Deletion of p66Shc in mice increases the frequency of size-change mutations in the lacZ transgene.
Upon oxidative challenge the genome accumulates adducts and breaks that activate the DNA damage response to repair, arrest, or eliminate the damaged cell. Thus, reactive oxygen species (ROS) generated by endogenous oxygen metabolism are thought to affect mutation frequency. However, few studies determined the mutation frequency when oxidative stress is reduced. To test whether in vivo spontaneous mutation frequency is altered in mice with reduced oxidative stress and cell death rate, we crossed p66Shc knockout (p66KO) mice, characterized by reduced intracellular concentration of ROS and by impaired apoptosis, with a transgenic line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from organs into Escherichia coli to measure mutation rate. Liver and small intestine from 2- to 24-month-old, lacZ (p66Shc+/+) and lacZp66KO mice, were investigated revealing no difference in overall mutation frequency but a significant increase in the frequency of size-change mutations in the intestine of lacZp66KO mice. This difference was further increased upon irradiation of mice with X-ray. In addition, we found that knocking down cyclophilin D, a gene that facilitates mitochondrial apoptosis acting downstream of p66Shc, increased the size-change mutation frequency in small intestine. Size-change mutations also accumulated in death-resistant embryonic fibroblasts from lacZp66KO mice treated with H2 O2 . These results indicate that p66Shc plays a role in the accumulation of DNA rearrangements and suggest that p66Shc functions to clear damaged cells rather than affect DNA metabolism.


A CLAVATA3-like Gene Acts as a Gynoecium Suppression Function in White Campion.
How do separate sexes originate and evolve? Plants provide many opportunities to address this question as they have diverse mating systems and separate sexes (dioecy) that evolved many times independently. The classic "two-factor" model for evolution of separate sexes proposes that males and females can evolve from hermaphrodites via the spread of male and female sterility mutations that turn hermaphrodites into females and males, respectively. This widely accepted model was inspired by early genetic work in dioecious white campion (Silene latifolia) that revealed the presence of two sex-determining factors on the Y-chromosome, though the actual genes remained unknown. Here, we report identification and functional analysis of the putative sex-determining gene in S. latifolia, corresponding to the gynoecium suppression factor (GSF). We demonstrate that GSF likely corresponds to a Y-linked CLV3-like gene that is specifically expressed in early male flower buds and encodes the protein that suppresses gynoecium development in S. latifolia. Interestingly, GSFY has a dysfunctional X-linked homolog (GSFX) and their synonymous divergence (dS = 17.9%) is consistent with the age of sex chromosomes in this species. We propose that female development in S. latifolia is controlled via the WUSCHEL-CLAVATA feedback loop, with the X-linked WUSCHEL-like and Y-linked CLV3-like genes, respectively. Evolution of dioecy in the S. latifolia ancestor likely involved inclusion of ancestral GSFY into the nonrecombining region on the nascent Y-chromosome and GSFX loss of function, which resulted in disbalance of the WUSCHEL-CLAVATA feedback loop between the sexes and ensured gynoecium suppression in males.


[Effects of complex therapy with emoxipin on the course of diabetic retinopathy].
The efficacy of 1% emoxipin solution (eye drops) in the nonproliferative stage of diabetic retinopathy was studied. The inhibition of lipid peroxidation and an enhancement of antioxidizing guard were observed both after the therapy by the above preparation and 3 months later. It was concluded that emoxipin was effective for leveling the biochemical violations in the "lipid peroxidation--antioxidants" system of lachrymal fluid in patients with the nonproliferative stage of diabetic retinopathy. The prescription of emoxipin eye drops can enhance the efficacy of therapy at the early stages of the disease.


A 3-year survey quantifying the risk of dose escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more rationale prescribing.
This study investigated and quantified risk factors of dose escalation, as an indication of drug misuse and dependency of benzodiazepines and congeners, among presumably drug naïve patients in the Norwegian drug prescription database, observed over 3 years. Observational study. Prescription database study. We defined an excessive user as one redeeming more than two defined daily doses per day in 3 months. We examined the risk of excessive use over time and the effect of risk factors through multistate logistic regression and scenarios. Most of the 81 945 patients had zopiclone or zolpidem as the initial drug (63.8%), followed by diazepam (25.3%), oxazepam (6.1%), nitrazepam/flunitrazepam (2.9%), hydroxyzine/buspirone (1.6%) and alprazolam (0.3%). At any time 23% redeemed prescriptions, about 34% did not redeem any prescriptions beyond any 3-month period and 0.9% ended up as excessive users. Patients previously using drugs, such as opioids, antialcohol or smoke cessation treatment, had a higher risk to become excessive users compared to patients who had not. Patients whose first prescription was for oxazepam or nitrazepam/flunitrazepam had a higher risk of becoming an excessive user compared to those who started with diazepam. A specialist in general practice as the first-time prescriber was associated with a lower risk compared to doctors without specialty. Most benzodiazepine use occurred according to guidelines. Still, some experienced dose escalation over time, and risk factors were previous use of other psychotropic drugs, long time use, choice of first-time drug and prescriber's specialty. This could incite doctors to have a cessation plan when issuing first-time prescriptions.


[An electron microscopic study of the vegetative mycelia of Actinomyces flavus during flavofungin biosynthesis].
The vegetative mycelium of a submerged culture of Actinomyces flavus 12 was studied by complex electron microscopy (negative and positive contrasting, cryofractography) in the course of biosynthesis of flavofungin. The antibiotic is accumulated first in the cytoplasm as singular small granules which later grow larger. Accumulation of flavofungin is accompanied with destruction of the cytoplasm, nucleoid and other structures. Secretion of the antibiotic is supposed to be accomplished according to holocrine type.


Human saliva and model saliva at bulk to adsorbed phases - similarities and differences.
Human saliva, a seemingly simple aqueous fluid, is, in fact, an extraordinarily complex biocolloid that is not fully understood, despite many decades of study. Salivary lubrication is widely believed to be a signature of good oral health and is also crucial for speech, food oral processing and swallowing. However, saliva has been often neglected in food colloid research, primarily due to its high intra- to inter-individual variability and altering material properties upon collection and storage, when used as an ex vivo research material. In the last few decades, colloid scientists have attempted designing model (i.e. 'saliva mimicking fluid') salivary formulations to understand saliva-food colloid interactions in an in vitro set up and its contribution on microstructural aspects, lubrication properties and sensory perception. In this Review, we critically examine the current state of knowledge on bulk and interfacial properties of model saliva in comparison to real human saliva and highlight how far such model salivary formulations can match the properties of real human saliva. Many, if not most, of these model saliva formulations share similarities with real human saliva in terms of biochemical compositions, including electrolytes, pH and concentrations of salivary proteins, such as α-amylase and highly glycosylated mucins. This, together with similarities between model and real saliva in terms of surface charge, has led to significant advancement in decoding various colloidal interactions (bridging, depletion) of charged emulsion droplets and associated sensory perception in the oral phase. However, model saliva represents significant dissimilarity to real saliva in terms of lubricating properties. Based on in-depth examination of properties of mucins derived from animal sources (e.g. pig gastric mucins (PGM) or bovine submaxillary mucin (BSM)), we can recommend that BSM is currently the most optimal commercially available mucin source when attempting to replicate saliva based on surface adsorption and lubrication properties. Even though purification via dialysis or chromatographic techniques may influence various physicochemical properties of BSM, such as structure and surface adsorption, the lubricating properties of model saliva formulations based on BSM are generally superior and more reliable than the PGM counterpart at orally relevant pH. Comparison of mucin-containing model saliva with ex vivo human salivary conditioning films suggests that mucin alone cannot replicate the lubricity of real human salivary pellicle. Mucin-based multi-layers containing mucin and oppositely charged polyelectrolytes may offer promising avenues in the future for engineering biomimetic salivary pellicle, however, this has not been explored in oral tribology experiments to date. Hence, there is a strong need for systematic studies with employment of model saliva formulations containing mucins with and without polycationic additives before a consensus on a standardized model salivary formulation can be achieved. Overall, this review provides the first comprehensive framework on simulating saliva for a particular bulk or surface property when doing food oral processing experiments.


Synthesis and biological activity of phosphoglycolipids from Thermus thermophilus.
An extreme thermophile, Thermus thermophilus, has very unique glycolipids on the cell surface. The acidic immunostimulatory phosphoglycolipid of T. thermophilus was synthesized for the first time, with newly developed glycosylation methods using 3-nitropyridyl (3NPy) and 4,6-dimethoxy-1,3,5-triazin-2-yl (DMT) glycosides as glycosyl donors. The analogues of the phosphoglycolipid, which include a diastereomer possessing the opposite configuration at the diacyl glycerol moiety, were also synthesized. The biological activities of the synthesized compounds were elucidated with cytokine inductions (IL-6 and TNF-α). A synthetic phosphoglycolipid with a natural-type diacyl glycerol configuration showed apparent immunostimulatory activity, whereas its diastereomer did not. The present study revealed that the configuration at the diacyl glycerol moiety of the phosphoglycolipids is important for immunostimulation, suggesting the existence of the particular receptor/recognizing protein that can recognize the stereochemistry of the glycerol part.


