Maternal intimate partner violence victimization and child maltreatment.
There is some limited evidence of an association between maternal intimate partner victimization (IPV) and children's experience of maltreatment. Using data from a longitudinal study, we examine whether this relationship is independent of range of potential confounders including socio-economic, familial and psychological factors. Data were taken from the 14 and 30-year follow-ups of the Mater-University of Queensland Study of Pregnancy (MUSP) in Australia. A subsample of 2064 mothers and children (59.0% female) whose data on maternal IPV and child maltreatment was available, were analysed. In families with maternal IPV, two in five children reported being maltreated, compared to one in five children maltreated in families without maternal IPV. Except for sexual maltreatment which was consistently higher in female offspring, there was no gender differences in experiencing different types of maltreatment in families manifesting maternal IPV. Although both males and females were at increased risk of child maltreatment in families where mothers were victimized by their male partners, male children were more likely to be emotionally maltreated. The main associations were substantially independent of measured confounders, except for father's history of mental health problems which attenuated the association of maternal IPV victimization and male offspring's physical abuse. Our findings confirm that there is a robust association between maternal IPV and child maltreatment. Both maternal IPV victimization and child maltreatment co-occur in a household characterized by conflict and violence. Consequences of IPV go beyond the incident and influence all family members. Efforts to reduce child maltreatment may need to address the greater level of IPV associated with the cycle of family violence.


Georeferenced dataset of maritime piracy in the Gulf of Guinea from 2010 to 2021.
Piracy has been a global concern and a threat to the safety of people performing maritime trade around the globe. Since ancient times maritime piracy has been a common practice that, unfortunately, has not ended in the current days. A georeferenced dataset providing the position, meteorologic conditions, and a description of the occurrence can provide essential information for analyzing this global phenomenon. The dataset focuses on the Gulf of Guinea (GoG) as an area dominated by corruption and weak supervision capacity by the local authorities. The time interval considered in this paper is between 2010 and 2021. Using this simple dataset, it is possible to analyze attributes such as when the piracy occurred or if the illegal activity involved deaths or kidnapping. The accuracy of the data was guaranteed by cross-referencing data sources, so we have 595 pirate attacks accurately described. This dataset can easily be used for data mining, allowing further analysis of the patterns and trends of pirate attacks in the GoG over time.


Aqueous misdirection syndrome: an interesting case presentation.
To report a case of an aqueous misdirection-like presentation in a pseudophakic patient. Retrospective case review. An 84-year-old pseudophakic gentleman presented with bilateral blurred vision 8 years after cataract surgery. A refractive shift with shallow anterior chambers and elevated intraocular pressures were noted. No corneal edema was noted. Although aqueous suppression and topical atropine would relieve the signs and symptoms, the effect was temporary with fluctuating and variable changes in refraction, anterior chamber depth, and intraocular pressure. The presence of patent iridotomies had no effect on the fluctuations. A pars plana vitrectomy and surgical iridectomy were successful in preventing further fluctuations. Aqueous misdirection is a form of secondary angle closure glaucoma marked by elevated intraocular pressures, myopic shift in refraction, and central shallowing of the anterior chamber. Here, a case of a pseudophakic patient experiencing bilateral and fluctuating signs and symptoms resembling aqueous misdirection is presented. Surgical intervention with a pars plana vitrectomy and iridectomy prevented further fluctuations.


Addressing the needs of the cognitively impaired elderly from a family policy perspective.
Management of the cognitively impaired elderly person in the community is presumed to be cost-efficient and the American way. Although this is what should be done, most would agree that paying for the services that make it possible to do so is not currently within the means of the median income of the family ($25,986) or of the female head of household ($15,350) in this country. This paper reviews the changes in the family, current family policies, and practices of our businesses and government and proposes the services that could be used to support both the impaired person and the family in the management of this evolving societal issue. Strategies for development of payment mechanisms for the proposed services are presented.


[Antigenic characteristics of influenza B virus strains isolated in an orphanage during an influenza outbreak in Moscow in the winter of 1988].
Examinations of ARD patients in an orphanage for defective children in Moscow during an influenza outbreak in the winter of 1988 yielded 12 influenza virus strains, including 6 influenza B strains and 6 influenza A (H3N2) strains. The antigenic analysis of hemagglutinin of influenza B virus isolates showed that with respect to the B/Leningrad/179/86 strain (an antigenic analogue of B/Ann Arbor/1/86 strain recommended for inclusion into the influenza vaccine for 1987-1988) they could be divided into 2 groups: antigenically close to the B/Leningrad/86 strain (isolate B/712) and markedly differing from it (the remaining isolates). As compared with reference strains of the previous years, all the new virus isolates fell into 4 groups: isolate B/712 antigenically related to B/Hong Kong/73 and B/Leningrad/86 strains; B/722 antigenically close to B/Singapore/222/79 and B/USSR/100/83 strains; B/724, an antigenic analogue to B/USSR/100/83; and the remaining isolates, to some or other extent, differing from various reference strains. This attests to simultaneous circulation of various antigenic variants of influenza B virus during the 1988 winter outbreak of influenza in Moscow. An interesting feature of the B/712/88 isolate consists in its antigenic specificity of hemagglutinin being indistinguishable from that of B/Hong Kong/8/73 strains.


Oncological translational research in the Spanish national health system: the INTRO study.
Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.


DNA methylation maintenance consolidates RNA-directed DNA methylation and transcriptional gene silencing over generations in Arabidopsis thaliana.
In plants, 24 nucleotide short interfering RNAs serve as a signal to direct cytosine methylation at homologous DNA regions in the nucleus. If the targeted DNA has promoter function, this RNA-directed DNA methylation may result in transcriptional gene silencing. In a genetic screen for factors involved in RNA-directed transcriptional silencing of a ProNOS-NPTII reporter transgene in Arabidopsis thaliana, we captured alleles of DOMAINS REARRANGED METHYLTRANSFERASE 2, the gene encoding the DNA methyltransferase that is mainly responsible for de novo DNA methylation in the context of RNA-directed DNA methylation. Interestingly, methylation of the reporter gene ProNOS was not completely erased in these mutants, but persisted in the symmetric CG context, indicating that RNA-directed DNA methylation had been consolidated by DNA methylation maintenance. Taking advantage of the segregation of the transgenes giving rise to ProNOS short interfering RNAs and carrying the ProNOS-NPTII reporter in our experimental system, we found that ProNOS DNA methylation maintenance was first evident after two generations of ongoing RNA-directed DNA methylation, and then increased in extent with further generations. As ProNOS DNA methylation had already reached its final level in the first generation of RNA-directed DNA methylation, our findings suggest that establishment of DNA methylation at a particular region may be divided into distinct stages. An initial phase of efficient, but still fully reversible, de novo DNA methylation and transcriptional gene silencing is followed by transition to efficient maintenance of cytosine methylation in a symmetric sequence context accompanied by persistence of gene silencing.


Novel somatic single nucleotide variants within the RNA binding protein hnRNP A1 in multiple sclerosis patients.
Some somatic single nucleotide variants (SNVs) are thought to be pathogenic, leading to neurological disease. We hypothesized that heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an autoantigen associated with multiple sclerosis (MS) would contain SNVs. MS patients develop antibodies to hnRNP A1 (293-304), an epitope within the M9 domain (AA (268-305)) of hnRNP A1. M9 is hnRNP A1's nucleocytoplasmic transport domain, which binds transportin-1 (TPNO-1) and allows for hnRNP A1's transport into and out of the nucleus. Genomic DNA sequencing of M9 revealed nine novel SNVs that resulted in an amino acid substitution in MS patients that were not present in controls. SNVs occurred within the TPNO-1 binding domain (hnRNP A1 (268-289)) and the MS IgG epitope (hnRNP A1 (293-304)), within M9. In contrast to the nuclear localization of wild type (WT) hnRNP A1, mutant hnRNP A1 mis-localized to the cytoplasm, co-localized with stress granules and caused cellular apoptosis. Whilst WT hnRNP A1 bound TPNO-1, mutant hnRNP A1 showed reduced TPNO-1 binding. These data suggest SNVs in hnRNP A1 might contribute to pathogenesis of MS.


Patterns of tree growth in relation to environmental variability in the tropical dry deciduous forest at Mudumalai, southern India.
Tree diameter growth is sensitive to environmental fluctuations and tropical dry forests experience high seasonal and inter-annual environmental variation. Tree growth rates in a large permanent plot at Mudumalai, southern India, were examined for the influences of rainfall and three intrinsic factors (size, species and growth form) during three 4-year intervals over the period 1988-2000. Most trees had lowest growth during the second interval when rainfall was lowest, and skewness and kurtosis of growth distributions were reduced during this interval. Tree diameter generally explained less than 10% of growth variation and had less influence on growth than species identity or time interval. Intraspecific variation was high, yet species identity accounted for up to 16% of growth variation in the community. There were no consistent differences between canopy and understory tree growth rates; however, a few subgroups of species may potentially represent canopy and understory growth guilds. Environmentally-induced temporal variations in growth generally did not reduce the odds of subsequent survival. Growth rates appear to be strongly influenced by species identity and environmental variability in the Mudumalai dry forest. Understanding and predicting vegetation dynamics in the dry tropics thus also requires information on temporal variability in local climate.


[Characteristics of toxigenic properties of Myrothecium cinctum (Corda) sacc., 1886 and Myrothecium commune pidopl., 1969].
The comparative study of toxigenic potential of Myrothecium cinctum (12 strains) and Myrothecium commune (7 strains) was conducted. The ability to produce the complex of macrocyclic trichothecenes (MCTC) presented in ethanol soluble fraction (ESF), as well as fungistatic activity against yeasts test-cultures (strains Saccharomyces vini "Feodosia" and Candida stellatoidea 62) and rabbit skin test were evaluated. It was established that ESF output varied within wide limits in all studied strains of both species but it was significantly lower in M. commune strains. Higher ESF yields were accompanied as a rule by higher fungistatic activity and skin reaction in rabbits. The separate strains showed high biological activity with minor ESF output that could be possible caused by domination of more toxic components in complex preparation. The study of MCTC component structure by high performance liquid chromatography method (HPLC) showed with a few exceptions the presence of verrucarins A and J, roridins A, E, and H as well as unidentified components whose column retention times were 2.1 and 4.9 minutes. The production of roridin H and unknown component with 2.1 min. retention time was typical of M. cinctum strains while verrucarin A and unidentified component with 4.9 min. retention time was typical of M. commune strains.


