The role of catecholamines in the etiology of infertility in diabetes mellitus.
Patients suffering from diabetes mellitus often develop reproductive dysfunction including anovulation, infertility and disrupted pregnancy. The biochemical basis of these phenomena is yet to be provided. The current study utilizes a neuroendocrine paradigm involving an in vitro microdissection technique in conjunction with jugular catheterization to examined the proestrus dynamics of norepinephrine (NE) and the preovulatory luteinizing hormone (LH) surge in streptozotocin (STZ) treated female rats, an animal model for insulin dependent diabetes mellitus. Radioimmunoassays revealed that in control subjects LH was at basal level during the morning of proestrus (900-1200 h); the first significant increase in the level of this pituitary hormone occurred at 1400-1500 h. A maximum peak concentration of LH was attained at 1700 h. In contrast, plasma levels of LH in diabetic subjects showed the first significant increase at 1500 h and peaked at 2000 h. The peak of the LH curve in diabetic rats was reduced by about 65% with a 3 h shift to the right. Alpha-methyl-p-tyrosine-induced blockade of newly synthesized NE-based assay showed that NE turnover rates in several hypothalamic nuclei (e.g. medial preoptic nucleus, MPN; median eminence, ME; suprachiasmatic nucleus, SCN; arcuate nucleus, AN) of control subjects were at basal level during the morning of proestrus (0900-1100 h). However, they increased by the 1200-1400 h interval and remained elevated during the 1500-1700 h. This time dependent increase in hypothalamic NE turnover rates during proestrus was not observed in the STZ diabetic rats. Most of the above metabolic derangements were partially reversed following the institution of insulin replacement therapy. Overall, our data support the concept that the endocrine abnormalities (e.g. infertility, delayed preovulatory LH surge) in diabetes are due, at least in part, to a functional deficit in noradrenergic neurons within the hypothalamus.


Effects of Acute Laboratory Stress on Executive Functions.
Recent research indicates that stress can affect executive functioning. However, previous results are mixed with respect to the direction and size of effects, especially when considering different subcomponents of executive functions. The current study systematically investigates the effects of stress on the five components of executive functions proposed by Smith and Jonides (1999): attention and inhibition; task management; planning; monitoring; and coding. Healthy participants (N = 40) were either exposed to the computerized version of the Paced Auditory Serial Addition Test as a stressor (N = 20), or to a rest condition (N = 20). Stress reactions were assessed with heart rate and subjective measures. After the experimental manipulation, all participants performed tasks that measure the different executive functions. The manipulation check indicates that stress induction was successful (i.e., the stress group showed a higher heart rate and higher subjective responses than the control group). The main results demonstrate that stressed participants show a poorer performance compared with unstressed participants in all executive subcomponents, with the exception of monitoring. Effect sizes for the tasks that reveal differences between stressed and unstressed participants are high. We conclude that the laboratory stressor used here overall reduced executive functioning.


Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review.
On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug-metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol-O-methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non-malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish.


All-optical, thermo-optical path length modulation based on the vanadium-doped fibers.
This paper presents an all-fiber, fully-optically controlled, optical-path length modulator based on highly absorbing optical fiber. The modulator utilizes a high-power 980 nm pump diode and a short section of vanadium-co-doped single mode fiber that is heated through absorption and a non-radiative relaxation process. The achievable path length modulation range primarily depends on the pump's power and the convective heat-transfer coefficient of the surrounding gas, while the time response primarily depends on the heated fiber's diameter. An absolute optical length change in excess of 500 µm and a time-constant as short as 11 ms, were demonstrated experimentally. The all-fiber design allows for an electrically-passive and remote operation of the modulator. The presented modulator could find use within various fiber-optics systems that require optical (remote) path length control or modulation.


An exploratory analysis of demography and movement patterns of dogs: New insights in the ecology of endemic Rocky Mountain-Spotted Fever in Mexicali, Mexico.
An outbreak of Rocky Mountain spotted fever (RMSF) transmitted by the brown dog tick (Rhipicephalus sanguineus sensu lato) has emerged as a major human and animal health concern in Mexicali, Mexico. Due to high rates of brown dog tick infestation, susceptibility, and association with humans, dogs serve as sentinels and have a key role in the ecology of RMSF. A cross-sectional household questionnaire study was conducted in six rural and urban locations to characterize dog ecology and demography in RMSF high-and low-risk areas of Mexicali. In addition, we tracked movement patterns of 16 dogs using a GPS data logger. Of 253 households, 73% owned dogs, and dog ownership tended to be higher in high-risk areas, with a mean dog:human ratio of 0.43, compared with 0.3 in low-risk areas. Dogs in high-risk areas had higher fecundity and roamed more, but the dog density and numbers of free-roaming dogs were comparable. There was a higher proportion of younger dogs and lower proportion of older dogs in high-risk areas. The high proportion of immunologically naïve puppies in high risk areas could result in a lack of herd immunity leading to a more vulnerable dog and human population. The marked increase of space use of free-roaming dogs in high-risk areas suggests that unrestrained dogs could play an important role in spreading ticks and pathogens. As means to limit RMSF risk, practical changes could include increased efforts for spay-neuter and policies encouraging dog restraint to limit canine roaming and spread of ticks across communities; due to dog density is less impactful such policies may be more useful than restrictions on the number of owned dogs.


COVID-19 prediction using Caviar Squirrel Jellyfish Search Optimization technique in fog-cloud based architecture.
In the pandemic of COVID-19 patients approach to the hospital for prescription, yet due to extreme line up the patient gets treatment after waiting for more than one hour. Generally, wearable devices directly measure the preliminary data of the patient stored in capturing mode. In order to store the data, the hospitals require large storage devices that make the progression of data more complex. To bridge this gap, a potent scheme is established for COVID-19 prediction based fog-cloud named Caviar Squirrel Jellyfish Search Optimization (CSJSO). Here, CSJSO is the amalgamation of CAViar Squirrel Search Algorithm (CSSA) and Jellyfish Search Optimization (JSO), where CSSA is blended by the Conditional Autoregressive Value-at-Risk (CAViar) and Squirrel Search Algorithm (SSA). This architecture comprises the healthcare IoT sensor layer, fog layer and cloud layer. In the healthcare IoT sensor layer, the routing process with the collection of patient health condition data is carried out. On the other hand, in the fog layer COVID-19 detection is performed by employing a Deep Neuro Fuzzy Network (DNFN) trained by the proposed Remora Namib Beetle JSO (RNBJSO). Here, RNBJSO is the combination of Namib Beetle Optimization (NBO), Remora Optimization Algorithm (ROA) and Jellyfish Search optimization (JSO). Finally, in the cloud layer, the detection of COVID-19 employing Deep Long Short Term Memory (Deep LSTM) trained utilizing proposed CSJSO is performed. The evaluation measures utilized for CSJSO_Deep LSTM in database-1, such as Mean Squared Error (MSE) and Root Mean Squared Error (RMSE) observed 0.062 and 0.252 in confirmed cases. The measures employed in database-2 are accuracy, sensitivity and specificity achieved 0.925, 0.928 and 0.925 in K-set.


[The characterization of Biomphalaria orbignyi Paraense, 1974, a mollusk of medico-epidemiological importance recently reported for Cuba].
The conchological, anatomical and radular characteristics of Biomphalaria orbignyi are described, as well as the morphometric ratio between maximal height and maximal diameter, in which the regression coefficient value is 0.9. The life tables of Biomphalaria orbignyi shows a life range (L phi = 10.37) much higher than in the rest of the species available in Cuba; the value of k = 0.17 is similar to that of Biomphalaria havanensis. It has 2 reproductive peaks at middle age. Differently from other species of the genus, it has lower mortality at early ages and the highest peak is seen when it reaches the adult stage, which means it is a strong species. The zymograms that have been obtained confirm this species is different from B. havanensis. Since there are no marked differences on an individual basis, its correct identification requires to take into consideration every biological and ecological evidence available.


Conserved C-terminal threonine of hepatitis C virus NS3 regulates autoproteolysis and prevents product inhibition.
Inspection of over 250 hepatitis C virus (HCV) genome sequences shows that a threonine is strictly conserved at the P1 position in the NS3-NS4A (NS3-4A) autoproteolysis junction, while a cysteine is maintained as the P1 residue in all of the putative trans cleavage sites (NS4A-4B, NS4B-5A, and NS5A-5B). To understand why T631 is conserved at the NS3-4A junction of HCV, a series of in vitro transcription-translation studies were carried out using wild-type and mutant (T631C) NS3-4A constructs bearing native, truncated, and mutant NS4A segments. The autocleavage of the wild-type junction was found to be dependent on the presence of the central cofactor domain of NS4A (residues 21 to 34). In contrast, all NS3-4A T631C mutant proteins underwent self-cleavage even in the absence of the cofactor. Subgenomic replicons derived from the Con1 strain of HCV and bearing the T631C mutation showed reduced levels of colony formation in transfection studies. Similarly, replicons derived from a second genotype 1b virus, HCV-N, demonstrated a comparable reduction in replication efficiency in transient-transfection assays. These data suggest that the threonine is conserved at position 631 because it serves two functions: (i) to slow processing at the NS3-4A cleavage site, ensuring proper intercalation of the NS4A cofactor with NS3 prior to polyprotein scission, and (ii) to prevent subsequent product inhibition by the NS3 C terminus.