Ab initio molecular crystal structures, spectra, and phase diagrams.
Conspectus Molecular crystals are chemists' solids in the sense that their structures and properties can be understood in terms of those of the constituent molecules merely perturbed by a crystalline environment. They form a large and important class of solids including ices of atmospheric species, drugs, explosives, and even some organic optoelectronic materials and supramolecular assemblies. Recently, surprisingly simple yet extremely efficient, versatile, easily implemented, and systematically accurate electronic structure methods for molecular crystals have been developed. The methods, collectively referred to as the embedded-fragment scheme, divide a crystal into monomers and overlapping dimers and apply modern molecular electronic structure methods and software to these fragments of the crystal that are embedded in a self-consistently determined crystalline electrostatic field. They enable facile applications of accurate but otherwise prohibitively expensive ab initio molecular orbital theories such as Møller-Plesset perturbation and coupled-cluster theories to a broad range of properties of solids such as internal energies, enthalpies, structures, equation of state, phonon dispersion curves and density of states, infrared and Raman spectra (including band intensities and sometimes anharmonic effects), inelastic neutron scattering spectra, heat capacities, Gibbs energies, and phase diagrams, while accounting for many-body electrostatic (namely, induction or polarization) effects as well as two-body exchange and dispersion interactions from first principles. They can fundamentally alter the role of computing in the studies of molecular crystals in the same way ab initio molecular orbital theories have transformed research practices in gas-phase physical chemistry and synthetic chemistry in the last half century. In this Account, after a brief summary of formalisms and algorithms, we discuss applications of these methods performed in our group as compelling illustrations of their unprecedented power in addressing some of the outstanding problems of solid-state chemistry, high-pressure chemistry, or geochemistry. They are the structure and spectra of ice Ih, in particular, the origin of two peaks in the hydrogen-bond-stretching region of its inelastic neutron scattering spectra, a solid-solid phase transition from CO2-I to elusive, metastable CO2-III, pressure tuning of Fermi resonance in solid CO2, and the structure and spectra of solid formic acid, all at the level of second-order Møller-Plesset perturbation theory or higher.


[Meningococcal disease: early clinical diagnosis and emergency care].
Late diagnosis of meningococcal disease leads to high mortality. Early diagnosis of its generalized forms plays a crucial role in the pre-hospital phase and mainly based on the clinical picture of the disease. In most cases, pre-hospital typical mistake is late diagnosis of meningococcal disease: We propose an algorithm of early diagnosis of generalized forms of the disease in order to reduce the number of diagnostic errors. Proper and timely diagnosis will enable the physician pre-hospital fully implement measures to provide emergency and urgent care in generalized meningococcal infection, leading to. a more.favourable course and a significant improvement in the outcomes of the disease in the course of further hospital treatment.


Comparison of the efficacy and tolerability of lisinopril and sustained-release verapamil in older patients with hypertension.
The efficacy and tolerability of lisinopril and sustained release (SR) verapamil hydrochloride were compared in 68 patients (mean age, 60 years) with mild to moderate uncomplicated essential hypertension. The goal of therapy was to achieve and maintain a supine diastolic blood pressure (SDBP) of less than 90 mmHg or a fall in SDBP greater than or equal to 10 mmHg. Patients received lisinopril (10 to 40 mg QD) or verapamil SR (120 to 480 mg QD) during a variable titration period (two to eight weeks) to achieve goal blood pressure prior to a four-week maintenance treatment period. Among the 62 patients who completed the titration period, the mean baseline supine systolic/diastolic blood pressures were 155/97 mmHg for the lisinopril group and 150/95 mmHg for the verapamil SR group. Ninety-seven percent of patients in the lisinopril group and 100% of patients in the verapamil SR group achieved SDBP control at the end of titration therapy. At the end of the maintenance treatment period, 82% of the lisinopril-treated patients and 81% of the verapamil SR-treated patients had SDBP control. Mean decreases in SDBP from baseline were comparable for both treatment groups. At the end of titration, mean decreases were 11.3 mmHg for the lisinopril group and 10.7 mmHg for the verapamil SR group; at the end of maintenance treatment, mean decreases were 10.5 mmHg and 8.5 mmHg. Thus both drugs were equally effective in older patients with mild to moderate essential hypertension. Both drugs were generally well tolerated. One patient in the lisinopril group and four patients in the verapamil SR group experienced adverse effects that required withdrawal from the study.


Adiposity Change Over the Life Course and Mammographic Breast Density in Postmenopausal Women.
Mammographic breast density is a strong risk factor for breast cancer. We comprehensively investigated the associations of body mass index (BMI) change from ages 10, 18, and 30 to age at mammogram with mammographic breast density in postmenopausal women. We used multivariable linear regression models, adjusted for confounders, to investigate the associations of BMI change with volumetric percent density, dense volume, and nondense volume, assessed using Volpara in 367 women. At the time of mammogram, the mean age was 57.9 years. Compared with women who had a BMI gain of 0.1-5 kg/m2 from age 10, women who had a BMI gain of 5.1-10 kg/m2 had a 24.4% decrease [95% confidence interval (CI), 6.0%-39.2%] in volumetric percent density; women who had a BMI gain of 10.1-15 kg/m2 had a 46.1% decrease (95% CI, 33.0%-56.7%) in volumetric percent density; and women who had a BMI gain of >15 kg/m2 had a 56.5% decrease (95% CI, 46.0%-65.0%) in volumetric percent density. Similar, but slightly attenuated associations were observed for BMI gain from ages 18 and 30 to age at mammogram and volumetric percent density. BMI gain over the life course was positively associated with nondense volume, but not dense volume. We observed strong associations between BMI change over the life course and mammographic breast density. The inverse associations between early-life adiposity change and volumetric percent density suggest that childhood adiposity may confer long-term protection against postmenopausal breast cancer via its effect of mammographic breast density.


Thermodynamic Assessment of Coating Materials for Solid-State Li, Na, and K Batteries.
The development of all-solid-state batteries (ASSBs) presents a pathway to enhance the energy density and safety of conventional Li-ion batteries that use liquid electrolytes. However, one of the more promising categories of solid electrolytes (SEs), sulfides, are generally unstable in contact with common electrode materials, resulting in SE decomposition and high interfacial resistance. Recent studies have indicated that the application of coatings can, in some cases, stabilize the electrode/SE interface, reducing the likelihood for harmful interfacial reactions. Here, stable coatings for Li, Na, and K ASSBs are identified. In total, the stability windows for 1112 ternary alkali-metal-based compounds were assessed, including fluorides, chlorides, oxides, sulfides, phosphides, and nitrides. In general, the fluorides and chlorides exhibit the highest oxidative stability, suggesting that they are good choices for stabilizing SE/cathode interfaces. In contrast, sulfides, phosphides, and nitrides exhibit much lower oxidative stabilities, with many of these materials predicted to decompose above 2 V. At the anode/SE interface, nitrides and oxides are predicted to be the most effective coatings, as they are generally the most stable against reductive decomposition. As expected, sulfides and phosphides are the least stable class of materials under reducing conditions. Overall, oxides appear to be the most versatile class of coating materials: several oxides are predicted to exhibit stability windows ranging from 0 to 3 V with respect to Li/Li+, Na/Na+, or K/K+. Examples of promising oxides for stabilizing the SE/anode interface include Li5AlO4, Li4SiO4, NaAlO2, Na3PO4, KAlO2, and K3PO4. Similarly, promising compounds for stabilizing the SE/cathode interface include NaPO3 and KPO3. Finally, the possibility for kinetic stabilization suggests that additional ternary oxides (e.g., based on Ga, Nb, Sb, and Ta) may be viable coatings at the SE/cathode interface.


A familial syndrome of susceptibility to chronic active Epstein-Barr virus infection.
In two members of a family (daughter and father) active Epstein-Barr virus (EBV) infections persisted over periods of 4 and 3 years respectively (possibly 10 years in the father). Both had persistent splenomegaly and occasional bouts of unexplained fever but lived otherwise normal lives. The other members of the family (mother and son) were healthy. The titres of antibody to the EBV viral capsid antigen (VCA) and early antigen (EA) were extremely high in the daughter's blood, whereas the titres of antibody to the Epstein-Barr nuclear antigen were low in the daughter's blood and undetectable in the father's. Target cells of the EBV infection that were obtained from the daughter's blood were established in culture with great difficulty and showed increased expression of VCA and EA. Other immunologic investigations in the two patients revealed that the ratio of helper to suppressor T lymphocytes was inverted, natural killer-cell activity was abnormally low, lymphocyte responses to certain mitogens were depressed and there was a serum factor blocking mitogen-induced transformation. The possibility that the patients' unusual susceptibility to EBV infection represented an inherited syndrome (perhaps X-linked) is discussed.


The KIBRA-aPKC connection: A potential regulator of membrane trafficking and cell polarity.
The kidney and brain protein (KIBRA) is a scaffold or an adaptor-like protein with WW, C2-like and atypical protein kinase C (aPKC)-binding domains. Genetic studies in Drosophila revealed that KIBRA is an upstream regulator of the conserved Hippo pathway, which is implicated in organ size determination. In addition, genome-wide studies revealed an association between the single nucleotide polymorphism in the KIBRA gene locus and human episodic memory performance. However, the mechanism of action through which KIBRA is linked to these functions remains poorly understood. Recent studies on the biochemical and cellular properties of KIBRA reveal the role of KIBRA as a regulator of membrane trafficking. Further, KIBRA directly inhibits the activity of the cell polarity regulator, aPKC, which is required for apical protein exocytosis. Here, we discuss how this KIBRA-aPKC connection, a potential regulator of membrane trafficking and cell polarity, can contribute to the recently discovered functions of KIBRA.


A Review of the Composition of the Essential Oils and Biological Activities of Angelica Species.
A number of Angelica species have been used in traditional systems of medicine to treat many ailments. Especially, essential oils (EOs) from the Angelica species have been used for the treatment of various health problems, including malaria, gynecological diseases, fever, anemia, and arthritis. EOs are complex mixtures of low molecular weight compounds, especially terpenoids and their oxygenated compounds. These components deliver specific fragrance and biological properties to essential oils. In this review, we summarized the chemical composition and biological activities of EOs from different species of Angelica. For this purpose, a literature search was carried out to obtain information about the EOs of Angelica species and their bioactivities from electronic databases such as PubMed, Science Direct, Wiley, Springer, ACS, Google, and other journal publications. There has been a lot of variation in the EO composition among different Angelica species. EOs from Angelica species were reported for different kinds of biological activities, such as antioxidant, anti-inflammatory, antimicrobial, immunotoxic, and insecticidal activities. The present review is an attempt to consolidate the available data for different Angelica species on the basis of major constituents in the EOs and their biological activities.


