Synthesis, antibacterial activities, and 3D-QSAR of sulfone derivatives containing 1, 3, 4-oxadiazole moiety.
A series of sulfone derivatives containing 1, 3, 4-oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC50 values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b, and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC50 values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC50 values of 45.91 and 216.70 μg/mL, respectively. The structure-activity relationship (SAR) of compounds was studied using three-dimensional quantitative structure-activity relationship (3D-QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D-QSAR models effectively predicted the correlation between inhibitory activity and steric-electrostatic properties of compounds.


Ophthalmologists and WhatsApp: Teleophthalmology is already here.
To estimate the extent of WhatsApp utilization using text and media messages for inter-physician consultations among ophthalmologists (residents and specialists) at various clinical settings and its perceived benefits for ophthalmologists and their patients. We also aimed to detect obstacles that concern ophthalmologists when using WhatsApp as a consultation platform. This was a cross-sectional study using a self-administered survey through Google Forms, which was sent to 660 practicing ophthalmologists during April to May 2020. One hundred and ninety-two ophthalmologists completed the questionnaire, 151 of which (78.6%) were specialists and 41 (21.4%) were residents. Most ophthalmologists reported using WhatsApp at least once a day for both personal and professional use. Residents reported lower rates of contacting patients using WhatsApp than specialists (1.51 ± 0.98 vs 2.72 ± 1.32, p < 0.001). Respondents reported WhatsApp consultations frequently replaced referrals of patients to other physicians, with a median of once a week. 97.8% of residents and 91.4% of specialists reported the ability to share media is a major advantage of WhatsApp over other medias, followed by rapid responses for consultations. Many ophthalmologists already use WhatsApp as a tool for professional consultations with other providers, mainly thanks to its simplicity and wide availability. Residents use it more frequently than specialists, and ranked it higher when asked how much WhatsApp has improved the clinical setting. Policy makers should address concerns brought up by physicians, such as documentation in medical records and proper compensation for consulting ophthalmologists during and after work hours.


Seizures and EEG features in 74 patients with genetic-dysmorphic syndromes.
Epilepsy is one of the most common findings in chromosome aberrations. Types of seizures and severity may significantly vary both between different conditions and within the same aberration. Hitherto specific seizures and EEG patterns are identified for only few syndromes. We studied 74 patients with defined genetic-dysmorphic syndromes with and without epilepsy in order to assess clinical and electroencephalographic features, to compare our observation with already described electro-clinical phenotypes, and to identify putative electroencephalographic and/or seizure characteristics useful to address the diagnosis. In our population, 10 patients had chromosomal disorders, 19 microdeletion or microduplication syndromes, and 32 monogenic syndromes. In the remaining 13, syndrome diagnosis was assessed on clinical grounds. Our study confirmed the high incidence of epilepsy in genetic-dysmorphic syndromes. Moreover, febrile seizures and neonatal seizures had a higher incidence compared to general population. In addition, more than one third of epileptic patients had drug-resistant epilepsy. EEG study revealed poor background organization in 42 patients, an excess of diffuse rhythmic activities in beta, alpha or theta frequency bands in 34, and epileptiform patterns in 36. EEG was completely normal only in 20 patients. No specific electro-clinical pattern was identified, except for inv-dup15, Angelman, and Rett syndromes. Nevertheless some specific conditions are described in detail, because of notable differences from what previously reported. Regarding the diagnostic role of EEG, we found that--even without any epileptiform pattern--the generation of excessive rhythmic activities in different frequency bandwidths might support the diagnosis of a genetic syndrome.


Computed tomographic and cross-sectional anatomic characterization of myofascial compartments and soft tissue spaces in the manus in cadavers of dogs without forelimb disease.
To characterize the computed tomographic (CT) and cross-sectional anatomic features of myofascial compartments and soft tissue spaces in the manus of cadavers of dogs without forelimb disease. 33 cadavers of adult medium- to large-breed dogs without forelimb disease. Forelimbs were removed from the cadavers within 4 hours after euthanasia or within 6 hours after thawing from initial freezing. Specimens were then frozen for variable periods and thawed for approximately 16 hours before use. Each manus of 60 forelimbs underwent CT before and after injection of a radiopaque, blue-staining contrast medium into locations where soft tissue spaces and myofascial compartments were predicted (on the basis of pilot study data [6 forelimbs]). Two veterinary radiologists reviewed CT images and recorded the presence or absence of a discrete space or compartment at each injection site. Each manus was subsequently dissected or sectioned transversely. Locations of blue-staining contrast medium accumulation were compared with locations of contrast enhancement in CT images. Anatomic structures within each soft tissue space or myofascial compartment were described. 13 soft tissue spaces and 5 myofascial compartments were identified in the manus. Three myofascial structures that were examined were determined not to be compartments. Knowledge of soft tissue spaces and myofascial compartments are used to map the likely spread of disease in the hands and feet of humans. Thus, understanding the locations and extent of similar structures in the canine manus may improve the effectiveness of surgical interventions in dogs with injury or inflammation of this region of the forelimb.


Target 5000: Target Capture Sequencing for Inherited Retinal Degenerations.
There are an estimated 5000 people in Ireland who currently have an inherited retinal degeneration (IRD). It is the goal of this study, through genetic diagnosis, to better enable these 5000 individuals to obtain a clearer understanding of their condition and improved access to potentially applicable therapies. Here we show the current findings of a target capture next-generation sequencing study of over 750 patients from over 520 pedigrees currently situated in Ireland. We also demonstrate how processes can be implemented to retrospectively analyse patient datasets for the detection of structural variants in previously obtained sequencing reads. Pathogenic or likely pathogenic mutations were detected in 68% of pedigrees tested. We report nearly 30 novel mutations including three large structural variants. The population statistics related to our findings are presented by condition and credited to their respective candidate gene mutations. Rediagnosis rates of clinical phenotypes after genotyping are discussed. Possible causes of failure to detect a candidate mutation are evaluated. Future elements of this project, with a specific emphasis on structural variants and non-coding pathogenic variants, are expected to increase detection rates further and thereby produce an even more comprehensive representation of the genetic landscape of IRDs in Ireland.


Male facial attractiveness and masculinity may provide sex- and culture-independent cues to semen quality.
Phenotype-linked fertility hypothesis (PLFH) predicts that male secondary sexual traits reveal honest information about male fertilization ability. However, PLFH has rarely been studied in humans. The aim of the present study was to test PLFH in humans and to investigate whether potential ability to select fertile partners is independent of sex or cultural background. We found that on the contrary to the hypothesis, facial masculinity was negatively associated with semen quality. As increased levels of testosterone have been demonstrated to impair sperm production, this finding may indicate a trade-off between investments in secondary sexual signalling (i.e. facial masculinity) and fertility or status-dependent differences in investments in semen quality. In both sexes and nationalities (Spanish and Colombian), ranked male facial attractiveness predicted male semen quality. However, Spanish males and females estimated facial images generally more attractive (gave higher ranks) than Colombian raters, and in both nationalities, males gave higher ranks than females. This suggests that male facial cues may provide culture- and sex-independent information about male fertility. However, our results also indicate that humans may be more sensitive to facial attractiveness cues within their own populations and also that males may generally overestimate the attractiveness of other men to females.


[Presence of Pneumocystis carinii in cerebrospinal fluid].
Pneumocistis carinii is a ubiquitous protozoan present in mammals which frequently causes pulmonary problems in immunodeficient patients, especially those infected with the Human Immunodeficiency Virus. Given its particular affinity with the lung area, it is rarely present in other tissues. It has on occasions been detected in the liver, spleen and lymphatic ganglia, external auditory canal, skin and to a lesser extent, other organs. It is extremely rare that the pathogen in question produces extra-pulmonary clinical conditions. The case presented is that of an ex-intravenous drug user diagnosed as a carrier of the HIV/C-3 virus, who presented indications of meningeal pathology and in whose cephalorachidian fluid samples were detected Pneumocistis carinii cysts.