A GroEL homologue from endosymbiotic bacteria of the whitefly Bemisia tabaci is implicated in the circulative transmission of tomato yellow leaf curl virus.
Evidence for the involvement of a Bemisia tabaci GroEL homologue in the transmission of tomato yellow leaf curl geminivirus (TYLCV) is presented. A approximately 63-kDa protein was identified in B. tabaci whole-body extracts using an antiserum raised against aphid Buchnera GroEL. The GroEL homologue was immunolocalized to a coccoid-shaped whitefly endosymbiont. The 30 N-terminal amino acids of the whitefly GroEL homologue showed 80% homology with that from different aphid species and GroEL from Escherichia coli. Purified GroEL from B. tabaci exhibited ultrastructural similarities to that of the endosymbiont from aphids and E. coli. In vitro ligand assays showed that tomato yellow leaf curl virus (TYLCV) particles displayed a specific affinity for the B. tabaci 63-kDa GroEL homologue. Feeding whiteflies anti-Buchnera GroEL antiserum before the acquisition of virions reduced TYLCV transmission to tomato test plants by >80%. In the haemolymph of these whiteflies, TYLCV DNA was reduced to amounts below the threshold of detection by Southern blot hybridization. Active antibodies were recovered from the insect haemolymph suggesting that by complexing the GoEL homologue, the antibody disturbed interaction with TYLCV, leading to degradation of the virus. We propose that GroEL of B. tabaci protects the virus from destruction during its passage through the haemolymph.


Remimazolam for Sedation During Fiberoptic Intubation in an Adolescent.
In specific clinical scenarios, fiberoptic intubation (FOI) may be the preferred technique for airway management and endotracheal intubation. In addition to topical anesthesia of the airway, sedation is frequently necessary, especially in younger patients, to facilitate the procedure. The goal is to facilitate the procedure by providing sedation, anxiolysis, and analgesia with maintenance of spontaneous ventilation. Remimazolam is a novel benzodiazepine with a short half-life and limited context sensitive half-life that can be titrated by continuous infusion. These novel properties may make it a suitable agent for sedation during FOI of the trachea. We report the novel use of a combination of remimazolam and remifentanil infusions to provide sedation during FOI in an adolescent. The basic pharmacology of remimazolam is presented and previous reports of its use for sedation during FOI are reviewed.


SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors.
Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that β-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring β-catenin mutations at its effective concentration. To confirm that β-catenin mutations and mutant β-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated β-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated β-catenin accelerated it. Our findings show that β-catenin mutations are an important responder biomarker for MEK1/2 inhibitors.


Simultaneous determination of selected endocrine disrupters (pesticides, phenols and phthalates) in water by in-field solid-phase extraction (SPE) using the prototype PROFEXS followed by on-line SPE (PROSPEKT) and analysis by liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry.
In this study, a new procedure, based on on-line solid-phase extraction (SPE) and analysis by liquid-chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS), has been developed for the simultaneous, multianalyte determination of 21 selected pesticides, phenols and phthalates in water. SPE was carried out on polymeric PLRP-s cartridges by percolating 20 mL-samples. For sample preconcentration, the performance of a prototype programmable field extraction system (PROFEXS) was evaluated against the commercial laboratory bench Prospekt system used for method development. The Profexs is designed for the automated on-site sampling, SPE preconcentration, and storage of up to 16 samples in SPE cartridges. These cartridges are further eluted and on-line analyzed with the Prospekt coupled to the chromatographic system. In the optimized method, where completely on-line SPE-LC-MS analysis of the samples is carried out with the Prospekt in the laboratory, detection limits lower than 100 ng/L, and satisfactory precision (relative standard deviations <25%) and accuracies (recovery percentages >75%) were obtained for most investigated compounds from the analysis of spiked Milli-Q water. The extraction efficiency achieved with the Profexs was comparable to that of the Prospekt for most compounds and somewhat lower for the most apolar analytes, probably due to adsorption on the pump filters. The completely on-line optimized method was applied to the analysis of surface water, ground water and drinking water from a waterworks in Barcelona. Some pesticides and phenols were found in both surface water and groundwater at ng/L or microg/L levels, but not in the final drinking water. Di(2-ethylhexyl)phthalate (DEHP) was present in all samples investigated, including blanks. To the author's knowledge, this is the first work describing the application of a fully automated on-line SPE-LC-MS method for the simultaneous analysis of pesticides, phenols, and phthalates in water, and the second one that examines the possibilities of the prototype Profexs for automated on-site SPE preconcentration of organic pollutants from water samples.


Structural and biophysical properties of a [4Fe4S] ferredoxin-like protein from Synechocystis sp. PCC 6803 with a unique two domain structure.
Electron carrier proteins (ECPs), binding iron-sulfur clusters, are vital components within the intricate network of metabolic and photosynthetic reactions. They play a crucial role in the distribution of reducing equivalents. In Synechocystis sp. PCC 6803, the ECP network includes at least nine ferredoxins. Previous research, including global expression analyses and protein binding studies, has offered initial insights into the functional roles of individual ferredoxins within this network. This study primarily focuses on Ferredoxin 9 (slr2059). Through sequence analysis and computational modeling, Ferredoxin 9 emerges as a unique ECP with a distinctive two-domain architecture. It consists of a C-terminal iron‑sulfur binding domain and an N-terminal domain with homology to Nil-domain proteins, connected by a structurally rigid 4-amino acid linker. Notably, in contrast to canonical [2Fe2S] ferredoxins exemplified by PetF (ssl0020), which feature highly acidic surfaces facilitating electron transfer with photosystem I reaction centers, models of Ferredoxin 9 reveal a more neutral to basic protein surface. Using a combination of electron paramagnetic resonance spectroscopy and square-wave voltammetry on heterologously produced Ferredoxin 9, this study demonstrates that the protein coordinates 2×[4Fe4S]2+/1+ redox-active and magnetically interacting clusters, with measured redox potentials of -420 ± 9 mV and - 516 ± 10 mV vs SHE. A more in-depth analysis of Fdx9's unique structure and protein sequence suggests that this type of Nil-2[4Fe4S] multi-domain ferredoxin is well conserved in cyanobacteria, bearing structural similarities to proteins involved in homocysteine synthesis in methanogens.


Proteins in action: femtosecond to millisecond structural dynamics of a photoactive flavoprotein.
Living systems are fundamentally dependent on the ability of proteins to respond to external stimuli. The mechanism, the underlying structural dynamics, and the time scales for regulation of this response are central questions in biochemistry. Here we probe the structural dynamics of the BLUF domain found in several photoactive flavoproteins, which is responsible for light activated functions as diverse as phototaxis and gene regulation. Measurements have been made over 10 decades of time (from 100 fs to 1 ms) using transient vibrational spectroscopy. Chromophore (flavin ring) localized dynamics occur on the pico- to nanosecond time scale, while subsequent protein structural reorganization is observed over microseconds. Multiple time scales are observed for the dynamics associated with different vibrations of the protein, suggesting an underlying hierarchical relaxation pathway. Structural evolution in residues directly H-bonded to the chromophore takes place more slowly than changes in more remote residues. However, a point mutation which suppresses biological function is shown to 'short circuit' this structural relaxation pathway, suppressing the changes which occur further away from the chromophore while accelerating dynamics close to it.


Detection of mesenchymal chondrosarcoma in pleural effusion with immunocytochemistry and determination of HEY1::NCOA2 fusion by next-generation sequencing on cell block.
Mesenchymal chondrosarcoma (MC) is a rare but extremely aggressive type of chondrosarcoma distinguished by the presence of both primitive mesenchymal cells and fully developed chondroid tissue. The identification of a biphasic morphology in pleural effusion, along with detection of the HEY1::NCOA2 fusion using next-generation sequencing, serve as vital indicators for an accurate diagnosis.


Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques.
The immune modulatory molecule CTLA-4 (CD152), through interactions with the B7 costimulatory molecules, has been shown to be a negative regulator of T cell activation in various murine model systems. Abs that block CTLA-4 function can enhance immune responses that mediate potent antitumor activity. However, CTLA-4 blockade can also exacerbate autoimmune disease. The safety and activity of anti-CTLA-4 Abs in primates has not been addressed. To that end, we generated human Abs against CTLA-4 using transgenic mice expressing human Ig genes. A high affinity Ab (10D1) that blocked the binding of CTLA-4 to the B7-1 and B7-2 ligands and had cross-reactivity with macaque CTLA-4 was chosen for further development. Administration of 10D1 to cynomolgus macaques significantly enhanced Ab responses to hepatitis surface Ag and a human melanoma cell vaccine. Anti-self Ab responses as measured by immunoassays using lysate from melanocyte-rich tissues were elicited in those animals receiving the melanoma cell vaccine and anti-CTLA-4 Ab. Remarkably, chronic administration of 10D1 did not result in measurable polyclonal T cell activation, significant alteration of the lymphocyte subsets, or induce clinically observable autoimmunity. Repeated dosing of the 10D1 did not elicit monkey anti-human Ab responses in the monkeys. These observations support the development of CTLA-4 blockade for human immunotherapy.