A single amino acid substitution affects substrate specificity in cysteine proteinases from Fasciola hepatica.
The trematode Fasciola hepatica secretes a number of cathepsin L-like proteases that are proposed to be involved in feeding, migration, and immune evasion by the parasite. To date, six full cDNA sequences encoding cathepsin L preproproteins have been identified. Previous studies have demonstrated that one of these cathepsins (L2) is unusual in that it is able to cleave substrates with a proline in the P2 position, translating into an unusual ability (for a cysteine proteinase) to clot fibrinogen. In this study, we report the sequence of a novel cathepsin (L5) and compare the substrate specificity of a recombinant enzyme with that of recombinant cathepsin L2. Despite sharing 80% sequence identity with cathepsin L2, cathepsin L5 does not exhibit substantial catalytic activity against substrates containing proline in the P2 position. Molecular modeling studies suggested that a single amino acid change (L69Y) in the mature proteinases may account for the difference in specificity at the S2 subsite. Recombinant cathepsin L5/L69Y was expressed in yeast and a substantial increase in the ability of this variant to accommodate substrates with a proline residue in the P2 position was observed. Thus, we have identified a single amino acid substitution that can substantially influence the architecture of the S2 subsite of F. hepatica cathepsin L proteases.


The autistic brain can process local but not global emotion regularities in facial and musical sequences.
Whether autism spectrum disorder (ASD) is associated with a global processing deficit remains controversial. Global integration requires extraction of regularity across various timescales, yet little is known about how individuals with ASD process regularity at local (short timescale) versus global (long timescale) levels. To this end, we used event-related potentials to investigate whether individuals with ASD would show different neural responses to local (within trial) versus global (across trials) emotion regularities extracted from sequential facial expressions; and if so, whether this visual abnormality would generalize to the music (auditory) domain. Twenty individuals with ASD and 21 age- and IQ-matched individuals with typical development participated in this study. At an early processing stage, ASD participants exhibited preserved neural responses to violations of local emotion regularity for both faces and music. At a later stage, however, there was an absence of neural responses in ASD to violations of global emotion regularity for both faces and music. These findings suggest that the autistic brain responses to emotion regularity are modulated by the timescale of sequential stimuli, and provide insight into the neural mechanisms underlying emotional processing in ASD.


Cinnamaldehyde inhibits the growth of Phytophthora capsici through disturbing metabolic homoeostasis.
Phytophthora capsici Leonian (P. capsici) can cause wilting and roots rotting on pepper and other cash crops. The new fungicide cinnamaldehyde (CA) has high activity against this pathogen. However, its potential mechanism is still unknown. In order to gain insights into the mechanism, isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics was used to analyze P. capsici treated with CA. The iTRAQ results were evaluated by parallel reaction monitoring (PRM) analysis and quantitative real-time PCR (qRT-PCR) analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to speculate the biochemical pathways that the agent may act on. The results showed that 1502 differentially expressed proteins were identified, annotated and classified into 209 different terms (like metabolic process, cellular process, single-organism process) based on Gene Ontology (GO) functional enrichment analysis and nine different pathways (glyoxylate and dicarboxylate metabolism, fatty acid metabolism and so on) based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. This study suggested that CA disordered fatty acid metabolism, polysaccharide metabolism and leucine metabolism. Based on PRM analysis, five proteins including CAMK/CAMK1 protein kinase, glucan 1,3-beta-glucosidase, 1,3-beta-glucanosyltransferase, methylcrotonoyl-CoA carboxylase subunit alpha and isovaleryl-CoA dehydrogenase were down-regulated in P. capsici treated with CA. Furthermore, the qRT-PCR analysis showed that the gene expression level of the interested proteins was consistent with the protein expression level, except for CAMK/CAMK1 protein kinase, acetyl-CoA carboxylase and fatty acid synthase subunit alpha. CA destroyed the metabolic homoeostasisof P. capsici, which led to cell death. This is the first proteomic analysis of P. capsici treated with CA, which may provide an important information for exploring the mechanism of the fungicide CA against P. capsici.


Generation of an induced pluripotent stem cell line (SHETi004-A) from a Chinese Han child with left bundle branch block.
Desmin (DES) is an important intermediate filament protein associated with the extrasarcomeric cytoskeleton and cellular function that was first reported to be associated with cardiac conduction disease and cardiomyopathy in 1998. We generated an induced pluripotent stem cell (iPSC) line from the left bundle branch block (LBBB) patient's peripheral blood mononuclear cells using Sendai virus-mediated reprogramming. The iPSCs exhibited stable amplification, expressed pluripotent markers, and spontaneously differentiated into three layers in vitro. Additionally, it showed a normal diploid karyotype and maintained the pathogenic mutation in DES. Hence, the iPSC line provided a platform for exploring LBBB mechanisms associated with DES mutations.


The role of the potato (Solanum tuberosum) CCD8 gene in stolon and tuber development.
· Strigolactones (SLs) are a class of phytohormones controlling shoot branching. In potato (Solanum tuberosum), tubers develop from underground stolons, diageotropic stems which originate from basal stem nodes. As the degree of stolon branching influences the number and size distribution of tubers, it was considered timely to investigate the effects of SL production on potato development and tuber life cycle. · Transgenic potato plants were generated in which the CAROTENOID CLEAVAGE DIOXYGENASE8 (CCD8) gene, key in the SL biosynthetic pathway, was silenced by RNA interference (RNAi). · The resulting CCD8-RNAi potato plants showed significantly more lateral and main branches than control plants, reduced stolon formation, together with a dwarfing phenotype and a lack of flowering in the most severely affected lines. New tubers were formed from sessile buds of the mother tubers. The apical buds of newly formed transgenic tubers grew out as shoots when exposed to light. In addition, we found that CCD8 transcript levels were rapidly downregulated in tuber buds by the application of sprout-inducing treatments. · These results suggest that SLs could have an effect, solely or in combination with other phytohormones, in the morphology of potato plants and also in controlling stolon development and maintaining tuber dormancy.


On Correlation Effect of the Van-der-Waals and Intramolecular Forces for the Nucleotide Chain - Metallic Nanoparticles - Carbon Nanotube Binding.
The tertiary system of nucleotide chain (NC) - gold nanoparticles (NPs) - carbon nanotube (CNT) represents a great interest in the modern research and application of the bio-nano-technologies. The application aspects include, for example, the development of electronic mobile diagnostic facilities, nanorobotic design for a drug delivery inside living cell, and so on. The small NC chain represents an important stage in the understanding of the interaction mechanism of a full DNA or RNA molecule with NP and CNT. In this regard, one has to mention the development of the DNA-CNT devices for the purposes of diagnostic applications in the chemical or drug delivery. For the NC-NP-CNT system, we have built up a series of the molecular dynamics (MD) models with different NC-NP configurations and performed their MD analysis. The entire system (the NC chain, gold NPs and CNT) was allowed to interact with each other by the only VdW forces. The Lennard-Jones short-ranged interaction was assumed between the NC, NP and CNT. For the CNT a many body Tersoff potential having a quantum-chemistry nature was used. So far, the so-called hybrid MD approach was realized, where the quantum-chemistry potential in combination with a classical trajectory calculation applied . The peculiarities of the NC-NP interaction and bond formation inside of a CNT matrix were investigated along with the structural and dynamical behavior. The correlation effects between the weak Van der Waals (VdW) forces and intramolecular vibrations were enlighten for the molecular system consisting of a small nucleotide chain (NC), gold nanoparticles (NPs) and carbon nanotube (CNT) using molecular dynamics (MD) simulation method. The NC intermolecular motions were estimated from MD data thereby building the distance distributions, the angular and dihedral (torsional) bond energy graphs versus simulation time at different temperatures from T=100 K up to 300 K. The MD simulation results have shown that depending on the relative NC-NP position a different scenario of bonding between the NC-NP, within CNT matrix, is possible. We have observed the possibilities of formation of weak, strong and intermediate bonds between the NP-NC, which are overestimated by a presence of CNT matrix as confined environment. The NC chain can form with a particular gold atom a close contact, while with another under the same positional and temperature conditions the weak resultant bonding formation might be possible. We estimated the fluctuations in the NP-NC bonding processes for a single gold atomic case (models 1-3, NC-1NP-CNT), for the two (model 4-6, NC-2NP-CNT) and three (model 7, NC-3NP-CNT) gold particle ones. Thus, a concurrent effect between the NC intramolecular vibrations and a weak VdW interaction between the NC and gold NP were studied in detail.


The boundary of holistic processing in the appraisal of facial attractiveness.
Facial attractiveness is often studied on the basis of the internal facial features alone. This study investigated how this exclusion of the external features affects the perception of attractiveness. We studied the effects of two most commonly used methods of exclusion, where the shape of an occluding mask was defined by either the facial outline or an oval. Participants rated attractiveness of the same faces under these conditions. Results showed that faces were consistently rated more attractive when they were masked by an oval shape rather than by their outline (Experiment 1). Attractive faces were more strongly affected by this effect than were less attractive faces when participants were able to control the viewing time. However, unattractive faces benefited more from this effect when the same face stimuli were presented briefly for only 20 ms (Experiment 2). Further manipulation confirmed that the effect was mainly due to the occlusion of a larger area of the external features rather than the regular and symmetrical features of the oval shape (Experiment 3) or lacks contextual cues about the face boundary (Experiment 4). The effect was only relative to masked faces, with no advantage over unmasked faces (Experiment 5), and is likely a result of the interaction between the shape of a mask and the internal features of the face. This holistic effect in the appraisal of facial attractiveness is striking, because the oval shape of the mask is not a part of the face but is the edge of an occluding object.


