational webpages or social media. The survey remained open for 5 months. Data were summarized with frequencies and percentages. The survey had 222 responses from 43 countries representing 6 continents. Most respondents were from tertiary care facilities, with broad access to medical and neurosurgical resources. There was significant heterogeneity in general supportive care, and TBM-specific management demonstrated considerable divergence from current standard-of-care practices. The lack of standardized guidelines was identified as a major challenge in TBM management. General and neurocritical care were largely absent. Resources for bedside supportive care and noninvasive monitoring were broadly accessible. These findings suggest that current TBM management could be improved by the establishment of internationally accepted treatment guidelines based on available evidence, and that numerous centers have resources available to participate in future multicenter trials, even for basic interventions, that may further improve patient outcomes globally.


Comparison of outcomes following thrombolytic therapy among patients with prior stroke and diabetes in the Virtual International Stroke Trials Archive (VISTA).
The use of alteplase in patients who have had a prior stroke and concomitant diabetes is not approved in Europe. To examine the influence of diabetes and prior stroke on outcomes, we compared data on thrombolysed patients with nonthrombolysed comparators. We selected patients with ischemic stroke on whom we had data on age, pretreatment baseline National Institutes of Health Stroke Scale (b-NIHSS), and 90-day outcome measures (functional modified Rankin score [mRS]) and neurological measures [NIHSS]) in the Virtual International Stroke Trials Archive. We compared outcomes between thrombolysed patients and nonthrombolysed comparators in those with and without diabetes, those who have had a prior stroke, or both and report findings using the Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression analyses. We report an age-adjusted and b-NIHSS-adjusted CMH P value and odds ratio (OR). Rankin data were available for 5,817 patients: 1,585 thrombolysed patients and 4,232 nonthrombolysed comparators. A total 1,334 (24.1%) patients had diabetes, 1,898 (33.7%) patients have had a prior stroke, and 491 (8%) patients had both. Diabetes and nondiabetes had equal b-NIHSS (median 13; P = 0.3), but patients who have had a prior stroke had higher b-NIHSS than patients who have not had a prior stroke (median 13 vs. 12; P < 0.0001). Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P < 0.0001; OR 1.4 [95% CI 1.3-1.6]) and diabetic (P = 0.1; 1.3 [1.05-1.6 ]) subjects. Similarly, outcomes were better for thrombolysed patients versus nonthrombolysed comparators among who have not had a prior stroke (P < 0.0001; 1.4 [1.2-1.6 ]) and those who have (P = 0.02; 1.3 [1.04-1.6 ]). There was no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes were consistent with the mRS. Outcomes from thrombolysis are better among patients with diabetes and/or those who have had a prior stroke than in control subjects. Withholding thrombolytic treatment from otherwise-eligible patients may not be justified.


Predicting the effect of various ISA penetration grades on pedestrian safety by simulation.
Intelligent speed adaption (ISA) is one type of vehicle-based intelligent transportation systems (ITS), which warns and regulates driving speed according to the speed limits of the roads. Early field studies showed that ISA could reduce general mean speed levels and their variances in different road environments. This paper studies the effects of various ISA penetration grades on pedestrian safety in a single lane road. A microscopic traffic simulation tool, TPMA, was further developed and used to implement different ISA penetration grades. Momentary spot speed and traffic flow data are first logged in the traffic simulation for later prediction of pedestrian safety. Then a hypothetical vehicle-pedestrian collision model is extended from early researches in order to estimate two safety indicators: probability of collision, and risk of death. Finally, Monte Carlo method is applied iteratively to compute those safety indices. The computational result shows that raising ISA penetration in traffic flow will reduce both the probability of mid-block collision between vehicle and pedestrian and the risk of death in the collision accidents. Furthermore, the decrease of the risk of death will be more prominent than that of the collision probability according to this method.


Instability at the FRA8I common fragile site disrupts the genomic integrity of the KIAA0146, CEBPD and PRKDC genes in colorectal cancer.
Specific patterns of genomic aberrations have been associated with different types of malignancies. In colorectal cancer, losses of chromosome arm 8p and gains of chromosome arm 8q are among the most common chromosomal rearrangements, suggesting that the centromeric portion of chromosome 8 is particularly sensitive to breakage. Genomic alterations frequently occur in the early stages of tumorigenesis at specific genomic regions known as common fragile sites (cFSs). CFSs represent parts of the normal chromosome structure that are prone to breakage under replication stress. In this study, we identified the genomic location of FRA8I, spanning 530 kb at 8q11.21 and assessed the composition of the fragile DNA sequence. FRA8I encompasses KIAA0146, a large protein-coding gene with yet unknown function, as well as CEBPD and part of PRKDC, two genes encoding proteins involved in tumorigenesis in a variety of cancers. We show that FRA8I is unstable in lymphocytes and epithelial cells, displaying similar expression rates. We examined copy number alteration patterns within FRA8I in a panel of 25 colorectal cancer cell lines and surveyed publically available profiles of 56 additional colorectal cancer cell lines. Combining these data shows that focal recombination events disrupt the genomic integrity of KIAA0146 and neighboring cFS genes in 12.3% of colorectal cancer cell lines. Moreover, data analysis revealed evidence that KIAA0146 is a translocation partner of the immunoglobulin heavy chain gene in recurrent t(8;14)(q11;q32) translocations in a subset of patients with B-cell precursor acute lymphoblastic leukemia. Our data molecularly describe a region of enhanced chromosomal instability in the human genome and point to a role of the KIAA0146 gene in tumorigenesis.


Intracranial complications associated with spinal surgery.
Though rare, intracranial complications have been reported as a result from spinal surgery. Most if not all of these are a result of intracranial hypotension from durotomy and cerebrospinal fluid (CSF) leak. We aimed to characterize these complications across a large postoperative population at our institution. We conducted a retrospective review of all patients who underwent spinal surgery at our institution by four neurosurgeons from July 2008 to August 2013. Our review yielded 1113 consecutive patients who underwent spinal surgery for a total of 1396 procedures. Intracranial imaging using either computed tomography or magnetic resonance imaging was obtained on 59 (4.2%) patients after a procedure due to neurologic change. Six patients (0.4%) were found to have intracranial findings of subdural hygroma (4 patients), remote cerebellar hemorrhage (1 patient), or subdural hematoma (1 patient). Intracranial complications from spinal surgery are a rare event. We demonstrate an incidence of 0.4% of total intracranial pathology after spinal surgery. A strong clinical suspicion must be maintained after durotomy or CSF leak due to these infrequent but potentially life-threatening complications.