Sequential expression of macrophage anti-microbial/inflammatory and wound healing markers following innate, alternative and classical activation.
The present study examines the temporal dynamics of macrophage activation marker expression in response to variations in stimulation. We demonstrate that markers can be categorized as 'early' (expressed most abundantly at 6 h post-stimulation) or 'late' (expressed at 24 h post-stimulation). Thus nos2 and p40 (IL-12/IL-23) are early markers of innate and classical activation, while dectin-1 and mrc-1 are early markers and fizz1 (found in inflammatory zone-1) and ym1 are late markers of alternative activation. Furthermore, argI is a late marker of both innate and alternative activation. The ability of interferon (IFN)-gamma to alter these activation markers was studied at both the protein level and gene level. As reported previously, IFN-gamma was able to drive macrophages towards the classical phenotype by enhancing nos2 gene expression and enzyme activity and p40 (IL-12/IL-23) gene expression in lipopolysaccharide (LPS)-stimulated macrophages. IFN-gamma antagonized alternative macrophage activation, as evident by reduced expression of dectin-1, mrc-1, fizz1 and ym1 mRNA transcripts. In addition, IFN-gamma antagonized arginase activity irrespective of whether macrophages were activated innately or alternatively. Our data explain some apparent contradictions in the literature, demonstrate temporal plasticity in macrophage activation states and define for the first time 'early' and 'late' markers associated with anti-microbial/inflammatory and wound healing responses, respectively.


Rotatable magnetic anisotropy in Si/SiO2/(Co2Fe)(x)Ge(1-x) Heusler alloy films.
Polycrystalline (Co2Fe)(x)Ge(1-x) Heusler alloy films are fabricated by sputtering on amorphous substrates and shown to possess three types of magnetic anisotropy. The nearly stoichiometric composition of x = 50 m.f.% shows a rectangular hysteresis loop and isotropic coercive and ferromagnetic resonance fields when the film is field-magnetized along any in-plane direction, thus predominantly possessing rotatable in-plane magnetic anisotropy. Higher-x compositions show evidence of two- and fourfold in-plane anisotropy superposed on the rotatable one. A qualitative model of the observed anisotropic magnetic properties is proposed. The model explains the rotatable anisotropy by taking into account dry friction for the in-plane rotation of the magnetization direction in a fine-grained polycrystalline film with the magnetic grain size smaller than the correlation length of the inter-grain exchange interaction. The observed two- and fourfold magnetic anisotropy contributions are attributed to partial texturing of the fine-grained films, even though the films are grown on amorphous SiO2 substrates. These results should be valuable for understanding and controlling the magnetic behaviour of highly spin-polarized Heusler alloy films used in various magnetic nanodevices.


Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers.
Specific and sensitive non-invasive biomarkers for the detection of human epithelial malignancies are urgently required to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are 19-24 nt noncoding RNAs that are frequently dysregulated in cancer and have shown great promise as tissue-based markers for cancer classification. Once thought to be unstable RNA molecules, miRNAs are now shown to be stably expressed in serum, plasma, urine, saliva, and other body fluids. Moreover, the unique expression patterns of these circulating miRNAs are correlated with certain human diseases, including various types of cancer. Therefore, tumor-derived miRNAs in serum or plasma are emerging as novel blood-based fingerprints for the detection of human cancers, especially at an early stage. This review presented newly uncovered cellular and molecular mechanisms of the sources and stability of circulating miRNAs, revealing their great potential as a class of highly specific and sensitive biomarkers for tumor classification and prognostication. Meanwhile, this review also addressed certain critical issues that hinder the wide application of this new approach. Some potential challenges for the transition of circulating miRNAs from a research setting to a clinical application were also highlighted, with a future perspective of the incorporation of circulating miRNAs in the field of clinical oncology, especially their great potential from diagnostic to prognostic and predictive applications.


Rotavirus epidemiology and genotype distribution in hospitalised children, Greece, 2008 to 2020: A prospective multicentre study.
BackgroundTwo rotavirus (RV) vaccines were licensed in Greece in late 2006 and included in the national immunisation programme in 2012.AimTo study the epidemiology and genotype distribution of RV in children during the post-vaccination period and assess the impact of increased vaccination coverage.MethodsIn a prospective multicentre hospital-based study, hospitalised children (≤ 16 years) with an RV-positive faecal sample were recruited. Epidemiological and genotyping analyses were performed; periods of low (2008-12) and moderate (2012-20) RV vaccination coverage were compared. Statistical analysis was performed with a chi-squared or Mann-Whitney U test and logistic regression.ResultsA total of 3,874 children (55.6% male; n = 2,153) with median age of 1.4 years (IQR: 0.5-3.3) were studied during 2008-20. Most RV-infected children were aged ≤ 3 years (72.2%) and hospitalised during December-May (69.1%). Common RV genotypes (G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], G12P[8]) were detected in 92.2% of samples; G-P combinations with prevalence above 1% were G4P[8] (44.1%), G1P[8] (25.4%), G2P[4] (14.9%), G9P[8] (3.5%), G12P[8] (2.2%), G3P[8] (2.1%), other (4.3%) and mixed (3.5%). Of all samples, 97.6% were homotypic or partially heterotypic to vaccines' genotypes. With moderate vaccination coverage, the seasonal peak was detected earlier, children were older and partially or fully heterotypic genotypes were increased (p < 0.001).ConclusionsIn the era of moderate RV vaccination coverage in Greece, epidemiology of RV in hospitalised children seemed to change. However, most circulating genotypes remain homotypic or partially heterotypic to RV vaccines. Continuous epidemiological surveillance and genotyping are important to monitor possible changes arising from RV vaccines' implementation.


Traumatized mothers can change their minds about their toddlers: Understanding how a novel use of videofeedback supports positive change of maternal attributions.
This study explored the use of a brief experimental intervention that integrates principles of infant-parent psychotherapy, videofeedback, controlled exposure to child distress in the context of parental posttraumatic stress disorder (PTSD), and stimulation of parental reflective functioning (RF). The Clinician Assisted Videofeedback Exposure Session (CAVES) was applied to 32 interpersonal violence-exposed mothers of very young children (8-50 months) with respect to change of maternal perception of her child. While we found no significant reduction over two videotaped assessment visits with a mental health professional, we did find a significant reduction in the degree of negativity of maternal attributions towards her child following the videotaped visit focused on the CAVES (p<.01). Maternal RF, a mother's capacity to think about mental states in herself and her child, accounted for 11% of the variance in reduction of maternal negativity after accounting for baseline levels of negativity. Clinician-assisted videofeedback appears to support emotional self-regulation of mothers with violence-related PTSD. Focusing with a therapist on videofeedback of child separation distress exposes mothers to avoided mental states of helplessness and perceived loss of protection. Negative maternal attributions may mark violent trauma-associated emotion dysregulation and projected self-representations of the maltreated mother.


What is an organ? Heidegger and the phenomenology of organ transplantation.
This paper investigates the question of what an organ is from a phenomenological perspective. Proceeding from the phenomenology of being-in-the-world developed by Heidegger in Being and Time and subsequent works, it compares the being of the organ with the being of the tool. It attempts to display similarities and differences between the embodied nature of the organs and the way tools of the world are handled. It explicates the way tools belong to the totalities of things of the world that are ready to use and the way organs belong to the totality of a bodily being able to be in this very world. In so doing, the paper argues that while the organ is in some respects similar to a bodily tool, this tool is nonetheless different from the tools of the world in being tied to the organism as a whole, which offers the founding ground of the being of the person. However, from a phenomenological point of view, the line between organs and tools cannot simply be drawn by determining what is inside and outside the physiological borders of the organism. We have, from the beginning of history, integrated technological devices (tools) in our being-in-the-world in ways that make them parts of ourselves rather than parts of the world (more organ- than tool-like), and also, more recently, have started to make our organs more tool-like by visualising, moving, manipulating, and controlling them through medical technology. In this paper, Heidegger's analysis of organ, tool, and world-making is confronted with this development brought about by contemporary medical technology. It is argued that this development has, to a large extent, changed the phenomenology of the organ in making our bodies more similar to machines with parts that have certain functions and that can be exchanged. This development harbours the threat of instrumentalising our bodily being but also the possibility of curing or alleviating suffering brought about by diseases which disturb and destroy the normal functioning of our organs.


Cost variation in a laparoscopic cholecystectomy and the association with outcomes across a single health system: implications for standardization and improved resource utilization.
Payers and regulatory bodies are increasingly placing emphasis on cost containment, quality/outcome measurement and transparent reporting. Significant cost variation occurs in many operative procedures without a clear relationship with outcomes. Clear cost-benefit associations will be necessary to justify expenditures in the era of bundled payment structures. All laparoscopic cholecystectomies (LCCKs) performed within a single health system over a 1-year period were analysed for operating room (OR) supply cost. The cost was correlated with American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) outcomes. From July 2013 to June 2014, 2178 LCCKs were performed by 55 surgeons at seven hospitals. The median case OR supply cost was $513 ± 156. There was variation in cost between individual surgeons and within an individual surgeon's practice. There was no correlation between cost and ACS NSQIP outcomes. The majority of cost variation was explained by selection of trocar and clip applier constructs. Significant case OR cost variation is present in LCCK across a single health system, and there is no clear association between increased cost and NSQIP outcomes. Placed within the larger context of overall cost, the opportunity exists for improved resource utilization with no obvious risk for a reduction in the quality of care.