Olfactory stimulation variables. Which model best predicts the olfactory nerve response?
Mozell et al. (1984. J. Gen. Physiol. 83:233-267) have examined the traditional manner in which olfactory stimulus-response relationships have been addressed. They developed a model that describes the olfactory nerve response as a function of three factors, viz., the number of odorant molecules (N), the stimulus duration (T), and the stimulus volume (V). In addition, two models derived from this three-variable model were also found to predict the response well. These were the [F, N] model involving flow rate (F = V/T) and, ranking closely behind, the [C, T] model involving concentration (C = N/V). A model involving the delivery rate (D = N/T) and volume was found to predict the response poorly. These models imply very different stimulus-response relationships. The present study was designed to assess the validity of this earlier approach by testing specific predictions drawn from each of the models. Because of the excellence of the [F, N] model, one would predict that the response will not change when F and N are held constant in spite of proportional increases in V and T. Similarly, one would predict from the [C, T] model that the response will be constant when C and T are held constant in spite of proportional increases in N and V. Because of the poor showing of the [D, V] model, one would predict changes in the response even when D and V are held constant while N and T are increased proportionately. It was observed that when F and N were held constant, the response was, in fact, constant. When D and V were held constant, the response increased dramatically. When C and T were held constant, there was a statistically significant, but small, change in the response. These results support the approach taken by Mozell et al. (op. cit.) and highlight the applicability of the [F, N] model to peripheral olfactory processing. The results are discussed in terms of their impact on the traditional manner in which olfactory stimulus-response relationships are conceived.


A Systematic Review of Dietary Influences on Fecal Microbiota Composition and Function among Healthy Humans 1-20 Years of Age.
Diet is a key modulator of fecal microbiota composition and function. However, the influence of diet on the microbiota from toddlerhood to adolescence and young adulthood is less well studied than for infancy and adulthood. We aimed to complete a qualitative systematic review of the impacts of diet on the fecal microbiota of healthy humans 1-20 y of age. English-language articles, published after 2008, indexed in the PubMed/MEDLINE, Cochrane, Web of Science, and Scopus databases were searched using keywords and Medical Subject Headings terms. Quality assessment of included studies was conducted using the Quality Criteria Checklist derived from the Nutrition Evidence Library of the Academy of Nutrition and Dietetics. A total of 973 articles were identified through database searching and 3 additional articles were included via cross-reference. Subsequent to de-duplication, 723 articles were screened by title and abstract, of which 709 were excluded based on inclusion criteria established a priori. The remaining 14 studies were independently screened by 2 reviewers for final inclusion. Included studies were published between 2010 and 2019 and included 8 comparative cross-sectional studies, 4 cross-sectional studies, 1 randomized crossover study, and 1 substudy of a randomized 2-period crossover trial. Associations of a diet rich in indigestible plant polysaccharides with Prevotella, or with an enterotype dominated by this genus, often comprised of the species Prevotella copri, were observed. In addition, associations of a high-fat and -sugar diet with Bacteroides, or with an enterotype dominated by this genus, were observed predominantly in comparative cross-sectional and cross-sectional studies spanning the ages of 1-15 y. This review identified a gap in the literature for ages 16-20 y. In addition, randomized controlled trials for dietary intervention are needed to move from association-based observations to causal relations between diet and microbiota composition and function. This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42020129824.


Late diagnosis of multidrug-resistant tuberculosis in a child at Dr George Mukhari Academic Hospital, Ga-Rankuwa, South Africa: A case report.
South Africa has one of the top ten tuberculosis burdens in the world, only lagging behind countries with significantly larger populations. Increased awareness of extrapulmonary tuberculosis, specifically spinal tuberculosis, is necessary, because of the HIV epidemic. This report describes the case of a 9-year-old male patient who was suspected of having multidrug-resistant (MDR) tuberculosis, based on failure to recover clinically and radiologically after 6 months on first-line anti-tuberculosis treatment. Pus samples were sent to an accredited academic laboratory for histopathology, microscopy, culture, line-probe assay (MTBDRplus assay) and phenotypic MGIT 960 drug susceptibility tests. Second-line MDR tuberculosis treatment was introduced. Clinical, radiological, physical processes and more laboratory tests were conducted to document whether or not there was improvement in the patient. After laboratory diagnosis of MDR tuberculosis, the patient was started on MDR tuberculosis treatment. The patient started improving remarkably after the introduction of anti-tuberculosis treatment and rehabilitation, although he also required surgery to stabilise the spine. Neurological improvement was observed in the patient and he fully recovered. Although the diagnosis of spinal MDR tuberculosis may not be achieved easily by culture, the well-known gold standard method of tuberculosis diagnosis, it is of great importance to rapidly initiate an effective anti-tuberculosis treatment of drug-resistant strains to reduce the deformity of the spine.


A Long-Term Safety and Efficacy Report on Intravitreal Delivery of Adipose Stem Cells and Secretome on Visual Deficits After Traumatic Brain Injury.
We compared intravitreal injection of human adipose stem cell concentrated conditioned media (ASC-CCM) to injection of live ASCs for their long-term safety and effectiveness against the visual deficits of mild traumatic brain injury (mTBI). We first tested different intravitreal ASC doses for safety. Other C57BL/6 mice then received focal cranial blast mTBI and were injected with the safe ASC dose (1000 cells/eye), ASC-CCM (∼200 ng protein/eye), or saline solution. At five and 10 months after blast injury, visual, molecular, and histological assessments evaluated treatment efficacy. Histological evaluation of eyes and other organs at 10 months after blast injury assessed safety. Human ASCs at 1000 cells/eye were found to be safe, with >10,000 cells causing retinal damage. Blast-injured mice showed significant vision deficits compared to sham blast mice up to 10 months. Blast mice receiving ASC or ASC-CCM showed improved vision at five months but marginal effects at 10 months, correlated with changes in glial fibrillary acidic protein and proinflammatory gene expression in retina. Immunostaining for human IgG failed to detect ASCs in retina. Peripheral organs examined histologically at 10 months after blast injury were normal. Intravitreal injection of ASCs or ASC-CCM is safe and effective against the visual deficits of mTBI. Considering the unimproved glial response and the risk of retinal damage with live cells, our studies suggest that ASC-CCM has better safety and effectiveness than live cells for the treatment of visual dysfunction in mTBI. This study demonstrates the safety and efficacy of mesenchymal stem cell-based therapeutics, supporting them for phase 1 clinical studies.


Knowledge, Perceived Beliefs, and Preventive Behaviors Related to COVID-19 Among Chinese Older Adults: Cross-Sectional Web-Based Survey.
The COVID-19 pandemic continues to pose an international public health threat. Prevention is of paramount importance to protect the high-risk group of older adults until specific treatments for COVID-19 become available; however, little work has been done to explore factors that promote preventive behaviors among this population. This study aims to investigate the knowledge, perceived beliefs, and preventive behaviors towards COVID-19 of older adults in China and determine the factors that influence their practice of preventive behaviors. From February 19 to March 19, 2020, a cross-sectional, web-based survey was administered to Chinese older adults in all 31 provinces of mainland China using a convenience sampling method to assess the respondents' knowledge, perceived beliefs, and preventive behaviors towards COVID-19. Standard descriptive statistics and hierarchical linear regression analyses were conducted to analyze the data. A total of 1501 participants responded to the survey, and 1263 valid responses (84.1%) were obtained for further analysis. The overall correct rate on the knowledge questionnaire was 87%, overall positive beliefs regarding COVID-19 were found, and the mean behavior score was 13.73/15 (SD 1.62, range 5-15). The hierarchical linear regression showed that respondents who were married or cohabitating and who lived in areas with community-level control measures were more likely to practice preventive behaviors (P<.01). Knowledge (β=0.198, P<.001), perceived susceptibility (β=0.263, P=.03), perceived benefits (β=0.643, P<.001), and self-efficacy in preventing COVID-19 (β=0.468, P<.001) were also found to be significantly associated with preventive behaviors. Most older residents had adequate knowledge and positive beliefs regarding COVID-19 and engaged in proactive behaviors to prevent the disease. Knowledge and beliefs were confirmed to be significantly associated with behavior responses. Our findings have significant implications in enhancing the effectiveness of COVID-19 prevention programs targeting the older population; these programs must be continued and strengthened as the epidemic continues.


Starch Derived Nanosized Graphene Oxide Functionalized Bioactive Porous Starch Scaffolds.
A fully starch-derived bioactive 3D porous scaffold is developed. The bioactivity is introduced through nanosized graphene oxide (nGO) derived from starch by microwave-assisted degradation to carbon spheres and further oxidation to GO nanodots. nGO is covalently attached to starch to prepare functionalized starch (SNGO) via an esterification reaction. nGO and SNGO exhibit no cytotoxicity to MG63 at least up to 1000 µg mL-1 under (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Porous scaffolds consisting of starch and SNGO (S/SNGO) or nGO (S/nGO) are prepared by freeze drying. The porosity and water uptake ability of the scaffolds depend on the concentration of nGO. Moreover, nGO, as a bioactive nanofiller, functions as an effective anchoring site for inducing CaP recrystallization in simulated body fluid. Among all modified starch-based scaffolds, the S/SNGO scaffold containing the highest concentration of covalently attached SNGO (50%) induces the largest amount of hydroxyapatite, a type of CaP crystal that is closest to bone. The prepared 3D porous nGO functionalized scaffold, thus, exhibits potential promise for bone/cartilage tissue engineering.


Altered glucose metabolism in mouse and humans conceived by IVF.
In vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation (OS) and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus natural birth under energy-balanced and high-fat-overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80 mU/m(2)/min), was lower in IVF patients (n = 14) versus control subjects (n = 20) after 3 days of an energy-balanced diet (30% fat). In response to 3 days of overfeeding (+1,250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P = 0.02). Mice conceived after either OS alone or IVF weighed significantly less at birth versus controls (P < 0.01). However, only mice conceived by IVF displayed increased fasting glucose levels, impaired glucose tolerance, and reduced insulin-stimulated Akt phosphorylation in the liver after 8 weeks of consuming either a chow or high-fat diet (60% fat). Thus, OS impaired fetal growth in the mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of the development of metabolic diseases later in life, in both mice and humans.


Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene.
Avian erythroblastosis virus (AEV) contains two distinct oncogenes, erbA and erbB . The erbB oncogene, which is homologous to a portion of the epidermal growth factor receptor, is related to the src family of oncogenes and efficiently transforms erythroblasts, whereas erbA potentiates the effects of erbB by blocking the differentiation of erythroblasts at an immature stage. This "potentiator" was sequenced; the amino acid sequence deduced from it was clearly different from the sequences of other known oncogene products and was related to carbonic anhydrases. These enzymes participate in the transport of carbon dioxide by erythrocytes, the precursors of which are main targets of avian erythroblastosis virus. A src-related oncogene such as erbB in synergy with an activated specific cell-derived gene such as erbA can profoundly affect early erythroid differentiation.


[Indicators of bioelectric activity of the myocardium and gas exchange in threshold physical exertion of old patients with ischemic heart diseases].
ECG, pulmonary ventilation and gas exchange were recorded in 36 patients with ischemic heart disease and in 8 practically healthy persons of advanced age bearing a stepwise increasing physical load. In case of an obvious ischemic heart disease the tolerance of physical exertions was found to decline. Under a threshold physical load such patients demonstrate an excess ventilation; a decreased oxygen pulse and a lesser increment of the respiratory quotient, as well as a reduced coefficient of recovery, of the restored oxygen consumption rate, the respiratory rate, minute respiratory volume after exertion. In cases of a possible ischemic heart disease at advanced age the tolerance of physical efforts and a number of spiroergometric indices under a threshold load continue at the same level as in healthy people.


Psychosis in sleep apnoea.
A 30-year-old man presenting with intellectual impairment and recurrent psychotic episodes was subsequently found to have suffered from a chronically untreated obstructive sleep apnoea syndrome. Polysomnography revealed sleep fragmentation, slow wave sleep deprivation and abnormal arterial oxygen desaturation. Tonsillectomy led to complete resolution of sleep apnoea and remission of psychosis at 2 years' follow-up, but his apparent intellectual impairment persisted. The limited literature on psychosis associated with sleep apnoea is briefly reviewed.


Identification of novel tumor suppressor proteases by degradome profiling of colorectal carcinomas.
Proteolytic enzymes play important roles during tumor development and progression through their ability to promote cell growth or by facilitating the invasion of surrounding tissues. The human genome contains more than 570 protease-coding genes, many of them forming functional networks, which has forced the use of global strategies for the analysis of this group of enzymes. In this study, we have designed a new quantitative PCR-based device for profiling the entire degradome in human malignancies. We have used this method to evaluate protease expression levels in colorectal carcinomas with the finding that most proteases with altered expression in these tumors exert their function in the extracellular compartment. In addition, we have found that among genes encoding repressed proteases there was a higher proportion with somatic mutations in colorectal cancer when compared to genes coding for upregulated proteases (14% vs. 4%, p<0.05). One of these genes, MASP3, is consistently repressed in colorectal carcinomas as well as in colorectal cancer cell lines when compared to normal colonic mucosa. Functional analysis of this gene revealed that ectopic expression of MASP3 reduces cell proliferation in vitro and restrains subcutaneous tumor growth, whereas its downregulation induces an increase in the tumorigenic potential of colorectal cancer cells. These results provide new insights into the diversity of proteases associated with cancer and support the utility of degradome profiling to identify novel proteases with tumor-defying functions.


Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary.
Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients. Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response. Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases. In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis.


Organizational climate and culture: Reflections on the history of the constructs in the Journal of Applied Psychology.
We review the literature on organizational climate and culture paying specific attention to articles published in the Journal of Applied Psychology (JAP) since its first volume in 1917. The article traces the history of the 2 constructs though JAP has been far more important for climate than culture research. We distinguish 4 main periods: the pre-1971 era, with pioneering work on exploring conceptualization and operationalizations of the climate construct; the 1971-1985 era, with foundational work on aggregation issues, outcome-focused climates (on safety and service) and early writings on culture; the 1986-1999 era, characterized by solidification of a focused climate approach to understanding organizational processes (justice, discrimination) and outcomes (safety, service) and the beginnings of survey approaches to culture; and the 2000-2014 era, characterized by multilevel work on climate, climate strength, demonstrated validity for a climate approach to outcomes and processes, and the relationship between leadership and climate and culture. We summarize and comment on the major theory and research achievements in each period, showing trends observed in the literature and how JAP has contributed greatly to moving research on these constructs, especially climate, forward. We also recommend directions for future research given the current state of knowledge. (PsycINFO Database Record


Systemic Induction of the Small Antibacterial Compound in the Leaf Exudate During Benzothiadiazole-elicited Systemic Acquired Resistance in Pepper.
Plants protect themselves from diverse potential pathogens by induction of the immune systems such as systemic acquired resistance (SAR). Most bacterial plant pathogens thrive in the intercellular space (apoplast) of plant tissues and cause symptoms. The apoplastic leaf exudate (LE) is believed to contain nutrients to provide food resource for phytopathogenic bacteria to survive and to bring harmful phytocompounds to protect plants against bacterial pathogens. In this study, we employed the pepper-Xanthomonas axonopodis system to assess whether apoplastic fluid from LE in pepper affects the fitness of X. axonopodis during the induction of SAR. The LE was extracted from pepper leaves 7 days after soil drench-application of a chemical trigger, benzothiadiazole (BTH). Elicitation of plant immunity was confirmed by significant up-regulation of four genes, CaPR1, CaPR4, CaPR9, and CaCHI2, by BTH treatment. Bacterial fitness was evaluated by measuring growth rate during cultivation with LE from BTH- or water-treated leaves. LE from BTH-treatment significantly inhibited bacterial growth when compared to that from the water-treated control. The antibacterial activity of LE from BTH-treated samples was not affected by heating at 100°C for 30 min. Although the antibacterial molecules were not precisely identified, the data suggest that small (less than 5 kDa), heat-stable compound(s) that are present in BTH-induced LE directly attenuate bacterial growth during the elicitation of plant immunity.


Bias correction of risk estimates in vaccine safety studies with rare adverse events using a self-controlled case series design.
The self-controlled case series (SCCS) method is often used to examine the temporal association between vaccination and adverse events using only data from patients who experienced such events. Conditional Poisson regression models are used to estimate incidence rate ratios, and these models perform well with large or medium-sized case samples. However, in some vaccine safety studies, the adverse events studied are rare and the maximum likelihood estimates may be biased. Several bias correction methods have been examined in case-control studies using conditional logistic regression, but none of these methods have been evaluated in studies using the SCCS design. In this study, we used simulations to evaluate 2 bias correction approaches-the Firth penalized maximum likelihood method and Cordeiro and McCullagh's bias reduction after maximum likelihood estimation-with small sample sizes in studies using the SCCS design. The simulations showed that the bias under the SCCS design with a small number of cases can be large and is also sensitive to a short risk period. The Firth correction method provides finite and less biased estimates than the maximum likelihood method and Cordeiro and McCullagh's method. However, limitations still exist when the risk period in the SCCS design is short relative to the entire observation period.


Synthesis and biosynthetic utilization of radioactive photoreactive fatty acids.
A synthesis of a homologous series of highly radioactive photoreactive fatty acids has been developed. Oxidative cleavage of the cis double bonds of unsaturated fatty acids by NaIO4/OsO4 produced the omega-oxo fatty acids; subsequent reduction by [3H]NaBH4 afforded a series of highly radioactive [omega-3H]hydroxy fatty acids to which a variety of photoreactive probes can be readily attached. In this study, the m-diazirinophenoxy group was coupled to the omega-hydroxy groups of the fatty acids, yielding the omega-(m-diazirinophenoxy) derivatives of nonanoic, undecanoic, tridecanoic, and pentadecanoic acid. These photoreactive derivatives were incorporated by L-cells into their major phospholipids; in addition, a number of proteins were shown to be acylated by these fatty acids. The photoreactive group was shown to remain intact as indicated by the cross-linking of the resulting photoreactive phospholipids to other phospholipids as well as to a number of L-cell proteins upon photolysis. This procedure thus identifies integral membrane proteins and directly produces photoaffinity derivatives of those proteins normally acylated by fatty acids.


Long-term management and outcomes after repair of cerebrospinal fluid rhinorrhea related to idiopathic intracranial hypertension.
To identify long-term management strategies and outcomes for the treatment of spontaneous cerebrospinal fluid (CSF) rhinorrhea related to idiopathic intracranial hypertension (IIH). Adjuvant treatments following surgical repair of spontaneous CSF leaks are aimed at normalizing intracranial pressure (ICP) to minimize the risk of recurrence. IIH is closely linked to obesity, and growing evidence suggests that weight loss, both through conservative and surgical approaches, is effective at addressing the root cause of this disorder. Recent data also support the use of acetazolamide and dural venous sinus stenting as adjuncts for reducing ICP. Spontaneous CSF rhinorrhea associated with IIH represents a challenging clinical entity, with an increased risk of recurrence compared to CSF leaks because of other causes. Adjunct therapies intended to reduce ICP likely improve outcomes after surgical repair, but further research is necessary to better characterize the effects of these treatment modalities.


Usability evaluation of an NHS library website.
To carry out a usability evaluation of the recently launched South London and Maudsley NHS Trust library website. A variety of standard methodologies were employed: content and design evaluation of selected comparable sites, focus groups, a questionnaire survey of library and Web development staff, heuristic evaluation, observation testing, card sorting/cluster analysis, and label intuitiveness/category membership testing. All test participants were staff of or providers of services to the trust. Demographic information was recorded for each participant. Test participants' overall responses to the site were enthusiastic and favourable, indicating the scope and content of the site to be broadly appropriate to the user group. Testers made numerous suggestions for new content. Usability problems were discovered in two main areas: in the organization of the site, and in the terminology used to refer to information services and sources. Based on test results, proposals for a revised menu structure, improved accessibility, and changes to the terminology used within the site are presented. Usability evaluation methods, appropriately scaled, can be advantageously applied to NHS library websites by an individual Web editor working alone.


