General practitioners' knowledge, attitudes and views of providing preconception care: a qualitative investigation.
Preconception health and care aims to reduce parental risk factors before pregnancy through health promotion and intervention. Little is known about the preconception interventions that general practitioners (GPs) provide. The aim of this study was to examine GPs' knowledge, attitudes, and views towards preconception health and care in the general practice setting. As part of a large mixed-methods study to explore preconception care in England, we surveyed 1,173 women attending maternity units and GP services in London and interviewed women and health professionals. Seven GPs were interviewed, and the framework analysis method was used to analyse the data. Seven themes emerged from the data: Knowledge of preconception guidelines; Content of preconception advice; Who should deliver preconception care?; Targeting provision of preconception care; Preconception health for men; Barriers to providing preconception care; and Ways of improving preconception care. A lack of knowledge and demand for preconception care was found, and although reaching women before they are pregnant was seen as important it was not a responsibility that could be adequately met by GPs. Specialist preconception services were not provided within GP surgeries, and care was mainly targeted at women with medical conditions. GPs described diverse patient groups with very different health needs. Implementation of preconception policy and guidelines is required to engage women and men and to develop proactive delivery of care with the potential to improve pregnancy and neonatal outcomes. The role of education and of nurses in improving preconception health was acknowledged but remains under-developed.


Multiple mechanisms for the carcinogenic effects of asbestos and other mineral fibers.
Asbestos and other mineral fibers are carcinogenic to humans and animals but differ from many carcinogens in that they do not induce gene mutations. An understanding of these interesting human carcinogens, therefore, is an important problem in cancer research. Asbestos and other fibers induce predominantly two types of cancers: mesotheliomas and bronchogenic carcinomas. Fiber size is an important factor in the carcinogenic activity of these substances as has been shown for mesothelioma induction. For bronchogenic carcinomas, but not for mesotheliomas, a synergistic effect of asbestos exposure and cigarette smoke has been observed in humans. The mechanisms by which fibers alone versus fibers in concert with other carcinogens induce cancers are probably distinct. In addition to fiber dimensions, fiber durability and surface properties of fibers are important properties affecting carcinogenicity. Evidence exists that asbestos is a complete carcinogen, an initiator and a promoter. Multiple mechanisms must be operative to explain the diverse effects of mineral fibers. Although asbestos is inactive as a gene mutagen, there is now clear evidence that it induces chromosomal mutations (aneuploidy and aberrations) in a wide variety of mammalian cells including mesothelial cells. Asbestos also induces transformation of cells in culture including mesothelial cells and fibroblasts. A mechanism for cell transformation, which is dependent on fiber dimension, has been proposed. The fibers are phagocytized by the cells and accumulate in the perinuclear region of the cells. When the cell undergoes mitosis, the physical presence of the fibers interferes with chromosome segregation and results in anaphase abnormalities. The transformed cells show aneuploidy and other chromosome abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)


Stereotactic breast biopsy: a less-invasive option.
Until recently, a woman with a nonpalpable lesion detected on mammography had to undergo the emotional and physical trauma of surgical excision. However, a new technique, percutaneous core needle biopsy, guided by digital three-dimensional x-ray imaging, offers a reasonable alternative to standard surgical biopsy. This method produces no pseudolesions, subjects the patient to less physical and emotional trauma, is done on an outpatient basis with local anesthesia, and costs far less than the surgical method.


Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India.
Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGβ2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGβ2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.


Causes and nursing countermeasures in pediatric PICC catheter complications.
To analyze the complications and nursing countermeasures of PICC (Peripherally Inserted Central Catheter) catheters using children PICC catheter technique 40 cases, complications were observed, and analyze the original causes, in order to propose a solution. There were 10 cases of catheter blockage, 5 cases of catheter infection, 6 cases of phlebitis, 5 cases of puncture difficulties, 2 cases of poor feeding tube, 2 cases of bleeding puncture site with the continuous exploration and research of nursing intervention, the production of clinical complications from PICC has been used in children were greatly reduced.


Strategies and Challenges in Identifying Function for Thousands of sORF-Encoded Peptides in Meiosis.
Recent genomic analyses have revealed pervasive translation from formerly unrecognized short open reading frames (sORFs) during yeast meiosis. Despite their short length, which has caused these regions to be systematically overlooked by traditional gene annotation approaches, meiotic sORFs share many features with classical genes, implying the potential for similar types of cellular functions. We found that sORF expression accounts for approximately 10-20% of the cellular translation capacity in yeast during meiotic differentiation and occurs within well-defined time windows, suggesting the production of relatively abundant peptides with stage-specific meiotic roles from these regions. Here, we provide arguments supporting this hypothesis and discuss sORF similarities and differences, as a group, to traditional protein coding regions, as well as challenges in defining their specific functions.


Microscopy and spectroscopy approaches to study GPCR structure and function.
The GPCR signalling cascade is a key pathway responsible for the signal transduction of a multitude of physical and chemical stimuli, including light, odorants, neurotransmitters, and hormones. Understanding the structural and functional properties of the GPCR cascade requires direct observation of signalling processes in high spatial and temporal resolution with minimal perturbation to endogenous systems. Optical microscopy and spectroscopy techniques are uniquely suited to this purpose because they excel at multiple spatial and temporal scales and can be used in living objects. Here, we review recent developments in microscopy and spectroscopy technologies which enable new insights into GPCR signalling. We focus on advanced techniques with high spatial and temporal resolution, single-molecule methods, labelling strategies, and approaches suitable for endogenous systems and large living objects. This review aims to assist researchers in choosing appropriate microscopy and spectroscopy approaches for a variety of applications in the study of cellular signalling.


Effects of low-level laser therapy on wound healing.
To gather and clarify the actual effects of low-level laser therapy on wound healing and its most effective ways of application in human and veterinary medicine. We searched original articles published in journals between the years 2000 and 2011, in Spanish, English, French and Portuguese languages, belonging to the following databases: Lilacs, Medline, PubMed and Bireme; Tey should contain the methodological description of the experimental design and parameters used. doses ranging from 3 to 6 J/cm(2) appear to be more effective and doses 10 above J/cm(2) are associated with deleterious effects. The wavelengths ranging from 632.8 to 1000 nm remain as those that provide more satisfactory results in the wound healing process. Low-level laser can be safely applied to accelerate the resolution of cutaneous wounds, although this fact is closely related to the election of parameters such as dose, time of exposure and wavelength.


Characterization of adrenocortical tumors by 18F-FDG PET/CT: Does steroid hormone hypersecretion status modify the uptake pattern?
adrenal tumor-to-liver uptake value (Tmx:Lmx) on 18F-FDG PET/CT is an accurate and reproducible PET parameter in the distinction between benign and malignant adrenal masses. The potential impact of steroid hormone secretion on 18F-FDG uptake is still debatable. The aim of this study was to evaluate this relationship. 2010-2015: 73 patients who underwent adrenalectomy for adrenocortical tumors [49 secreting/(SA) and 24 non-secreting/(NSA)] were retrospectively included in the study. Fourteen were malignant. All patients underwent hormonal evaluation, functional and anatomical imaging, Weiss scoring and Ki 67 evaluation. malignant tumors exhibit higher SUVmax than benign tumors (median 7.75 vs 3.06 respectively, p < 0.001) and Tmx:Lmx was 2.7 vs 1.17 for benign tumors, p < 0.001. Tmx:Lmx was positively correlated to Weiss score (p < 0.001). No significant difference was observed for Tmx:Lmx between SA and NSA overall (p = 0.851), regardless of the subgroup of tumors analyzed. Tmx:Lmx was not correlated to tumor size (p < 0.508) or 24 h free urinary cortisol level (p < 0.522). no correlation was observed between Tmx:Lmx and hormonal status, however the correlation between ratio, malignancy and Weiss score confirm the utility of 18F-FDG PET/CT for the differentiation of benign from malignant adrenal lesions, irrespective of the hormone secretory status of the tumor. 18F-FDG PET/CT is a useful biomarker in the diagnosis of adrenal tumors, regardless of the secretion status.


Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility.
Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.