A Deep Cascade of Convolutional Neural Networks for Dynamic MR Image Reconstruction.
Inspired by recent advances in deep learning, we propose a framework for reconstructing dynamic sequences of 2-D cardiac magnetic resonance (MR) images from undersampled data using a deep cascade of convolutional neural networks (CNNs) to accelerate the data acquisition process. In particular, we address the case where data are acquired using aggressive Cartesian undersampling. First, we show that when each 2-D image frame is reconstructed independently, the proposed method outperforms state-of-the-art 2-D compressed sensing approaches, such as dictionary learning-based MR image reconstruction, in terms of reconstruction error and reconstruction speed. Second, when reconstructing the frames of the sequences jointly, we demonstrate that CNNs can learn spatio-temporal correlations efficiently by combining convolution and data sharing approaches. We show that the proposed method consistently outperforms state-of-the-art methods and is capable of preserving anatomical structure more faithfully up to 11-fold undersampling. Moreover, reconstruction is very fast: each complete dynamic sequence can be reconstructed in less than 10 s and, for the 2-D case, each image frame can be reconstructed in 23 ms, enabling real-time applications.


Critical Role of Synovial Tissue-Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation.
Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.


Nipple Discharge: Imaging Variability Among U.S. Radiologists.
The purpose of this study was to assess radiologists' choice of imaging modality for the evaluation of clinical symptoms of physiologic nipple discharge (e.g., bilateral discharge, multiple-duct orifices, and yellow, green, or white color) and pathologic nipple discharge (e.g., unilateral discharge, single-duct orifices, spontaneous and serous discharge, and clear or bloodstained color). An online survey was sent to lead interpreting physicians at mammography facilities accredited by the American College of Radiology (ACR). Statistical analysis was performed using chi-square tests for frequency data and multinomial logistic regression. A total of 849 responses to 8170 distributed surveys were received, for a response rate of 10.4%. For the workup of physiologic nipple discharge, 30% of respondents recommended screening mammography (SM); 24%, diagnostic mammography (DM) only; and 46%, both DM and targeted ultrasound (US) (DM plus US). For the workup of physiologic nipple discharge, practitioners in nonacademic settings and those who read breast images during less than 50% of their practice were significantly more likely to recommend DM (with or without US), compared with SM (the standard recommended by the ACR). Those reading breast images less than 50% of the time were also more likely to recommend MRI after conventional imaging revealed negative results. For the workup of pathologic nipple discharge, 91.0% of respondents recommended DM plus US; 8.5%, DM only; and fewer than 1.0%, SM. Nonacademic providers and those who read breast images less than 50% of the time were significantly less likely to recommend DM plus US (the standard recommended by the ACR), compared with DM only. The present study shows variability in imaging modality selection among U.S. radiologists handling the imaging workflow for benign and pathologic nipple discharge. Radiologists do not uniformly follow ACR practice guidelines, which potentially leads to unnecessary workups and extra health care costs.


[Intraparotid facial neurofibroma].
A 56-year-old man with a solitary neurofibroma involving the main trunk of the intraparotid facial nerve is presented. Because its small frequency it's an unexpected tumour of which the definitive diagnosis is only established after its removal. Literature is revised.


Spindly is a nucleocytosolic O-fucosyltransferase in Dictyostelium and related proteins are widespread in protists and bacteria.
O-GlcNAcylation is a prominent modification of nuclear and cytoplasmic proteins in animals and plants and is mediated by a single O-GlcNAc transferase (OGT). Spindly (Spy), a paralog of OGT first discovered in higher plants, has an ortholog in the apicomplexan parasite Toxoplasma gondii, and both enzymes are now recognized as O-fucosyltransferases (OFTs). Here we investigate the evolution of spy-like genes and experimentally confirm OFT activity in the social amoeba Dictyostelium-a protist that is more related to fungi and metazoa. Immunofluorescence probing with the fucose-specific Aleuria aurantia lectin (AAL) and biochemical cell fractionation combined with western blotting suggested the occurrence of nucleocytoplasmic fucosylation. The absence of reactivity in mutants deleted in spy or gmd (unable to synthesize GDP-Fuc) suggested monofucosylation mediated by Spy. Genetic ablation of the modE locus, previously predicted to encode a GDP-fucose transporter, confirmed its necessity for fucosylation in the secretory pathway but not for the nucleocytoplasmic proteins. Affinity capture of these proteins combined with mass spectrometry confirmed monofucosylation of Ser and Thr residues of several known nucleocytoplasmic proteins. As in Toxoplasma, the Spy OFT was required for optimal proliferation of Dictyostelium under laboratory conditions. These findings support a new phylogenetic analysis of OGT and OFT evolution that indicates their occurrence in the last eukaryotic common ancestor but mostly complementary presence in its eukaryotic descendants with the notable exception that both occur in red algae and plants. Their generally exclusive expression, high degree of conservation, and shared monoglycosylation targets suggest overlapping roles in physiological regulation.


Time to death of hospitalized injured patients as a measure of quality of care.
In population-based studies, the quality of care delivered to injured patients is commonly judged by hospital survival rates. Evidence suggests injured patients surviving hospitalization remain at risk for death from their injuries after discharge. Patient characteristics associated with higher risk of late death are not completely defined. The National Death Index is a government-maintained database composed of death certificate records from all decedents in the United States. Patients in a trauma registry were cross-linked to decedents in National Death Index on the basis of Social Security number or other unique identifiers. Decedents' time from injury to death was calculated. Logistic regression models were fit to those who died at hospital discharge and those who died in the first year after injury. Among 4293 hospitalized injured patients recorded in a trauma registry, 157 died during hospitalization. Among the 4136 discharged alive, 91 patients were linked to death certificate records filed in the 365 days after discharge. Patients over the age of 65 had a 15-fold greater odds of death than younger patients. Trauma registry data cross-linked to vital statistics records is practicable. Patients who die in the year after injury differ from the traditional population used to evaluate quality of trauma care, and new standards are needed that evaluate long-term survival.


Cell cycle-dependent localization of macroH2A in chromatin of the inactive X chromosome.
One of several features acquired by chromatin of the inactive X chromosome (Xi) is enrichment for the core histone H2A variant macroH2A within a distinct nuclear structure referred to as a macrochromatin body (MCB). In addition to localizing to the MCB, macroH2A accumulates at a perinuclear structure centered at the centrosome. To better understand the association of macroH2A1 with the centrosome and the formation of an MCB, we investigated the distribution of macroH2A1 throughout the somatic cell cycle. Unlike Xi-specific RNA, which associates with the Xi throughout interphase, the appearance of an MCB is predominantly a feature of S phase. Although the MCB dissipates during late S phase and G2 before reforming in late G1, macroH2A1 remains associated during mitosis with specific regions of the Xi, including at the X inactivation center. This association yields a distinct macroH2A banding pattern that overlaps with the site of histone H3 lysine-4 methylation centered at the DXZ4 locus in Xq24. The centrosomal pool of macroH2A1 accumulates in the presence of an inhibitor of the 20S proteasome. Therefore, targeting of macroH2A1 to the centrosome is likely part of a degradation pathway, a mechanism common to a variety of other chromatin proteins.


Giant adrenal myelolipoma associated with small bowel leiomyosarcoma: a case report.
Adrenal myelolipoma is a rare, benign and biochemically inactive tumor. It is usually diagnosed incidentally by radiological methods and is known to be associated with obesity, hypertension, endocrinological disorders and some malignancies. We report herein the association of a myelolipoma with a gastrointestinal stromal tumor. To our knowledge this is the first report of such an association to date. A 67-year-old male patient admitted to our clinic with abdomimal pain and fever; he had a history of hypertension and diabetes mellitus. In physical examination, a mass involving the right quadrants was palpated. Computerized tomography revealed a right retroperitoneal mass, probably originating from the kidney or cecum. In laparotomy, the tumor (12 cm radius and 1500 g) localized on the superior of right kidney was excised. Abdomen exploration revealed another mass with 10 cm radius 100 cm distal to the ligamentum of Treitz and segmental jejunal resection and anastomosis were applied. The pathological diagnosis was reported as myelolipoma for the retroperitoneal mass and leiomyosarcoma for the jejunal mass. Myelolipoma is a benign tumor, involving mature fat and hematopoietic stem cells. Pathogenesis is still not clear and the microscopical characteristics are hematopoietic, lipoid, and reticuloid cells and megakaryocytes. Myelolipomas are reported to be associated with some other malignancies (especially renal), but this is the first report showing the association with a leiomyosarcoma. Therefore, leiomyosarcoma should also be one of the possible associations kept in mind by the physician in the diagnosis and treatment of myelolipomas.