[Ultrastructural characteristics of the biological action of an endotoxin on sensorimotor cortical neurons].
The work is devoted to the ultrastructural investigation of the state of the sensomotor cortex neurons after intravenous and intracisternal administration of endotoxin. The evidences are presented concerning ultrastructural alterations in mitochondria and the presence of compensatory reaction in them after intravenous injection of endotoxin. Besides, coated vesicles and subsurface cisternae whose formation is induced by the endotoxin action have been studied.


Early Proteinuria Lowering by Angiotensin-Converting Enzyme Inhibition Predicts Renal Survival in Children with CKD.
Background Although pharmacotherapeutic proteinuria lowering was found to be nephroprotective in adults, the predictive value of early drug-induced proteinuria reduction for long-term renal survival in pediatric CKD is unknown. We analyzed data from the ESCAPE Trial for a potential association between initial antiproteinuric effect of standardized angiotensin-converting enzyme (ACE) inhibition and renal disease progression in children with CKD.Methods In total, 280 eligible children with CKD stages 2-4 (mean age 11.7 years old, median eGFR 46 ml/min per 1.73 m2, 71% congenital renal malformations) received a fixed dose of ramipril (6 mg/m2 per day) and were subsequently randomized to conventional or intensified BP control. We assessed initial proteinuria reduction from baseline to first measurement on ramipril (at 2.5±1.3 months). We used multivariable Cox modeling to estimate the association between initial proteinuria reduction and the risk of reaching a renal end point (50% eGFR decline or ESRD), which occurred in 80 patients during 5 years of observation.Results Ramipril therapy lowered proteinuria by a mean of 43.5% (95% confidence interval, 36.3% to 49.9%). Relative to proteinuria reduction <30%, 30%-60% and >60% reduction resulted in hazard ratios (95% confidence intervals) of 0.70 (0.40 to 1.22) and 0.42 (0.22 to 0.79), respectively. This association was independent of age, sex, CKD diagnosis, baseline eGFR, baseline proteinuria, initial BP, and concomitant BP reduction.Conclusions The early antiproteinuric effect of ACE inhibition is associated with long-term preservation of renal function in children with CKD. Proteinuria lowering should be considered an important target in the management of pediatric CKD.


Third-Order Nonlinear Optical Properties of Aqueous Silver Sulfide Quantum Dots.
Wide spectral wavelength range (500-1600 nm) measurements of nonlinear optical properties of silver sulfide (Ag2S, with 2- or 3-mercaptopropionic acid, 2 or 3MPA ligands) quantum dots (QDs) in aqueous colloidal solutions were performed using the Z-scan technique with tunable ∼55 fs laser pulses at 1 kHz. We have identified regions of the occurrence of various NLO effects including two-photon absorption, nonlinear refraction, as well as saturation of one-photon absorption. At the same time, we evaluated the relationship between the properties of the QDs and the variation of the material that covers their surface. The peak two-photon absorption cross section (σ2) values were determined to be 632 ± 271 GM (at 850 nm) for Ag2S-2MPA QDs and 772 ± 100 GM (at 875 nm) for Ag2S-3MPA QDs. The physicochemical factors influencing the three-dimensional self-organization of Ag2S QDs in water as well as their impact on spectroscopic properties were also investigated.


[New guidelines for the treatment of arterial hypertension].
The International Society of Hypertension and the World Health Organisation have recently published new guidelines for the management of hypertension. Epidemiologic studies have shown that management of hypertension still remains unsatisfactory. The aim of the treatment is to reduce the cardiovascular morbidity and mortality by normalizing blood pressure. The target blood pressure under treatment must be less than 140/90 mmHg, and even lower for diabetic or chronic renal failure patients. In parallel, all cardio-vascular risk factors have to be corrected to decrease the global cardio-vascular risk.


Transcriptional regulation of the CO2-concentrating mechanism in a euryhaline, coastal marine cyanobacterium, Synechococcus sp. Strain PCC 7002: role of NdhR/CcmR.
Cyanobacterial photosynthesis occurs in radically diverse habitats and utilizes various forms of a CO(2)-concentrating mechanism (CCM) featuring multiple inorganic carbon (C(i)) transporters. Cyanobacteria from dynamic environments can transform CCM activity depending on C(i) availability, and yet the molecular basis for this regulation is unclear, especially in coastal strains. LysR family transcription factors resembling the Calvin cycle regulator CbbR from proteobacteria have been implicated in the expression of C(i) transporter genes in freshwater cyanobacteria. Our survey of related factors revealed a group of divergent CbbR-like sequences confined to freshwater and coastal or offshore cyanobacteria. Inactivation of the single gene (termed ccmR) from this variable cluster in the euryhaline (coastal) strain Synechococcus sp. strain PCC 7002 led to constitutive expression of a high-affinity CCM. Derepression of HCO(3)(-) transporter gene transcription, including that of BicA, a recently discovered HCO(3)(-) transporter (G. D. Price et al., Proc. Natl. Acad. Sci. USA 101:18228-18233, 2004), was observed. A unique CcmR-regulated operon containing bicA plus 9 open reading frames encoding likely Na(+)/H(+) antiporters from the CPA1 and Mnh families was defined that is essential for maximal HCO(3)(-)-dependent oxygen evolution. The promoter region required for C(i)-regulated transcription of this operon was defined. We propose that CcmR (and its associated regulon) represents a specialization for species inhabiting environments subject to fluctuating C(i) concentrations.


A Facile and Novel Approach to Manufacture Paclitaxel-Loaded Proliposome Tablet Formulations of Micro or Nano Vesicles for Nebulization.
The aim of this study was to develop novel paclitaxel-loaded proliposome tablet formulations for pulmonary drug delivery. Proliposome powder formulations (i.e. F1 - F27) were prepared employing Lactose monohydrate (LMH), Microcrystalline cellulose (MCC) or Starch as a carbohydrate carriers and Soya phosphatidylcholine (SPC), Hydrogenated soya phosphatidylcholine (HSPC) or Dimyristoly phosphatidylcholine (DMPC) as a phospholipid. Proliposome powder formulations were prepared in 1:5, 1:15 or 1:25 w/w lipid phase to carrier ratio (lipid phase; comprising of phospholipid and cholesterol in 1:1 M ratio) and Paclitaxel (PTX) was used as model anticancer drug. Based on flowability studies, out of 27 formulations; F3, F6, and F9 formulations were selected as they exhibited an excellent angle of repose (AOR) (17.24 ± 0.43, 16.41 ± 0.52 and 15.16 ± 0.72°), comparatively lower size of vesicles (i.e. 5.35 ± 0.76, 6.27 ± 0.59 and 5.43 ± 0.68 μm) and good compressibility index (14.81 ± 0.36, 15.01 ± 0.35 and 14.56 ± 0.14) via Carr's index. The selected formulations were reduced into Nano (N) vesicles via probe sonication, followed by spray drying (SD) to get a dry powder of these formulations as F3SDN, F6SDN and F9SDN, and gave high yield (>53%) and exhibited poor to very poor compressibility index values via Carr's Index. Post tablet manufacturing, F3 tablets formulation showed uniform weight uniformity (129.40 ± 3.85 mg), good crushing strength (14.08 ± 1.95 N), precise tablet thickness (2.33 ± 0.51 mm) and a short disintegration time of 14.35 ± 0.56 min, passing all quality control tests in accordance with British Pharmacopeia (BP). Upon nebulization of F3 tablets formulation, Ultrasonic nebulizer showed better nebulization time (8.75 ± 0.86 min) and high output rate (421.06 ± 7.19 mg/min) when compared to Vibrating mesh nebulizer. PTX-loaded F3 tablet formulations were identified as toxic (60% cell viability) to cancer MRC-5 SV2 cell lines while safe to normal MRC-5 cell lines. Overall, in this study LMH was identified as a superior carbohydrate carrier for proliposome tablet manufacturing in a 1:25 w/w lipid to carrier ratio for in-vitro nebulization via Ultrasonic nebulizer.


Epithelial ovarian tumours of low malignant potential.
The available literature and the management of epithelial tumours of low malignant potential (LMP) is reviewed. The criteria for a diagnosis of LMP at the University of the Witwatersrand are delineated in detail. Based on the records in the Ovarian Tumour Registry of this University, experience with 29 such tumours over 4 years is presented. Of these, 14 (48.3%) were of the serous variety, 12 were mucinous (41.4%), and 2 (6.9%) were mucinous-serous, the remaining 1 (3.4%) being endometrioid. LMP tumours accounted for 12.9% of proliferating epithelial ovarian tumours in black patients compared with 16.9% in white patients. Pelviperitoneal cytological washings for detection of malignant cells in patients with LMP tumours is mandatory.