Cost and Effectiveness of Blended Versus Standard Cognitive Behavioral Therapy for Outpatients With Depression in Routine Specialized Mental Health Care: Pilot Randomized Controlled Trial.
Cognitive behavioral therapy (CBT) is an effective treatment, but access is often restricted due to costs and limited availability of trained therapists. Blending online and face-to-face CBT for depression might improve cost-effectiveness and treatment availability. This pilot study aimed to examine the costs and effectiveness of blended CBT compared with standard CBT for depressed patients in specialized mental health care to guide further research and development of blended CBT. Patients were randomly allocated to blended CBT (n=53) or standard CBT (n=49). Blended CBT consisted of 10 weekly face-to-face sessions and 9 Web-based sessions. Standard CBT consisted of 15 to 20 weekly face-to-face sessions. At baseline and 10, 20, and 30 weeks after start of treatment, self-assessed depression severity, quality-adjusted life-years (QALYs), and costs were measured. Clinicians, blinded to treatment allocation, assessed psychopathology at all time points. Data were analyzed using linear mixed models. Uncertainty intervals around cost and effect estimates were estimated with 5000 Monte Carlo simulations. Blended CBT treatment duration was mean 19.0 (SD 12.6) weeks versus mean 33.2 (SD 23.0) weeks in standard CBT (P<.001). No significant differences were found between groups for depressive episodes (risk difference [RD] 0.06, 95% CI -0.05 to 0.19), response to treatment (RD 0.03, 95% CI -0.10 to 0.15), and QALYs (mean difference 0.01, 95% CI -0.03 to 0.04). Mean societal costs for blended CBT were €1183 higher than standard CBT. This difference was not significant (95% CI -399 to 2765). Blended CBT had a probability of being cost-effective compared with standard CBT of 0.02 per extra QALY and 0.37 for an additional treatment response, at a ceiling ratio of €25,000. For health care providers, mean costs for blended CBT were €176 lower than standard CBT. This difference was not significant (95% CI -659 to 343). At €0 per additional unit of effect, the probability of blended CBT being cost-effective compared with standard CBT was 0.75. The probability increased to 0.88 at a ceiling ratio of €5000 for an added treatment response, and to 0.85 at €10,000 per QALY gained. For avoiding new depressive episodes, blended CBT was deemed not cost-effective compared with standard CBT because the increase in costs was associated with negative effects. This pilot study shows that blended CBT might be a promising way to engage depressed patients in specialized mental health care. Compared with standard CBT, blended CBT was not considered cost-effective from a societal perspective but had an acceptable probability of being cost-effective from the health care provider perspective. Results should be carefully interpreted due to the small sample size. Further research in larger replication studies focused on optimizing the clinical effects of blended CBT and its budget impact is warranted. Netherlands Trial Register NTR4650; https://www.trialregister.nl/trial/4408. RR2-10.1186/s12888-014-0290-z.


[Effect of hyperbaric oxygenation on the recovery of motor functions in vertebrogenic myelopathies].
The use of hyperbaric oxygenation (HBO) in the treatment of vertebrogenic ischemic myelopathies makes it possible not only to arrest the progression of the disease but also to achieve stable regress of motor disturbances in a relatively short period, which helps to reduce the time of treatment and hospitalization. In lateral amyotrophic sclerosis HBO therapy produces a minimum and short positive effect only in some patients. In most cases the therapy failed to control or stabilize neurological disorders. Clinical data are confirmed by dynamic electromyographic studies. The results obtained make it possible to recommend HBO in a complex of therapeutic measures in cases of vascular damage to the spinal cord.


Inhibition of cell spreading on the band of extracellular fibres in early chick and quail embryos.
The ventral surface of the upper layer shows a band of extracellular fibrils around the anterior and lateral border of the area pellucida during gastrulation of the chick embryo. Using scanning electron microscopy, we found that this disposition is correlated with the motility of the middle-layer cells of gastrulating chick and quail embryos. Outside the fibrous band, single middle-layer cells and a sheet of mesoblast cells were spread out and possessed lamellae. Single cells on the fibrous band did not form lamellae. The same cell behaviour was obtained with the explants of deep layer on the fibrous band. The fibrous band is assumed to operate as a barrier that inhibits cell motility during gastrulation.


Local Surgery Improves Survival in Patients with Primary Metastatic Breast Cancer: A Population-Based Study.
The clinical value of local surgery in the breast cancer patients with distant metastasis is still unclear. A total of 8,922 primary metastatic breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed in the current study. Primary outcome variables included breast cancer-specific survival (BCSS) and overall survival (OS). Among the patients, 1,724 (19.3%) who underwent surgical treatment (ST) of primary breast tumor had increased OS (p < 0.001) and BCSS (p < 0.001) compared with those in the nonsurgical treatment (NST) group. Multivariate analysis revealed that surgery improved survival and was an independent prognostic factor for OS (hazard ratio [HR] = 0.617; 95% confidence interval [CI], 0.562-0.676, p < 0.001) and BCSS (HR = 0.623; 95% CI, 0.565-0.686, p < 0.001). Further result showed that ST tended to prolong the survival of patients with 1 or 2 distant metastatic sites (p < 0.05 for OS, p < 0.05 for BCSS). However, no differences were found in prognostic outcomes between different surgical procedure groups (p = 0.886 for OS, p = 0.943 for BCSS). In conclusion, our study suggested that local surgery appeared to confer a survival benefit, which may provide new understanding of treatment for these patients.


The role of mesencephalic tegmentum in regulating female rat sexual behaviors.
Feminine sexual behaviors were tested in estradiol benzoate (EB) and progesterone (P) primed ovariectomized rats following four types of radiofrequency lesions in the midbrain tegmentum. The dorsomedial lesion (DML) which destroyed the ventromedial central gray including the dorsal raphe nucleus and adjacent area induced high sexual receptivity in the females primed with low dose (0.5 micrograms) of EB-P. All females with DML exhibited lordosis and ear wiggling, the mean lordosis quotient (LQ) being significantly higher than that of castrated controls or sham operated rats. Sexual receptivity in females with ventromedial tegmental lesion was not significantly different from those of the control and sham groups. In contrast to the medially lesioned groups, the mean LQ was low in the animals with bilateral lateral tegmental lesions even when the dose of EB was increased to 2 micrograms which was sufficient to induce high sexual receptivity in castrated and sham operated control females. In the animals with dorsolateral tegmental lesions (DLL), a much more severe loss of lordosis was seen than in those with ventrolateral tegmental lesions (VLL). None of the DLL females displayed sexual behavior throughout the present experiments. These results lead us to conclude that the midbrain dorsomedial tegmental area (ventral central gray and the adjacent area) is concerned with female sexual behavior inhibiting system, whereas the lateral tegmental area may be involved in the facilitatory system.


Reproductive and transcriptional effects of the antiandrogenic progestin chlormadinone acetate in zebrafish (Danio rerio).
Chlormadinone acetate (CMA) is a frequently used progestin with antiandrogenic activity in humans. Residues may enter the aquatic environment but potential adverse effects in fish are unknown. While our previous work focused on effects of CMA in vitro and in zebrafish eleuthero-embryos, the present study reports on reproductive and transcriptional effects in adult female and male zebrafish (Danio rerio). We performed a reproductive study using breeding groups of zebrafish. After 15 days of pre-exposure, we exposed zebrafish to different measured concentrations between 6.4 and 53,745 ng/L CMA for 21 days and counted produced eggs daily to determine fecundity. Additionally, transcriptional effects of CMA in brains, livers, and gonads were analyzed. CMA induced a slight but statistically significant reduction in fecundity at 65 ng/L and 53,745 ng/L compared to pre-exposure. Furthermore, we observed differential expression for gene transcripts of steroid hormone receptors, genes related to the hypothalamic-pituitary-gonadal axis, and steroidogenesis. In particular, we found a significant decrease of transcript levels of vitellogenin (vtg1) in ovaries and liver, and of cyp2k7 in the liver of males, as well as a significant increase of transcripts of the progesterone receptor (pgr) in testes, and cyp2k1 in the liver of females. The observed effects were weaker than those of other very potent progestins, which is probably related to the lack of interaction of CMA with the zebrafish progesterone receptor.


Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?
Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro-arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC-CM-based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine. This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.


Demonstration of terahertz ferroelectric metasurface using a simple and scalable fabrication method.
We report on experimental implementation of a ferroelectric metasurface using an x-cut KTiOPO4 (KTP) crystal for efficient manipulation of terahertz (THz) radiation. Based on the multipolar resonances that are accommodated in KTP micro-blocks in a square array, the metasurface is fabricated by precision diamond-blade dicing. Adjusting the size of the KTP micro-blocks to tailor the relative spectral positions of the anisotropic multipolar resonances, we demonstrate a subwavelength-thin THz polarizer that functions as a transparent film in the y-direction and a magnetic mirror in the z-direction with a transmission contrast of 13 dB near 0.37 THz (820 µm). The ferroelectric-based all-dielectric metasurface will provide a versatile platform to engineer the THz waves in the far field and could potentially be combined with THz generation in the same material.


PROTEIN PHOSPHATASE 2A-B'γ Controls Botrytis cinerea Resistance and Developmental Leaf Senescence.
Plants optimize their growth and survival through highly integrated regulatory networks that coordinate defensive measures and developmental transitions in response to environmental cues. Protein phosphatase 2A (PP2A) is a key signaling component that controls stress reactions and growth at different stages of plant development, and the PP2A regulatory subunit PP2A-B'γ is required for negative regulation of pathogenesis responses and for maintenance of cell homeostasis in short-day conditions. Here, we report molecular mechanisms by which PP2A-B'γ regulates Botrytis cinerea resistance and leaf senescence in Arabidopsis (Arabidopsis thaliana). We extend the molecular functionality of PP2A-B'γ to a protein kinase-phosphatase interaction with the defense-associated calcium-dependent protein kinase CPK1 and present indications this interaction may function to control CPK1 activity. In presenescent leaf tissues, PP2A-B'γ is also required to negatively control the expression of salicylic acid-related defense genes, which have recently proven vital in plant resistance to necrotrophic fungal pathogens. In addition, we find the premature leaf yellowing of pp2a-b'γ depends on salicylic acid biosynthesis via SALICYLIC ACID INDUCTION DEFICIENT2 and bears the hallmarks of developmental leaf senescence. We propose PP2A-B'γ age-dependently controls salicylic acid-related signaling in plant immunity and developmental leaf senescence.