Complement C5b-9 complex activates phospholipases in glomerular epithelial cells.
In rat membranous nephropathy, formation of the C5b-9 membrane attack complex (MAC) leads to proteinuria in association with glomerular visceral epithelial cell (GEC) injury. These alterations in GEC function and morphology might result from changes in intracellular free Ca2+ concentration [( Ca2+]i) and activation of phospholipases. We demonstrate that in cultured rat GEC, antibody-directed formation of noncytolytic amounts of the MAC induced a rapid and sustained increase in [Ca2+]i that was partly inhibited by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). The MAC elevated levels of inositol bis- (IP2) and trisphosphate (IP3), as well as 1,2-diacylglycerol (DAG) and phosphatidic acid (PA). In permeabilized GEC, IP3 released Ca2+ from intracellular stores. Cellular 45Ca2+ uptake was also increased by the MAC. Thus, in GEC, the MAC induced Ca2+ mobilization from intracellular stores secondary to activation of phospholipase C and production of IP3, as well as enhanced Ca2+ influx. In addition, C5b-9 stimulated release of arachidonic acid (AA), prostaglandin F2 alpha, and thromboxane A2. Indomethacin partially inhibited the increase in DAG levels observed with the MAC, whereas the prostaglandin H2/thromboxane A2 analogue U46619 elevated DAG, suggesting that an eicosanoid product of MAC-induced AA release may enhance the activation of phospholipase C. Activation of phospholipases by the MAC may lead to altered GEC function and thereby contribute to the pathophysiological changes that characterize complement-dependent rat membranous nephropathy.


Venus Flytrap Rarely Traps Its Pollinators.
Because carnivorous plants rely on arthropods as pollinators and prey, they risk consuming would-be mutualists. We examined this potential conflict in the Venus flytrap (Dionaea muscipula), whose pollinators were previously unknown. Diverse arthropods from two classes and nine orders visited flowers; 56% of visitors carried D. muscipula pollen, often mixed with pollen of coflowering species. Within this diverse, generalized community, certain bee and beetle species appear to be the most important pollinators, on the basis of their abundance, pollen load size, and pollen fidelity. Dionaea muscipula prey spanned four invertebrate classes and 11 orders; spiders, beetles, and ants were most common. At the family and species levels, few taxa were shared between traps and flowers, yielding a near-zero value of niche overlap for these potentially competing structures. Spatial separation of traps and flowers may contribute to partitioning the invertebrate community between nutritional and reproductive functions in D. muscipula.


Neuromuscular synapses can form in vivo by incorporation of initially aneural postsynaptic specializations.
Synapse formation requires the coordination of pre- and postsynaptic differentiation. An unresolved question is which steps in the process require interactions between pre- and postsynaptic cells, and which proceed cell-autonomously. One current model is that factors released from presynaptic axons organize postsynaptic differentiation directly beneath the nerve terminal. Here, we used neuromuscular junctions (NMJs) of the zebrafish primary motor system to test this model. Clusters of neurotransmitter (acetylcholine) receptors (AChRs) formed in the central region of the myotome, destined to be synapse-rich, before axons extended and even when axon extension was prevented. Time-lapse imaging revealed that pre-existing clusters on early-born slow (adaxial) muscle fibers were incorporated into NMJs as axons advanced. Axons were, however, required for the subsequent remodeling and selective stabilization of synaptic clusters that precisely appose post- to presynaptic elements. Thus, motor axons are dispensable for the initial stages of postsynaptic differentiation but are required for later stages. Moreover, many AChR clusters on later-born fast muscle fibers formed at sites that had already been contacted by axons, suggesting heterogeneity in the signaling mechanisms leading to synapse formation by a single axon.


Influence of Sterilization and Preservation Procedures on the Integrity of Serum Protein-Coated Magnetic Nanoparticles.
Protein-coated magnetic nanoparticles are promising candidates for various medical applications. Prior to their application into a biological system, one has to guarantee that the particle dispersions are free from pathogens or any other microbiologic contamination. Furthermore, to find entrance into clinical routine, the nanoparticle dispersions have to be storable for several months. In this study, we tested several procedures for sterilization and preservation of nanoparticle containing liquids on their influence on the integrity of the protein coating on the surface of these particles. For this, samples were treated by freezing, autoclaving, lyophilization, and ultraviolet (UV) irradiation, and characterized by means of dynamic light scattering, determination of surface potential, and gel electrophoresis afterwards. We found that the UV sterilization followed by lyophilization under the addition of polyethylene glycol are the most promising procedures for the preparation of sterilized long-term durable protein-coated magnetic nanoparticles. Ongoing work is focused on the optimization of used protocols for UV sterilization and lyophilization for further improvement of the storage time.


Too clever to care?
Alan Glasper assesses the controversy surrounding the Chief Nursing Officer's BBC Radio 4 interview on graduate entry to nursing on 12 November 2009.


In vitro tumoricidal activity of immunoadsorbed leukemic serum.
We studied the ability of untreated or immunoadsorbed acute myelogenous leukemia (AML) sera to kill AML blasts. Culture of blasts with sera adsorbed to protein A-bearing Staphylococcus aureus Cowan I (SAC), resulted in a marked loss of blast viability (42.7% of control). Immunoadsorption against non-protein A-bearing Wood 46 strain of S. aureus did not induce serum cytotoxic activity (94.8% viable cells). Sera adsorbed to Sepharose-bound protein A also killed blasts in vitro (64.3% viable cells). The addition of untreated sera to SAC-treated cultures partly abrogated the effect, suggesting a blocking substance in untreated serum. Cytotoxicity was not complement-dependent nor did it appear to be cell mediated. It was, however, eliminated by trypsin treatment of SAC-treated sera. These studies suggest that SAC-treated AML serum contains a protein that is cytotoxic to AML blasts, and that this protein is partly inactivated by untreated AML serum, possibly through interaction with immunoglobulins. The mechanism described here may be one of several mechanisms leading to tumor necrosis in tumor-bearing hosts treated with SAC-immunoadsorbed plasma.


Is the protein expression window during testicular development affected in patients at risk for stem cell loss?
Is the protein expression window during testicular development affected in prepubertal patients at risk for stem cell loss? Nuclear ubiquitin carboxyl-terminal esterase L1 (UCHL1) expression in Sertoli cells and interstitial expression of inhibin α (INHA), sex-determining region Y-box 9 (SOX9) and steroidogenic acute regulatory protein (STAR) was affected in patients with Klinefelter syndrome. Some patients undergoing testicular tissue banking have already been treated before the testis biopsy is taken. These treatments include chemotherapy or hydroxyurea, which can have an influence on the stem cell number and function. A germinal loss occurs in Klinefelter patients, but its cause is currently unknown. Parrafin-embedded testicular tissue from 5 fetuses, 25 prepubertal patients and 5 adults was used to characterize the spatial and temporal distribution of different testicular marker proteins during testicular development. Expression of the markers was evaluated in germ cells, Sertoli cell and interstitial cells. The integrity of this time window was analyzed in patients at risk for germ cell loss: patients treated with hydroxyurea (n = 7), patients treated with chemotherapy (n = 6) and patients affected by Klinefelter syndrome (n = 5). Immunohistochemistry was performed in normal fetal, prepubertal and adult testicular tissue to set up a timeline for the expression of melanoma antigen family A4 (MAGE-A4), ubiquitin carboxyl-terminal esterase L1 (UCHL1), octamer-binding transcription factor 4 (OCT4), stage-specific embryonic antigen-4 (SSEA4), homeobox protein NANOG, INHA, anti-Müllerian hormone, androgen receptor (AR), SOX9 and STAR. The established timeline was used to evaluate whether the expression of these markers was altered in patients at risk for germ cell loss (patients treated for sickle cell disease (hydroxyurea) or cancer (chemotherapy) and patients with Klinefelter syndrome). A protein expression timeline was created using different markers expressed in different testicular cell types. Less positive tubules and less positive cells per tubule were observed for MAGE-A4 and UCHL1 expression in the KS compared with the non-treated group (P < 0.01). Higher nuclear UCHL1 Sertoli cell expression was observed in the KS group compared with the non-treated group (P < 0.05). Higher interstitial expression of INHA (P < 0.05), SOX9 (P < 0.01) and STAR (P < 0.05) was observed in KS compared with the non-treated group. Important age variations exist in the prepubertal groups. Therefore, data were represented in three age groups. However, owing to the limited access to prepubertal tissue, no statistical comparison was possible between these groups. For the Klinefelter group, tissue was only available from patients older than 12 years. The expression timeline can add knowledge to the process of spermatogenesis and be used to evaluate altered protein patterns in patients undergoing potentially gonadotoxic treatments, to monitor spermatogenesis established in vitro and to unravel causes of germ cell loss in Klinefelter patients.


Plasma Double Layers at the Boundary Between Venus and the Solar Wind.
The solar wind is slowed, deflected, and heated as it encounters Venus's induced magnetosphere. The importance of kinetic plasma processes to these interactions has not been examined in detail, due to a lack of constraining observations. In this study, kinetic-scale electric field structures are identified in the Venusian magnetosheath, including plasma double layers. The double layers may be driven by currents or mixing of inhomogeneous plasmas near the edge of the magnetosheath. Estimated double-layer spatial scales are consistent with those reported at Earth. Estimated potential drops are similar to electron temperature gradients across the bow shock. Many double layers are found in few high cadence data captures, suggesting that their amplitudes are high relative to other magnetosheath plasma waves. These are the first direct observations of plasma double layers beyond near-Earth space, supporting the idea that kinetic plasma processes are active in many space plasma environments.


Epidemiology of Chikungunya in the Americas.
Chikungunya virus (CHIKV) emerged in the Americas in late 2013 to cause substantial acute and chronic morbidity. About 1.1 million cases of chikungunya were reported within a year, including severe cases and deaths. The burden of chikungunya is unclear owing to inadequate disease surveillance and underdiagnosis. Virus evolution, globalization, and climate change may further CHIKV spread. No approved vaccine or antiviral therapeutics exist. Early detection and appropriate management could reduce the burden of severe atypical and chronic arthritic disease. Improved surveillance and risk assessment are needed to mitigate the impact of chikungunya.