Single-cell analysis reveals diversity of tumor-associated macrophages and their interactions with T lymphocytes in glioblastoma.
Glioblastoma (GBM) is an aggressive primary CNS malignancy and clinical outcomes have remained stagnant despite introduction of new treatments. Understanding the tumor microenvironment (TME) in which tumor associated macrophages (TAMs) interact with T cells has been of great interest. Although previous studies examining TAMs in GBM have shown that certain TAMs are associated with specific clinical and/or pathologic features, these studies used an outdated M1/M2 paradigm of macrophage polarization and failed to include the continuum of TAM states in GBM. Perhaps most significantly, the interactions of TAMs with T cells have yet to be fully explored. Our study uses single-cell RNA sequencing data from adult IDH-wildtype GBM, with the primary aim of deciphering the cellular interactions of the 7 TAM subtypes with T cells in the GBM TME. Furthermore, the interactions discovered herein are compared to IDH-mutant astrocytoma, allowing for focus on the cellular ecosystem unique to GBM. The resulting ligand-receptor interactions, signaling sources, and global communication patterns discovered provide a framework for future studies to explore methods of leveraging the immune system for treating GBM.


[Lumbar sympathectomy literature review over the past 15 years].
Lumbar sympathectomy (LS) irreversibly damages a part of the sympathetic trunk and adjacent ganglia between L1 and L5, typically between L2 and L4. The first LS was performed in 1923. Initially, it used to be performed very often; however, with the progress of vascular and endovascular surgery its importance gradually continues to decline. The aim of the paper is to present literature review focusing on LS over the past 15 years. Literature review of 113 academic articles found in academic journal databases. Irreversible interruption of the efferent innervation leads to relative vasodilation of small vessels in lower extremities (α1-receptors blockade), and it reduces the volume of sweat due to inactivation of eccrine glands and nociception from lower limbs. Raynaud´s phenomenon, thromboangitis obliterans, non-revascularizable peripheral arterial disease (PAD) (Fontain grade III-IV), hyperhidrosis, persistent pain in lower extremities, chronic pain of amputation stump, frostbites, chilblains.Effect: The three largest studies showed a positive effect in 63.6-93.4% cases of PAD and in 97%100% cases of hyperhidrosis. The positive effect was defined as warmer lower extremities, increased blood flow, acceleration of chronic defects healing, sweating disappearance and pain reduction. Lumbar sympathectomy still remains a useful method in the treatment of above mentioned diseases if properly indicated. lumbar sympathectomy - Raynaud´s phenomenon - thromboangitis obliterans -peripheral arterial disease - hyperhidrosis.


Neuronal adaptation translates stimulus gaps into a population code.
Neurons in sensory pathways exhibit a vast multitude of adaptation behaviors, which are assumed to aid the encoding of temporal stimulus features and provide the basis for a population code in higher brain areas. Here we study the transition to a population code for auditory gap stimuli both in neurophysiological recordings and in a computational network model. Independent component analysis (ICA) of experimental data from the inferior colliculus of Mongolian gerbils reveals that the network encodes different gap sizes primarily with its population firing rate within 30 ms after the presentation of the gap, where longer gap size evokes higher network activity. We then developed a computational model to investigate possible mechanisms of how to generate the population code for gaps. Phenomenological (ICA) and functional (discrimination performance) analyses of our simulated networks show that the experimentally observed patterns may result from heterogeneous adaptation, where adaptation provides gap detection at the single neuron level and neuronal heterogeneity ensures discriminable population codes for the whole range of gap sizes in the input. Furthermore, our work suggests that network recurrence additionally enhances the network's ability to provide discriminable population patterns.


Ozone alleviates MSU-induced acute gout pain via upregulating AMPK/GAS6/MerTK/SOCS3 signaling pathway.
Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism. MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage. Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group. Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway.


Ultrasonic bonding method for heterogeneous microstructures using self-balancing jig.
Perfect sealing of heterogeneous microstructures in plastic-based microfluidic devices is a significant and urgent challenge to be able to apply them in various microfluidic-based applications, including biosensing, biofiltering, chemical reactors and lab-on-a-chip. In this study we report a simple but practical and effective method to bond a microstructure-incorporated microfluidic device using an ultrasonic bonding method. The specially designed hemisphere-shaped jig, which is called a self-balancing jig, provides a free motion in all x, y, and z directions. These unique properties of the jig allow us to precisely adjust and bond the heterogeneous microstructures in the device. A conventional jig shows in solution leakages around the heterogeneous microstructures while the self-balancing jig did not show any leakages in devices. Furthermore, the bonding performance was also confirmed by using a black ink and fluorescent dye solution. The micro-pillar arrays in the device also demonstrated its capability for selective filtering of microbeads. We believe that this technique would be a useful tool for producing microfluidic devices with heterogeneous microstructures.


Secondhand smoke exposure and hair nicotine in children: age-dependent differences.
A significant proportion of children in the United States remain exposed to secondhand smoke (SHS). We are reporting on relationships observed between parental report of their child's SHS exposure in two groups of children (ages 2-5 years and 9-14 years) with a biological marker of long-term SHS exposure, hair nicotine. Participants were healthy children recruited via convenience sampling for two age groups: 2-5 years and 9-14 years. The presence and amount of SHS exposure were assessed by both questionnaire and hair sampling for nicotine determination. A total of 115 participants were recruited (54 toddlers and 61 youth). The groups were similar in terms of demographics and reported SHS exposure. Hair nicotine levels were significantly different by age group, with toddlers having higher levels than youth. The most important independent determinants of hair nicotine were toddler age group, receiving Medicaid for health insurance, and number of smokers the subject was exposed to in 24 hr. Our findings suggest that young children who are insured by Medicaid have higher levels of hair nicotine, a biomarker of SHS exposure, when compared with an older age group. Further efforts to protect this vulnerable population and mitigate their lifetime risks of SHS exposure-related morbidities are warranted.


Murine norovirus infection does not cause major disruptions in the murine intestinal microbiota.
Murine norovirus (MNV) is the most common gastrointestinal pathogen of research mice and can alter research outcomes in biomedical mouse models of inflammatory bowel disease (IBD). Despite indications that an altered microbiota is a risk factor for IBD, the response of the murine intestinal microbiota to MNV infection has not been examined. Microbiota disruption caused by MNV infection could introduce the confounding effects observed in research experiments. Therefore, this study investigated the effects of MNV infection on the intestinal microbiota of wild-type mice. The composition of the intestinal microbiota was assessed over time in both outbred Swiss Webster and inbred C57BL/6 mice following MNV infection. Mice were infected with both persistent and non-persistent MNV strains and tissue-associated or fecal-associated microbiota was analyzed by 16S rRNA-encoding gene pyrosequencing. Analysis of intestinal bacterial communities in infected mice at the phylum and family level showed no major differences to uninfected controls, both in tissue-associated samples and feces, and also over time following infection, demonstrating that the intestinal microbiota of wild-type mice is highly resistant to disruption following MNV infection. This is the first study to describe the intestinal microbiota following MNV infection and demonstrates that acute or persistent MNV infection is not associated with major disruptions of microbial communities in Swiss Webster and C57BL/6 mice.


Multiplex analysis of cytokines in the serum and cerebrospinal fluid of patients with Alzheimer's disease by color-coded bead technology.
The availability and promise of effective treatments for neurodegenerative disorders are increasing the importance of early diagnosis. Having molecular and biochemical markers of Alzheimer's disease (AD) would complement clinical approaches, and further the goals of early and accurate diagnosis. Combining multiple biomarkers in evaluations significantly increases the sensitivity and specificity of the biochemical tests. In this study, we used color-coded bead-based Luminex technology to test the potential of using chemokines and cytokines as biochemical markers of AD. We measured the levels of 22 chemokines and cytokines in the serum and cerebrospinal fluid (CSF) of 32 de novo patients (13 controls, 11 AD, and 8 Parkinson's disease [PD]). MCP-1 was the only cytokine detectable in CSF, and its levels did not differ between control and disease groups. However, the serum concentration of eotaxin was significantly higher in AD patients than in the control group. The analysis of multiple inflammatory mediators revealed marginal differences in their CSF and serum concentrations for the differential diagnosis of AD and PD. These results provide evidence that immunological responses are not major contributors to the pathogenesis of AD and PD.