Dopaminergic-GABAergic interplay and alcohol binge drinking.
The dopamine D3 receptor (D3R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D3R increases GABAA α6 subunit in the ventral striatum. Here we tested the hypothesis that D3R-dependent changes in GABAA α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D3R knockout (D3R -/-) mice and wild type littermates (D3R +/+). Ro 15-4513, a high affinity α6-GABAA ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D3R+/+, whereas it was robust in D3R-/-; other relevant GABAA subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D3R+/+, but increased it in D3R-/-; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABAA antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D3R-/- compared to D3R+/+; Ro 15-4513 reduced the peak amplitude in the NAc of D3R-/-, but not in D3R+/+. We conclude that D3R-dependent enhanced expression of α6 GABAA subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.


NMR crystallography of campho[2,3-c]pyrazole (Z' = 6): combining high-resolution 1H-13C solid-state MAS NMR spectroscopy and GIPAW chemical-shift calculations.
(1)H-(13)C two-dimensional magic-angle spinning (MAS) solid-state NMR correlation spectra, recorded with the MAS-J-HMQC experiment, are presented for campho[2,3-c]pyrazole. For each (13)C moiety, there are six resonances associated with the six distinct molecules in the asymmetric unit cell (Z' = 6). The one-bond C-H correlations observed in the 2D (1)H-(13)C MAS-J-HMQC spectra allow the experimental determination of the (1)H and (13)C chemical shifts associated with the separate CH, CH(2), and CH(3) groups. (1)H and (13)C chemical shifts calculated by using the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach are presented. Calculations for the whole unit cell (12 × 29 = 348 atoms, with geometry optimization of all atoms) allow the assignment of the experimental (1)H and (13)C chemical shifts to the six distinct molecules. The calculated chemical shifts for the full crystal structure are compared with those for isolated molecules as extracted from the geometry-optimized crystal structure. In this way, the effect of intermolecular interactions on the observed chemical shifts is quantified. In particular, the calculations are sufficiently precise to differentiate the small (<1 ppm) differences between the (1)H chemical shifts of the six resonances associated with each distinct CH or CH(2) moiety.


Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses.
The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.


Spatial-temporal survey of Microcystis oligopeptide chemotypes in reservoirs with dissimilar waterbody features and their relation to genetic variation.
The ability of cyanobacteria to produce toxins and other secondary metabolites is patchily distributed in natural populations, enabling the use of cellular oligopeptide compositions as markers to classify strains into ecologically-relevant chemotypical subpopulations. The composition and spatiotemporal distribution of Microcystis chemotypes within and among waterbodies was studied at different time scales by analyzing (i) Microcystis strains isolated between 1998 and 2007 from different Spanish reservoirs and (ii) individual Microcystis aeruginosa colonies collected from pelagic and littoral habitats in Valmayor reservoir (Spain) during a bloom. No agreement between chemotypes and both morphotypes and genotypes (based on cpcBA-IGS, 16S-23S rRNA ITS and mcyB genes) was found, suggesting that oligopeptide profiles in individual strains evolve independently across morphospecies and phylogenetic genotypes, and that the diversity of microcystin variants produced cannot be explained by mcyB gene variations alone. The presence of identical chemotypes in spatially-distant reservoirs with dissimilar trophic state, lithology or depth indicate that waterbody characteristics and geographical boundaries weakly affect chemotype composition and distribution. At smaller spatiotemporal scales (i.e. during bloom), M. aeruginosa populations showed high number of chemotypes, as well as marked differences in chemotype composition and relative abundance among the littoral and pelagic habitats. This indicates that the factors influencing chemotype composition, relative abundance and dynamics operate at short spatial and temporal scales, and supports emerging hypotheses about interactions with antagonistic microorganisms as possible drivers for widespread chemical polymorphisms in cyanobacteria.


Myrtle Seeds (Myrtus communis L.) as a Rich Source of the Bioactive Ellagitannins Oenothein B and Eugeniflorin D2.
The increasing popularity of "Mirto" liqueur, produced from Myrtus communis berries, has led to the planting of domesticated cultivars, expanding myrtle berry production. To promote the use of cultivated berries, the content in the nutraceutical compounds ellagitannins has been investigated both in spontaneous and cultivated fruits. Oenothein B and eugeniflorin D2, characterized by 1H and 13C NMR, were isolated and quantified using ultrahigh-performance liquid chromatography-diode array detector-tandem mass spectrometry (UPLC-DAD-MS/MS). The antifungal and anti-inflammatory activities of oenothein B were assayed in vitro. Large amounts of oenothein B and eugeniflorin D2 were detected in seeds (12 ± 2.4 and 5.8 ± 1.2 mg/g). The oenothein B concentration in liqueurs was 194 ± 22 mg/L. This macrocyclic ellagitannin dimer showed anti-Candida (minimal inhibitory concentration <8-64 μg/mL) and anti-inflammatory properties. Cultivated myrtle berries are a source of nutraceutical compounds. The high concentration of oenothein B in liqueur suggests a possible contribution to the organoleptic and biological properties of the beverage.


Is voluntary vitamin and mineral supplementation associated with better outcome in non-small cell lung cancer patients? Results from the Mayo Clinic lung cancer cohort.
Some previous studies report that 80% of cancer patients take multivitamin and/or mineral supplements. To our knowledge, the consequences of such self-directed supplementation have not been examined previously in non-small cell lung cancer (NSCLC) patients. The goal of this study was to determine whether vitamin/mineral supplementation is associated with improved survival and quality of life in a cohort of NSCLC patients. NSCLC patients or their proxies who responded to a questionnaire on vitamin/mineral use were assessed for survival and quality of life. A total of 1129 patients or their proxies responded to a vitamin/mineral questionnaire. Seven hundred and fourteen were vitamin/mineral users of either multivitamins or other specific vitamin/mineral supplements, and the rest non-users. Median survival was 4.3 years versus 2.0 years for vitamin/mineral users and non-users, respectively. A Cox proportional hazards model showed a relative risk of death of 0.74 (95% confidence interval (CI): 0.44, 0.65) (p < 0.01) in favor of vitamin/mineral use after adjustment for multiple prognostic factors, including tumor stage. The Lung Cancer Symptom Scale (LCSS) showed better quality of life among vitamin/mineral users (mean difference in score of 3 (95% CI: 0.8, 5.1) (p < 0.01); and after adjusting for related variables, there remained a trend in favor of vitamin/mineral use mean difference 1.8 (95% CI: 0.2, 3.9) (p = 0.08). Vitamin/mineral supplementation is associated with better survival and quality of life in this cohort of NSCLC patients. Future prospective clinical trials should focus on the role of such supplements in patients with NSCLC.


Public health nurse delivered group cognitive behavioral therapy (CBT) for postpartum depression: A pilot study.
Although postpartum depression (PPD) affects 1 in 5 women, just 15% receive treatment. Cognitive Behavioural Therapy (CBT) is a first-line treatment for PPD. The objective of this pilot study was to determine the feasibility and acceptability of public health nurse (PHN)-delivered group CBT for PPD and to determine preliminary estimates of effect. A pre-posttest design was used. Participants provided data before and after the CBT groups. Seven women who were over the age of 18 and had given birth in the past year participated. Feasibility and acceptability focused on PHN training, recruitment, retention, and adherence to the intervention. Participants provided data on depression, worry, health care utilization and mother-infant relations. Women and their partners reported on infant temperament. Participants attended a 9-week CBT group delivered by two PHNs. The PHN training, CBT intervention and our study protocol were found to be feasible and acceptable to participants. Reductions were seen in depression and worry. The number of health care visits decreased; mother-infant relations improved. These findings highlight the feasibility of PHN-delivered group CBT for PPD and suggest that it could reduce the burden of PPD on women and their children.


[Iatrogenic damages of the exocrine pancreas (author's transl)].
In a survey, damages of the exocrine pancreas in form of pancreatopathies and particularly of pancreatitis caused by diagnostic and therapeutic procedures are discussed under the special consideration of pathomorphological aspects. For the underpinning of pathogenetical conceptions, additional results of animal experiments are included. Main subjects of the treatise are those injuries of the exocrine pancreas which may be induced by biopsy of the pancreas, endoscopic retrograde pancreatography, operations in the upper abdomen, and medicaments.