Demographic and socioeconomic correlates of powder cocaine and crack use among high school seniors in the United States.
Rates of powder cocaine and crack use have fluctuated among adolescents over recent decades. Little attention has been paid to recent trends, particularly regarding differences between users of powder cocaine and crack-two forms of the substance that are commonly reported together as "cocaine" use, despite having different effects and rates of adverse outcomes. We examined data from nationally representative samples of high school seniors who participated in the Monitoring the Future study during years 2005-2011 (weighted N = 65 717). Many demographic and socioeconomic variables were similarly correlated with lifetime use of powder cocaine and crack. Income of >$50/week from job increased the odds for use, and income of >$50/week from sources other than a job more than doubled the odds for use. High religiosity, high parent education, identifying as black, and residing with one or two parents reduced odds for use. Hispanic students were at higher odds for use of crack and females were at lower odds for using powder cocaine. Among cocaine users, residing with one or two parents lowered odds for using both forms, and more religious students and Hispanics were at higher odds for crack-only use. Those interested in preventing initiation and adverse consequences of cocaine use should take into account the overlapping, yet different risk profiles of powder cocaine and crack users when developing programming. This is particularly important when considering differences in legal consequences for these pharmacologically similar forms of cocaine.


Oncologists' attitudes towards prophylaxis of cancer associated venous thromboembolism: A prospective, descriptive study.
Cancer-associated venous thromboembolism creates a big burden on both patients and healthcare systems. Clinical guidelines have a consensus on the initiation of prophylactic treatment for hospitalised patients, however a debate still exists for ambulatory cancer patients. Therefore, this study aimed to identify attitudes and practices of medical oncologists on cancer-associated venous thromboembolism management. An online survey consisting of 22 questions was developed by researchers in the view of previous studies and delivered to 100 medical oncologists registered to the national society of medical oncology by e-mail between September and October 2018. Descriptive and statistical analyses were performed using Statistical Package for Social Science (SPSS) version 23.0 (ICM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp). A total of 62 medical oncologists (75.8% male) responded to the survey (response rate of 62%). The most critical three risk factors considered for initiating prophylaxis were prior venous thromboembolism history, immobilisation and tumour/cancer type for inpatients and outpatients (χ2 test, p < 0.001). The first choice of drug for prophylaxis was mostly low molecular weight heparins (n = 60, 96.8%). In the absence of contraindications, physicians initiate prophylaxis 'usually' for inpatients (n = 25, 40.3%) and outpatients (n = 5, 8.1%). However routine use of the Khorana score is not incorporated into the risk assessment process of cancer patients. Attitudes of oncologists towards thromboprophylaxis in cancer patients are consistent with previous studies in the literature. The respondents are aware of the venous thromboembolism risk of cancer patients, however raising awareness on both cancer-associated venous thromboembolism and current guideline recommendations is needed.


Bloodstream infections caused by Stenotrophomonas maltophilia: a seven-year review.
Stenotrophomonas maltophilia is a significant nosocomial pathogen, responsible for an increasing number of infections, particularly in immunocompromised patients. This study describes the clinical and microbiological characteristics of patients with Stenotrophomonas maltophilia bacteraemia. We reviewed the charts of 102 patients with Stenotrophomonas maltophilia bacteraemia over a seven-year period from 2001 to 2007 in two tertiary care centres in New York, USA. There were 79 episodes (77.5%) related to nosocomial acquisition, 21 (20.6%) were healthcare-associated and two episodes (2%) were community-acquired. The most common source of bacteraemia was an infected central catheter in 44 patients (43.1%); 17 (16.6%) were related to neutropenic sepsis; nine (8.8%) were from an abdominal source; six (5.9%) were from a respiratory source, and the source of the bacteraemia was unclear in 26 cases (25.5%). The majority (94.1%) of the patients had central venous access devices. Intensive care unit stay, intubation, septic shock, neutropenia at the time of bacteraemia or carbapenem antibiotic use within 30 days of the episode were associated with mortality according to univariate analysis. By multivariate analysis, hypotensive shock and carbapenem use within 30 days of the episode were factors significantly correlated with mortality. The 102 isolates were mostly susceptible in vitro to trimethoprim-sulfamethoxazole (97.1%), levofloxacin (92.9%), ceftazidime (53.0%) and ticarcillin-clavulanic acid (49.2%). Our data describe the characteristics of patients with Stenotrophomonas maltophilia bacteraemia and emphasize the importance of careful evaluation of vascular access devices in those patients.


Relative amino acid composition signatures of organisms and environments.
Identifying organism-environment interactions at the molecular level is crucial to understanding how organisms adapt to and change the chemical and molecular landscape of their habitats. In this work we investigated whether relative amino acid compositions could be used as a molecular signature of an environment and whether such a signature could also be observed at the level of the cellular amino acid composition of the microorganisms that inhabit that environment. To address these questions we collected and analyzed environmental amino acid determinations from the literature, and estimated from complete genomic sequences the global relative amino acid abundances of organisms that are cognate to the different types of environment. Environmental relative amino acid abundances clustered into broad groups (ocean waters, host-associated environments, grass land environments, sandy soils and sediments, and forest soils), indicating the presence of amino acid signatures specific for each environment. These signatures correlate to those found in organisms. Nevertheless, relative amino acid abundance of organisms was more influenced by GC content than habitat or phylogeny. Our results suggest that relative amino acid composition can be used as a signature of an environment. In addition, we observed that the relative amino acid composition of organisms is not highly determined by environment, reinforcing previous studies that find GC content to be the major factor correlating to amino acid composition in living organisms.


Recurrent locked knee caused by an impaction fracture following inferior patellar dislocation: a case report.
Locked knee caused by inferior patellar dislocation is considered rare in elderly patients. It was originally thought that, in the osteoarthritic knee, osteophytes on the pole of the patella become entrapped in the inter-condylar notch, which is managed by performing closed reduction and immobilization in a knee splint for three to four weeks. We present an unusual case of a locked knee with an impaction fracture. To the best of our knowledge, there have been no previous reports of such impaction fractures managed with arthroscopy. We present an unusual case of an 88-year-old Caucasian woman with moderate arthritis who had a locked knee caused by an impaction fracture of the patella into the lateral femoral condyle. In this case report, we describe the need for arthroscopic surgery to prevent relocking of the knee in these patients. This case report emphasizes the need for careful assessment of locked knees in elderly patients. Impaction fractures should be considered in all rare cases of patellar dislocation, and we advocate arthroscopic assessment of the articular cartilage in these patients. This is an important consideration, as the population demographics change and such impaction fractures may become more common in patients with degeneration in the knees.


Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis.
Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome. In our prior study of 575 patients at high risk for acute respiratory distress syndrome, concurrent statin and aspirin use was associated with reduced acute respiratory distress syndrome. However, the largest study (n = 3,855) to date found no significant benefit of prehospital aspirin in a lower-risk population when adjusted for the propensity for aspirin use. We aimed to determine whether prehospital aspirin use is associated with decreased acute respiratory distress syndrome in patients at high risk for acute respiratory distress syndrome after adjusting for the propensity to receive aspirin. Secondary analysis of patients enrolled prospectively in the Validating Acute Lung Injury Markers for Diagnosis study. A total of 1,149 critically ill patients (≥40 years old) admitted to the medical or surgical ICUs of an academic tertiary care hospital including 575 previously reported patients as well as additional patients who were enrolled after completion of the prior statin and aspirin study. None. Of 1,149 patients, 368 (32%) developed acute respiratory distress syndrome during the first 4 ICU days and 287 (25%) patients had prehospital aspirin use. Patients with prehospital aspirin had significantly lower prevalence of acute respiratory distress syndrome (27% vs 34%; p=0.034). In a multivariable, propensity-adjusted analysis including age, gender, race, sepsis, and Acute Physiology and Chronic Health Evaluation score II, prehospital aspirin use was associated with a decreased risk of acute respiratory distress syndrome (odds ratio, 0.66; 95% CI, 0.46-0.94) in the entire cohort and in a subgroup of 725 patients with sepsis (odds ratio, 0.60; 95% CI, 0.41-0.90). In this selected cohort of critically ill patients, prehospital aspirin use was independently associated with a decreased risk of acute respiratory distress syndrome even after adjusting for the propensity of prehospital aspirin use. These findings support the need for prospective clinical trials to determine whether aspirin may be beneficial for the prevention of clinical acute respiratory distress syndrome.


Regional cerebral blood flow during submergence asphyxia in Pekin duck.
The cerebrovascular response to submergence asphyxia was studied in the Pekin duck (Anas platyrhynchos var.) by use of the cerebral blood flow (CBF) tracer [14C]isopropyliodoamphetamine and quantitative autoradiography. Blood flow of the whole brain was 158 +/- 14 (SE) ml.min-1 x 100 g-1 (n = 7) in control animals. There was a doubling of flow to 320 +/- 61 ml.min-1 x 100 g-1 (n = 6) during submergence asphyxia. The hypothesis that CBF is redistributed within the brain during asphyxia was not supported. There were no regional reductions in CBF during submergence asphyxia. Mean arterial blood pressure was similar (approximately 140 mmHg), but heart rate, arterial blood gas tensions, and arterial pH were significantly different in control and submerged ducks at the time CBF was measured. The differences in CBF among submerged animals correlated strongly with arterial PCO2 and mean arterial blood pressure. The smallest proportional difference in regional CBF between control and submerged ducks occurred in the ectostriatum (+141%) and the largest in the locus ceruleus (+241%). The largest absolute difference in regional CBF was in the nucleus ruber (+322 ml.min-1 x 100 g-1). These are the first measurements of blood flow in discrete nuclei and regions of the avian brain.