Controlling persister cells of Pseudomonas aeruginosa PDO300 by (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one.
Pseudomonas aeruginosa is a major pathogen causing chronic pulmonary infections; for example, 80% of cystic fibrosis patients get infected by this bacterium as the disease progresses. Such chronic infections are challenging because P. aeruginosa exhibits high-level tolerance to antibiotics by forming biofilms (multicellular structures attached to surfaces), by entering dormancy and forming antibiotic tolerant persister cells, and by conversion to the mucoid phenotype. Recently, we reported that a synthetic quorum sensing inhibitor, (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one (BF8), can sensitize both planktonic and biofilm-associated persister cells of P. aeruginosa PAO1 to antibiotics at the concentrations non-inhibitory to its growth. In this study, we further characterized the effects of this compound on the mucoid strain P. aeruginosa PDO300. BF8 was found to reduce persistence during the growth of PDO300 and effectively kill the persister cells isolated from PDO300 cultures. In addition to planktonic cells, BF8 was also found to inhibit biofilm formation of PDO300 and reduce associated persistence. These findings broaden the activities of this class of compounds and indicate that BF8 also has other targets in P. aeruginosa in addition to quorum sensing.


Role of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and viral pathogenesis.
The purpose of this study was to investigate the significance of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and role in viral virulence. To accomplish this, a recombinant myxoma virus was created in which the C-terminal RDEL motif of M-T4 was deleted and a selectable marker (Ecogpt) was inserted immediately downstream. We hypothesized that removal of the RDEL motif from M-T4 would alter the subcellular localization of the protein and provide insight into its antiapoptotic role. Surprisingly, removal of the RDEL motif from M-T4 did not affect localization of the protein within the endoplasmic reticulum (ER), but it did reduce the stability of the mutant protein. Pulse-chase immunoprecipitation and endoglycosidase H analysis coupled with confocal fluorescent light microscopy demonstrated that the M-T4 RDEL(-) mutant protein is retained in the ER like wildtype M-T4 and suggests that the C-terminal RDEL motif is not the sole determinant for M-T4 localization to the ER. Infection of cultured rabbit lymphocytes with the M-T4 RDEL(-) mutant virus results in an intermediate apoptosis phenotype compared with the wildtype and M-T4 knockout mutant viruses. A novel myxomatosis phenotype was observed in European rabbits when infected with the recombinant M-T4 RDEL(-) mutant virus. Rabbits infected with the M-T4 RDEL(-) virus on day 9 postinfection exhibited an exacerbated edematous and inflammatory response at secondary sites of infections, particularly the ears. Our results indicate that the C-terminal RDEL motif may not be solely responsible for retention of M-T4 to the ER and that M-T4 may have a dual function in protecting infected lymphocytes from apoptosis and in modulating the inflammatory response to virus infection.


Effect of infection of the genital tract on the concentration of IgG and albumin in bull serum and semen.
Bovine IgG and albumin concentrations were determined from serum and semen of 59 bulls that were divided into 4 groups: 35 non-infected bulls (Group 1); 10 with vesiculitis due to Corynebacterium pyogenes (Group 2); 10 bulls with orchitis due to Chlamydia psittaci (Group 3); and 4 bulls with infectious vesiculitis (Group 4) sampled both before and after antibiotic treatment. Serum IgG concentrations (25 mg/ml approximately) were similar in non-infected (Gp 1) and infected bulls (Gp 2,3,4) whereas serum albumin concentrations were greater in infected than in non-infected bulls (51 mg/ml vs.41 mg/ml; p less than 0.01). By contrast, both semen IgG and albumin concentrations in infected bulls (0.47 and 0.54 mg/ml respectively) were significantly different from those of non-infected bulls (0.14 and 0.32 mg/ml; p less than 0.01). In addition, bulls with chlamydial orchitis had both semen (but not serum) IgG and albumin levels higher than those suffering from vesiculitis (p less than 0.01). Antibiotic therapy led to recovery and simultaneously to decreased concentrations of semen IgG and albumin. These results strongly suggest a local IgG synthesis or selective diffusion after such genital infections and further indicate that semen IgG and albumin assays could be a new and valuable tool for diagnosis and evaluation of genital infections.


Coactivator recruitment is essential for liganded thyroid hormone receptor to initiate amphibian metamorphosis.
Thyroid hormone receptors (TRs) can repress or activate target genes depending on the absence or presence of thyroid hormone (T3), respectively. This hormone-dependent gene regulation is mediated by recruitment of co-repressors in the absence of T3 and coactivators in its presence. Many TR-interacting coactivators have been characterized in vitro. In comparison, few studies have addressed the developmental roles of these cofactors in vivo. We have investigated the role of coactivators in transcriptional activation by TR during postembryonic tissue remodeling by using amphibian metamorphosis as a model system. We have previously shown that steroid receptor coactivator 3 (SRC3) is expressed and upregulated during metamorphosis, suggesting a role in gene regulation by liganded TR. Here, we have generated transgenic tadpoles expressing a dominant negative form of SRC3 (F-dnSRC3). The transgenic tadpoles exhibited normal growth and development throughout embryogenesis and premetamorphic stages. However, transgenic expression of F-dnSRC3 inhibits essentially all aspects of T3-induced metamorphosis, as well as natural metamorphosis, leading to delayed or arrested metamorphosis or the formation of tailed frogs. Molecular analysis revealed that F-dnSRC3 functioned by blocking the recruitment of endogenous coactivators to T3 target genes without affecting corepressor release, thereby preventing the T3-dependent gene regulation program responsible for tissue transformations during metamorphosis. Our studies thus demonstrate that coactivator recruitment, aside from corepressor release, is required for T3 function in development and further provide the first example where a specific coactivator-dependent gene regulation pathway by a nuclear receptor has been shown to underlie specific developmental events.


Quiescent Cells Actively Replenish CENP-A Nucleosomes to Maintain Centromere Identity and Proliferative Potential.
Centromeres provide a robust model for epigenetic inheritance as they are specified by sequence-independent mechanisms involving the histone H3-variant centromere protein A (CENP-A). Prevailing models indicate that the high intrinsic stability of CENP-A nucleosomes maintains centromere identity indefinitely. Here, we demonstrate that CENP-A is not stable at centromeres but is instead gradually and continuously incorporated in quiescent cells including G0-arrested tissue culture cells and prophase I-arrested oocytes. Quiescent CENP-A incorporation involves the canonical CENP-A deposition machinery but displays distinct requirements from cell cycle-dependent deposition. We demonstrate that Plk1 is required specifically for G1 CENP-A deposition, whereas transcription promotes CENP-A incorporation in quiescent oocytes. Preventing CENP-A deposition during quiescence results in significantly reduced CENP-A levels and perturbs chromosome segregation following the resumption of cell division. In contrast to quiescent cells, terminally differentiated cells fail to maintain CENP-A levels. Our work reveals that quiescent cells actively maintain centromere identity providing an indicator of proliferative potential.


Colon and rectal cancer survival in seven high-income countries 2010-2014: variation by age and stage at diagnosis (the ICBP SURVMARK-2 project).
As part of the International Cancer Benchmarking Partnership (ICBP) SURVMARK-2 project, we provide the most recent estimates of colon and rectal cancer survival in seven high-income countries by age and stage at diagnosis. Data from 386 870 patients diagnosed during 2010-2014 from 19 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were analysed. 1-year and 5-year net survival from colon and rectal cancer were estimated by stage at diagnosis, age and country, RESULTS: (One1-year) and 5-year net survival varied between (77.1% and 87.5%) 59.1% and 70.9% and (84.8% and 90.0%) 61.6% and 70.9% for colon and rectal cancer, respectively. Survival was consistently higher in Australia, Canada and Norway, with smaller proportions of patients with metastatic disease in Canada and Australia. International differences in (1-year) and 5-year survival were most pronounced for regional and distant colon cancer ranging between (86.0% and 94.1%) 62.5% and 77.5% and (40.7% and 56.4%) 8.0% and 17.3%, respectively. Similar patterns were observed for rectal cancer. Stage distribution of colon and rectal cancers by age varied across countries with marked survival differences for patients with metastatic disease and diagnosed at older ages (irrespective of stage). Survival disparities for colon and rectal cancer across high-income countries are likely explained by earlier diagnosis in some countries and differences in treatment for regional and distant disease, as well as older age at diagnosis. Differences in cancer registration practice and different staging systems across countries may have impacted the comparisons.


[Women and alcohol, the addictologist's point of view and treatment].
Women have difficulty seeking help for alcohol-related problems. Shame and guilt are often present, which is why the caregiver must succeed in establishing a climate of trust so that things can be said, in order to best assess the impact of consumption and find alternatives. Treatment is often multidisciplinary. The nurse's role is essential, not only to identify drug use, but also to provide a link between the various players involved.


Enhanced in vitro efficacy for inhibiting hypertrophic scar by bleomycin-loaded dissolving hyaluronic acid microneedles.
Hypertrophic scarring is a widespread skin disorder that affects a patient's confidence and quality of life. Intralesional injection of bleomycin is one of the most commonly employed treatments for hypertrophic scars, which, however, always brings pain and requires long-term treatment. To overcome these limitations, new methods for bleomycin delivery enabling painlessness, self-administration, the fast onset of action, and good bioavailability are urgently needed. In this study, we developed bleomycin-loaded dissolving microneedles (BMN) made up of hyaluronic acid (HA) with excellent aqueous solubility and enhanced efficacy for inhibiting hypertrophic scars. The as-obtained BMN possesses sufficient mechanical strength to pierce porcine skin ex vivo with an insertion depth of over 300 μm. Moreover, BMN can dissolve rapidly and release 20% of loaded bleomycin within 1 min and 52% within 10 min, and the BMN-treated skin could recover to its original status within 3 h, demonstrating good biocompatibility. Besides, the HA matrix also maintains the stability and activity of bleomycin. Furthermore, we show that BMN consisting of HA and bleomycin can inhibit the proliferation of human hypertrophic scar fibroblasts (hHSFs) and the secretion of transforming growth factor-β (TGF-β1) in vitro. Therefore, bleomycin-loaded dissolving HA microneedles provide a potential route to treat hypertrophic scars in a convenient, efficient, and minimally invasive manner.