Age at Menarche and Risk of Multiple Sclerosis: A Prospective Cohort Study Based on the Danish National Birth Cohort.
Few studies have addressed the possible association between age at menarche and multiple sclerosis (MS), and results are conflicting. We studied this issue in a large prospective cohort study. The study cohort comprised 77,330 women included in the Danish National Birth Cohort (1996-2002). Information on menarcheal age was ascertained at the first interview, which took place in the 16th week of pregnancy. Women were followed for MS from the first interview to December 31, 2011. Associations between age at menarche and risk of MS were evaluated with hazard ratios and 95% confidence intervals using Cox proportional hazards regression models. Overall, 226 women developed MS during an average follow-up period of 11.7 years. Age at menarche among women with MS was generally lower than that among women without MS (Wilcoxon rank-sum test; P = 0.002). We observed an inverse association between age at menarche and MS risk. For each 1-year increase in age at menarche, risk of MS was reduced by 13% (hazard ratio = 0.87, 95% confidence interval: 0.79, 0.96). Early age at menarche appears to be associated with an increased risk of MS. The mechanisms behind this association remain to be established.


[The effect of acute fatal blood loss on post-resuscitation changes in heart phospholipids and prevention of them].
Acute lethal hemorrhage and resuscitation led to a decrease in content of phosphatidyl-choline, -ethanolamine, -serine and cardiolipin but increased lysophosphatidyl choline in rat heart muscle. Within the first week catabolism of phospholipids predominated, maximal rate of which was detected at the end of the first day. Within the subsequent three days phospholipid composition of cardiomyocyte membranes was gradually normalized. Qualitative and quantitative alterations in the membranes phospholipid composition with frequency of heart rhythm impairments, with increased consumption of glucose by functioning heart as well as with amount of enzymes, liberated from isolated isometrically contracting heart into coronary circulation. Preadministration of gamma-hydroxybutyric acid, guthimine, inderal, ionol and isophthine enabled to decrease or even to normalize the cardiomyocyte membranes phospholipid composition.


A new treatment paradigm for trigeminal neuralgia using Botulinum toxin type A.
To review the current data for the use of Botulinum toxin type A (BoNT-A) in trigeminal neuralgia (TN) and to describe the preferred injection technique of BoNT-A in TN. To propose a new treatment paradigm for TN incorporating the use BoNT-A. MEDLINE and Google Scholar databases. The current data on BoNT-A for TN were reviewed and analyzed for outcomes. Seven studies examining the use of BoNT-A were identified: Two randomized double-blind, placebo-controlled studies and five prospective case series. All studies found BoNT-A to be an effective treatment in the majority of patients; and the results of the two randomized double-blind placebo-controlled study showed significant benefit over placebo. The majority of studies used an intradermal or subcutaneous injection technique. The most common side effect was transient facial paresis. BoNT-A offers a safe, effective, local treatment for TN that is nonablative in nature. BoNT-A should be considered in patients who have failed, become refractory to, or are unable to tolerate first-line pharmacologic treatments. N/A.


Formation of M4Se4 cuboids (M = As, Sb, Bi) via secondary pnictogen-chalcogen interactions in the co-crystals MX3·Se=P(p-FC6)H4)3 (M = As, X = Br; M = Sb, X = Cl; M = Bi, X = Cl, Br).
The reactions of the group 15 trihalides, MX(3) (M = As, Sb, Bi; X = Cl, Br), with the phosphine selenide SeP(p-FC(6)H(4))(3) result in the formation of co-crystals of formula MX(3)·SeP(p-FC(6)H(4))(3). No reaction was observed with MI(3) (M = As, Sb, Bi). The structures of MX(3)·SeP(p-FC(6)H(4))(3) (M = As, X = Br 2; M = Sb, X = Cl 3; M = Bi, X = Cl 5; M = Bi, X = Br 6) have been established, and are isomorphous, crystallising in the cubic I23 space group. All the structures feature a primary MX(3) unit, which has three weak secondary MSe interactions to SeP(p-FC(6)H(4))(3) molecules. However, each of these SeP(p-FC(6)H(4))(3) molecules bridges three MX(3) molecules, resulting in the generation of an M(4)Se(4) (M = As, Sb, Bi) distorted cuboid linked by the pnictogen-chalcogen interactions. Four opposing corners of the cuboid are occupied by the M atom (M = As, Sb, Bi) of an MX(3) pyramid, and the other four by the selenium atom of the phosphine selenide.


Localized surface plasmon resonance sensors based on wavelength-tunable spectral dips.
Localized surface plasmon resonance (LSPR) sensors serve as sensitive analytical tools based on refractive index changes, which can be applied to affinity-based chemical sensing and biosensing. However, to select the monitoring wavelength, monodisperse Au or Ag nanoparticles must be synthesized. Here we developed LSPR sensors that operate at arbitrary wavelengths after preirradiation at the corresponding wavelength. Polydisperse plasmonic Ag nanospheroids or nanorods are photocatalytically deposited on TiO2. The nanoparticle ensemble shows a broad absorption band over the visible and near infrared regions, and absorption dips can be formed at desired wavelengths simply by photoexciting the ensemble at the wavelengths, on the basis of plasmon-induced charge separation. The dips redshift linearly in response to a positive change of refractive index, and the refractive index sensitivity linearly increases with increasing dip wavelength (e.g., 356 nm RIU(-1) at 1832 nm). The dip-based sensor is applied to monitoring of selective binding between biotin and streptavidin. The present system would allow development of miniaturized and cost-effective sensors that operate at the optimum wavelength at which the sensitivity is highest within the optical window of the sample.


Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma.
Epithelial-to-mesenchymal transition (EMT), in which epithelial cells loose their polarity and become motile mesenchymal cells, is a determinant of melanoma metastasis. We compared gene expression signatures of mesenchymal-like melanoma cells with those of epithelial-like melanoma cells, and identified Thrombospondin 1 (THBS1) as highly up-regulated in the mesenchymal phenotype. This study investigated whether THBS1, a major physiological activator of transforming growth factor (TGF)-beta, is involved in melanoma EMT-like process. We sought to examine expression patterns in distinct melanoma phenotypes including invasive, de-differentiated, label-retaining and drug resistant populations that are putatively associated with an EMT-like process. Here we show that THBS1 expression and secretion was elevated in melanoma cells exhibiting invasive, drug resistant, label retaining and mesenchymal phenotypes and correlated with reduced expression of genes involved in pigmentation. Elevated THBS1 levels were detected in Vemurafenib resistant melanoma cells and inhibition of THBS1 led to significantly reduced chemoresistance in melanoma cells. Notably, siRNA-mediated silencing of THBS1 and neutralizing antibody to THBS1 reduced invasion in mesenchymal-like melanoma cells, while ectopic THBS1 expression in epithelial-like melanoma cells enhanced invasion. Furthermore, the loss of THBS1 inhibited in vivo motility of melanoma cells within the embryonic chicken neural tube. In addition, we found aberrant THBS1 protein expression in metastatic melanoma tumor biopsies. These results implicate a role for THBS1 in EMT, and hence THBS1 may serve as a novel target for strategies aimed at the treatment of melanoma invasion and drug resistance.