Understanding medical ethics.
Moral thinking is embedded within cultures, and we use ethics all the time in our dealings with one another. Many functioning communities tend to share some values that reflect a particular view of the importance of human life in quantity and quality. Rights and duties form an interconnected network of obligations that protect the security of individuals and groups. In health care, the motives and virtues of practitioners are important sources of the determination to provide care for the ill within the limits of resource constraints. Ethics and the law have similarities, but also significant differences that may cause tension between the two systems. Health care is morally grounded, and provides a bulwark against the widespread fear of disease and suffering. The way in which health care is delivered depends on both national wealth and community values. Ethical problems can be seen as dilemmas, in which there are conflicting values. Modern ethical thinking in health is complicated by the need to consider the values and interests of many stakeholders--patients, health care workers, families, politicians, administrators, health bureaucrats and many others. There are ways of ethical thinking that take account of these often countervailing interests. No universally 'right' answers can be specified. The mode and the thoroughness of ethical consideration, and the careful consideration of local community values, will help to assure that we make the best possible decisions for the time and place.


Functional porous carbon-ZnO nanocomposites for high-performance biosensors and energy storage applications.
A one-pot synthesis method for the fabrication of biomass-derived activated carbon-zinc oxide (ZAC) nanocomposites using sugarcane bagasse as a carbon precursor and ZnCl2 as an activating agent is reported. For the first time, we used ZnCl2 as not only an activating agent and also for the synthesis of ZnO nanoparticles on the AC surface. ZAC materials with varying ZnO loading were prepared and characterized by a variety of analytical and spectroscopic techniques such as FE-SEM, FE-TEM, XRD, EA, XPS, and Raman spectroscopy. ZAC-modified glassy carbon electrodes (GCEs) were found to exhibit remarkable electrochemical properties for simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) as well as hazardous pollutants such as hydrogen peroxide (H2O2) and hydrazine (N2H4) with desirable sensitivity, selectivity, and detection limits. Moreover, ZAC-modified stainless steel electrodes also showed superior performances for supercapacitor applications. The ZAC nanocomposites, which may be mass produced by the reported facile direct route from sugarcane bagasse, are not only eco-friendly but also cost-effective, and thus, are suitable as a practical platform for bio-sensing and energy storage applications.


Pre-Analytical Variables Influencing Stability of Blood-Based Biomarkers of Neuropathology.
Sample collection and preanalytical protocols may significantly impact the results of large-scale epidemiological studies incorporating blood-based biomarkers of neuropathology. To evaluate the stability and assay variability of several blood-based biomarkers of neuropathology for common preanalytical conditions. We collected serum and plasma samples from 41 participants and evaluated the effect of processing delay of up to 72 h when stored at 4∘C, three freeze-thaw cycles, and a combination of 48-h processing delay when stored at 4∘C and three freeze-thaw cycles on biomarker stability. Using the Simoa assay (Quanterix Inc.), we measured amyloid-β 40 (Aβ40), amyloid-β 42 (Aβ42), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 181 (p-tau-181). We found that Aβ40 and Aβ42 levels significantly decreased after a 24-h processing delay in both plasma and serum samples, and a single freeze-thaw cycle (p < 0.0001). Nevertheless, serum Aβ42/40 ratio remained stable with a processing delay up to 48 h while plasma Aβ42/40 ratio showed only small but significant increase with a delay up to 72 h. Both plasma and serum GFAP and NfL levels were only modestly affected by processing delay and freeze-thaw cycles. Plasma p-tau-181 levels notably increased with a 24-, 48-, and 72-h processing delay, but remained stable in serum. Intra-individual variation over two weeks was minimal for all biomarkers and their levels were substantially lower in serum when compared with plasma. These results suggest that standardizing preanalytical variables will allow robust measurements of biomarkers of neuropathology in population studies.


Flexible proton-responsive ligand-based Mn(i) complexes for CO2 hydrogenation: a DFT study.
A series of flexible proton-responsive group substituted N^N-bidentate ligand based Mn(i) complexes have been studied for base free CO2 hydrogenation. We show here that proton responsive ligands play a critical role in base free CO2 hydrogenation. Our calculated reaction free energy barrier values for heterolytic H2 cleavage show that such flexible proton-responsive ligands require a very low activation energy (∼3 kcal mol-1) barrier. Such flexible proton responsive ligands improve the strong dihydrogen (HH) bonding, which in turn improves heterolytic H2 cleavage - an important step for base free CO2 hydrogenation. Therefore, we believe that such flexible proton responsive ligand-substituted metal complexes can be promising for base free CO2 hydrogenation reactions.


[Very low frequency electric and magnetic fields and the immune system].
Recent residential and occupational epidemiological studies indicate a statistical association between 50-60 Hz magnetic field exposure and the risk of developing some kinds of tumors. Several experimental researches have been carried out in vitro and in vivo to verify the possibility that some cell functions may be influenced by ELF (Extremely Low Frequencies: 0-300 Hz) electric and magnetic fields. Such researchers are very important to assess if the statistical association indicated by the epidemiological studies is actually due to a cause-effect relationship between ELF electric and magnetic fields and carcinogenesis. In this review we describe the present state of the experimental research, focusing our attention on the effects of ELF fields on the immune system. We also describe some theoretical researches whose aim is to identify possible mechanisms of interaction between ELF fields and biological systems which may provide biological plausibility to the observed effects.


[The side effects of antibiotics in chronic bronchitis].
The author investigated the frequency and character of side-effects to penicillin, levomycetin, tetracycline in the treatment of 92 patients with different forms of chronic bronchitis. Clinically all side-effects were subdivided in dysbacteriosis, allergic, toxic and mixed. It was established that the high incidence of side-effects furthers allergization of the body and potentiation of bronchial spasm. That is why the employment of antibiotics in these cases is not indicated. The low incidence of side-effect of antibiotics in purulent bronchitis requires their use under thorough medical surveillance.


Decompression sickness risk in rats by microbial removal of dissolved gas.
We present a method for reducing the risk of decompression sickness (DCS) in rats exposed to high pressures of H2. Suspensions of the human colonic microbe Methanobrevibacter smithii were introduced via a colonic cannula into the large intestines of the rats. While the rats breathed H2 in a hyperbaric chamber, the microbe metabolized some of the H2 diffusing into the intestine, converting H2 and CO2 to methane and water. Rate of release of methane from the rats, which was monitored by gas chromatography, varied with chamber H2 pressure. This rate was higher during decompression than during compression, suggesting that during decompression the microbe was metabolizing H2 stored in the rats' tissues. Rats treated with M. smithii had a 25% (5 of 20) incidence of DCS, which was significantly lower (P < 0.01) than the 56% (28 of 50) incidence of untreated controls, brought on by a standardized compression and decompression sequence. Thus using a microbe in the intestine to remove an estimated 5% of the body burden of H2 reduced DCS risk by more than one-half. This method of biochemical decompression may potentially facilitate human diving.


A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A.
Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. Patient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t90). Data from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40 h mg l⁻¹), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t90 was 5.8 days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4 days (6.4-11.7) for short dialysis times (10th percentile). A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.


Plant pathogens provide clues to the potential origin of bat white-nose syndrome Pseudogymnoascus destructans.
White-nose syndrome has killed millions of bats, yet both the origins and infection strategy of the causative fungus, Pseudogymnoascus destructans, remain elusive. We provide evidence for a novel hypothesis that P. destructans emerged from plant-associated fungi and retained invasion strategies affiliated with fungal pathogens of plants. We demonstrate that P. destructans invades bat skin in successive biotrophic and necrotrophic stages (hemibiotrophic infection), a mechanism previously only described in plant fungal pathogens. Further, the convergence of hyphae at hair follicles suggests nutrient tropism. Tropism, biotrophy, and necrotrophy are often associated with structures termed appressoria in plant fungal pathogens; the penetrating hyphae produced by P. destructans resemble appressoria. Finally, we conducted a phylogenomic analysis of a taxonomically diverse collection of fungi. Despite gaps in genetic sampling of prehistoric and contemporary fungal species, we estimate an 88% probability the ancestral state of the clade containing P. destructans was a plant-associated fungus.


Social anxiety disorder and memory for positive feedback.
Clinical theorists postulate that individuals with social anxiety disorder (SAD) display memory biases such that recall of social events becomes more negative with time; however, alternative memory models have also been proposed. Research has focused predominantly on selective recall of negative information with inconsistent findings. The goal of the current study was to examine potential biases in recall of positive social feedback. Individuals with SAD (n = 59) and nonanxious community controls (n = 63) engaged in an unexpected public speaking task and received standardized positive or neutral feedback on their speech. Participants were asked to recall the feedback after 5 minutes and after 1 week. Results indicated that at delayed recall, individuals with SAD recalled positive feedback as less positive than it had been. The findings support cognitive models of SAD and extend the model to positive social information. Research is needed to understand the mechanisms that underlie fading positivity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The mediating role of cutaneous sensitivity within neonatal psychoneuroimmunology.
Preliminary results of this study have been presented at the ICIS Conferences held in Atlanta, 1998; a Summary of results has been quoted in Adamson-Macedo (1997; 1998). OBJECTIVES: Despite knowledge that preterm infants in intensive care are in distress and need to be provided with appropriate intervention, studies with ventilated babies are still rare particularly during their first weeks of life. This study tested the hypothesis that cutaneous stimulation in the form of TAC-TIC therapy, involving only light stroking and NOT massage or kinesthetic massage, has a mediating role in eliciting beneficial psychoneuroimmunological coactions in the ventilated preterm during the first week of post-natal life. METHODS: A repeated measure, counterbalanced design, was used to collect data twice daily for three consecutive days. This intervention was compared with a control condition consisting of a period of spontaneous activity during which the same infants lay alone with no intervention taking place. For the first time, monitoring facilities were made available for immunological, physiological and behavioral responses to be assessed simultaneously before and after intervention and before and after spontaneous activities. RESULTS. A one tailed t-test indicated that the cutaneous intervention resulted in significantly more episodes of beneficial coactions than matched sessions of spontaneous activity. CONCLUSION: It is suggested that the sensory nerves endings in the skin receive the stimulation from the stroking actions; consequently impulses are being sent via afferent nerve fibers to the limbic system where the sensation is interpreted, by 68% of the neonates, as being comforting or not distressing.