Prehospital midthigh trauma and traction splint use: recommendations for treatment protocols.
The present study was completed to establish an epidemiologic database defining the prehospital occurrence of midthigh trauma/suspected femoral shaft fractures, and the use of/need for traction splints (TS) in hope of developing recommendations for further treatment protocols. On review of 4,513 paramedic run reports for the 12-month period from January 1999 through December 1999, from a low-volume urban emergency medical services (EMS) system, 16 persons (0.35% total patients) presented with midthigh injuries. Data collected included patient chief complaint/injury, mechanism of injury, clinical findings, splint application, additional interventions, iatrogenic complications, patient age, and ambulance field time. Paramedics noted injuries suspicious for femoral shaft fractures in 5 patients (31.25% study patients, 0.11% total patients). TSs were applied successfully only twice (12.50% study patients, 0.04% total patients). Fourteen patients (87.50% study patients) were managed with long backboard immobilization, rigid splinting, and/or patient transportation in a position of comfort. No sequelae as a result of such care occurred. No inappropriate use, point estimate (PE) [(0)/(16) (0.00% to 20.60%)] or unmet need, PE [(0)/(4), 497) (0.00% to 0.08%)] of care was noted. The data presented in this study suggest that given similar EMS system characteristics, prehospital midthigh injuries/suspected femoral shaft fractures occur on an extremely rare basis, and treatment with long backboard immobilization, rigid splinting, and/or patient transportation in a position of comfort may constitute an acceptable course of care. Including TSs as essential ambulance equipment may be unnecessary.


Tissue Resident CCR2- and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury.
Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in the context of tissue injury or disease, large numbers of monocytes infiltrate the heart and are thought to contribute to adverse remodeling and heart failure pathogenesis. Little is understood about the diversity of monocytes and monocyte-derived macrophages recruited to the heart after myocardial injury, including the mechanisms that regulate monocyte recruitment and fate specification. We sought to test the hypothesis that distinct subsets of tissue-resident CCR2- (C-C chemokine receptor 2) and CCR2+ macrophages orchestrate monocyte recruitment and fate specification after myocardial injury. We reveal that in numerous mouse models of cardiomyocyte cell death (permanent myocardial infarction, reperfused myocardial infarction, and diphtheria toxin cardiomyocyte ablation), there is a shift in macrophage ontogeny whereby tissue-resident macrophages are predominately replaced by infiltrating monocytes and monocyte-derived macrophages. Using syngeneic cardiac transplantation to model ischemia-reperfusion injury and distinguish tissue-resident from recruited cell populations in combination with intravital 2-photon microscopy, we demonstrate that monocyte recruitment is differentially orchestrated by distinct subsets of tissue-resident cardiac macrophages. Tissue-resident CCR2+ macrophages promote monocyte recruitment through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism that results in release of MCPs (monocyte chemoattractant proteins) and monocyte mobilization. In contrast, tissue-resident CCR2- macrophages inhibit monocyte recruitment. Using CD (cluster of differentiation) 169-DTR (diphtheria toxin receptor) and CCR2-DTR mice, we further show that selective depletion of either tissue-resident CCR2- or CCR2+ macrophages before myocardial infarction results in divergent effects on left ventricular function, myocardial remodeling, and monocyte recruitment. Finally, using single-cell RNA sequencing, we show that tissue-resident cardiac macrophages differentially instruct monocyte fate specification. Collectively, these observations establish the mechanistic basis by which monocytes are initially recruited to the injured heart and provide new insights into the heterogeneity of monocyte-derived macrophages.


Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages.
Flavonoids are a class of chemically related polyphenols that are nearly ubiquitous in nature. Of the more-than 4000 flavonoids thus identified, citrus fruit-derived flavonoids are suggested to have an inverse association with the occurrence of coronary heart disease via their ability to reduce plasma cholesterol concentrations. Our current studies examined whether citrus flavonoids possess an additional antiatherogenic effect by modulating macrophage metabolism of the specific class A scavenger receptor (SR-A) ligand, acetylated LDL (acLDL). In this study, both acLDL-metabolism and SR-A expression by cultured murine J774A.1 macrophages was examined following 24 h pretreatment (100 microM) with the flavonoids: naringenin (from grapefruit), hesperetin (from oranges), and tangeretin and nobiletin (from tangerines). Of these flavonoids, only nobiletin inhibited (50-72%) acLDL metabolism as measured by both cellular cholesterol ester mass and [3H]oleate incorporation into cholesterol esters. This nobiletin-mediated effect was specific for SR-A and not a global effect on lipoprotein metabolism by the macrophage, as all four citrus flavonoids significantly reduce the metabolism of beta-VLDL, which is primarily taken up by macrophages via the LDL receptor. Nevertheless, nobiletin did not affect SR-A protein expression, as measured by Western blot analysis, nor was cell surface expression of SR-A affected as measured by 4 degrees C binding studies using [125I]acLDL. In conclusion, our findings suggest that in addition to reducing plasma cholesterol concentrations, nobiletin may prevent atherosclerosis at the level of the vascular wall by inhibiting macrophage foam-cell formation.


[Umbilical cord hernias].
The authors observed 38 children with umbilical cord hernias. In 27 of them some other defects were noted. Among 25 children there were 14 deaths (56.2%). Conservative therapy was conducted in 13 patients with umbilical cord hernia, 10 children died (76.9%).


The action of cells from patients with chronic granulomatous disease on Staphylococcus aureus.
Contrary to current opinion, neutrophil leucocytes from patients with the inherited immunodeficiency syndrome chronic granulomatous disease (CGD) killed 80% of ingested Staphylococcus aureus. Bacterial killing was not impaired by increasing the ratio of bacteria to cells from 1:1 to 10:1. The organisms that survived within the patients' cells did not themselves appear to constitute an unduly resistant subpopulation because they were killed when exposed to fresh cells, and no growth phase of a synchronous culture was found to be particularly resistant. The pH within the phagocytic vacuoles of CGD neutrophils and monocytes is abnormally low and methylamine, which has been shown to normalise this vacuolar pH, improved killing. Clumped bacteria appeared to be more resistant to killing than dispersed ones, suggesting that organisms near the centre of a clump might be protected from the toxicity of the compromised killing systems in cells of these patients.


Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma.
In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287- 7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.


[Comparative characteristic of Burkholderiae pseudomallei group].
Comparative characteristic of diagnostic value of main cultural-biological characteristics of Burkholderiae pseudomallei group. 59 strains of B. pseudomallei, 14 --B. mallei and 5--B. thailandensis were used in the study. Biochemical characteristics were studied by generally accepted methods, antigenic properties were evaluated in agglutination reaction and immunoelectrophoresis, virulence was determined by Dlm for laboratory animals, antibiotic sensitivity was verified by disc-diffusion method. Passaging of B. pseudomallei and B. mallei in mice results in increase of virulence, preservation of initial sensitivity to antibiotics, contraction of precipitogen specter. During therapy of experimental melioidosis in guinea pigs resistance to chemopreparations of various groups is formed. Varying degree of virulence and sensitivity to antibiotics of various B. thailandensis strains was established. Dependence of sensitivity on in vitro cultivation was not detected. Stability of diagnostically significant tests used for identification of Burkholderiae pseudomallei group was established. Relevance of attribute set expansion that facilitates their differentiation is justified.


Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity.
Depression and insulin resistance are becoming increasingly prevalent in younger populations. The origin and consequence of insulin resistance in depressed youth may, in part, be rooted in exposure to environmental stressors, such as early life abuse, that may lead to aberrant brain motivational networks mediating maladaptive food-seeking behaviors and insipient insulin resistance. In this paper, we aimed to investigate the impact of early life abuse on the development of insulin resistance in depressed and overweight youth aged 9 to 17 years. We hypothesized that youth with the greatest burden of early life abuse would have the highest levels of insulin resistance and corresponding aberrant reward network connectivities. To test this hypothesis, we evaluated sixty-nine depressed and overweight youth aged 9 to 17, using multimodal assessments of early life abuse, food-seeking behavior, and insulin resistance. Based on results of the Childhood Trauma Questionnaire (CTQ), we separated our study participants into two groups: 35 youth who reported high levels of the sum of emotional, physical, or sexual abuse and 34 youth who reported insignificant or no levels of any abuse. Results of an oral glucose tolerance test (OGTT) and resting state functional connectivity (RSFC), using the amygdala, insula, and nucleus accumbens (NAcc) as seed-based reward network regions of interest, were analyzed for group differences between high abuse and low abuse groups. High abuse youth exhibited differences from low abuse youth in amygdala-precuneus, NAcc-paracingulate gyrus, and NAcc-prefrontal cortex connectivities, that correlated with levels of abuse experienced. The more different their connectivity from of that of low abuse youth, the higher were their fasting glucose and glucose at OGTT endpoint. Importantly, level of abuse moderated the relation between reward network connectivity and OGTT glucose response. In contrast, low abuse youth showed hyperinsulinemia and more insulin resistance than high abuse youth, and their higher OGTT insulin areas under the curve correlated with more negative insula-precuneus connectivity. Our findings suggest distinct neural and endocrine profiles of youth with depression and obesity based on their histories of early life abuse.