Addressing long-standing controversies in conceptual knowledge representation in the temporal pole: A cross-modal paradigm.
Conceptual knowledge allows us to comprehend the multisensory stimulation impinging on our senses. Its representation in the anterior temporal lobe is a subject of considerable debate, with the "enigmatic" temporal pole (TP) being at the center of that debate. The controversial models of the organization of knowledge representation in TP range from unilateral to fully unified bilateral representational systems. To address the multitude of mutually exclusive options, we developed a novel cross-modal approach in a multifactorial brain imaging study of the blind, manipulating the modality (verbal vs pictorial) of both the reception source (reading text/verbal vs images/pictorial) and the expression (writing text/verbal vs drawing/pictorial) of conceptual knowledge. Furthermore, we also varied the level of familiarity. This study is the first to investigate the functional organization of (amodal) conceptual knowledge in TP in the blind, as well as, the first study of drawing based on the conceptual knowledge from memory of sentences delivered through Braille reading. Through this paradigm, we were able to functionally identify two novel subdivisions of the temporal pole - the TPa, at the apex, and the TPdm - dorso-medially. Their response characteristics revealed a complex interplay of non-visual specializations within the temporal pole, with a diversity of excitatory/inhibitory inversions as a function of hemisphere, task-domain and familiarity, which motivate an expanded neurocognitive analysis of conceptual knowledge. The interplay of inter-hemispheric specializations found here accounts for the variety of seemingly conflicting models in previous research for conceptual knowledge representation, reconciling them through the set of factors we have investigated: the two main knowledge domains (verbal and pictorial/sensory-motor) and the two main knowledge processing modes (receptive and expressive), including the level of familiarity as a modifier. Furthermore, the interplay of these factors allowed us to also reveal for the first time a system of complementary symmetries, asymmetries and unexpected anti-symmetries in the TP organization. Thus, taken together these results constitute a unifying explanation of the conflicting models in previous research on conceptual knowledge representation.


The initiation of GTP hydrolysis by the G-domain of FeoB: insights from a transition-state complex structure.
The polytopic membrane protein FeoB is a ferrous iron transporter in prokaryotes. The protein contains a potassium-activated GTPase domain that is essential in regulating the import of iron and conferring virulence to many disease-causing bacteria. However, the mechanism by which the G-domain of FeoB hydrolyzes GTP is not well understood. In particular, it is not yet known how the pivotal step in GTP hydrolysis is achieved: alignment of a catalytic water molecule. In the current study, the crystal structure of the soluble domains from Streptococcus thermophilus FeoB (NFeoB(St)) in complex with the activating potassium ion and a transition-state analogue, GDP⋅AlF(4) (-), reveals a novel mode of water alignment involving contacts with the protein backbone only. In parallel to the structural studies, a series of seven mutant proteins were constructed that targeted conserved residues at the active site of NFeoB(St), and the nucleotide binding and hydrolysis properties of these were measured and compared to the wild-type protein. The results show that mutations in Thr35 abolish GTPase activity of the protein, while other conserved residues (Tyr58, Ser64, Glu66 and Glu67) are not required for water alignment by NFeoB(St). Together with the crystal structure, the findings suggest a new mechanism for hydrolysis initiation in small G-proteins, in which the attacking water molecule is aligned by contacts with the protein backbone only.


Protein extracts from early embryonic hearts initiate cardiac endothelial cytodifferentiation.
Prior to the formation of multiple chambers, the embryonic heart consists of two epithelial tubes, one within the other. As development proceeds, portions of the inner epithelium, i.e., the endothelium, undergo a morphological transformation into a migrating mesenchymal cell population. Our results show that this transformation is affected by proteins secreted by the outer epithelium, i.e., the myocardium, into the extracellular matrix between these two tissues. This conclusion is based on tissue autoradiographic studies of whole embryo cultures with 3H-amino acids. Continuous labeling conditions generated an apparent gradient of proteins extending away from the myocardium and contacting the endothelium just prior to the formation of mesenchyme, i.e., activation of the transformation sequence. Pulse/chase studies confirmed this directional movement of matrix protein. By performing sequential extractions of preactivation staged embryonic hearts with EDTA and testicular hyaluronidase followed by ammonium sulfate precipitation we obtained an enriched preparation of cardiac extracellular matrix. This fraction was capable of eliciting several of the events characteristic of endothelial activation in vitro. These events included: (i) cell-cell separation, (ii) lateral cell mobility, and (iii) hypertrophy and polarization of intracellular PAS staining (Golgi apparati). The biological activity of the extract was sensitive to heat denaturation: a homogenate of the remaining extracted tissue would not substitute for the matrix extract. Morphologically the extracted hearts appeared intact, however, the extracellular matrix space was significantly diminished. No more than 6% of the total lactic dehydrogenase activity, a cytosolic enzyme, was found in the extract. Preliminary electrophoretic characterization of the extract (metabolically labeled with 14C-amino acids) indicated that it may contain as many as 35 proteins or subunits. The relationship of ECM to endothelial differentiation in cardiac morphogenesis is discussed as a model for other developmental systems.


Boron Compound-Based Treatments Against Multidrug-Resistant Bacterial Infections in Lung Cancer In Vitro Model.
Multidrug-resistant bacteria is one of the most important public health problems. Increasing rates of antibacterial resistance also affect the outcomes of medical approaches. Cancer treatment because of immune system deficiency (chemotherapy or steroids usage) commonly can cause infection. Lung cancer is the dominant cause of cancer-related deaths, and infection is the most common cause of death among those patients. In this study, it was aimed to determine the antimicrobial, antibiofilm, and anticancer activity of boron compounds. A549 lung cancer cell line was infected with Acinetobacter baumannii (ATCC 19606), Klebsiella pneumoniae (ATCC 700603), and Pseudomonas aeruginosa (ATCC 27853). In order to determine the fractional inhibitory concentration (FIC) index, antibiotics and boron compound concentrations prepared according to the minimum inhibitory concentration (MIC) values were determined by the checkerboard method. In our study results, the antibiofilm activity was an average of 46% in A. baumannii+boron compounds, 45% in P. aeruginosa+boron compounds, and 43% in K. pneumoniae. Cell culture analysis results show a decrease in viability and antioxidant capacity and an increase in total oxidant status after adding boron compounds to the culture. Immunofluorescence results show a correlation with MTT, and boron compounds increased 8-OHdG expression in comparison to antibiotic administration. In conclusion, boron compounds have promising effects on bacteria, especially in resistant bacteria spp.


Fibroblast growth factor receptor 2 homodimerization rapidly reduces transcription of the pluripotency gene Nanog without dissociation of activating transcription factors.
Nanog or Gata6-positive cells co-exist and are convertible within the inner cell mass of murine blastocysts and embryonic stem (ES) cells. Previous studies demonstrate fibroblast growth factor receptor 2 (FGFR2) triggers Nanog gene down-regulation and differentiation to primitive endoderm (PE); however, the underlying mechanisms responsible for reversible and fluctuating cell fate are poorly understood. Using an inducible FGFR2 dimerization system in ES cells, we demonstrate that FGFR2 activation rapidly down-regulated Nanog gene transcription through activation of the Mek pathway and subsequently differentiated ES cells into PE cells. FGFR2 rather selectively repressed the Nanog gene with minimal effect on other pluripotency genes, including Oct4 and Sox2. We determined the Nanog promoter region containing minimum Oct4/Sox2 binding sites was sufficient for this transcriptional down-regulation by FGFR2, when the reporter transgenes were integrated with insulators. Of interest, FGFR2-mediated Nanog transcriptional reduction occurred without dissociation of RNA polymerase II, p300, Oct4, Sox2, and Tet1 from the Nanog proximal promoter region and with no increase in repressive histone methylation marks or DNA methylation, implying the gene repression is in the early and transient phase. Furthermore, addition of a specific FGFR inhibitor readily reversed this Nanog repression status. These findings illustrate well how FGFR2 induces rapid but reversible Nanog repression within ES cells.


Ultradian variations of chromogranin A in humans.
Chromogranin A (CgA) is an acidic soluble protein exocytotically released from virtually all neuroendocrine secretory vesicles. Here we examined spontaneous variations in CgA and catecholamine concentrations in humans. In normal subjects, basal CgA showed no day-to-day, week-to-week, or diurnal variability. Plasma CgA had significant ultradian variation in normotensives and hypertensives, and in bilaterally adrenalectomized subjects. Gender, but not age or blood pressure, influenced CgA variations, males having fewer (P less than 0.05) peaks per 8 h. Plasma catecholamines had significant ultradian variations in both controls and bilaterally adrenalectomized subjects. Within individuals, neither basal nor peak plasma CgA correlated with catecholamines, nor was there concordance between plasma CgA and catecholamine peaks. Somatostatin, a widespread inhibitor of nonsympathoadrenal neuroendocrine secretion, diminished both the frequency and amplitude of plasma CgA peaks. Thus spontaneous variations in basal CgA are not directly linked to alterations in sympathoadrenal catecholamine secretion. Furthermore, neuroendocrine secretion at sites other than the sympathoadrenal system contributes to spontaneous variations in CgA concentration.


Tetrandrine, a calcium antagonist of Chinese herbal origin, interacts with vascular muscle alpha 1-adrenoceptor.
The effects of tetrandrine (TET) on the contractile responses of rat aortic rings and perfused rat mesenteric arteries to phenylephrine (PE) were investigated. TET inhibited the maximal contraction to PE in a concentration-dependent manner. TET significantly inhibited the transient contraction in Ca(2+)-free medium presumably due to release of intracellular Ca2+ after activation of alpha 1-adrenoceptors. However, it caused a stronger inhibition of the sustained contraction in Ca(2+)-containing medium presumably the result of Ca2+ influx. TET has no inhibitory effect on caffeine-induced transient contraction. Radioligand receptor binding study using isolated dog aortic muscle membranes indicated that TET inhibited the binding of 3H-prazosin in a competitive manner, hence showing that TET interacted directly with the alpha 1-adrenoceptors. Thus, TET affected PE-induced aortic contractions by multiple mechanisms, inhibiting interaction of PE with alpha 1-adrenoceptors and interfering with PE-induced responses involving both Ca2+ entry and release.