Identification of effective anti-HCV and anti-HIV royal jelly constituents and their acute toxicity evaluation in Albino rats.
Few studies on royal jelly's (RJ) antiviral activities and toxicity have been conducted. Here, we investigated the antioxidant properties of RJ that was fractionated into soluble fraction (SF), non-soluble fraction (NSF), water-soluble protein fraction (crude protein fraction, CPF), PF30, PF40, PF50, and PF60. The PFs were identified by SDS-PAGE, and phenolic constituents of SF were detected by HPLC. The qualitative anti-HCV, immunomodulatory, and predicted impact of the studied fractions on ERK2/MAPK14 (activated by HCV) were investigated. The influences of RJ fractions on HIV CD4, reverse-transcriptase, and integrase were examined. The acute toxicity of RJ, SF, NSF, and CPF-PF50 (all CPF except PF50) was tested. Results showed that RJ had potent antioxidant efficiency, and its SF contains functional phenolic compounds. PF30, PF40, and PF50 only showed anti-HCV potency, and PF50 had an immunomodulatory effect against HCV and predicted inhibitory influence on ERK2/MAPK14. RJ-PFs, particularly PF60, showed the most effective anti-HIV ingredients. A single ip injection of RJ fractions at different concentrations revealed that SF was the safest one. Whereas NSF was the most toxic at 700-5000 mg/kg b.w., its toxicity was reversed spontaneously after seven days. Thus, this study provides valuable information about the antiviral activities and toxicity of RJ constituents.


Large-scale brain functional network topology disruptions underlie symptom heterogeneity in children with attention-deficit/hyperactivity disorder.
Accumulating evidence suggests brain network dysfunction in attention-deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between-network functional connectivity (FC) changes in children with ADHD combined (ADHD-C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter-network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD-I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity.


The Importance of Excluding Cutaneous T-Cell Lymphomas in Patients with a Working Diagnosis of Papuloerythroderma of Ofuji: A Case Series.
Papuloerythroderma of Ofuji (PEO) is an erythroderma-like eruption with flat-topped papules that spare the skin folds (a "deck-chair sign" finding). Many infections, medications, and systemic diseases have been associated with PEO, including cutaneous T-cell lymphomas (CTCL). The relationship between the clinical presentation of PEO and CTCL remains poorly elucidated. Clinical, laboratory, and histopathological data were obtained from the Lymphoma Clinic at the Ottawa Hospital, Canada. We report 5 patients with deck-chair-sign-positive CTCL, mycosis fungoides, and Sézary syndrome variants. We contend that PEO should be viewed as a diagnosis of exclusion and that these patients should be monitored carefully for possible emergence of CTCL. Skin biopsy alone is not sufficient to exclude CTCL in these patients. A skin eruption demonstrating a positive deck-chair sign may signify systemic/leukemic CTCL and, therefore, warrants a thorough investigation, including skin biopsy, flow cytometry, and T-cell receptor clonality studies.


A Novel Fibrinogen Mutation p.BβAla68Asp Causes an Inherited Dysfibrinogenemia.
Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis. The one-stage clotting method was used to test the fibrinogen activity (FIB:C), whereas immunoturbidimetry was performed to quantify the fibrinogen antigen (FIB:Ag). Furthermore, DNA sequence analysis was conducted to confirm the site of mutation. Conservation analysis and protein model analysis were performed using online bioinformatics software. The FIB:C and FIB:Ag of the proband were 1.28 and 2.20 g/L, respectively. Gene analysis revealed a heterozygous c.293C > A (p.BβAla68Asp) mutation in FGB. Bioinformatics and modeling analysis suggested that the missense mutation could potentially have a deleterious effect on fibrinogen. The BβAla68Asp mutation in exon 2 of FGB may account for the reduced FIB:C levels observed in the pedigree. To our knowledge, this point mutation is the first report in the world.


A SIMULATION-BASED FRAMEWORK FOR ASSESSING THE FEASIBILITY OF RESPONDENT-DRIVEN SAMPLING FOR ESTIMATING CHARACTERISTICS IN POPULATIONS OF LESBIAN, GAY AND BISEXUAL OLDER ADULTS.
Respondent-driven sampling (RDS) is a method for sampling from a target population by leveraging social connections. RDS is invaluable to the study of hard-to-reach populations. However, RDS is costly and can be infeasible. RDS is infeasible when RDS point estimators have small effective sample sizes (large design effects) or when RDS interval estimators have large confidence intervals relative to estimates obtained in previous studies or poor coverage. As a result, researchers need tools to assess whether or not estimation of certain characteristics of interest for specific populations is feasible in advance. In this paper, we develop a simulation-based framework for using pilot data-in the form of a convenience sample of aggregated, egocentric data and estimates of subpopulation sizes within the target population-to assess whether or not RDS is feasible for estimating characteristics of a target population. in doing so, we assume that more is known about egos than alters in the pilot data, which is often the case with aggregated, egocentric data in practice. We build on existing methods for estimating the structure of social networks from aggregated, egocentric sample data and estimates of subpopulation sizes within the target population. We apply this framework to assess the feasibility of estimating the proportion male, proportion bisexual, proportion depressed and proportion infected with HIV/AIDS within three spatially distinct target populations of older lesbian, gay and bisexual adults using pilot data from the caring and Aging with Pride Study and the Gallup Daily Tracking Survey. We conclude that using an RDS sample of 300 subjects is infeasible for estimating the proportion male, but feasible for estimating the proportion bisexual, proportion depressed and proportion infected with HIV/AIDS in all three target populations.


A 3 1/2 year old girl with distal trisomy 19q defined by FISH.
A 3 1/2 year old girl was evaluated because of developmental delay. Short stature was evident with height between the 3rd and 10th centiles, while weight and head circumference were on the 50th centile. Dysmorphic features consisted of a high bossed forehead, pointed short ear lobes, small nose, bilateral convergent strabismus, left simian crease, a gap between the first and second toes bilaterally, mild clinodactyly, and a broad, barrel shaped thorax. Cytogenetic investigations showed an unbalanced karyotype, 46,XX,10q+, which was de novo in origin. Fluorescence in situ hybridisation (FISH) using three library probes (from chromosomes 10, 19, and 19q) and a YAC probe (from 10q telomere) showed that the additional material on 10q was derived from chromosome 19q. The patient had an unbalanced translocation, 46,XX,-10,+der(10)t(10;19)(q26.3; q13.3), which resulted in distal trisomy 19q. Few other cases of proven distal trisomy 19q are available for comparison of clinical features.


Cognitive impairment and risk of future stroke: a systematic review and meta-analysis.
Several studies have assessed the link between cognitive impairment and risk of future stroke, but results have been inconsistent. We conducted a systematic review and meta-analysis of cohort studies to determine the association between cognitive impairment and risk of future stroke. We searched MEDLINE and Embase (1966 to November 2013) and conducted a manual search of bibliographies of relevant retrieved articles and reviews. We included cohort studies that reported multivariable adjusted relative risks and 95% confidence intervals or standard errors for stroke with respect to baseline cognitive impairment. We identified 18 cohort studies (total 121 879 participants) and 7799 stroke events. Pooled analysis of results from all studies showed that stroke risk increased among patients with cognitive impairment at baseline (relative risk [RR] 1.39, 95% confidence interval [CI] 1.24-1.56). The results were similar when we restricted the analysis to studies that used a widely adopted definition of cognitive impairment (i.e., Mini-Mental State Examination score < 25 or nearest equivalent) (RR 1.64, 95% CI 1.46-1.84). Cognitive impairment at baseline was also associated with an increased risk of fatal stroke (RR 1.68, 95% CI 1.21-2.33) and ischemic stroke (RR 1.65, 95% CI 1.41-1.93). Baseline cognitive impairment was associated with a significantly higher risk of future stroke, especially ischemic and fatal stroke.


Gradient structures and geodesic convexity for reaction-diffusion systems.
We consider systems of reaction-diffusion equations as gradient systems with respect to an entropy functional and a dissipation metric given in terms of a so-called Onsager operator, which is a sum of a diffusion part of Wasserstein type and a reaction part. We provide methods for establishing geodesic λ-convexity of the entropy functional by purely differential methods, thus circumventing arguments from mass transportation. Finally, several examples, including a drift-diffusion system, provide a survey on the applicability of the theory.


Thrombopoietin and the humoral regulation of thrombocytopoiesis.
In 1994 four biotechnology research groups reported the isolation and cloning of the ligand for the cytokine receptor c-Mpl and showed it to be the long-sought regulator of platelet production, thrombopoietin. Thrombopoietin is a hematopoietic growth factor of 332 amino acids composed of an amino terminal domain homologous to erythropoietin and a highly glycosylated carboxyl domain. The erythropoietin-like domain is the functional domain, whereas the glycosylated domain appears to stabilize circulating thrombopoietin. Thrombopoietin stimulates both proliferation of progenitor megakaryocytes and their maturation to platelet-producing megakaryocytes. Thrombopoietin induces dramatic increases in megakaryocyte number and platelet production in mice, indicating that it regulates both thrombopoiesis and megakaryocytopoiesis. Thrombopoietin also accelerates the recovery of platelets in myelosuppressed animals, suggesting that it will be clinically useful for the treatment of thrombocytopenia.


Autophagy Regulatory Network - a systems-level bioinformatics resource for studying the mechanism and regulation of autophagy.
Autophagy is a complex cellular process having multiple roles, depending on tissue, physiological, or pathological conditions. Major post-translational regulators of autophagy are well known, however, they have not yet been collected comprehensively. The precise and context-dependent regulation of autophagy necessitates additional regulators, including transcriptional and post-transcriptional components that are listed in various datasets. Prompted by the lack of systems-level autophagy-related information, we manually collected the literature and integrated external resources to gain a high coverage autophagy database. We developed an online resource, Autophagy Regulatory Network (ARN; http://autophagy-regulation.org), to provide an integrated and systems-level database for autophagy research. ARN contains manually curated, imported, and predicted interactions of autophagy components (1,485 proteins with 4,013 interactions) in humans. We listed 413 transcription factors and 386 miRNAs that could regulate autophagy components or their protein regulators. We also connected the above-mentioned autophagy components and regulators with signaling pathways from the SignaLink 2 resource. The user-friendly website of ARN allows researchers without computational background to search, browse, and download the database. The database can be downloaded in SQL, CSV, BioPAX, SBML, PSI-MI, and in a Cytoscape CYS file formats. ARN has the potential to facilitate the experimental validation of novel autophagy components and regulators. In addition, ARN helps the investigation of transcription factors, miRNAs and signaling pathways implicated in the control of the autophagic pathway. The list of such known and predicted regulators could be important in pharmacological attempts against cancer and neurodegenerative diseases.