Effect of Gamma Irradiation on Fecundity, Sterility, and Female Sex Pheromone Production of Callosobruchus chinensis (Coleoptera: Bruchidae).
Azuki bean beetle, Callosobruchus chinensis (L.) (Coleoptera: Bruchidae), is a field-to-storage pest of legumes and its females produce sex pheromone components with two isomers: (2Z,6E)-7-ethyl-3,11-dimethyl-2,6,10-dodecatrienal (2Z-homofarnesal) and (2E,6E)-7-ethyl-3,11-dimethyl-2,6,10-dodecatrienal (2E-homofarnesal). Two-day-old virgin adults were treated with different doses (0, 200, 300, 400, 500, and 600 Gy) of gamma radiation and the effects on adult survivorship, fecundity, sterility, and pheromone production were studied. The longevity of both sexes and female fecundity were dose dependently affected by the gamma irradiation revealing that the fecundity was more reduced when the female adults were irradiated. Adults of both sexes were totally sterilized by the doses of gamma radiation tested in this study as depicted by the null hatchability of the laid eggs. The results from analyses by gas chromatography-mass spectrometry for solid phase micro-extraction revealed that both of the female sex pheromone components were significantly reduced by 300 Gy. Though significantly less, there was release of some amount of pheromone components by the irradiated female azuki bean beetles revealing the possibility of pheromonal attraction of males to the irradiated females. It is a pre-requisite for the successful sterile insect technology that the sterility of azuki bean beetle is induced without the total disruption of the calling behavior.


Inhibition of histone acetylation as a tool in bone tissue engineering.
Our approach to bone tissue engineering is the in vitro expansion and osteogenic differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs) and their subsequent implantation on porous ceramic materials. Current osteogenic differentiation protocols use dexamethasone to initiate the osteogenic process, thus ignoring the multiple signaling pathways that control osteogenesis in vivo. Supporting osteogenesis at multiple stages might further enhance the bone-forming capacity of hMSCs. As reported previously, inhibition of so-called histone deacetylases (HDACs) stimulates osteoblast maturation, and in this report, we investigated whether trichostatin A (TSA), a widely used HDAC inhibitor, can be implemented in bone tissue engineering. We confirmed that TSA treatment of hMSCs results in increased expression of alkaline phosphatase (ALP) with concomitant increase in mineralization. Flow cytometry demonstrated that TSA increases the percentage of ALP-positive hMSCs as well as their average ALP expression level, but the robustness of the response differs between donors. Unfortunately, TSA has a profound negative effect on cell proliferation, so we investigated whether hMSCs respond to TSA after reaching confluence. Confluent hMSCs on tissue culture plastic displayed enhanced ALP expression. Therefore, we seeded TSA-treated hMSCs onto ceramic particles and analyzed ectopic bone formation upon implantation in immune-deficient mice. Unfortunately, TSA-treated hMSCs did not display better bone formation in vivo than control cells. Finally, we observed that TSA treatment strongly enhanced bone formation of ex vivo cultured mouse calvaria, which warrants further exploration of TSA in bone tissue engineering.


Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy.
Phytoestrogens, which are abundant in flaxseed and soy, have chemical structures resembling those of endogenous estrogens and have been shown to exert hormonal effects, thereby affecting chronic diseases. We compared the effects of consuming equal amounts of flaxseed or soy on estrogen metabolism and biochemical markers of bone metabolism in postmenopausal women. In a parallel design, the diet of postmenopausal women (n = 46) was supplemented with either a placebo, soy (25 g soy flour), or flaxseed (25 g ground flaxseed) muffin for 16 wk. Blood and 24-h urine samples were collected at baseline and at the endpoint. Urine samples were analyzed for phytoestrogens, estrogen metabolites (2-hydroxyestrone, 16alpha-hydroxyestrone), and serum hormones (estradiol, estrone, estrone sulfate). Serum and urine samples were also analyzed for biochemical markers of bone metabolism. Urinary concentrations of 2-hydroxyestrone, but not of 16alpha-hydroxyestrone, increased significantly in the flaxseed group (P = 0.05). In the flaxseed group, the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone was positively correlated with urinary lignan excretion (r = 0.579, P = 0.02). In the soy and placebo groups, no significant correlation was observed. No significant change in serum hormones or biochemical markers of bone metabolism was observed within or between the treatment groups. Supplementation with flaxseed modifies urinary estrogen metabolite excretion to a greater extent than does supplementation with an equal amount of soy. This modification by flaxseed is associated with an increase in urinary lignan excretion. Despite the shift in estrogen metabolism to favor the less biologically active estrogens, a negative effect on bone cell metabolism was not observed.


Postoperative cognitive disorders.
The elderly are the fastest growing segment of the population and undergo 25-30% of all surgical procedures. Postoperative cognitive problems are common in older patients following major surgery. The socioeconomic implications of these cognitive disorders are profound; cognitive decline is associated with a loss of independence, a reduction in the quality of life, and death. This review will focus on the two most common cognitive problems following surgery: postoperative delirium and postoperative cognitive dysfunction (POCD). For years, preoperative geriatric consultation/screening was the only intervention proven to decrease postoperative delirium. There are, however, several recent publications indicating that preoperative and postoperative pharmacological and medical (hydration, oxygenation) management can reduce postoperative delirium. Spinal anesthesia with minimal propofol sedation has been shown to decrease the incidence of postoperative delirium in hip-fracture patients. Likewise, dexmedetomidine sedation in mechanically ventilated patients in the ICU is associated with less postoperative delirium and shorter ventilator times. Preoperative levels of education and brain function (cognitive reserve) may predict patients at risk for postoperative cognitive problems. Reduced white matter integrity is reported to place patients at a higher risk for both postoperative delirium and POCD. The etiology of postoperative cognitive problems is unknown, but there is emerging evidence that decreased preoperative cognitive function contributes to the development of postoperative delirium and POCD. There is growing concern that inhalation anesthetics may be neurotoxic to the aging brain, but there are no human data evaluating this hypothesis to date. Randomized controlled trials evaluating interventions to improve long-term cognitive outcomes in elderly patients are urgently needed.


Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease.
The presence or absence of minimal residual disease (MRD) in patients with multiple myeloma (MM) has emerged as a useful marker to determine the depth of remission. MRD negativity as an endpoint has been shown to be associated with improved progression-free survival in many studies. MRD detection is therefore part of numerous clinical trial protocols for MM. At the present time, two methodologies are most widely accepted for MRD detection: (1) multicolor flow cytometry and (2) next-generation sequencing-based clonotype detection. While both of those methodologies enable accurate quantification of MRD in the bone marrow (BM), with sensitivity as low as 10-5 to 10-6, there are several limitations to these methods. First, these approaches reveal the presence or absence of MRD but provide limited molecular information about MM. More comprehensive characterization of MM cells at the MRD stage may identify molecular mechanisms of drug resistance. Second, MRD detection in the BM is typically performed at one time point only, but more frequent detection may define the duration of the MRD status and thus refine its prognostic value. Third, less-invasive approaches that avoid the discomfort and risk associated with BM biopsy would be highly desirable, especially in elderly or frail patients. "Liquid biopsy" for the detection and characterization of circulating MM cells may address these issues. Although MRD detection in the peripheral blood at the same sensitivity as in the BM may be challenging, the identification of patients who do not achieve MRD negativity might reduce the need for BM biopsies. Here, we give an overview of approaches that have been described to detect and characterize MM cells when they occur at very low frequencies in the peripheral blood or in the BM, emphasizing recently described next-generation sequencing approaches for more comprehensive characterization of circulating MM cells.


A Randomized Control Trial of Cardiopulmonary Feedback Devices and Their Impact on Infant Chest Compression Quality: A Simulation Study.
In effort to improve chest compression quality among health care providers, numerous feedback devices have been developed. Few studies, however, have focused on the use of cardiopulmonary resuscitation feedback devices for infants and children. This study evaluated the quality of chest compressions with standard team-leader coaching, a metronome (MetroTimer by ONYX Apps), and visual feedback (SkillGuide Cardiopulmonary Feedback Device) during simulated infant cardiopulmonary resuscitation. Seventy voluntary health care providers who had recently completed Pediatric Advanced Life Support or Basic Life Support courses were randomized to perform simulated infant cardiopulmonary resuscitation into 1 of 3 groups: team-leader coaching alone (control), coaching plus metronome, or coaching plus SkillGuide for 2 minutes continuously. Rate, depth, and frequency of complete recoil during cardiopulmonary resuscitation were recorded by the Laerdal SimPad device for each participant. American Heart Association-approved compression techniques were randomized to either 2-finger or encircling thumbs. The metronome was associated with more ideal compression rate than visual feedback or coaching alone (104/min vs 112/min and 113/min; P = 0.003, 0.019). Visual feedback was associated with more ideal depth than auditory (41 mm vs 38.9; P = 0.03). There were no significant differences in complete recoil between groups. Secondary outcomes of compression technique revealed a difference of 1 mm. Subgroup analysis of male versus female showed no difference in mean number of compressions (221.76 vs 219.79; P = 0.72), mean compression depth (40.47 vs 39.25; P = 0.09), or rate of complete release (70.27% vs 64.96%; P = 0.54). In the adult literature, feedback devices often show an increase in quality of chest compressions. Although more studies are needed, this study did not demonstrate a clinically significant improvement in chest compressions with the addition of a metronome or visual feedback device, no clinically significant difference in Pediatric Advanced Life Support-approved compression technique, and no difference between compression quality between genders.