The Functional Mobility Scale: ability to detect change following single event multilevel surgery.
The aim of this study was to examine the ability of the Functional Mobility Scale (FMS) to detect change in children with cerebral palsy (CP) undergoing single event multilevel surgery (SEMLS). A retrospective study was conducted of gait laboratory records and video assessments for a consecutive sample of children with CP aged 4 to 18 years who were managed by multilevel surgery. FMS ratings and Gross Motor Function Classification System (GMFCS) levels were recorded preoperatively and at regular postoperative time points. The sample comprised 66 children (32 females, 34 males) with spastic diplegia, GMFCS Levels I (n=18), II (n=24), and III (n=24). The mean age at surgery was 10 years (SD 2y 6mo, range 6-16y). For each FMS distance (5, 50, and 500m) odds ratios showed significant deterioration in mobility at 3 and 6 months postoperatively. Mobility then improved to baseline levels by 12 months and improved further by 24 months postoperatively. GMFCS level remained stable throughout most of the postoperative period for children classified as GMFCS Level III preoperatively but not for children classified as Levels I or II. The FMS was found to be a clinically feasible tool for quantifying change after SEMLS in children with CP.


[Taxonomy and typology: are they really synonymous?].
Typology and taxonomy constructions are increasingly used as a method of analysis in health services and public health research. Although taxonomy and typology have different definitions in the dictionary, these terms are often used synonymously. The objective of this paper is to propose a theoretical framework derived from organizational theory in which the concepts of taxonomy and typology are clearly defined. The configurational approach emerged in the 1980s. It is designed to analyse the elements constituting an entity under study as a whole and not in isolation. In this approach, conceptually developed configurations are defined as typologies, while empirically derived configurations are defined as taxonomies. Based on this theoretical framework, taxonomies are used much more often than typologies in the scientific literature in the field of public health. Taxonomies can process large sets of multidimensional variables by generating relatively homogeneous groups that take into account interactions between variables. Taxonomies are usually built from classification methods or factor analyses combined with a classification. In conclusion, this paper proposes a theoretical framework to differentiate typologies from taxonomies to provide public health stakeholders with a common language in relation to classifications. This article provides the basis for discussion of theoretical frameworks underlying the definition of these concepts.


Egress of mature murine regulatory T cells from the thymus requires RelA.
The mechanism of egress of mature regulatory T cells (Tregs) from the thymus to the periphery remains enigmatic, as does the nature of those factors expressed in the thymic environment. In this study, we examined the fate of thymic Tregs in TNF-α/RelA double-knockout (TA-KO) mice, because TA-KO mice retain a Treg population in the thymus but have only a small Treg population at the periphery. Transplantation of whole TA-KO thymus to under the kidney capsule of Rag1-null mice failed to induce the production of donor-derived splenic Tregs expressing neuropilin-1, which is reported to be a marker of naturally occurring Tregs, indicating that TA-KO thymic Tregs either do not leave the thymus or are lost at the periphery. We next transplanted enriched TA-KO thymic Tregs to the peripheries of TA-KO mice and traced mouse survival. Transplantation of TA-KO thymic Tregs rescued the lethality in TA-KO mice, demonstrating that TA-KO thymic Tregs remained functional at the periphery. The TA-KO thymic Treg population had highly demethylated CpG motifs in the foxp3 locus, indicating that the cells were arrested at a late mature stage. Also, the population included a large subpopulation of Tregs expressing IL-7Rα, which is a possible marker of late-stage mature Tregs. Finally, TA-KO fetal liver chimeric mice developed a neuropilin-1(+) splenic Treg population from TA-KO cells, suggesting that Treg arrest was caused by a lack of RelA in the thymic environment. Taken together, these results suggest that egress of mature Tregs from the thymus depends on RelA in the thymic environment.


Efficacy and safety of a hydrocortisone aceponate-containing ear spray solution in dogs with erythemato-ceruminous otitis externa: A randomised, multicentric, single-blinded, controlled trial.
Erythemato-ceruminous otitis externa (ECOE) is frequently seen in dogs affected with an allergic skin disease, with recurrent secondary bacteria and yeast overgrowths (detected on cytological examination). The objective of the study was to compare the efficacy and safety of an ear spray containing only hydrocortisone aceponate glucocorticoid diester (HCA) to a control product (CTRL), an approved otic formulation containing prednisolone-miconazole-polymyxin combination, in dogs with ECOE. In total, 97 and 104 dogs with ECOE were respectively randomly assigned to the tested ear treatment product group (HCA) or the commercially available ear treatment control product group (CTRL). Dogs were treated for 7-14 days, as needed. At Day (D)0, D7, D14, D28 and D42, Otitis Index Score-3, hearing test, pruritus and pain visual analogue scales, and cytological scores were graded. The overall response to treatment also was assessed. All clinical parameters decreased rapidly and in a similar way without any significant difference at any time between treatment groups. A good-to-excellent response to treatment was seen in >90% of dogs of both groups as early as D14. The treatment was considered safe in all dogs. A 7- to 14-day ear topical application of HCA alone to dogs with ECOE accompanied with bacterial and/or fungal (yeast) overgrowth was safe and led to no statistical difference in improvement of clinical scores relative to the CTRL combination. Based on these results, it may be necessary to reconsider the routine use of antimicrobial drugs such as antibiotics and antifungals as a first-line treatment for ECOE that is likely to have been caused by an allergic reaction.


Altered gut microbiome associated with metabolic-associated fatty liver disease in Chinese children.
Limited studies have investigated the association between gut microbiota and metabolic dysfunction-associated fatty liver disease (MAFLD) in children and adolescents. We aimed to identify differences in gut microbiota composition and diversity between children with MAFLD and healthy counterparts. Data were collected from a nested case-control study (October to December, 2021) of the "Huantai Childhood Cardiovascular Health Cohort Study" in Huantai County, Zibo City, China. The study included 52 children aged 5-11 years with new-onset MAFLD and 52 healthy children matched by age and sex. Stool samples were collected and analyzed using 16S rRNA gene sequencing. Shannon index and Chao index were used to assess the α diversity of gut microbiota and Principal coordinates analysis (PCoA) was performed to evaluate β diversity between the two groups. The differences in the relative abundance of gut microbiota between MAFLD group and control group were compared by the Wilcoxon rank-sum test after false discovery rate (FDR) correction. Additionally, the gut-microbial metabolic pathways were identified using the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). We found that children with MAFLD had significant different gut microbiota composition and reduced α diversity compared with the control group. PCoA showed that the two groups can be significantly distinguished based on the unweighted unifrac distance algorithm. Gut microbiota at the phylum level such as Verrucomicrobia and Desulfobacterial, genus level such as Blautia, Lachnospiraceae_NK4A136_group, Coprococcus, Erysipelotrichaceae_UCG-003, UCG-002 and Akkermansia, and species level such as Bifidobacterium_longum abundances were significantly decreased in children with MAFLD compared with that in children without MAFLD. Notably, the abundance of these bacteria were found to be associated with HDL-C, SBP, DBP, WC, BMI, etc. In addition, our analysis of gut-microbial metabolic pathways identified differences in carbohydrate transport and metabolism, as well as amino acid transport and metabolism between the two groups. Significant differences in gut microbiota composition are observed between children with and without MAFLD, which indicate that gut microbiota may be a potential contributor to the development of MAFLD in childhood.


Potentiation and depression of the M wave in human biceps brachii.
1. The effects of repeated excitation on the compound action potential, or M wave, of mammalian muscle fibres have been investigated in the human biceps brachii. 2. During continuous indirect stimulation at 10 and 20 Hz the mean voltage-time area of the M wave doubled within the first minute, while the mean peak-to-peak amplitude increased by approximately half. The enlargement of the M wave was sustained during stimulation at 10 Hz but not at 20 Hz. Stimulation at 3 Hz caused a small increase which was significant for M wave amplitude only. 3. When the 20 Hz stimulation was performed under ischaemic conditions, the M wave first enlarged and then gradually declined. After 20 Hz stimulation was discontinued, the M wave increased in size; in the ischaemic experiments the release of the cuff produced a further, rapid augmentation. In both the ischaemic and non-ischaemic experiments, the amplitudes and areas of the M waves during the recovery period became significantly larger than the resting values (range, 15-60% at the endplate zone). 4. The mean muscle fibre impulse conduction velocity decreased to less than half the resting value during 20 Hz stimulation, with or without ischaemia, and then increased above the resting value during recovery. 5. On the basis of previous experiments in animals, the augmentation of the M wave was attributed to enhanced electrogenic Na(+)-K+ pumping, and the biceps brachii appeared to be an excellent preparation for studying the time course of this enhancement.