Transcriptional profiling of the chick retina identifies down-regulation of VIP and UTS2B genes during early lens-induced myopia.
Gene expression of the chick retina was examined during the early development of lens-induced myopia (LIM) using whole transcriptome sequencing. Monocular treatment of the right eyes with -10 diopter (D) lenses was performed on newly born chicks for one day (LIM-24) or two days (LIM-48), while the contralateral eyes without lenses served as controls. Myopia development was confirmed by demonstrating significant elongation of the optical axis in lens-treated eyes compared to untreated control eyes. RNA was extracted and RNA-seq was performed using the Illumina HiSeqTM 2000 platform. Data analysis was carried out on a Partek® Flow platform. Using screening criteria of ≥1.30-fold change and a false discovery rate <1%, 11 (five down-regulated and six up-regulated) and 35 differentially expressed genes (six down-regulated and twenty-nine up-regulated) were identified at 24 hours and 48 hours, respectively. Using another cohort for validation, Quantitative PCR confirmed significant changes in the expression of VIP and UTS2B mRNA (P <0.05) after only 24 hours of LIM treatment and numerical changes in the expression for PCGF5 and FOXG1, which were consistent with transcriptome sequencing but did not reach statistical significance. These data suggest that concerted changes of retinal gene expression may be instrumental in the initiation of axial elongation and myopia development.


Persistence of environmental DNA in freshwater ecosystems.
The precise knowledge of species distribution is a key step in conservation biology. However, species detection can be extremely difficult in many environments, specific life stages and in populations at very low density. The aim of this study was to improve the knowledge on DNA persistence in water in order to confirm the presence of the focus species in freshwater ecosystems. Aquatic vertebrates (fish: Siberian sturgeon and amphibian: Bullfrog tadpoles) were used as target species. In control conditions (tanks) and in the field (ponds), the DNA detectability decreases with time after the removal of the species source of DNA. DNA was detectable for less than one month in both conditions. The density of individuals also influences the dynamics of DNA detectability in water samples. The dynamics of detectability reflects the persistence of DNA fragments in freshwater ecosystems. The short time persistence of detectable amounts of DNA opens perspectives in conservation biology, by allowing access to the presence or absence of species e.g. rare, secretive, potentially invasive, or at low density. This knowledge of DNA persistence will greatly influence planning of biodiversity inventories and biosecurity surveys.


Decline in native renal function early after bladder-drained pancreas transplantation alone.
Pancreas transplant alone (PTA) has become accepted therapy for select nonuremic patients with type 1 diabetes mellitus. However, PTA may lead to significant complications including a decline in native renal function. This study examines trends in native renal function during the first posttransplant year in PTA recipients with a spectrum of pretransplant glomerular filtration rates (GFR). Renal function was studied in 23 recipients of bladder-drained PTA who underwent transplantation from April 1998 through September 2001. GFR was measured by corrected iothalamate clearance at the time of transplant evaluation and 1 year posttransplant and also calculated using the Cockcroft-Gault method at the transplant evaluation; at the day of transplantation; and at 1, 6, and 12 months posttransplant. Iothalamate clearance decreased in the first year in 96% of patients (22 of 23). The mean measured GFR decreased from 84 +/- 33 mL/min/1.73 m2 pretransplant to 52 +/- 26 mL/min/1.73 m2 at 1 year (P <0.001). Calculated creatinine clearance declined in the majority of patients at both 1 and 12 months after PTA, but some patients, including a few with low GFR, maintained stable renal function. Calculated GFR generally correlated well with measured GFR in most patients, with a few notable exceptions. One patient (baseline GFR, 42 mL/min/1.73 m2) developed renal failure in the first year after transplant and required kidney transplantation. Bladder-drained PTA results in a decline in native renal function in the majority of patients regardless of the pretransplant GFR. These data suggest the need for strategies to prevent or minimize the decline in renal function after PTA.


First report of the root-knot nematode, Meloidogyne morocciensis infecting peach in Southern Brazil.
The peach tree (Prunus persica) is the third most cultivated temperate fruit species in Brazil. In August 2017, peach seedling plants showing symptoms of stunting and multiple galls in the roots were detected in the municipality of Pelotas, state of Rio Grande do Sul, Brazil. Samples of peach roots were collected and they were subsequently processed to obtain eggs and second-stage juveniles (J2), to determine the number of nematodes per gram of roots and to proceed with morphological studies. Additionally, individual females were extracted from the peach roots and submitted to Meloidogyne species identification by electrophoresis using α-esterase (Est) and malate dehydrogenase (Mdh) phenotypes and perineal pattern. The nematode population density in the samples was 283 eggs + J2s per gram of fresh roots. The polymorphism analysis revealed the A3N1 phenotype, typical to Meloidogyne morocciensis. Perineal patterns of females showed oval squared shapes, with moderately high to high dorsal arches, streaks widely separated, generally continuous, sometimes broken; the phasmids were separate by 29.3 μm (25.43-31.94 μm), similar to M. arenaria and M. incognita, as observed by Hammah and Hirschmann (1990). The second-stage juveniles had the following morphometric characters: L = 389.3 ± 3.8 (377.5-425.1) μm, stylet = 13.9 ± 0.2 (12.7-14.9) μm, DGO = 3.6 ± 0.1 (3.3-4.2) μm, tail length 47.5 ± 0.6 (45.3-48.9) µm, hyaline tail terminus = 14.1 ± 0.3 (12.5-17.0) µm, a = 25.6 ± 0.4 (23.8-28.8) µm and c = 8.6 ± 0.1 (8.0-9.3). The known SCAR marker obtained for M. arenaria is the same as that amplified for M. morocciensis. Under greenhouse conditions, peach plants seedlings inoculated with 1,000 eggs (Pi) with M. morocciensis were evaluated 28 days after inoculation compared to non-inoculated plants. The inoculated peach plants showed a mean of 338 galls per root system, and a nematode reproduction factor of 10.3. Besides this plants exhibited a reduction in fresh weight of shoots and roots compared to the non-inoculated plants. These results confirm M. morocciensis pathogenicity on P. persica. The peach tree (Prunus persica) is the third most cultivated temperate fruit species in Brazil. In August 2017, peach seedling plants showing symptoms of stunting and multiple galls in the roots were detected in the municipality of Pelotas, state of Rio Grande do Sul, Brazil. Samples of peach roots were collected and they were subsequently processed to obtain eggs and second-stage juveniles (J2), to determine the number of nematodes per gram of roots and to proceed with morphological studies. Additionally, individual females were extracted from the peach roots and submitted to Meloidogyne species identification by electrophoresis using α-esterase (Est) and malate dehydrogenase (Mdh) phenotypes and perineal pattern. The nematode population density in the samples was 283 eggs + J2s per gram of fresh roots. The polymorphism analysis revealed the A3N1 phenotype, typical to Meloidogyne morocciensis. Perineal patterns of females showed oval squared shapes, with moderately high to high dorsal arches, streaks widely separated, generally continuous, sometimes broken; the phasmids were separate by 29.3 μm (25.43-31.94 μm), similar to M. arenaria and M. incognita, as observed by Hammah and Hirschmann (1990). The second-stage juveniles had the following morphometric characters: L = 389.3 ± 3.8 (377.5-425.1) μm, stylet = 13.9 ± 0.2 (12.7-14.9) μm, DGO = 3.6 ± 0.1 (3.3-4.2) μm, tail length 47.5 ± 0.6 (45.3-48.9) µm, hyaline tail terminus = 14.1 ± 0.3 (12.5-17.0) µm, a = 25.6 ± 0.4 (23.8-28.8) µm and c = 8.6 ± 0.1 (8.0-9.3). The known SCAR marker obtained for M. arenaria is the same as that amplified for M. morocciensis. Under greenhouse conditions, peach plants seedlings inoculated with 1,000 eggs (Pi) with M. morocciensis were evaluated 28 days after inoculation compared to non-inoculated plants. The inoculated peach plants showed a mean of 338 galls per root system, and a nematode reproduction factor of 10.3. Besides this plants exhibited a reduction in fresh weight of shoots and roots compared to the non-inoculated plants. These results confirm M. morocciensis pathogenicity on P. persica.


Modeling of 24-hour glucose and insulin profiles in patients with type 2 diabetes mellitus treated with biphasic insulin aspart.
Insulin therapy for diabetes patients is designed to mimic the endogenous insulin response of healthy subjects and thereby generate normal blood glucose levels. In order to control the blood glucose in insulin-treated diabetes patients, it is important to be able to predict the effect of exogenous insulin on blood glucose. A pharmacokinetic/pharmacodynamic model for glucose homoeostasis describing the effect of exogenous insulin would facilitate such prediction. Thus the aim of this work was to extend the previously developed integrated glucose-insulin (IGI) model to predict 24-hour glucose profiles for patients with Type 2 diabetes following exogenous insulin administration. Clinical data from two trials were included in the analysis. In both trials, 24-hour meal tolerance tests were used as the experimental setup, where exogenous insulin (biphasic insulin aspart) was administered in relation to meals. The IGI model was successfully extended to include the effect of exogenous insulin. Circadian variations in glucose homeostasis were assessed on relevant parameters, and a significant improvement was achieved by including a circadian rhythm on the endogenous glucose production in the model. The extended model is a useful tool for clinical trial simulation and for elucidating the effect profile of new insulin products.


Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine.
To compare the incidence and define the risk factors associated with liver toxicity in patients beginning treatment with nevirapine (NVP) and efavirenz (EFZ). This was a retrospective chart review of all HIV-infected patients starting any antiretroviral regimen containing at least two nucleoside analogues plus either NVP or EFZ between January 1998 and January 2000. Liver toxicity was defined as an increase in transaminase levels 5-fold above the upper limits of normal if they were normal at baseline or 3.5-fold above baseline levels if they were previously elevated. Out of 298 patients included in the study, 162 received NVP and 136 EFZ. Overall, 75% were men, and 45% were coinfected with the hepatitis C virus (HCV). Median (interquartile range) time on follow-up was 10 (6-12) months. Liver toxicity was more frequently associated with NVP (12%) than with EFZ (4%) (p =.016). Overall, it was first recognized at a median time of 5.5 months (2.7-9.2) on therapy, with no differences between treatment arms. Both univariate and multivariate analyses identified the use of NVP, HCV coinfection, alcohol abuse, and female gender as independent risk factors for liver toxicity. Liver damage is three times more common in patients receiving NVP than in those taking EFZ. In both groups of patients, it is recognized late, after an average of 5.5 months on therapy. Coinfection with HCV, alcohol abuse, and female gender increase the risk for developing liver toxicity with both drugs.


Development and implementation of a food store-based intervention to improve diet in the Republic of the Marshall Islands.
Effective approaches for the prevention and reduction of obesity and obesity-related chronic diseases are urgently needed. Food store-centered programs represent one approach that may be both effective and sustainable. The authors developed a food store-based intervention in the Marshall Islands using qualitative and quantitative formative research methods, including a store usage survey (n = 184) and in-depth interviews with large-store managers (n = 13), small-store managers (n = 7), customers (n = 10), and community leaders (n = 4). This process was followed up by development and piloting of specific intervention components and workshops to finalize materials. The final intervention combined mass media (newspaper articles, video, radio announcements) and in-store components (shelf labels, cooking demonstrations, posters, recipe cards) and had high store-owner support and participation. High levels of exposure to the intervention were achieved during the 10-week period of implementation. This model for developing food store-based interventions is applicable to other settings.


Toward Efficient and Metal-Free Emissive Devices: A Solution-Processed Host-Guest Light-Emitting Electrochemical Cell Featuring Thermally Activated Delayed Fluorescence.
The next generation of emissive devices should preferably be efficient, low-cost, and environmentally sustainable, and as such utilize all electrically generated excitons (both singlets and triplets) for the light emission, while being free from rare metals such as iridium. Here, we report on a step toward this vision through the design, fabrication, and operation of a host-guest light-emitting electrochemical cell (LEC) featuring an organic thermally activated delayed fluorescence (TADF) guest that harvests both singlet and triplet excitons for the emission. The rare-metal-free active material also consists of a polymeric electrolyte and a polymeric compatibilizer for the facilitation of a cost-efficient and scalable solution-based fabrication, and for the use of air-stable electrodes. We report that such TADF-LEC devices can deliver uniform green light emission with a maximum luminance of 228 cd m-2 when driven by a constant-current density of 770 A m-2, and 760 cd m-2 during a voltage ramp, which represents a one-order-of-magnitude improvement in comparison to previous TADF-emitting LECs.


The relationship between tumor necrosis factor and human immunodeficiency virus gene expression in lymphoid tissue.
In tissue culture models of chronic human immunodeficiency virus type 1 (HIV-1) infection, cytokines such as tumor necrosis factor alpha (TNF-alpha) activate viral gene expression. We sought evidence that TNF-alpha might similarly regulate viral gene expression in vivo in the major lymphoid tissue (LT) reservoir. We used in situ hybridization, quantitative image analysis, and double-label techniques to compare cytokine and HIV-1 RNA levels in sections of tonsil and lymph node tissues obtained from individuals in early and later stages of HIV-1 infection. The levels of TNF-alpha gene expression in LT from HIV-1-infected an uninfected individuals were indistinguishable, and we found no correlation between TNF-alpha gene expression in LT and the level of HIV-1 gene expression in LT. There is thus little evidence that in vivo TNF-alpha significantly influences HIV production in LT.


[Interhemispheric transmission of visual information: behavioral and electrophysiologic aspects].
Efficiency of callosal and extracallosal channels of interhemispheric transfer of visual information was studied by behavioural and electrophysiological methods on cats with sections of classical and commissural pathways of the visual system. The results showed a high ability of the operated animals to form conditioned defensive reflex to visual stimuli. The primary complexes of evoked potentials to light flashes in the projection cortex of both hemispheres were also preserved. The data show the significant role of the callosal and extracallosal pathways of the transmission of visual information across the midline.


Crohn's disease in adults: observations in a multiracial Asian population.
To determine the demography and clinical presentation of CD and secondly to determine any differences in the prevalence between the different ethnic groups in a multiracial Asian population. Patients with CD who were seen in 2001-2003 in the University of Malaya Medical Centre (UMMC) were enrolled in this study. Prevalence of disease was calculated for the group as a whole and by race with hospital admissions per ethnic group as the denominator. Thirty-four patients were diagnosed to have CD. Basic demographic data of patients; male:female 17:17; mean age 29.1 years (+/-13.5 years); ethnic group: Malays 5 (14.7%), Chinese 12 (35.3%) and Indians 17 (50%).Twenty-six (76.5%) were diagnosed under the age of 40 and 8 (23.5%) were diagnosed over the age of 40. Location of the disease was as follows:ileocolonic 13 (38.2%), terminal ileum only 9 (26.5%), colon only 8 (23.5%), and upper gastrointestinal 4 (11.8%). Sixteen (47.1%) had penetrating disease, 9 (26.5%) had stricturing disease and 9 (26.5%) had non-penetrating and non-stricturing disease. The hospital admission prevalence of CD was 26.0 overall, Indians 52.6, Chinese 6.9, and Malays 9.3 per 10(5) admissions per ethnic group. The difference between Indians and Malays: [OR 5.67 (1.97, 17.53) P<0.001] was statistically significant but not between the Indians and the Chinese [OR 1.95 (0.89, 4.35) P=0.700]. The difference between the Chinese and the Malays was also not statistically significant. [OR 2.90 (0.95, 9.42) P=0.063]. The clinical presentation of CD is similar to the Western experience. Although the overall prevalence is low,there appears to be a clear racial predominance among the Indians.


Controllability of an aversive stimulus in depressed patients and health controls: a study using slow brain potentials.
Slow brain potentials (CNV and PINV) were recorded from 18 patients with primary depression and 18 health controls under three experimental conditions. A short tone (S1) indicated the occurrence of an aversive tone stimulus (S2) which could not be terminated by a motor reaction in Condition 1 (C1) but was terminated in C2. In C3 the reaction time (RT) had to be faster than the shortest mean RT from C1 and C2 in order to stop the aversive stimulus. For both groups the RT decreased from C1 to C2 to C3 and the CNV increased from C2 to C3. CNV and RT did not differ between the groups in either condition. In C1 and C3 (uncontrollability and restricted control over the aversive stimulus) patients developed a marked PINV which was not observed in the control group. In view of other investigations which found a PINV in normal subjects in situations of sudden, unexpected uncontrollability, the present results demonstrate that depressed patients are more sensitive to levels and variation of uncontrollability than healthy subjects. A possible relationship to Seligman's concept of helplessness is discussed.


Destructive posttraumatic subtalar synovitis.
Destructive posttraumatic synovitis is a rare entity usually involving the knee. This case report details the evaluation and treatment of a rapidly progressive and destructive subtalar lesion that occurred in a healthy 27-year-old man after incidental trauma. Initial orthopedic evaluation revealed diffuse ankle tenderness and mild effusion. Radiographic and laboratory studies showed normal findings. Bone scan revealed significantly increased uptake in the talus. Subsequent computed tomography scan and magnetic resonance imaging studies showed a lateral soft-tissue mass invading both the talus and calcaneus with destruction of the subtalar joint. Tissue biopsy samples revealed hypertrophic synovium with villous projections, occasional giant cells, and occasional hemosiderin deposits. The lesion caused rapid and progressive destruction of the subtalar joint despite aggressive conservative measures. Ultimately, the patient underwent a subtalar arthrodesis that led to the resolution of his symptoms and resumption of work and recreational activities. While posttraumatic synovitis is a rarely encountered condition, the orthopedic surgeon must have an index of suspicion, perform a systematic evaluation, and render definitive treatment to ensure a successful outcome.


Protective effects of Lycium barbarum polysaccharide on ovariectomy‑induced cognition reduction in aging mice.
Women experience cognitive decline as they age due to the decrease in estrogen levels following menopause. Currently, effective pharmaceutical treatments for age‑related cognitive decline are lacking; however, several Traditional Chinese medicines have shown promising effects. Lycium barbarum polysaccharides (LBPs) were found to exert a wide variety of biological activities, including anti‑inflammatory, antioxidant and anti‑aging effects. However, to the best of our knowledge, the neuroprotective actions of LBP on cognitive impairment induced by decreased levels of estrogen have not yet been determined. To evaluate the effects of LBP on learning and memory impairment in an animal model of menopause, 45 female ICR mice were randomly divided into the following three groups: i) Sham; ii) ovariectomy (OVX); and iii) OVX + LBP treatment. The results of open‑field and novel object recognition tests revealed that mice in the OVX group had learning and memory impairments, and lacked the ability to recognize and remember new objects. Notably, these deficits were attenuated following LBP treatment. Immunohistochemical staining confirmed the protective effects of LBP on hippocampal neurons following OVX. To further investigate the underlying mechanism of OVX in mice, mRNA sequencing of the hippocampal tissue was performed, which revealed that the Toll‑like receptor 4 (TLR4) inflammatory signaling pathway was significantly upregulated in the OVX group. Moreover, reverse transcription‑quantitative PCR and immunohistochemical staining demonstrated that OVX induced hippocampal injury, upregulated the expression levels of TLR4, myeloid differentiation factor 88 and NF‑κB, and increased the expression of TNF‑α, IL‑6 and IL‑1β inflammatory factors. Conversely, LBP treatment downregulated the expression levels of mRNAs and proteins associated with the TLR4/NF‑κB signaling pathway, decreased the inflammatory response and reduced neuronal injury in mice that underwent OVX. In conclusion, the findings of the present study indicated that oral LBP treatment may alleviate OVX‑induced cognitive impairments by downregulating the expression levels of mRNAs and proteins associated with the TLR4/NF‑κB signaling pathway, thereby reducing neuroinflammation and damage to the hippocampal neurons. Thus, LBP may represent a potential agent for the prevention of learning and memory impairments in patients with accelerated aging caused by estrogen deficiency.