In-Depth Bioinformatic Analyses of Nidovirales Including Human SARS-CoV-2, SARS-CoV, MERS-CoV Viruses Suggest Important Roles of Non-canonical Nucleic Acid Structures in Their Lifecycles.
Non-canonical nucleic acid structures play important roles in the regulation of molecular processes. Considering the importance of the ongoing coronavirus crisis, we decided to evaluate genomes of all coronaviruses sequenced to date (stated more broadly, the order Nidovirales) to determine if they contain non-canonical nucleic acid structures. We discovered much evidence of putative G-quadruplex sites and even much more of inverted repeats (IRs) loci, which in fact are ubiquitous along the whole genomic sequence and indicate a possible mechanism for genomic RNA packaging. The most notable enrichment of IRs was found inside 5'UTR for IRs of size 12+ nucleotides, and the most notable enrichment of putative quadruplex sites (PQSs) was located before 3'UTR, inside 5'UTR, and before mRNA. This indicates crucial regulatory roles for both IRs and PQSs. Moreover, we found multiple G-quadruplex binding motifs in human proteins having potential for binding of SARS-CoV-2 RNA. Non-canonical nucleic acids structures in Nidovirales and in novel SARS-CoV-2 are therefore promising druggable structures that can be targeted and utilized in the future.


Keeping the home fires burning: AMP-activated protein kinase.
Living cells obtain energy either by oxidizing reduced compounds of organic or mineral origin or by absorbing light. Whichever energy source is used, some of the energy released is conserved by converting adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which are analogous to the chemicals in a rechargeable battery. The energy released by the conversion of ATP back to ADP is used to drive most energy-requiring processes, including cell growth, cell division, communication and movement. It is clearly essential to life that the production and consumption of ATP are always maintained in balance, and the AMP-activated protein kinase (AMPK) is one of the key cellular regulatory systems that ensures this. In eukaryotic cells (cells with nuclei and other internal membrane-bound structures, including human cells), most ATP is produced in mitochondria, which are thought to have been derived by the engulfment of oxidative bacteria by a host cell not previously able to use molecular oxygen. AMPK is activated by increasing AMP or ADP (AMP being generated from ADP whenever ADP rises) coupled with falling ATP. Relatives of AMPK are found in essentially all eukaryotes, and it may have evolved to allow the host cell to monitor the output of the newly acquired mitochondria and step their ATP production up or down according to the demand. Structural studies have illuminated how AMPK achieves the task of detecting small changes in AMP and ADP, despite the presence of much higher concentrations of ATP. Recently, it has been shown that AMPK can also sense the availability of glucose, the primary carbon source for most eukaryotic cells, via a mechanism independent of changes in AMP or ADP. Once activated by energy imbalance or glucose lack, AMPK modifies many target proteins by transferring phosphate groups to them from ATP. By this means, numerous ATP-producing processes are switched on (including the production of new mitochondria) and ATP-consuming processes are switched off, thus restoring energy homeostasis. Drugs that modulate AMPK have great potential in the treatment of metabolic disorders such as obesity and Type 2 diabetes, and even cancer. Indeed, some existing drugs such as metformin and aspirin, which were derived from traditional herbal remedies, appear to work, in part, by activating AMPK.


Physicians' reported needs of drug information at point of care in Sweden.
Relevant and easily accessible drug information at point-of-care is essential for physicians' decision making when prescribing. However, the information available by using Clinical Decision Support Systems (CDSSs) often does not meet physicians' requirements. The Summary of Product Characteristics (SmPC) is statutory information about drugs. However, the current structure, content and format of SmPCs make it difficult to incorporate them into CDSSs and link them to relevant patient information from the Electronic Health Records. The aim of the study was to evaluate the perceived needs for drug information among physicians in Sweden. We recruited three focus group discussions with 18 physicians covering different specialities. The information from the groups was combined with a questionnaire administered at the beginning of the group discussions. Physicians reported their needs for knowledge databases at the point of drug prescribing. This included more consistent information about existing and new drugs. They also wished to receive automatically generated alerts for severe drug-drug interactions and adverse effects, and to have functions for calculating glomerular filtration rate to enable appropriate dose adjustments to be made for elderly patients and those with impaired renal function. Additionally, features enhancing electronic communication with colleagues and making drug information more searchable were suggested. The results from the current study showed the need for knowledge databases which provide consistent information about new and existing drugs. Most of the required information from physicians appeared to be possible to transfer from current SmPCs to CDSSs. However, inconsistencies in the SmPC information have to be reduced to enhance their utility.


Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.
To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score ≥13 on the Center for Neurologic Studies-Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p= 0.0002 and p= 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. DMq markedly reduced PBA frequency and severity, decreasing the condition's detrimental impact on a patient's life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA.


Pairing Cholinergic Enhancement with Perceptual Training Promotes Recovery of Age-Related Changes in Rat Primary Auditory Cortex.
We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.


Acceptability and feasibility of potential intervention strategies for influencing sedentary time at work: focus group interviews in executives and employees.
Occupational sitting can be the largest contributor to overall daily sitting time in white-collar workers. With adverse health effects in adults, intervention strategies to influence sedentary time on a working day are needed. Therefore, the present aim was to examine employees' and executives' reflections on occupational sitting and to examine the potential acceptability and feasibility of intervention strategies to reduce and interrupt sedentary time on a working day. Seven focus groups (four among employees, n = 34; three among executives, n = 21) were conducted in a convenience sample of three different companies in Flanders (Belgium), using a semi-structured questioning route in five themes [personal sitting patterns; intervention strategies during working hours, (lunch) breaks, commuting; and intervention approach]. The audiotaped interviews were verbatim transcribed, followed by a qualitative inductive content analysis in NVivo 10. The majority of participants recognized they spend their working day mostly sitting and associated this mainly with musculoskeletal health problems. Participants suggested a variety of possible strategies, primarily for working hours (standing during phone calls/meetings, PC reminders, increasing bathroom use by drinking more water, active sitting furniture, standing desks, rearranging the office) and (lunch) breaks (physical activity, movement breaks, standing tables). However, several barriers were reported, including productivity concerns, impracticality, awkwardness of standing, and the habitual nature of sitting. Facilitating factors were raising awareness, providing alternatives for simply standing, making some strategies obligatory and workers taking some personal responsibility. There are some strategies targeting sedentary time on a working day that are perceived to be realistic and useful. However several barriers emerged, which future trials and practical initiatives should take into account.


Machado Joseph-Disease Is Rare in the Peruvian Population.
Spinocerebellar ataxia type 3 or Machado-Joseph disease (MJD/SCA3) is the most prevalent autosomal dominant cerebellar ataxia worldwide, but its frequency varies by geographic region. We describe MJD/SCA3 patients diagnosed in a tertiary healthcare institution in Peru. In a cohort of 341 individuals (253 probands) with clinical ataxia diagnosis, seven MJD/SCA3 probands were identified and their pedigrees extended, detecting a total of 18 MJD/SCA3 cases. Out of 506 alleles from all probands from this cohort, the 23-CAG repeat was the most common ATXN3 allele (31.8%), followed by the 14-CAG repeat allele (26.1%). Normal alleles ranged from 12 to 38 repeats while pathogenic alleles ranged from 64 to 75 repeats. We identified 80 large normal (LN) alleles (15.8%). Five out of seven families declared an affected family member traced back to foreign countries (England, Japan, China, and Trinidad and Tobago). MJD/SCA3 patients showed ataxia, accompanied by pyramidal signs, dysarthria, and dysphagia as well as abnormal oculomotor movements. In conclusion, ATXN3 allelic distribution in non-MJD/SCA3 patients with ataxia is similar to the distribution in normal individuals around the world, whereas LN allele frequency reinforces no correlation with the frequency of MJD/SCA3. Evidence of any atypical MJD/SCA3 phenotype was not found. Furthermore, haplotypes are required to confirm the foreign origin of MJD/SCA3 in the Peruvian population.


Fast beam steering with full polarization control using a galvanometric optical scanner and polarization controller.
Optical beam steering is a key element in many industrial and scientific applications like in material processing, information technologies, medical imaging and laser display. Even though galvanometer-based scanners offer flexibility, speed and accuracy at a relatively low cost, they still lack the necessary control over the polarization required for certain applications. We report on the development of a polarization steerable system assembled with a fiber polarization controller and a galvanometric scanner, both controlled by a digital signal processor board. The system implements control of the polarization decoupled from the pointing direction through a feed-forward control scheme. This enables to direct optical beams to a desired direction without affecting its initial polarization state. When considering the full working field of view, we are able to compensate polarization angle errors larger than 0.2 rad, in a temporal window of less than ∼ 20 ms. Given the unification of components to fully control any polarization state while steering an optical beam, the proposed system is potentially integrable and robust.