[Egg allergy].
Egg is one of the most important allergen in childhood feeding. The pathogenic mechanism in egg allergy is immediate, type I, IgE-mediated hypersensitivity, although other mechanisms are possible. The aim of this review is to point out that diagnosis of egg protein allergy is mainly clinical and double-blind placebo-controlled food challenge is nowadays the gold standard. Although reference values for prick test and sIgE have been proposed, which can foretell symptoms in groups of egg sensitive children, these values are not so accurate for a single diagnosis, since they mainly refer to children with atopic dermatitis, and to specific ranges of age. Children with atopic dermatitis can show allergy at the first egg ingestion, as for cow milk allergy, because the sensitization may happen in utero or through breast milk. The only available therapy in case of egg allergy is the complete removal of hen egg from the child's diet, yet considering cross-reaction with other birds' eggs, while cross- reaction with poultry and/or other birds' meat has been signalled only in 5% of cases. From this review it is clear how egg allergic children can be vaccinated against measles-mumps rubella.


Cellular oxidative stress response mediates radiosensitivity in Fus1-deficient mice.
Mechanism of radiosensitivity of normal tissues, a key factor in determining the toxic side effects of cancer radiotherapy, is not fully understood. We recently demonstrated that deficiency of mitochondrial tumor suppressor, Fus1, increases radiosensitivity at the organismal, tissue and cellular levels. Since Fus1-deficient mice and cells exhibit high levels of oxidative stress, we hypothesized that dysregulation of cellular antioxidant defenses may contribute to the increased radiosensitivity. To address this potential mechanism, we treated the Fus1 KO mice with an inhibitor of pathogenic oxidative reactions, pyridoxamine (PM). Treatment with PM ameliorated IR-induced damage to GI epithelium of Fus1 KO mice and significantly increased the survival of irradiated mice. In cultured Fus1 KO epithelial cells, IR-induced oxidative stress was enhanced because of inadequate cellular antioxidant defenses, such as low levels and/or activities of cytochrome C, Sod 2 and STAT3. This resulted in dysregulation of IR-induced DNA-damage response and DNA synthesis. Treatment of Fus1 KO cells with PM or Sod 2 mimetic Tempol normalized the oxidative stress response, thus compensating to a significant degree for inadequate antioxidant response. Our findings using Fus1 KO radiosensitive mice suggest that radiosensitivity is mediated via dysregulation of antioxidant response and defective redox homeostasis.


Safety profiles of Fe2+ and Fe3+ oral preparations in the treatment of iron deficiency anemia in children.
The major purpose of this study was to compare the oxidant-related toxicities of the different oral iron preparations in children with iron deficiency anemia (IDA); the second aim was to investigate the side effects of iron preparations. Seventy-two children with IDA were randomly included in the Fe(2+) group (n = 39) or the Fe(3+) group (n = 33). Some oxidizable substrates (erythrocytes malondialdehyde (MDA), urine 8-isoprostane, and basal and Cu-stimulated-oxidized LDL and antioxidant enzyme (superoxide dismutase (SOD), catalase and glutathione peroxidase) activities were evaluated at the beginning and at the 1st, 3rd, and 6th months of therapy. Side effects due to medication were recorded. While at the end of the 1st month SOD levels were significantly increased in Fe(3+) group, at the 6th month evaluation, basal-oxidized LDL levels were significantly increased in the Fe(3+) group, as was urine 8-isoprostane in the Fe(2+) group. No other difference was found between two groups. In conclusion, there were minimal differences between children treated with ferric or ferrous iron in antioxidant system activities, the status of oxidizable substrates, and clinical toxicities.


[Current problems in the use of probation with compulsory work].
In the framework of the Soviet law, probation accompanied by compulsory work represents an up-to-date measure of a criminal character that allows to rehabilitate a convicted offender without depriving him of his freedom. The Panfederal Institute for the study of the causes of criminal behaviour and for the formulation of measures for preventing it, has conducted a number of researches directed at clearing up some debated problems bearing on the implementation of the measures existing on the subject, and at collecting proposals of amendment. The present article deals with the assumptions and preconditions, of both an objective and subjective character, underlying the application of this juridical institute, and also tackles, by referring to some cases previously occurred, the problems posed by the various types of subjects. Special attention is devoted to the decision-making procedure followed by the tribunals in applying the said measures, and to the various elements on which it is to be based.


The perception of odor objects in everyday life: a review on the processing of odor mixtures.
Smelling monomolecular odors hardly ever occurs in everyday life, and the daily functioning of the sense of smell relies primarily on the processing of complex mixtures of volatiles that are present in the environment (e.g., emanating from food or conspecifics). Such processing allows for the instantaneous recognition and categorization of smells and also for the discrimination of odors among others to extract relevant information and to adapt efficiently in different contexts. The neurophysiological mechanisms underpinning this highly efficient analysis of complex mixtures of odorants is beginning to be unraveled and support the idea that olfaction, as vision and audition, relies on odor-objects encoding. This configural processing of odor mixtures, which is empirically subject to important applications in our societies (e.g., the art of perfumers, flavorists, and wine makers), has been scientifically studied only during the last decades. This processing depends on many individual factors, among which are the developmental stage, lifestyle, physiological and mood state, and cognitive skills; this processing also presents striking similarities between species. The present review gathers the recent findings, as observed in animals, healthy subjects, and/or individuals with affective disorders, supporting the perception of complex odor stimuli as odor objects. It also discusses peripheral to central processing, and cognitive and behavioral significance. Finally, this review highlights that the study of odor mixtures is an original window allowing for the investigation of daily olfaction and emphasizes the need for knowledge about the underlying biological processes, which appear to be crucial for our representation and adaptation to the chemical environment.


Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort.
To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Prospective multicentre cohort. Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. 3572 "healthy" nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Pre-eclampsia defined as ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks' gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37(+0) weeks' gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks' gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added. Trial registration ACTRN12607000551493.


Isolation of Pure Astrocytes and Microglia from the Adult Mouse Spinal Cord For In Vitro Assays and Transcriptomic Studies.
Astrocytes and microglia play pivotal roles in central nervous system development, injury responses, and neurodegenerative diseases. These highly dynamic cells exhibit rapid responses to environmental changes and display significant heterogeneity in terms of morphology, transcriptional profiles, and functions. While our understanding of the functions of glial cells in health and disease has advanced substantially, there remains a need for in vitro, cell-specific analyses conducted in the context of insults or injuries to comprehensively characterize distinct cell populations. Isolating cells from the adult mouse offers several advantages over cell lines or neonatal animals, as it allows for the analysis of cells under pathological conditions and at specific time points. Furthermore, focusing on spinal cord-specific isolation, excluding brain involvement, enables research into spinal cord pathologies, including experimental autoimmune encephalomyelitis, spinal cord injury, and amyotrophic lateral sclerosis. This protocol presents an efficient method for isolating astrocytes and microglia from the adult mouse spinal cord, facilitating immediate or future analysis with potential applications in functional, molecular, or proteomic downstream studies.


Mobile photographic screening for dental caries in children: Diagnostic performance compared to unaided visual dental examination.
This study was conducted to compare the use of intraoral photographs with the unaided visual dental examination as a means of dental caries detection in children. Children aged 4- to 14-year-olds were visually examined at their schools. Following dental examinations, children had five photographs of their teeth taken using a smartphone camera. Four dental reviewers, who are different from those who visually examined the children, assessed intraoral photographs for dental caries. Sensitivity, specificity, and inter-rater reliability agreement were estimated to assess the diagnostic performance of the photographic method relative to the benchmark visual dental assessments. Caries prevalence was measured using dft/DFT (decayed and filled teeth) index. One hundred thirty-eight children (67 male and 71 female) were enrolled and had a mean age of 7.8 ± 2.1 years. The caries prevalence (dft/DFT > 0) using photographic dental assessments ranged from 30 percent to 39 percent but was not significantly different from the prevalence (42 percent) estimated with the visual dental examination (P ≥ 0.07). The sensitivity and specificity of the photographic method for detection of dental caries compared to visual dental assessments were 58-80 percent and 99.7-99.9 percent, respectively. The sensitivity for the photographic assessments was high in the primary dentition (63-82 percent) and children ≤7-year-olds (67-78 percent). The inter-rater reliability for the photographic assessment versus the benchmark ranged from substantial to almost perfect agreement (Kappa = 0.72-0.87). The photographic approach to dental screening, used within the framework of its limitations, yielded an acceptable diagnostic level of caries detection, particularly in younger children with primary dentition.