Cytoplasmic molecular delivery with shock waves: importance of impulse.
Cell permeabilization using shock waves may be a way of introducing macromolecules and small polar molecules into the cytoplasm, and may have applications in gene therapy and anticancer drug delivery. The pressure profile of a shock wave indicates its energy content, and shock-wave propagation in tissue is associated with cellular displacement, leading to the development of cell deformation. In the present study, three different shock-wave sources were investigated; argon fluoride excimer laser, ruby laser, and shock tube. The duration of the pressure pulse of the shock tube was 100 times longer than the lasers. The uptake of two fluorophores, calcein (molecular weight: 622) and fluorescein isothiocyanate-dextran (molecular weight: 71,600), into HL-60 human promyelocytic leukemia cells was investigated. The intracellular fluorescence was measured by a spectrofluorometer, and the cells were examined by confocal fluorescence microscopy. A single shock wave generated by the shock tube delivered both fluorophores into approximately 50% of the cells (p < 0.01), whereas shock waves from the lasers did not. The cell survival fraction was >0.95. Confocal microscopy showed that, in the case of calcein, there was a uniform fluorescence throughout the cell, whereas, in the case of FITC-dextran, the fluorescence was sometimes in the nucleus and at other times not. We conclude that the impulse of the shock wave (i.e., the pressure integrated over time), rather than the peak pressure, was a dominant factor for causing fluorophore uptake into living cells, and that shock waves might have changed the permeability of the nuclear membrane and transferred molecules directly into the nucleus.


Deep mutational scanning and machine learning reveal structural and molecular rules governing allosteric hotspots in homologous proteins.
A fundamental question in protein science is where allosteric hotspots - residues critical for allosteric signaling - are located, and what properties differentiate them. We carried out deep mutational scanning (DMS) of four homologous bacterial allosteric transcription factors (aTFs) to identify hotspots and built a machine learning model with this data to glean the structural and molecular properties of allosteric hotspots. We found hotspots to be distributed protein-wide rather than being restricted to 'pathways' linking allosteric and active sites as is commonly assumed. Despite structural homology, the location of hotspots was not superimposable across the aTFs. However, common signatures emerged when comparing hotspots coincident with long-range interactions, suggesting that the allosteric mechanism is conserved among the homologs despite differences in molecular details. Machine learning with our large DMS datasets revealed global structural and dynamic properties to be a strong predictor of whether a residue is a hotspot than local and physicochemical properties. Furthermore, a model trained on one protein can predict hotspots in a homolog. In summary, the overall allosteric mechanism is embedded in the structural fold of the aTF family, but the finer, molecular details are sequence-specific.


Unique repetitive sequence and unexpected regulation of expression of rat endothelial receptor for oxidized low-density lipoprotein (LOX-1).
We report the identification of a unique repetitive sequence in the rat endothelial receptor for oxidized low-density lipoprotein (LOX-1) and unexpected blood-pressure-associated regulation of its expression, a new link between lipid metabolism and blood-pressure control. A rat aorta cDNA library was constructed and screened with a probe synthesized by degenerate PCR. Rat LOX-1 cDNA encoded a protein of 364 amino acids that showed approximately 60% similarity to its bovine and human counterparts. The protein consisted of intracellular N-terminal, transmembrane and extracellular lectin-like domains. Rat LOX-1 was unique in having three repeats of a 46-amino-acid motif between the transmembrane and lectin-like regions. Two isoforms of mRNA were found to be generated by alternative use of two polyadenylation signals in a tissue-specific manner. The 3'-untranslated region contained multiple A+U-rich elements for rapid degradation of mRNA. Northern-blot analysis revealed that LOX-1 mRNA was expressed predominantly in the lung. Quite unexpectedly, the expression was dramatically up-regulated in the aorta in hypertensive SHR-SP/Izm rats compared with very low levels in control WKY/Izm rats, suggesting a potential role for LOX-1 in the pathogenesis of hypertension as well as atherosclerosis.


Classification of longitudinal data through a semiparametric mixed-effects model based on lasso-type estimators.
We propose a classification method for longitudinal data. The Bayes classifier is classically used to determine a classification rule where the underlying density in each class needs to be well modeled and estimated. This work is motivated by a real dataset of hormone levels measured at the early stages of pregnancy that can be used to predict normal versus abnormal pregnancy outcomes. The proposed model, which is a semiparametric linear mixed-effects model (SLMM), is a particular case of the semiparametric nonlinear mixed-effects class of models (SNMM) in which finite dimensional (fixed effects and variance components) and infinite dimensional (an unknown function) parameters have to be estimated. In SNMM's maximum likelihood estimation is performed iteratively alternating parametric and nonparametric procedures. However, if one can make the assumption that the random effects and the unknown function interact in a linear way, more efficient estimation methods can be used. Our contribution is the proposal of a unified estimation procedure based on a penalized EM-type algorithm. The Expectation and Maximization steps are explicit. In this latter step, the unknown function is estimated in a nonparametric fashion using a lasso-type procedure. A simulation study and an application on real data are performed.


Foot static disturbances and clinical features in overweight patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic, inflammatory, connective tissue disease, leading to foot deformities, impairment of locomotive functions, and reducing patients' quality of life. Obesity prevalence is rising in early RA and is associated with worse disease activity, function and health-related quality of life, with a significant negative impact on achieving a low Disease Activity Score in 28 joints (DAS28). The aim of the study was to evaluate foot deformities in overweight RA patients according to the severity of the disease. The study was performed on 50 overweight women with RA. The control group consisted of 50 overweight women free of any disorders. Plantography examination was carried out by means of a CQ ST 2K podoscope. Rheumatoid arthritis disease activity was assessed by DAS28. Activity limitation was assessed using the Health Assessment Questionnaire (HAQ) and foot posture by the Foot Posture Index (FPI-6). Body composition analysis was performed using In Body 220. Hallux valgus was the most frequent deformation in RA patients with overweight. Longitudinal flat foot was much more frequent in RA patients than transverse flat foot. A relationship between fat tissue mass and presence of transverse flat foot in RA patients with overweight was found. In this group DAS28, VAS, and Clarke's angle were correlated with increased value of HAQ. Plantar contourography showed a trend of an increase of α angle values and the Sztriter-Godunow index (KY) in overweight RA patients with increasing severity of radiological changes and DAS28, requiring use of proper prevention and therapeutic strategies of destructive changes.


Municipal distribution of ovarian cancer mortality in Spain.
Spain was the country that registered the greatest increases in ovarian cancer mortality in Europe. This study describes the municipal distribution of ovarian cancer mortality in Spain using spatial models for small-area analysis. Smoothed relative risks of ovarian cancer mortality were obtained, using the Besag, York and Molliè autoregressive spatial model. Standardised mortality ratios, smoothed relative risks, and distribution of the posterior probability of relative risks being greater than 1 were depicted on municipal maps. During the study period (1989-1998), 13,869 ovarian cancer deaths were registered in 2,718 Spanish towns, accounting for 4% of all cancer-related deaths among women. The highest relative risks were mainly concentrated in three areas, i.e., the interior of Barcelona and Gerona (north-east Spain), the north of Lugo and Asturias (north-west Spain) and along the Seville-Huelva boundary (in the south-west). Eivissa (Balearic Islands) and El Hierro (Canary Islands) also registered increased risks. Well established ovarian cancer risk factors might not contribute significantly to the municipal distribution of ovarian cancer mortality. Environmental and occupational exposures possibly linked to this pattern and prevalent in specific regions, are discussed in this paper. Small-area geographical studies are effective instruments for detecting risk areas that may otherwise remain concealed on a more reduced scale.


Effect of current spreading on the efficiency droop of InGaN light-emitting diodes.
We investigate the effects of current spreading on the efficiency droop of InGaN blue light-emitting diodes with lateral injection geometry based on numerical simulation. Current crowding near the mesa edge and the decrease in the current spreading length with current density are shown to cause significant efficiency droop. It is found that the efficiency droop can be reduced considerably as the uniformity of current spreading is improved by increasing the resistivity of the p-type current spreading layer or decreasing the sheet resistance of the n-GaN layer. The droop reduction is well interpreted by the uniformity of carrier distribution in the plane of quantum wells.


Decalepis hamiltonii root fraction alleviates CCl4 hepatotoxicity in a rat model.
Decalepis hamiltonii (D. hamiltonii) is Indian folk medicine in herbal preparations, to reduce appetite, and cures dysentery, bronchitis, uterine hemorrhage, and other ailments. The current investigation focused on the hepatoprotective effect of D. hamiltonii roots fractions against liver damage. The current research discussed the fraction from D. hamiltonii root extracts was used. Male Wistar rats (albino strain) were grouped into 4 distinct groups of six animals each. Group I: plain water and vehicle whereas Group II (CCl4 control): CCl4 (1 ml/kg, 20 % v/v in olive oil) over 7 days and vehicle; Over 7 days, Group III received Silymarin 100 mg/kg/day and tap water with 20 % v/v of CCl4, whereas Group IV (treatment group) received DHE 50 mg/kg/day, 100 mg/kg/day, and water. Assessment of biochemical parameters, Mitochondrial modulation, gene expression analysis, and RT-PCR, was used to estimate the protective action of DHEF in CCl4-intoxicated rats. The administration of CCl4 increased levels of total bilirubin (0.63 ± 0.97 mg/dl) plasma amino transferases (110.36 ± 1.13 U/L, 86.56 ± 2.41 U/L and 1.51 ± 1.36 mg/dl respectively) which were mitigated by D. hamiltonii treatment. Activity like Lipid peroxidation and content of nitric oxide also augmented, while the antioxidant action measured by GSH (9.64 ± 0.18 U/mg protein), SOD (3.69 ± 0.22 U/mg protein), and CAT (1.47 ± 0.01 U/mg protein) was reduced. Decalepis hamiltonii root provided substantial restoration of GSH (14.92 ± 0.04 nmol/gm protein), SOD (4.20 ± 0.18 U/mg protein), and CAT (2.71 ± 0.04 U/mg protein) levels. In addition, the acute phase reactants stimulated by CCl4 administration enhanced mRNA expressions of IL-6, IL-10, TNF-a, NF-κβ, and COX-2, which were enhanced by D. hamiltonii treatment. In summary, DHEF protects the liver against CCl4-induced damage, possibly by mitochondrial modulation mechanism. These findings indicate that D. hamiltonii significantly moderates oxidative stress of CCl4-induced hepatotoxicity.