Grape seed extract given three hours after injury suppresses lipid peroxidation and reduces hypoxic-ischemic brain injury in neonatal rats.
We have reported that pretreatment with grape seed extract (GSE), a potent antioxidant, is neuroprotective. This study examined whether treatment after injury with GSE is protective. Seven-day-old rat pups had the right carotid artery ligated, and then 2.5 h of 8% oxygen. GSE (50 mg/kg) or vehicle was administered by i.p. initial injection at 5 min to 5 h after reoxygenation, with an additional three doses within 26 h after injury. Brain damage was evaluated by weight deficit of the right hemisphere at 22 d after hypoxia. Treatment at 3 h after reoxygenation reduced brain weight loss from 21.0 +/- 3.3% in vehicle-treated pups (n = 31) to 11.4 +/- 2.8% in treated pups (n = 31, p < 0.05). GSE lowered body temperature, but reduced brain injury even when body temperature was controlled. GSE reduced neurofunctional abnormalities caused by the hypoxia-ischemia (HI). GSE reduced a HI induced increase in 8-isoprostaglandin F2alpha (8-isoPGF2alpha) and reduced an HI-induced increase in the proapoptotic protein c-jun in the brain cortex. GSE up to 3 h after reoxygenation reduces brain injury in rat pups, probably by suppressing lipid peroxidation and the proapoptotic protein c-jun.


A physiologically based toxicokinetic model for dietary uptake of hydrophobic organic compounds by fish: I. Feeding studies with 2,2',5,5'-tetrachlorobiphenyl.
A physiologically based toxicokinetic (PBTK) model was developed to describe dietary uptake of hydrophobic organic compounds by fish. The gastrointestinal (GI) tract was modeled using four compartments corresponding to the stomach, pyloric ceca, upper intestine, and lower intestine, and the lumenal volume of each compartment was allowed to change in time as a function of bulk flow down the GI tract and (for the pyloric ceca and upper intestine) nutrient uptake. The model was developed using data from rainbow trout that were fed a single meal of 60-day-old fathead minnows contaminated with [UL-(14)C] 2,2',5,5'-tetrachlorobiphenyl ([(14)C] PCB 52). Chemical partitioning coefficients for the gut contents and tissues were adjusted to account for changes in chemical affinity associated with uptake of dietary lipid. Permeability constants for the absorbing gut segments were then fitted by modeling to measured [(14)C] PCB 52 concentrations in gut contents and tissues. The model accurately describes observed patterns of gastric evacuation and bulk flow of digesta, the concentration time course for [(14)C] PCB 52 in contents and tissues of the GI tract, and [(14)C] PCB 52 distribution to other major tissues. Most of the [(14)C] PCB 52 was taken up in the pyloric ceca and upper intestine during the period of peak lipid absorption. It is concluded, however, that a kinetic limitation acting along the entire length of the GI tract resulted in a chemical disequilibrium between feces and tissues of the lower intestine.


In vivo evidence for posttranslational translocation and signal cleavage of the killer preprotoxin of Saccharomyces cerevisiae.
A full-length cDNA of the M1 double-stranded RNA killer preprotoxin coding region successfully directed the synthesis of secreted K1 toxin when expressed in Saccharomyces cerevisiae from a plasmid vector. Three protein species immunoreactive with antitoxin antiserum were detected intracellularly in transformants harboring this killer cDNA plasmid. These toxin precursor species were characterized by using secretory-defective hosts, by comparative electrophoretic mobilities, and by tunicamycin susceptibility. Such studies indicate that these three protein species represent intermediates generated by signal cleavage of the preprotoxin and its subsequent glycosylation and provide evidence that these events occur posttranslationally.


Who Is Safe to Extubate in the Neuroscience Intensive Care Unit?
Patients admitted to the neuroscience intensive care unit (NICU) may have respiratory compromise from either central or peripheral neurological pathology, and may hence require intubation and mechanical ventilation for very diverse reasons. Liberation from invasive ventilation, that is, extubation, at the earliest possible time is a widely accepted principle in intensive care. For this, classic extubation criteria have been established in the general critical care setting, mainly targeting pulmonary function and cooperativeness of the patient. However, classic extubation criteria have failed to predict successful extubation in many studies on NICU patients, and extubation failure (EF) rates range between ∼20 and 40% in these. Not necessarily impaired consciousness, but neurological impairment of securing the airway and handling secretions (dysphagia, low pharyngeal muscle tone, weak cough, etc.) may be mainly responsible for this dilemma. Attempts have been made to identify predictors of EF or success, and to establish extubation scores for the NICU, but results have been partially controversial and the database is still weak. It is very important to have a stepwise protocol to approach extubation in the NICU patient and to be prepared for reintubation (at times in a difficult airway) and alternatives (such as tracheostomy). The particular challenges of safely extubating the NICU patient will be the focus of this review, including a suggestion for a standardized approach.


The contributions of breast density and common genetic variation to breast cancer risk.
We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.


The role of phytoplankton photosynthesis in global biogeochemical cycles.
Phytoplankton biomass in the world's oceans amounts to only ∽1-2% of the total global plant carbon, yet these organisms fix between 30 and 50 billion metric tons of carbon annually, which is about 40% of the total. On geological time scales there is profound evidence of the importance of phytoplankton photosynthesis in biogeochemical cycles. It is generally assumed that present phytoplankton productivity is in a quasi steady-state (on the time scale of decades). However, in a global context, the stability of oceanic photosynthetic processes is dependent on the physical circulation of the upper ocean and is therefore strongly influenced by the atmosphere. The net flux of atmospheric radiation is critical to determining the depth of the upper mixed layer and the vertical fluxes of nutrients. These latter two parameters are keys to determining the intensity, and spatial and temporal distributions of phytoplankton blooms. Atmospheric radiation budgets are not in steady-state. Driven largely by anthropogenic activities in the 20th century, increased levels of IR- absorbing gases such as CO2, CH4 and CFC's and NOx will potentially increase atmospheric temperatures on a global scale. The atmospheric radiation budget can affect phytoplankton photosynthesis directly and indirectly. Increased temperature differences between the continents and oceans have been implicated in higher wind stresses at the ocean margins. Increased wind speeds can lead to higher nutrient fluxes. Throughout most of the central oceans, nitrate concentrations are sub-micromolar and there is strong evidence that the quantum efficiency of Photosystem II is impaired by nutrient stress. Higher nutrient fluxes would lead to both an increase in phytoplankton biomass and higher biomass-specific rates of carbon fixation. However, in the center of the ocean gyres, increased radiative heating could reduce the vertical flux of nutrients to the euphotic zone, and hence lead to a reduction in phytoplankton carbon fixation. Increased desertification in terrestrial ecosystems can lead to increased aeolean loadings of essential micronutrients, such as iron. An increased flux of aeolean micronutrients could fertilize nutrient-replete areas of the open ocean with limiting trace elements, thereby stimulating photosynthetic rates. The factors which limit phytoplankton biomass and photosynthesis are discussed and examined with regard to potential changes in the Earth climate system which can lead the oceans away from steady-state. While it is difficult to confidently deduce changes in either phytoplankton biomass or photosynthetic rates on decadal time scales, time-series analysis of ocean transparency data suggest long-term trends have occurred in the North Pacific Ocean in the 20th century. However, calculations of net carbon uptake by the oceans resulting from phytoplankton photosynthesis suggest that without a supply of nutrients external to the ocean, carbon fixation in the open ocean is not presently a significant sink for excess atmospheric CO2.


MTiOpenScreen: a web server for structure-based virtual screening.
Open screening endeavors play and will play a key role to facilitate the identification of new bioactive compounds in order to foster innovation and to improve the effectiveness of chemical biology and drug discovery processes. In this line, we developed the new web server MTiOpenScreen dedicated to small molecule docking and virtual screening. It includes two services, MTiAutoDock and MTiOpenScreen, allowing performing docking into a user-defined binding site or blind docking using AutoDock 4.2 and automated virtual screening with AutoDock Vina. MTiOpenScreen provides valuable starting collections for screening, two in-house prepared drug-like chemical libraries containing 150 000 PubChem compounds: the Diverse-lib containing diverse molecules and the iPPI-lib enriched in molecules likely to inhibit protein-protein interactions. In addition, MTiOpenScreen offers users the possibility to screen up to 5000 small molecules selected outside our two libraries. The predicted binding poses and energies of up to 1000 top ranked ligands can be downloaded. In this way, MTiOpenScreen enables researchers to apply virtual screening using different chemical libraries on traditional or more challenging protein targets such as protein-protein interactions. The MTiOpenScreen web server is free and open to all users at http://bioserv.rpbs.univ-paris-diderot.fr/services/MTiOpenScreen/.


Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling.
Isoliquiritigenin (ISL, 4,2',4'-trihydroxychalcone), which is found in licorice, shallot and bean sprouts, is a potent antioxidant with anti-inflammatory and anti-carcinogenic effects. The purpose of this study was to investigate the effects of ISL treatment on the migration, invasion and adhesion characteristics of DU145 human prostate cancer cells. DU145 cells were cultured in the presence of 0-20 micromol/L ISL with or without 10 microg/L epidermal growth factor (EGF). ISL inhibited basal and EGF-induced cell migration, invasion and adhesion dose dependently. ISL decreased EGF-induced secretion of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and vascular endothelial growth factor (VEGF), but increased TIMP-2 secretion in a concentration-dependent manner. In addition, ISL decreased the protein levels of integrin-alpha2, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), and mRNA levels of uPA, MMP-9, VEGF, ICAM and integrin-alpha2. Furthermore, basal and EGF-induced activator protein (AP)-1 binding activity and phosphorylation of Jun N-terminal kinase (JNK), c-Jun and Akt were decreased after ISL treatment. However, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase was not altered. The JNK inhibitor SP600125 inhibited basal and EGF-induced secretion of uPA, VEGF, MMP-9 and TIMP-1, as well as AP-1 DNA binding activity and cell migration. These results provide evidence for the role of ISL as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of prostate cancer cells. The inhibition of JNK/AP-1 signaling may be one of the mechanisms by which ISL inhibits cancer cell invasion and migration.


Psychometric evaluation of the body investment scale for use with adolescents.
We conducted two studies to examine the psychometric properties of the Body Investment Scale (BIS; Orbach & Mikulincer, 1998) in U.S. adolescent samples. The BIS was designed to assess bodily experiences that are associated with suicide-related behaviors. In Study 1, confirmatory factor analysis (CFA) with data from a combined sample of 204 high school adolescents (83 boys, 121 girls) and 197 psychiatric inpatient (101 boys, 96 girls) adolescents provided moderate support for the oblique four-factor solution: Body Feelings (rho=.86, 95% CI=.83-.89), Body Touch (rho=.71, 95% CI=.65-.76), Body Care (rho=.78, 95% CI=.71-.81), and Body Protection (rho=.78, 95% CI=.73-.82); robust comparative fit index=.88 and the robust Tucker Lewis Index=.83. The second-order factor model also provided moderate fit to the data. In Study 2, results of the CFA with data from adolescent psychiatric inpatients (N=205; 101 boys, 104 girls) provided additional support for the four-factor solution. In addition, results of the receiver operating characteristic and logistic regression analyses showed that scores on the Body Feelings and Body Protection scales were most useful in differentiating the responses of suicidal and nonsuicidal adolescents, all Cohen's d values >.30. The study also examined associations between scores on the BIS scales and the validation self-report measures of hopelessness, suicide-related behavior, and reasons for living.


Neurosurgical management of a giant colloid cyst with atypical clinical and radiological presentation.
The finding of a colloid cyst on neuroimaging is often incidental. These lesions are usually located at the foramen of Monro, are hyperdense on CT scans, and generally demonstrate signal intensity of water on MR images, although this depends on their content. When symptomatic, they frequently present with headaches and nausea due to an obstructive hydrocephalus. The authors describe a case of a giant colloid cyst in a patient presenting with complete left-sided vision loss and progressive memory loss, two very atypical findings in colloid cyst presentation. Imaging findings were also atypical, and this case proved to be a diagnostic dilemma because of its clinical and radiological presentation. Histopathological investigation was of utmost importance in the final diagnosis of a colloid cyst. To the authors' knowledge this colloid cyst is larger than any other described in the literature.


Lower antibiotic prescription rates in hospitalized COVID-19 patients than influenza patients, a prospective study.
COVID-19 patients are extensively treated with antibiotics despite few bacterial complications. We aimed to study antibiotic use in hospitalized COVID-19 patients compared to influenza patients in two consecutive years. Furthermore, we investigated changes in antibiotic use from the first to second pandemic wave. This prospective study included both patients from two referral hospitals in Bergen, Norway, admitted with influenza (n = 215) during the 2018/2019 epidemic and with COVID-19 (n = 82) during spring/summer 2020, and national data on registered Norwegian COVID-19 hospital admissions from March 2020 to January 2021 (n = 2300). Patient characteristics were compared, and logistic regression analysis was used to identify risk factors for antibiotic use. National and local COVID-19 patients received significantly less antibiotics (53% and 49%) than influenza patients (69%, p < .001). Early antibiotics contributed to >90% of antibiotic prescriptions in the two local hospitals, and >70% of prescriptions nationally. When adjusted for age, comorbidities, symptom duration, chest X-ray infiltrates and oxygen treatment, local COVID-19 patients still had significantly lower odds of antibiotic prescription than influenza patients (aOR 0.21, 95%CI 0.09-0.50). At the national level, we observed a significant reduction in antibiotic prescription rates in the second pandemic wave compared to the first (aOR 0.35, 95% CI 0.29-0.43). Fewer COVID-19 patients received antibiotics compared to influenza patients admitted to the two local hospitals one year earlier. The antibiotic prescription rate was lower during the second pandemic wave, possibly due to increased clinical experience and published evidence refuting the efficacy of antibiotics in treating COVID-19 pneumonia.


Molecular and ultrastructural characterisation of EspA from different enteropathogenic Escherichia coli serotypes.
Enteropathogenic Escherichia coli (EPEC) encode a type III secretion system located on a pathogenicity island known as the locus for enterocyte effacement. Four proteins are known to be exported by this type III secretion system--EspA, EspB and EspD required for subversion of host cell signal transduction pathways and a translocated intimin receptor protein (Tir) required for intimin-mediated intimate attachment and attaching and effacing lesion formation. The espA gene is located within the locus for enterocyte effacement and the EspA polypeptide from the prototype EPEC strain E2348/69 (O127:H6) has recently been shown to be a component of a filamentous structure involved in bacteria-host cell interaction and locus for enterocyte effacement-encoded protein translocation involved in attaching and effacing lesion formation. In this study we have extended our investigation of EspA to strains belonging to other classical EPEC serotypes. DNA sequencing demonstrated that the espA gene from the different EPEC strains share at least 65% DNA identity. In addition, we detected morphologically and antigenically similar EspA filaments in all but one of the bacterial strains examined including recombinant, non-pathogenic E. coli expressing espA from a cloned locus for enterocyte effacement region (HB101(pCVD462)).


Urogenital myiasis caused by Psychoda albipennis in a child.
Urogenital myiasis results when flies lay their eggs near the exit of the urethra and the larvae proceed upward along the urogenital tract. In this case report, a 10 year-old female patient diagnosed with urogenital myiasis was reported. The patient presented with complaints including painful and frequent urination, genital pruritus and moving larvae in urine. The patient had received Enterobius vermicularis treatment previously for two times. A 24-hour urine sample was collected and two black larvae were found in the urine. It was found that these larvae were fourth-stage larvae of Psychoda albipennis. Although there was no risk factor, the patient was affected with this rare parasitological disease. This case was presented to draw attention to myiasis in children. Myiasis may be observed in individuals with a favourable hygiene status and a high socioeconomical level. If a detailed history is not taken and appropriate laboratory tests are not performed, the diagnosis may be missed.


Effects of environmental temperature on oviposition behavior in three blow fly species of forensic importance.
A number of factors are known to affect blow fly behavior with respect to oviposition. Current research indicates that temperature is the most significant factor. However temperature thresholds for oviposition in forensically important blow flies have not been well studied. Here, the oviposition behavior of three species of forensically important blow fly species (Calliphora vicina, Calliphora vomitoria and Lucilia sericata,) was studied under controlled laboratory conditions over a range of temperatures (10-40°C). Lower temperature thresholds for oviposition of 16°C and 17.5°C were established for C. vomitoria and L. sericata respectively, whilst C. vicina continued to lay eggs at 10°C. C. vomitoria and L. sericata both continued to lay eggs at 40°C, whilst the highest temperature at which oviposition occurred in C. vicina was 35°C. Within these thresholds there was considerable variation in the number of surviving pupae, with a general pattern of a single peak within the range of temperatures at which eggs were laid, but with the pattern being much less distinct for L. sericata.