Survey of acupuncturists: practice characteristics and pediatric care.
To describe the practice characteristics and pediatric care provided by licensed acupuncturists. Cross-sectional survey. Boston metropolitan area. 227 licensed acupuncturists were surveyed; 140 (62%) responded. (1) DEMOGRAPHICS, (2) practice characteristics, (3) pediatric care, (4) recommendations of peers recognized as experts in pediatric acupuncture. (1) DEMOGRAPHICS: 70% Caucasian, 61% female; (2) practice characteristics: average of 39 visits weekly with an average charge of $54 for a 57-minute visit; patients were typically scheduled for follow-up once or twice weekly; only 5% of fees were covered by insurance; 80% recommended herbal remedies and 66% dispensed herbs in the office; (3) few acupuncturists treated more than one child per week; most used non-needle techniques or Japanese-style acupuncture to stimulate points in children; 85% would refer a febrile two-week-old infant immediately to a physician; (4) only 17 acupuncturists were recommended by three or more peers and saw three or more patients weekly; their practices were all in wealthy suburban areas. Most acupuncturists in the Boston area are Caucasian and female. Compared with physicians, they schedule patients for more frequent follow-up, allocate more time, are less likely to be reimbursed by insurance, and treat fewer children. Additional studies are needed to assess effectiveness, quality, and access to acupuncture services for adults and children.


An overall evaluation of the Resistance (R) and Pathogenesis-Related (PR) superfamilies in soybean, as compared with Medicago and Arabidopsis.
Plants have the ability to recognize and respond to a multitude of pathogens, resulting in a massive reprogramming of the plant to activate defense responses including Resistance (R) and Pathogenesis-Related (PR) genes. Abiotic stresses can also activate PR genes and enhance pathogen resistance, representing valuable genes for breeding purposes. The present work offers an overview of soybean R and PR genes present in the GENOSOJA (Brazilian Soybean Genome Consortium) platform, regarding their structure, abundance, evolution and role in the plant-pathogen metabolic pathway, as compared with Medicago and Arabidopsis. Searches revealed 3,065 R candidates (756 in Soybean, 1,142 in Medicago and 1,167 in Arabidopsis), and PR candidates matching to 1,261 sequences (310, 585 and 366 for the three species, respectively). The identified transcripts were also evaluated regarding their expression pattern in 65 libraries, showing prevalence in seeds and developing tissues. Upon consulting the SuperSAGE libraries, 1,072 R and 481 PR tags were identified in association with the different libraries. Multiple alignments were generated for Xa21 and PR-2 genes, allowing inferences about their evolution. The results revealed interesting insights regarding the variability and complexity of defense genes in soybean, as compared with Medicago and Arabidopsis.


Autologous hematopoietic recovery after allogeneic hematopoietic stem cell transplantation: A case-based review.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely applied for the treatment of hematologic malignancies, but autologous hematopoietic recovery (AR) after allo-HSCT is rare clinically, especially after myeloablative conditioning (MAC). The mechanism of AR remains unclear so far, but the prognosis for most patients is relatively good. Second transplantation is preferred after disease relapse. Starting from a real-life clinical case scenario, herein we reviewed some of the crucial issues of AR in light of recent refinements, and discussed our patients based on the current evidence.


Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 during zidovudine (AZT) therapy.
Nucleotide sequences of regions of the envelope (env) and polymerase (pol) genes of human immunodeficiency virus type 1 (HIV-1) proviral DNA were obtained from sequential blood and autopsy samples from an AIDS patient who had been treated with zidovudine for 9 months. Phylogenetic analyses showed that a reduction in genetic heterogeneity of the env regions of viruses present in the proviral blood population occurred during therapy, and this coincided with an increased pol gene heterogeneity. Differences were observed in different organs obtained post mortem for both the env and pol coding regions. The cardiac blood proviral population consisted mainly of variants which possessed sequences containing mutations at position 215 of the pol gene, associated with drug resistance. By contrast, the brain population consisted entirely of zidovudine sensitive genotypes, and this organ also harboured variants with genetically distinct env sequences. The lymph tissues obtained after death held more diverse proviral env and pol populations, containing both zidovudine sensitive and resistant genotypes.


Macrophage derived cystatin B/cathepsin B in HIV replication and neuropathogenesis.
Mononuclear phagocytes including monocytes and macrophages, are important defense components of innate immunity, but can be detrimental in HIV-1 infection by serving as the principal reservoirs of virus in brain and triggering a strong immune response. These viral reservoirs represent a challenge to HIV-1 eradication since they continue producing virus in tissue despite antiretroviral therapy. HIV-1 associated neurocognitive disorders (HAND) involve alterations to the blood-brain barrier and migration of activated HIV-1 infected monocytes to the brain with subsequent induced immune activation response. Our group recently showed that HIV replication in monocyte-derived macrophages is associated with increased cystatin B. This cysteine protease inhibitor also inhibits the interferon-induced antiviral response by decreasing levels of tyrosine phosphorylated STAT-1. These recent discoveries reveal novel mechanisms of HIV persistence that could be targeted by new therapeutic approaches to eliminate HIV in macrophage reservoirs. However, cystatin B has been also associated with neuroprotection. Cystatin B is an inhibitor of the cysteine protease cathepsin B, a potent neurotoxin. During HIV-1 infection cystatin B and cathepsin B are upregulated in macrophages. Reduction in cystatin/cathepsin interactions in infected macrophages leads to increased cathepsin B secretion and activity which contributes to neuronal apoptosis. Increased intracellular expression of both proteins was recently found in monocytes from Hispanic women with HAND. These findings provide new evidence for the role of cathepsin /cystatin system in the neuropathogenesis induced by HIV-infected macrophages. We summarize recent research on cystatin B and one of its substrates, cathepsin B, in HIV replication in macrophages and neuropathogenesis.


Modified palliative biliary stenting in situs inversus totalis patient with carcinoma gallbladder: feasibility and technical details.
Knowledge of the anatomical variants is essential for all invasive hepatobiliary procedures such as endoscopy, surgery and radiologic interventions. Modification in standard therapeutic interventions may be required based on variant anatomy. We report a technical modification in a 75-year-old female with known situs inversus (SI) totalis with carcinoma gallbladder. Present case highlights the finer technical details of the modified percutaneous transhepatic biliary drainage (PTBD) procedure and biliary stenting in a SI patient with carcinoma gallbladder causing malignant biliary obstruction.


Targeted therapy of human glioblastoma via delivery of a toxin through a peptide directed to cell surface nucleolin.
Targeted anticancer therapies demand discovery of new cellular targets to be exploited for the delivery of toxic molecules and drugs. In this perspective, in the last few years, nucleolin has been identified as an interesting surface marker to be used for the therapy of glioblastoma. In this study, we investigated whether a synthetic antagonist of cell-surface nucleolin known as N6L, previously reported to decrease both tumor growth and tumor angiogenesis in several cancer cell lines, including glioblastoma cells, as well as endothelial cells proliferation, could be exploited to deliver a protein toxin (saporin) to glioblastoma cells. The pseudopeptide N6L cross-linked to saporin-S6 induced internalization of the toxin inside glioblastoma cancer cells. Our results in vitro demonstrated the effectiveness of this conjugate in inducing cell death, with an ID50 four orders of magnitude lower than that observed for free N6L. Furthermore, the preliminary in vivo study demonstrated efficiency in reducing the tumor mass in an orthotopic mouse model of glioblastoma.


2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice.
Cytochrome P450 1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1-/-, ovariectomized female, and Cyp1b1+/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 hours. 2-Methoxyestradiol reduced Ang II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1-/- and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1+/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1-/- and ovariectomized Cyp1b1+/+ and Cyp1b1-/- female mice and Cyp1b1+/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1-/- and ovariectomized Cyp1b1+/+ and Cyp1b1-/- female mice but not in Cyp1b1+/+ male mice. The G protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1+/+ female mice. These data suggest that 2-methoxyestradiol reduces Ang II-induced hypertension and associated end-organ damage in intact Cyp1b1-/-, ovariectomized Cyp1b1+/+ and Cyp1b1-/- female mice, and Cyp1b1+/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males.


Iodination of insulin in aqueous and organic solvents.
1. The iodination of insulin was studied under various experimental conditions in aqueous media and in some organic solvents, by measuring separately the uptake of iodine by the four tyrosyl groups and the relative amounts of monoiodotyrosine and di-iodotyrosine that are formed. In aqueous media from pH1 to pH9 the iodination occurs predominantly on the tyrosyl groups of the A chain. Some organic solvents increase the iodine uptake of the B-chain tyrosyl groups. Their efficacy in promoting iodination of Tyr-B-16 and Tyr-B-26 is in the order: ethylene glycol and propylene glycol approximately methanol and ethanol>dioxan>8m-urea. 2. It is suggested that each of the four tyrosyl groups in insulin has a different environment: Tyr-A-14 is fully exposed to the solvent; Tyr-A-19 is sterically influenced by the environmental structure, possibly by the vicinity of a disulphide interchain bond; Tyr-B-16 is embedded into a non-polar area whose stability is virtually independent of the molecular conformation; Tyr-B-26 is probably in a situation similar to Tyr-B-16 with the difference that its non-polar environment depends on the preservation of the native structure.


Magnetoreception attributed to the efficacy of light therapy.
A group of specialized photoreceptors are suggested to amplify the weak interaction of the geomagnetic field with a single electron spin to the level of photon detection, resulting in a modulation of the response to light. Under exposure to rotating magnetic field, the size of pinealocytes is bigger at night than during the day in spring, but there is no day-night difference in autumn. Specialized photoreceptors are hypothesized to modulate the response of the photoreceptive system to light, and the pineal response to a magnetic stimulus, in patients with winter seasonal affective disorder (SAD). This could explain why some winter SAD patients show excessive sensitivity to light in winter.