Focus on fatty acids in the neurometabolic pathophysiology of psychiatric disorders.
Continuous research into the pathophysiology of psychiatric disorders, such as major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and schizophrenia, suggests an important role for metabolism. This narrative review will provide an up-to-date summary of how metabolism is thought to be involved in the pathophysiology of these psychiatric disorders. We will focus on (I) the important role of fatty acids in these metabolic alterations, (II) whether fatty acid alterations represent epiphenomena or risk factors, and (III) similarities and dissociations in fatty acid alterations between different psychiatric disorders. (Historical) epidemiological evidence links fatty acid intake to psychiatric disorder prevalence, corroborated by altered fatty acid concentrations measured in psychiatric patients. These fatty acid alterations are connected with other concomitant pathophysiological mechanisms, including biological stress (hypothalamic-pituitary-adrenal (HPA)-axis and oxidative stress), inflammation, and brain network structure and function. Metabolomics and lipidomics studies are underway to more deeply investigate this complex network of associated neurometabolic alterations. Supplementation of fatty acids as disease-modifying nutraceuticals has clinical potential, particularly add-on eicosapentaenoic acid (EPA) in depressed patients with markers of increased inflammation. However, by interpreting the observed fatty acid alterations as partly (mal)adaptive phenomena, we attempt to nuance translational expectations and provide new clinical applications for these novel neurometabolic insights, e.g., to predict treatment response or depression recurrence. In conclusion, placing fatty acids in context can contribute to further understanding and optimized treatment of psychiatric disorders, in order to diminish their overwhelming burden of disease.


Can resveratrol in wine protect against the carcinogenicity of ethanol? A probabilistic dose-response assessment.
Resveratrol, which may occur in wine, was suggested to act as a chemopreventive agent against the carcinogenic effects of ethanol. The assumption was based on data from experimental animals, which have shown that resveratrol above certain thresholds may reduce the incidence of tumours in several of the alcohol-related cancer sites (colon, liver and female breast). Using a probabilistic Monte Carlo type methodology, we estimated daily intake based on chemical analysis of resveratrol (n = 672) and ethanol (n = 867). Benchmark dose (BMD)-response modelling was conducted for resveratrol based on eight animal experiments, whereas BMD data for ethanol were taken from the literature. The margin of exposure (MOE) was calculated for both substances as an indicator if the intake may reach effective dosages. For intake of one 100-mL glass of wine, the average MOE was found to be 4.1 for ethanol and 459,937 for resveratrol. In the best-case scenario for resveratrol (e.g., very high contents and assuming a low effective dosage), the minimum MOE would be 111, which means that 111 glasses of wine need to be consumed daily to reach the BMD. The MOE ratio between resveratrol and ethanol is 166,128 on average, meaning that per glass of wine, ethanol is more than 100,000 times more potent than resveratrol. As resveratrol intake may not optimally reach the effective dosage, our study excludes a preventive effect of this substance on alcohol-related cancer. Commercial information about cancer-preventive or -protective effects of resveratrol in wine is misleading and must be prohibited.


[Lymphocytes subpopulation in cancer's patients. Relationship with primitive anatomical location, histological type and clinical stage (author's transl)].
Several markers of humoral and cellular immunity were studied in 49 untreated patients with malignancies of different anatomical locations, histological types and clinical stages. The proportion of EAC rosettes, levels of immunoglobulins as well as levels of the C3 and C4 components of the complement system were within the normal range (p.n.s.). The proportion of T lymphocytes, measured by the classical E rosette method at 4 degrees C, was significantly decreased in the whole group when compared with a control population (mean 46,27 +/- 12,34, p less than 0.0005), regardless of the anatomical origin of the tumor. In patients with lung cancer (45,52 +/- 10,37), those with the epidermoid type (51 +/- 9,45) had a reduced number of E rosettes when compared with controls (58,87 +/- 5,53 p less than 0.005) but they were still greater in number than in the other histological types (43,16 +/ 9,97 p less than 0.025). We found no relationship between the proportion of E rosettes and the clinical stage. The number of T lymphocytes with E rosettes after incubation at 30 degrees C was within normal limits in most patients, except in those cases with lung cancer at an early clinical stage (23,94 +/- 5,85 p less than 0.005). Our findings would support the hypothesis of a deficiency in cellular immunity in patients with malignancies, which could favour the progression of the disease.


Gut Microbiota: The Brain Peacekeeper.
Gut microbiota regulates intestinal and extraintestinal homeostasis. Accumulating evidence suggests that the gut microbiota may also regulate brain function and behavior. Results from animal models indicate that disturbances in the composition and functionality of some microbiota members are associated with neurophysiological disorders, strengthening the idea of a microbiota-gut-brain axis and the role of microbiota as a "peacekeeper" in the brain health. Here, we review recent discoveries on the role of the gut microbiota in central nervous system-related diseases. We also discuss the emerging concept of the bidirectional regulation by the circadian rhythm and gut microbiota, and the potential role of the epigenetic regulation in neuronal cell function. Microbiome studies are also highlighted as crucial in the development of targeted therapies for neurodevelopmental disorders.


Turnover of FlhD and FlhC, master regulator proteins for Salmonella flagellum biogenesis, by the ATP-dependent ClpXP protease.
In enterobacteria such as Salmonella, flagellar biogenesis is dependent upon the master operon flhDC at the apex of the flagellar gene hierarchy, which is divided into three classes 1, 2 and 3. Previously we reported that depletion of the ClpXP ATP-dependent protease results in dramatic enhancement of class 2 and class 3 gene transcription, whereas the transcription level of the flhDC operon remains normal in Salmonella enterica serovar Typhimurium. This suggests that the ClpXP protease may be responsible for the turnover of the FlhD and FlhC master regulators (Tomoyasu, T., Ohkishi, T., Ukyo, Y., Tokumitsu, A., Takaya, A., Suzuki, M. et al., 2002, J Bacteriol 184:645-653). In this study, to establish the role of the ClpXP protease in the turnover of FlhD and FlhC proteins, we analysed levels of the FlhD and FlhC proteins in wild-type and ClpXP mutant cells using anti-FlhD and anti-FlhC antibodies. The results show that both FlhD and FlhC proteins are markedly accumulated in ClpXP mutant cells and the half-life of FlhC is approximately fivefold longer in the ClpXP mutant, suggesting that the ClpXP protease is responsible for the degradation of FlhD and FlhC. The results also show that the ClpXP protease degrades both proteins in FlhD2FlhC2 complex but does not seem to recognize the respective subunits synthesized individually. Taken together, it is suggested that the cellular concentration of the FlhD2FlhC2 master regulator is tightly controlled at the post-translational level by the ClpXP protease. We also examined the role of other members of the ATP-dependent protease family in the regulation of flagellar biogenesis and concluded that only ClpXP in this family functions as a negative regulator for flagellar biogenesis in Salmonella.


Differences in school environment, school policy and actions regarding overweight prevention between Dutch schools. A nationwide survey.
Schools are regarded as an important setting for the prevention of overweight. This study presents a nationally representative picture of the obesogenity of the school environment, the awareness of schools regarding overweight, and actions taken by the schools aiming at overweight prevention. In addition, differences between school levels were studied. In 2006-2007, questionnaires were sent to all Dutch secondary schools (age group 12-18 years). Prevalences of the outcome variables were calculated for the schools in total and by school level. The association between school level and outcome variables were analysed by a log linear regression. Unhealthy foods and drinks are widely available at secondary schools. One third of the schools indicated that overweight has increased among students and half of the schools agreed that schools were (co)responsible for the prevention of overweight. Only 3% of the schools have a policy on overweight prevention. Small differences were observed between vocational education schools and higher education schools. The presence of vending machines did not differ by school level, but at vocational education schools, the content of the vending machines was less healthy. This study describes the current situation at schools which is essential for the development and evaluation of future overweight prevention policies and interventions. In general, secondary schools are not actively involved in overweight prevention and the nutritional environment at most schools could be improved. The small differences between school levels do not give reason for a differential approach for a certain school level for overweight prevention.


Butting out: an analysis of support for measures to address tobacco product waste.
Cigarette butts are ubiquitous litter items, causing major environmental damage and imposing significant clean-up costs. Tobacco companies frame smokers as both the cause of this problem and the source of its solution. However, an extended producer responsibility perspective challenges this view and holds tobacco companies to account for the full life cycle costs of tobacco product waste (TPW). Using an online cross-sectional survey of 396 New Zealand smokers and 414 non-smokers, we estimated awareness of TPW, attribution of responsibility for TPW and support for interventions to reduce TPW. Descriptive analyses and logistic regression models examined associations between demographic attributes and smoking behaviours, and perceptions of TPW and potential solutions to this problem. Most respondents saw butt litter as toxic to the environment and held smokers primarily responsible for creating TPW. However, when knowledge of butt non-biodegradability increased, so too did the proportion holding tobacco companies responsible for TPW. Changes to product design, fines for littering and expanded smoke-free spaces were considered most likely to reduce TPW. Smokers and non-smokers held different views on measures to address TPW, with smokers favouring more educative approaches and non-smokers more restrictive policies. Strategies to increase awareness of tobacco companies' role in creating TPW could foster political support for producer responsibility measures that require the industry to manage TPW. Nevertheless, policy measures should continue to foster smoking cessation and decrease uptake, as reducing smoking prevalence presents the best long-term solution to addressing TPW.