Immunoglobulin concentrations and antigen-specific antibody levels in cervicovaginal lavages of rhesus macaques are influenced by the stage of the menstrual cycle.
The levels of antigen-specific antibodies (Abs) and immunoglobulins in the cervical mucus of women vary with the menstrual cycle; the highest levels occur during menses, and the lowest occur during the periovulatory period. The rhesus macaque is a widely used animal model of female genital tract immunity. We sought to determine whether rhesus macaques have a cyclical pattern of changing cervicovaginal Ab and immunoglobulin levels that is similar to that of the human female. This study examined the relationship of the stages of the menstrual cycle to genital mucosal and systemic immunoglobulin concentrations and Ab levels in rhesus macaques. In all seven rhesus macaques studied, the immunoglobulins G and A and some antibodies in cervicovaginal lavages varied with the stages of the menstrual cycle, and in many cases this variation reached the level of statistical significance. In a pattern similar to that of women, the highest levels of Abs and immunoglobulins occurred during menses, and the lowest levels occurred around the time of ovulation. However, the Ab and immunoglobulin levels in serum and rectal lavages did not change with the menstrual cycle stage. The results of this study are consistent with the hypothesis that the ovarian hormones that drive the menstrual cycle influence genital tract immunity in female primates.


Coupling efficiency between light pipes of different dimensions.
An expression for the transmitted fraction of the uniform and parallel radiation incident upon the coupler between two rectangular light pipes of different physical dimensions is derived. It is a function of the pipe dimension ratio and the angle of the incident radiation. It is shown that for radiation nearly parallel to the pipe axis, it is possible to design a coupler for any pipe dimension ratio so that all the radiation incident upon it is transmitted by it. Design curves for various incidence angles and the pipe dimensions are presented.


Glycosylated queuosines in tRNAs optimize translational rate and post-embryonic growth.
Transfer RNA (tRNA) modifications are critical for protein synthesis. Queuosine (Q), a 7-deaza-guanosine derivative, is present in tRNA anticodons. In vertebrate tRNAs for Tyr and Asp, Q is further glycosylated with galactose and mannose to generate galQ and manQ, respectively. However, biogenesis and physiological relevance of Q-glycosylation remain poorly understood. Here, we biochemically identified two RNA glycosylases, QTGAL and QTMAN, and successfully reconstituted Q-glycosylation of tRNAs using nucleotide diphosphate sugars. Ribosome profiling of knockout cells revealed that Q-glycosylation slowed down elongation at cognate codons, UAC and GAC (GAU), respectively. We also found that galactosylation of Q suppresses stop codon readthrough. Moreover, protein aggregates increased in cells lacking Q-glycosylation, indicating that Q-glycosylation contributes to proteostasis. Cryo-EM of human ribosome-tRNA complex revealed the molecular basis of codon recognition regulated by Q-glycosylations. Furthermore, zebrafish qtgal and qtman knockout lines displayed shortened body length, implying that Q-glycosylation is required for post-embryonic growth in vertebrates.


Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential hypertension. Multicenter Diuretic Cooperative Study Group.
A randomized, double-blind, multicenter study comparing amiloride hydrochloride, amiloride hydrochloride plus hydrochlorothiazide, and hydrochlorothiazide was conducted in 179 patients with mild to moderate essential hypertension (diastolic pressure, 95 to 115 mm Hg). After 12 weeks of treatment, significant reductions in pressure were observed for all three treatment groups. Systolic pressure reduction was greatest for amiloride plus hydrochlorothiazide. Baseline vs 12-week average supine pressures were 153/101 vs 139/93 mm Hg for amiloride, 160/100 vs 137/90 mm Hg for amiloride plus hydrochlorothiazide, and 154/101 vs 134/89 mm Hg for hydrochlorothiazide. Baseline vs treatment mean serum potassium levels were 4.24 vs 4.47 mEq/L for amiloride, 4.24 vs 3.86 mEq/L for the combination, and 4.15 vs 3.56 mEq/L for hydrochlorothiazide. The changes in serum potassium level from the baseline for amiloride plus hydrochlorothiazide were significantly different from those for hydrochlorothiazide throughout the study (except for week 6). All drugs were well tolerated, and no drug-related toxic reaction was detected. This study demonstrates the efficacy of amiloride and amiloride plus hydrochlorothiazide as diuretic antihypertensive potassium-conserving agents.


NMR Structural Study of Syndecan-4 Transmembrane Domain with Cytoplasmic Region.
Syndecan-4 (SDC4) consists of transmembrane heparan sulfate proteoglycan (HSPG) belonging to the syndecan family. It is present in most cell types of Mammalia. Its structure contains a heparan-sulfate-modified extracellular domain, a single transmembrane domain, and a short C-terminal cytoplasmic domain. Regarding the overall cellular function of SDC4, other cells or ligands can bind to its ecto-domain. In addition, 4,5-bisphosphate phosphatidylinositol (PIP2) or protein kinase Cα can bind to its cyto-domain to activate downstream signaling pathways. To understand the signal transduction mechanism of syndecan, it is important to know the interactions between their actual structure and function in vivo. Therefore, it is important to identify the structure of SDC4 to understand the ligand binding behavior of SDC4. In this study, expression and purification were performed to reveal structures of the short ecto-domain, the transmembrane domain, and the cytoplasmic domain of Syd4-eTC (SDC4). Solution-state NMR spectroscopy and solid-state NMR spectroscopy were used to study the structure of Syd4-eTC in membrane environments and to demonstrate the interaction between Syd4-eTC and PIP2.


Human Cell Surface Receptors as Molecular Imaging Candidates for Metastatic Prostate Cancer.
Existing clinical imaging procedures lack sensitivity and specificity in detecting early prostate cancer bone metastatic lesions. In this study, we developed a highly reproducible bone metastasis xenograft model and identified possible molecular imaging candidates for detecting early bone metastatic lesions. Bone trophic human prostate cells (PC-3B1) were isolated and characterized for their ability to reach bone after intracardiac injection into SCID mice. The appearances of skeletal metastases were evaluated using digital radiographic imaging and confirmed by necropsy and histology. The PC-3B1 cells retain a bone homing phenotype after long term propagation in tissue culture and exhibit progressive bone lesions within 3 weeks following intracardiac injection. Comparative transcription signatures of PC-3 and PC-3B1 cells were determined using a cancer specific microarray and confirmed by RT-PCR analysis. The analysis identified increased expression of four cell surface molecules in PC-3B1 cells that may be suitable as molecular imaging candidates to detect bone micro metastases.


Impaired Sensitivity to Thyroid Hormones Is Associated With Diabetes and Metabolic Syndrome.
Diabetes prevalence and incidence increase among individuals with hypothyroidism but also among those with hyperthyroxinemia, which seems contradictory. Both high free thyroxine (fT4) and high thyroid-stimulating hormone (TSH) are present in the resistance to thyroid hormone syndrome. A mild acquired resistance to thyroid hormone might occur in the general population and be associated with diabetes. We aimed to analyze the association of resistance to thyroid hormone indices (the Thyroid Feedback Quantile-based Index [TFQI], proposed in this work, and the previously used Thyrotroph T4 Resistance Index and TSH Index) with diabetes. We calculated the aforementioned resistance to thyroid hormone indices based on a U.S. representative sample of 5,129 individuals ≥20 years of age participating in the 2007-2008 National Health and Nutrition Examination Survey (NHANES). Also, to approximate TFQI, a U.S.-referenced Parametric TFQI (PTFQI) can be calculated with the spreadsheet formula =NORM.DIST(fT4_cell_in_pmol_per_L,10.075,2.155,TRUE)+NORM.DIST(LN(TSH_cell_in_mIU_per_L),0.4654,0.7744,TRUE)-1. Outcomes of interest were glycohemoglobin ≥6.5%, diabetes medication, diabetes-related deaths (diabetes as contributing cause of death), and additionally, in a fasting subsample, diabetes and metabolic syndrome. Logistic and Poisson regressions were adjusted for sex, age, and race/ethnicity. Odd ratios for the fourth versus the first quartile of TFQI were 1.73 (95% CI 1.32, 2.27) (P trend = 0.002) for positive glycohemoglobin and 1.66 (95% CI 1.31, 2.10) (P trend = 0.001) for medication. Diabetes-related death rate ratio for TFQI being above versus below the median was 4.81 (95% CI 1.01, 22.94) (P trend = 0.015). Further adjustment for BMI and restriction to normothyroid individuals yielded similar results. Per 1 SD in TFQI, odds increased 1.13 (95% CI 1.02, 1.25) for diabetes and 1.16 (95% CI 1.02, 1.31) for metabolic syndrome. The other resistance to thyroid hormone indices showed similar associations for diabetes-related deaths and metabolic syndrome. Higher values in resistance to thyroid hormone indices are associated with obesity, metabolic syndrome, diabetes, and diabetes-related mortality. Resistance to thyroid hormone may reflect energy balance problems driving type 2 diabetes. These indices may facilitate monitoring treatments focused on energy balance.