Systematic review and meta-analysis in cardiac surgery: a primer.
The purpose of this article is to review the strengths and weaknesses of systematic reviews and meta-analyses to inform our current understanding of cardiac surgery. A systematic review and meta-analysis of a focused topic can provide a quantitative estimate for the effect of a treatment intervention or exposure. In cardiac surgery, observational studies and small, single-center prospective trials provide most of the clinical outcomes that form the evidence base for patient management and guideline recommendations. As such, meta-analyses can be particularly valuable in synthesizing the literature for a particular focused surgical question. Since the year 2000, there are over 800 meta-analysis-related publications in our field. There are some limitations to this technique, including clinical, methodological and statistical heterogeneity, among other challenges. Despite these caveats, results of meta-analyses have been useful in forming treatment recommendations or in providing guidance in the design of future clinical trials. There is a growing number of meta-analyses in the field of cardiac surgery. Knowledge translation via meta-analyses will continue to guide and inform cardiac surgical practice and our practice guidelines.


Quasi-monochromatic x-rays for diagnostic radiology.
Monochromatic x-ray beams are desirable in various fields of diagnostic radiology; in fact a reduction of the dose and an enhancement of the contrast could be achieved. In this work two different methods to monochromatize x-ray beams produced by conventional tubes have been compared. In the first one the beam is obtained via Bragg diffraction on mosaic crystal and in the second one by attenuating the polychromatic beam with aluminium filters. We have simulated quasi-monochromatic x-ray spectra by setting suitable values of Bragg's angle to obtain beams tuned to 20, 30, 40 and 50 keV with the SHADOW code, an x-ray tracing program designed to study the propagation and the interaction of a photon beam through an optical system. We have validated such a program by comparing some calculated data with measurements carried out on an experimental apparatus. Attenuated polychromatic x-ray spectra have been simulated by setting appropriate values of aluminium filters and potential with the SPECTRUM PROCESSOR, the software version of the Catalogue of Spectral Data for Diagnostic X-Rays, which provides radiographic x-ray spectra that can be attenuated with several material filters. The relation between the energy resolution and the flux as a function of the mean energy has been investigated and results have been compared. Results show that quasi-monochromatic x-ray beams produced via Bragg diffraction exhibit, for a given mean energy and energy resolution, a higher total flux compared to attenuated spectra.


A fluorescent turn-on probe for cyanide anion detection based on an AIE active cobalt(ii) complex.
A new tetradentate polypyridine ligand that displays aggregation induced emission (AIE) characteristics has been synthesized. A coordination complex with CoCl2 has been prepared and characterized by X-ray crystallography. The Co(ii) complex retains the AIE activity of the ligand in aqueous solution while also exhibiting a selective turn-on fluorescence response in the presence of cyanide anion. A complex : CN- binding stoichiometry of 1 : 2 was indicated via Job plot analysis and the limit of detection for CN- was determined to be 0.59 μM. The fluorescence response is attributed to coordination of CN- by the AIE active Co(ii) complex, resulting in decreased solubility in aqueous medium and concomitant generation of larger nanoaggregates as revealed by dynamic light scattering (DLS) measurements. The sensitivity and selectivity displayed by this sensor for CN- over other anions renders it a candidate probe for CN- detection in aqueous environments.


A call for theory to support the use of causal-formative indicators: A commentary on Bollen and Diamantopoulos (2017).
In this issue, Bollen and Diamantopoulos (2017) defend causal-formative indicators against several common criticisms leveled by scholars who oppose their use. In doing so, the authors make several convincing assertions: Constructs exist independently from their measures; theory determines whether indicators cause or measure latent variables; and reflective and causal-formative indicators are both subject to interpretational confounding. However, despite being a well-reasoned, comprehensive defense of causal-formative indicators, no single article can address all of the issues associated with this debate. Thus, Bollen and Diamantopoulos leave a few fundamental issues unresolved. For example, how can researchers establish the reliability of indicators that may include measurement error? Moreover, how should researchers interpret disturbance terms that capture sources of influence related to both the empirical definition of the latent variable and to the theoretical definition of the construct? Relatedly, how should researchers reconcile the requirement for a census of causal-formative indicators with the knowledge that indicators are likely missing from the empirically estimated latent variable? This commentary develops 6 related research questions to draw attention to these fundamental issues, and to call for future research that can lead to the development of theory to guide the use of causal-formative indicators. (PsycINFO Database Record


Effect of pentoxifylline on cytokine patterns in the therapy of complicated Plasmodium falciparum malaria.
The effect of pentoxifylline (PTX) was tested for its capacity to modulate cytokine responses during therapy of severe Plasmodium falciparum malaria in a placebo-controlled, randomized study in 45 adult patients in Bangkok, Thailand. The patients received standard antimalarial treatment with artesunate (120 mg intravenously given immediately, then 60 mg every 12 hr for a total dose of 600 mg). The patients received either low-dose PTX (20 mg/kg/day, n = 15), high-dose PTX (40 mg/kg/day, n = 15), or placebo (n = 15) as continuous infusion for the first three days of antimalarial treatment. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were markedly elevated in all patients prior to treatment. After 6 hr of high-dose PTX treatment, TNF and IL-6 levels significantly decreased while an increase in TNF and IL-6 levels was seen after 6 hr of low-dose PTX or placebo treatment (P < 0.01). After 12 and 24 hr of high-dose PTX infusion, TNF-receptor plasma concentrations were lower than in low-dose PTX- or placebo-treated patients (P < 0.01), whereas no differences between the groups with regard to IL-6 receptor levels were observed. We conclude that 40 mg/kg/day of PTX reduces plasma levels of TNF, IL-6, and TNF-receptor in patients with severe malaria. Whether this reduction improves clinical outcome remains to be determined.


The role of reticulo-endothelial cells in hemopoiesis in the adult liver.
Form their sinusoidal position in the properly stimulated adult liver, the reticulo-endothelial cell invades the hepatic cords. Here, their cytoplasmic processes come in direct contact with the cytoplasm of the hepatic cells. Ferritin is transferred from cord cells to the reticulo-endothelial cell, initiating extravascular hemopoiesis. As the reticulo-endothelial cell regains an intravascular position, it takes on the characteristics of a proerythroblast. The activity described for the adult liver follows the pattern observed in the fetal liver where proerythroblasts appear within the hepatic sinusoids only after hemopoiesis is established in the adjacent extravascular hepatic cords.


Photodynamic diagnosis with methyl-5-aminolevulinate in squamous intraepithelial lesions of the vulva: Experimental research.
The incidence of the High-grade Squamous Intraepithelial Lesion of the vulva, formerly vulvar intra-epithelial neoplasia is progressively increasing. Today, an early detection and a precise localization of vulvar lesions are still problematic issues, due to the lack of accuracy of the available diagnostic tool. A new approach is the photodynamic diagnosis based on the fluorescence detection of protoporphyrin IX (PpIX) in cancer cells after topical application of a cream of methyl amino-levulinic acid. This study aimed to evaluate the effectiveness of photodiagnosis in order to discriminate the intensity of PpIX fluorescence between vulvar tumor and healthy skin. After topical application of the cream, the fluorescence on xenografted A431 tumor and adjacent skin was non-invasively measured with optical fiber. The tumor to skin fluorescence ratios were 1.38 and 1.41 at respectively 3h and 6h after application, which were significantly higher compared to those observed before application. PpIX accumulation at different depths of the tumor was investigated by spectrofluorimetry after PpIX chemical extraction from tumor sections at 3h and 6h post-application. It was noticed at both application times that the concentration of PpIX within the tumor progressively decreased. However PpIX fluorescence was always detectable up to 2.5 mm, a depth equivalent to more than three quarters of the tumor. The tumor to exposed skin ratios of PpIX fluorescence showed a good selectivity up to1mm depth at 3h post-application and up to 1.5mm at 6h post-m-ALA. Thus, the photodynamic diagnosis using in vivo topical methyl amino-levulinic acid appears to be a promising way to detect the intraepithelial lesions of the vulva. Our results open the possibility for implementation of topical methyl amino-levulinic acid in clinical settings for recognition of vulvar high-grade squamous intraepithelial lesions.


Engineering non-antibody human proteins as efficient scaffolds for selective, receptor-targeted drug delivery.
Self-assembling non-immunoglobulin scaffold proteins are a promising class of nanoscale carriers for drug delivery and interesting alternatives to antibody-based carriers that are not sufficiently efficient in systemic administration. To exploit their potentialities in clinics, protein scaffolds need to be further tailored to confer appropriate targeting and to overcome their potential immunogenicity, short half-life in plasma and proteolytic degradation. We have here engineered three human scaffold proteins as drug carrier nanoparticles to target the cytokine receptor CXCR4, a tumoral cell surface marker of high clinical relevance. The capability of these scaffolds for the selective delivery of Monomethyl auristatin E has been comparatively evaluated in a disseminated mouse model of human, CXCR4+ acute myeloid leukemia. Monomethyl auristatin E is an ultra-potent anti-mitotic drug used against a range of hematological neoplasias, which because of its high toxicity is not currently administered as a free drug but as payload in antibody-drug conjugates. The protein nanoconjugates generated here offer a collective strength of simple manufacturing process, high proteolytic and structural stability and multivalent ligand receptor interactions that result in a highly efficient and selective delivery of the payload drug and in a potent anticancer effect. The approach shown here stresses this class of human scaffold proteins as promising alternatives to antibodies for targeted drug delivery in the rapidly evolving drug development landscape.