Screening for alternative antibiotics: an investigation into the antimicrobial activities of medicinal food plants of Mauritius.
The present study was designed to evaluate the antimicrobial activities of 2 endemic medicinal plants; Faujasiopsis flexuosa (Asteraceae) (FF) and Pittosporum senacia (Pittosporaceae) (PS) and 2 exotic medicinal plants, Momordica charantia (Cucurbitaceae) (MC) and Ocimum tenuiflorum (Lamiaceae) (OT) that forms part of local pharmacopoeia of Mauritius and correlate any observed activity with its phytochemical profile. Aqueous and organic fractions of the leaves, fruits, and seeds of these plants were subjected to antimicrobial testing by the disc diffusion method against 8 clinical isolates of bacteria and 2 strains of fungus. It was found that MC, OT, and FF possessed antimicrobial properties against the test organisms. The MIC for MC ranged from 0.5 to 9 mg/mL and that of FF from 2 to 10 mg/mL and the lowest MIC value (0.5 mg/mL) was recorded for the unripe fruits of MC against E. coli. On the other hand, higher concentration of the unripe MC fruit extract of 9 mg/mL was needed to be effective against a resistant strain of Staphylococcus aureus (MRSA). The antimicrobial effect against MRSA was lost upon ripening of the fruits. The methanolic extract of both MC and FF showed highest MIC values compared to the corresponding aqueous extract, which indicates the low efficacy and the need of higher doses of the plant extract. Phytochemical screening of the plants showed the presence of at least tannins, phenols, flavonoids, and alkaloids, which are known antimicrobial phyto-compounds. In conclusion, the observed antimicrobial properties would tend to further validate the medicinal properties of these commonly used endemic medicinal and food plants of Mauritius.


Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees.
Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21-hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.


High-fidelity mapping of repetition-related changes in the parietal memory network.
fMRI studies of human memory have identified a "parietal memory network" (PMN) that displays distinct responses to novel and familiar stimuli, typically deactivating during initial encoding but robustly activating during retrieval. The small size of PMN regions, combined with their proximity to the neighboring default mode network, makes a targeted assessment of their responses in highly sampled subjects important for understanding information processing within the network. Here, we describe an experiment in which participants made semantic decisions about repeatedly-presented stimuli, assessing PMN BOLD responses as items transitioned from experimentally novel to repeated. Data are from the highly-sampled subjects in the Midnight Scan Club dataset, enabling a characterization of BOLD responses at both the group and single-subject level. Across all analyses, PMN regions deactivated in response to novel stimuli and displayed changes in BOLD activity across presentations, but did not significantly activate to repeated items. Results support only a portion of initially hypothesized effects, in particular suggesting that novelty-related deactivations may be less susceptible to attentional/task manipulations than are repetition-related activations within the network. This in turn suggests that novelty and familiarity may be processed as separable entities within the PMN.


Moral reasoning behind the veil of ignorance: An investigation into perspective-taking accessibility in the context of autonomous vehicles.
Perspective-taking (PT) accessibility has been recognized as an important factor in affecting moral reasoning, also playing a non-trivial role in moral investigation towards autonomous vehicles (AVs). A new proposal to deepen this effect leverages the principles of the veil of ignorance (VOI), as a moral reasoning device aimed to control self-interested decisions by limiting the access to specific perspectives and to potentially biased information. Throughout two studies, we deepen the role of VOI reasoning in the moral perception of AVs, disclosing personal and contingent information progressively throughout the experiment. With the use of the moral trilemma paradigm, two different VOI conditions were operationalized, inspired by the Original Position theory by John Rawls and the Equiprobability Model by John Harsanyi. Evidence suggests a significant role of VOI reasoning in affecting moral reasoning, which seems not independent from the order in which information is revealed. Coherently, a detrimental effect of self-involvement on utilitarian behaviours was detected. These results highlight the importance of considering PT accessibility and self-involvement when investigating moral attitudes towards AVs, since it can help the intelligibility of general concerns and hesitations towards this new technology.


Cancer Therapeutics-Related Cardiovascular Complications. Mechanisms, Diagnosis and Treatment.
Chemotherapy regimens have improved prognosis and mortality of patients with malignant diseases. The development of therapies, however, has widened the cardiotoxic spectrum and the cardiacrelated effects of antineoplastic drugs. A review of the literature under the search terms anthracyclines, oncology, cardiotoxicity, cardiooncology, chemotherapy and heart failure was used for the identification of the most relevant articles. Considerable variability exists in patients' characteristics, in mechanisms involved in cardiomyopathy progression and in its physical history, as well as in modalities used to screen myocardial competence. The anthracyclines and particularly doxorubicin are the most widely used antineoplastic drugs. Monoclonal antibodies, tyrosine kinase inhibitors and other targeted therapies have been associated with cardiovascular side-effects, such as cardiomyopathy and congestive heart failure. Moreover, some of these agents are associated with an increased risk of coronary artery disease with or without myocardial infarction. The current standard for the detection of cardiac toxicity is serial echocardiography. Biomarkers though could be proved helpful, they can be tested at closer intervals and are highly accurate and reproducible. Of note, a growing body of data has emerged suggesting that some agents could have cardioprotective properties. Since the number of long-term survivors following the diagnosis and treatment of malignant disease will continue to increase, cardio-oncology will continue to evolve. Therefore, a better understanding of potential cardiovascular effects of chemotherapeutic regiments and the earlier identification and treatment of high-risk patients would be the focus of research in the future.


[Sociotechnical healthcare networks for acupuncture: a case study on the basic training of medical students].
This is a qualitative study on the sociotechnical networks that underlie the University of São Paulo School of Medicine's Acupuncture League. The actor-network methodology, developed by Bruno Latour in studies on scientific productivity, is used. Consisting of field observations, semistructured interviews and a document analysis, the study presents relevant findings, with emphasis on understanding acupuncture as a therapeutic strategy effective in healthcare, modulating the use of drugs. It also identifies the need for regulation of the teaching and practice of acupuncture and recognition of other healthcare professionals as colleagues in the practice of this therapeutic method.


A genome-wide association study of suicide severity scores in bipolar disorder.
Suicide claims one million lives worldwide annually, making it a serious public health concern. The risk for suicidal behaviour can be partly explained by genetic factors, as suggested by twin and family studies (reviewed in (Zai et al. 2012)). Recently, genome-wide association studies (GWASs) of suicide attempt on large samples of bipolar disorder (BD) patients from multiple sites have identified a number of novel candidate genes. GWASs of suicide behaviour severity, from suicidal ideation to serious suicide attempt, have not been reported for BD. We conducted a GWAS of suicide behaviour severity in three independent BD samples:212 small nuclear families with BD probands from Toronto, Canada, 428 BD cases from Toronto, and 483 BD cases from the UK. We carried out imputation with 1000 Genome Project data as reference using IMPUTE2. Quality control and data analysis was conducted using PLINK and R. We conducted the quantitative analyses of suicide behaviour severity in the three samples separately, and derived an overall significance by a meta-analysis using the METAL software. We did not find genome-wide significant association of any tested markers in any of the BD samples, but we found a number of suggestive associations, including regions on chromosomes 8 and 10 (p < 1e-5). Our GWAS findings suggest that likely many gene variants of small effects contribute collectively to the risk for suicidal behaviour severity in BD. Larger independent replications are required to strengthen the findings from the GWAS presented here.


Disparities in the outcomes of lumbar spinal stenosis surgery based on insurance status.
Retrospective cohort study using Thomson Reuter's MarketScan database. To evaluate the extent to which Medicaid versus commercial insurance status affects outcomes after lumbar stenosis surgery. The Affordable Care Act aims to expand health insurance and to help narrow existing health care disparities. Medicaid patients have previously been noted to be at an increased risk for impaired access to health care. Conversely, those with commercial insurance may be subject to overtreatment. We examine the surgical treatment of low back pain as an example that has raised significant public health concerns. A total of 28,462 patients, ages 18 and older, were identified who had undergone laminectomy or fusion for spinal stenosis between 2000 and 2009. Patients were characterized by baseline demographic information, comorbidity burden, and type of insurance (Medicaid vs. commercial insurance). Multivariate analysis was performed comparing the relative effect of insurance status on reoperation rates, timing and type of reoperations, postoperative complications, and total postoperative health resource use. Medicaid patients had similar reoperation rates to commercially insured patients at 1 year (4.60% vs. 5.42%, P = .38); but had significantly lower reoperation rates at 2 (7.22% vs. 10.30%; adjusted odds ratio [aOR] = 0.661; 95% confidence interval [CI], 0.533-0.820; P = .0002) and more than 2 years (13.92% vs. 16.89%; aOR = 0.722; 95% CI, 0.612-0.851; P <.0001). Medicaid patients were particularly less likely to undergo fusion as a reoperation (aOR = 0.478; 95% CI, 0.377-0.606; P < 0001). Medicaid patients had greater health care resource utilization as measured by hospital days, outpatient services and medications prescribed; however, commercially insured patients had significantly higher overall health utilization costs at 1 and 2 years. There are insurance disparities that affect important surgical outcomes after initial surgery for spinal stenosis. Efforts for national health care reform should include explicit efforts to identify such system factors that will reduce current inequities in care. 2.


Reactivation of Rickettsia rickettsii in Dermacentor andersoni ticks: an ultrastructural analysis.
Virulent Rickettsia in Dermacentor andersoni lose their pathogenicity and virulence for guinea pigs when subjected to physiological stresses, such as starvation (overwintering), of its tick vector. However, incubation of infected ticks at an elevated temperature (37 degrees C) for 24 to 48 h or feeding for a time (usually greater than 10 h) induces R. rickettsii to revert to a virulent state, a phenomenon defined as "reactivation." Electron microscopy reveals that the microcapsular and slime layers of R. rickettsii undergo changes dependent upon the physiological conditions within the tick vector. In engorged ticks, the microcapsular layer is readily identified as a discrete layer, approximately 16 nm thick, composed of globular subunits that have a periodicity of approximately 10 nm. The slime layer external to the microcapsular layer forms a discrete electron-lucent zone around the rickettsia. In starved ticks, neither the microcapsular layer nor slime layer remains a discrete entity. Instead, they are shed and form stringy, shredded, and somewhat flocculent strands of low electron density without periodicity. Incubation at 37 degrees C or feeding of starved infected ticks results in the restoration of a discrete microcapsular and slime layer. These reversible structural modifications are linked to physiological changes in the tick host and correlate with reactivation, i.e., restoration of pathogenicity and virulence of R. rickettsii.