Selective flower abortion maintains moth cooperation in a newly discovered pollination mutualism.
The evolutionary stability of mutualisms is enhanced when partners possess mechanisms to prevent overexploitation by one another. In obligate pollination-seed consumption mutualisms, selective abortion of flowers containing excessive eggs represents one such mechanism, but empirical tests have long been limited to the yucca-yucca moth mutualism. We present evidence for selective abortion in the recently discovered mutualism between Glochidion trees and Epicephala moths. In Glochidion acuminatum, proportion of aborted flowers progressively increased both with higher egg load and increased ovule damage. Selective abortion resulted in a 16% seed production increase compared with expectations under random abortion, and moths suffered fitness losses as high as 62% when ovipositing into pre-infested flowers. Moth eggs were laid singly more often than expected under random oviposition, thus avoiding potential disadvantages from multiple infestations. As new pollination mutualisms are being discovered, selective abortion mechanisms may prove to be more widespread than previously thought.


Al27 NMR chemical shift of Al(OH)4 - calculated from first principles: Assessment of error cancellation in chemically distinct reference and target systems.
Predicting accurate nuclear magnetic resonance chemical shieldings relies upon cancellation of different types of errors between the theoretically calculated shielding constant of the analyte of interest and the reference. Often, the intrinsic error in computed shieldings due to basis sets, approximations in the Hamiltonian, description of the wave function, and dynamic effects is nearly identical between the analyte and reference, yet if the electronic structure or sensitivity to local environment differs dramatically, this cannot be taken for granted. Detailed prior work has examined the octahedral trivalent cation Al(H2O)6 3+, accounting for ab initio intrinsic errors. However, the use of this species as a reference for the chemically distinct tetrahedral anion Al(OH)4 - requires an understanding of how these errors cancel in order to define the limits of accurately predicting Al27 chemical shielding in Al(OH)4 -. In this work, we estimate the absolute shielding of the Al27 nucleus in Al(OH)4 - at the coupled cluster level (515.1 ± 5.3 ppm). Shielding sensitivity to the choice of method approximation and atomic basis sets used has been evaluated. Solvent and thermal effects are assessed through ensemble averaging techniques using ab initio molecular dynamics. The contribution of each type of intrinsic error is assessed for the Al(H2O)6 3+ and Al(OH)4 - ions, revealing significant differences that fundamentally hamper the ability to accurately calculate the Al27 chemical shift of Al(OH)4 - from first principles.


SURMOUNTing body weight barriers in type 2 diabetes.
The emergence of GIPR:GLP-1R co-agonists has heralded a renaissance of anti-obesity medication. In the recent SURMOUNT 2 trial, Garvey and colleagues set out to examine the weight loss efficacy of the GIPR:GLP-1R co-agonist tirzepatide in patients with obesity and type 2 diabetes, reporting that tirzepatide has unprecedented efficacy in a magnitude historically considered almost unattainable.1.


Automatic image segmentation by dynamic region growth and multiresolution merging.
Image segmentation is a fundamental task in many computer vision applications. In this paper, we propose a new unsupervised color image segmentation algorithm, which exploits the information obtained from detecting edges in color images in the CIE L *a *b * color space. To this effect, by using a color gradient detection technique, pixels without edges are clustered and labeled individually to identify some initial portion of the input image content. Elements that contain higher gradient densities are included by the dynamic generation of clusters as the algorithm progresses. Texture modeling is performed by color quantization and local entropy computation of the quantized image. The obtained texture and color information along with a region growth map consisting of all fully grown regions are used to perform a unique multiresolution merging procedure to blend regions with similar characteristics. Experimental results obtained in comparison to published segmentation techniques demonstrate the performance advantages of the proposed method.


Pneumonia Due to Human Coronavirus OC43 in an Immunocompetent Adult Detected by Multiplex Polymerase Chain Reaction.
A 40-year-old woman developed a fever, sore throat, and cough. Coronavirus disease 2019 (COVID-19) was suspected; chest CT showed pan-lobular ground-glass opacity in the bilateral lower lobes suggesting viral pneumonia. Although a reverse transcription loop-mediated isothermal amplification (RT-LAMP) test for COVID-19 using a nasopharyngeal swab was negative, she was hospitalized and isolated because COVID-19 could not be ruled out. After admission, multiplex polymerase chain reaction (PCR) with the FilmArray Respiratory Panel 2.1 from a nasopharyngeal swab was positive for human coronavirus (HCoV) OC43. Therefore, the diagnosis was pneumonia due to HCoV-OC43. Multiplex PCR is useful for differentiating pneumonia due to COVID-19 from that due to other viral pneumonias.


Vector-borne disease, climate change and perinatal health.
Vector-borne diseases (VBDs) are caused by infectious pathogens that spread from an infected human or animal reservoir to an uninfected human via a vector (mosquito, tick, rodent, others) and remain an important cause of morbidity and mortality worldwide. Pregnant individuals and their fetuses are especially at risk, as certain pathogens, such as Zika virus, have specific implications in pregnancy and for neonatal health. Global climate change is affecting the incidence and geographic spread of many VBDs. Thus, it is important for clinicians in the fields of obstetrics/gynecology and newborn medicine, regardless of geographic location, to familiarize themselves with a basic understanding of these conditions and how climate change is altering their distributions. In this chapter, we review the incidence, clinical presentation, implications during pregnancy and intersection with climate change for four of the most important VBDs in pregnancy: malaria, Zika, dengue and Chagas disease. Although not exhaustive of all VBDs, a more extensive table is included for reference, and our discussion provides a helpful framework for understanding other vector-borne pathogens and perinatal health.


Surveillance of fatal occupational injuries in France: 2002-2004.
Insufficient use is made of available information about workplace and commuting accidents covered by social insurance workers compensation funds in France. We sought to determine whether these data could be used to calculate national indicators for surveillance of fatal occupational injuries for 2002-2004. We calculated the number of deaths, mortality rate, and years of potential life lost from workplace and commuting accidents (by sex, age, economic activity, and cause of accident) for employees by collecting data from eight social insurance funds in France. The number of deaths, the mortality rates, and the attributable fraction of accidental deaths due to work were estimated for both employees and self-employed workers. The mean annual number of employee deaths from workplace and commuting accidents reached 1,330 in 2002-2004. The mortality rate from workplace accidents (6.0 per 100,000) increased with age among men and was especially high in three sectors: agriculture-forestry-fishing, transportation, and construction.Overall, for employees and the self-employed combined, the mean annual number of deaths from workplace and commuting accidents was estimated at 1,557 (95% CI: 1,478-1,640). The attributable fraction of accidental deaths due to work for those aged 15-59 years was estimated at almost 20% among men. Despite data limitations, it was possible to calculate previously unknown national indicators of fatal workplace and commuting accidents and to compare them with other work-related health problems. These results are consistent with those observed in comparable industrialized countries.


Efficiently solving general weapon-target assignment problem by genetic algorithms with greedy eugenics.
A general weapon-target assignment (WTA) problem is to find a proper assignment of weapons to targets with the objective of minimizing the expected damage of own-force asset. Genetic algorithms (GAs) are widely used for solving complicated optimization problems, such as WTA problems. In this paper, a novel GA with greedy eugenics is proposed. Eugenics is a process of improving the quality of offspring. The proposed algorithm is to enhance the performance of GAs by introducing a greedy reformation scheme so as to have locally optimal offspring. This algorithm is successfully applied to general WTA problems. From our simulations for those tested problems, the proposed algorithm has the best performance when compared to other existing search algorithms.


Ultrasonically activated device for parenchymal division during open hepatectomy.
The use of new technological devices has gained popularity and has been proposed to improve the safety of liver resection. This study was designed to evaluate the usefulness of the ultrasonically activated device (USAD) during open liver resection. Indication for surgery, type of resection, need to perform a Pringle manoeuvre, operation time, blood loss, number of blood transfusions, morbidity and mortality rate were analyzed in 60 patients undergoing a formal open liver resection by means of USAD. The overall mean operation time was 172 minutes (range 120-255 min); an intermittent warm ischemia was applied in 9 cases (15%). The overall mean blood loss was 410 mL (median 400 mL, range 50-950 ml). A median of one blood transfusion was administered in six patients (10%). The mean hospital stay was 10.2 days (median 11, range 8-16). The overall morbidity rate was 20% (12 out of 60 patients). No in-hospital mortality was recorded. By subdividing the patients according to the presence or absence of cirrhosis no statistical significant differences were found between the two subgroups in all peri-and postoperative outcomes. In conclusion, though there is a lack of data based on well conducted controlled studies and further on a greater number of patients are needed, the utilization of USAD may help to minimize blood loss during liver resection regardless of the condition of the liver, even in case of cirrhosis.