Understanding ligand interaction with different structures of G-quadruplex DNA: evidence of kinetically controlled ligand binding and binding-mode assisted quadruplex structure alteration.
The study of ligand interaction with G-quadruplex DNA is an active research area, because many ligands are shown to bind G-quadruplex structures, showing anticancer effects. Here, we show, for the first time, how fluorescence correlation spectroscopy (FCS) can be used to study binding kinetics of ligands with G-quadruplex DNA at the single molecule level. As an example, we study interaction of a benzo-phenoxazine ligand (Cresyl Violet, CV) with antiparallel and (3 + 1) hybrid G-quadruplex structures formed by human telomeric sequence. By using simple modifications in FCS setup, we describe how one can extract the reaction kinetics from diffusion-coupled correlation curves. It is found that the ligand (CV) binds stronger, by an order of magnitude, to a (3 + 1) hybrid structure, compared to an antiparallel one. Ensemble-averaged time-resolved fluorescence experiments are also carried out to obtain the binding equilibrium constants (K) of ligand-quadruplex interactions in bulk solution for the first time, which are found to match very well with FCS results. Global analysis of FCS data provides association (k(+)) and dissociation (k(-)) rates of the ligand in the two structures. Results indicate that stronger ligand binding to the (3 + 1) hybrid structure is controlled by the dissociation rate, rather than the association rate of ligand in the quadruplexes. Circular dichroism (CD) and induced-CD spectra show that the ligand not only binds at different conformations in the quadruplexes, but also induces antiparallel structure to form a mixed-type hybrid structure in Na(+) solution. However, in K(+) solution, the ligand stabilizes the (3 + 1) hybrid structure. Molecular docking studies predict the possible differences in binding sites of the ligand inside two quadruplexes, which strongly support the experimental observations. Results suggest that different binding modes of the ligand to the quadruplex structures actually assist the alteration of structures differently.


Immunohistochemical Investigation of Metastasis-Related Chemokines in Deep-Infiltrating Endometriosis and Compromised Pelvic Sentinel Lymph Nodes.
Endometriosis is a prevalent benign disease, despite sharing several similarities with malignancies, such as the possibility of lymphatic spread. In malignancies, chemokines play a sovereign role in the process of metastasis. Metastasis-related chemokine axes have not yet been assessed in deep-infiltrating endometriosis (DIE), and this investigation was the aim of our study. The expression of these chemokines was investigated by immunohistochemistry in rectovaginal DIE lesions and in matched pelvic sentinel lymph nodes (PSLNs) of patients with endometriosis (n = 27), and their expression in the eutopic endometrium (EE) of endometriosis-free women (n = 20) was used as controls. Their staining pattern in rectovaginal DIE, in endometriotic lesions affecting the PSLN as well as in the EE of patients without endometriosis was characterized for the first time. Overall, these chemokines were highly expressed in DIE and endometriosis in PSLN. Chemokines might be involved in the spread of endometriosis and should be further investigated.


Milk production response to dietary forage:grain ratio.
Forty-four multiparous and 49 primiparous Holstein cows were assigned randomly at parturition to one of five diets differing in forage:grain ratio and studied for the entire lactation for effects of diet on milk production and milk composition, body condition, BW gain, health, and reproductive performance. Total mixed rations fed once daily consisted of alfalfa silage, high moisture ear corn, soybean meal, vitamins, and minerals. Percentages of forage in the diet (dry basis) for treatments 1 to 5 were postpartum wk 1 to 12 (38.2, 48.2, 58.2, 68.2, and 98.2); wk 13 to 26 (48.2, 58.2, 68.2, 88.2, and 98.2); and wk 27 to 44 (68.2, 78.2, 88.2, 98.2, and 98.2). Milk production (3.5% FCM in 305 d) was 8295, 8659, 7563, 6849, and 6000 kg for multiparous cows in treatments 1 to 5, respectively, and 7334, 7177, 6976, 6014, and 4750 kg for primiparous cows. Primiparous cows had decreased milk protein, BW gain, DMI and gross feed efficiency as forage increased in the diet. Multiparous cows in treatment 1 had depressed milk fat and lower DMI and gross feed efficiency compared with other treatments. Body condition scores tended to be lower as forage increased in the diet with both age groups. Increased forage in the diet did not cause any adverse effects on health and reproductive performance in either age group.


Recombinational biases in the rearranged C1-inhibitor genes of hereditary angioedema patients.
DNA structural changes responsible for hereditary angioedema were sought in the C1-inhibitor gene, which contains unusually dense clusters of Alu repeats in various orientations. Among patients belonging to 45 unrelated families, eight partial C1-inhibitor gene deletions and a partial duplication were found. Four deletions had one of the boundaries within the gene and the other in extragenic regions--in three cases 5' of the gene and in one case 3' of the gene. The boundaries of the partial duplication and of the remaining four deletions mapped instead within a few kilobases of exon 4. The same element--Alu 1--the first of three tandem Alu repeats preceding exon 4, contained one of the breakpoints of each of these five rearrangements. Moreover, these recombination breakpoints spread over the entire length of Alu 1, in contrast with the tight clustering observed near the 5' end of Alu sequences rearranged in other human genes. Thus, two uncommon recombinational biases are observed in the Alu rearrangements of hereditary angioedema patients; one promotes the occurrence of intragenic breakpoints in a single Alu repeat, and the other allows the breaks to be distributed over the entire Alu structure rather than within the hot spot of the left Alu monomer. A region of potential Z-DNA structure, located 1.7 kb upstream of Alu 1, may contribute to both peculiarities.


A comparative study of 2 manual-based self-help interventions, acceptance and commitment therapy and applied relaxation, for persons with chronic pain.
The aim of this study was to compare 2 self-help-based interventions; a coping-oriented approach, applied relaxation (AR) and an acceptance-oriented approach, acceptance and commitment therapy (ACT), for persons with chronic pain. This study is a randomized control trial (N=90) with a mixed between-within participants design with repeated measures. Interventions in both conditions comprised an initial face-to-face session, a 7-week manual-based self-help intervention including weekly therapist telephone support and a concluding face-to-face session. Outcome measures included satisfaction with life, depression, anxiety, acceptance of chronic pain, level of function, and pain intensity. Effects were measured at preintervention and postintervention and at 6 and 12 months after the end of intervention. The results show that the ACT condition increased their level of acceptance significantly compared with the AR condition. There was also a marginally significant interaction effect regarding satisfaction with life in which the ACT condition had improved in comparison to the AR condition. Further, the ACT condition reported a higher level of function and decreased pain intensity compared with the AR condition. Both conditions improved significantly regarding depression and anxiety. A manual-based self-help intervention with weekly therapist support in an ACT format adds value to the treatment repertoire for persons suffering with chronic pain.


Pandemic GII.4 Sydney and Epidemic GII.17 Kawasaki308 Noroviruses Display Distinct Specificities for Histo-Blood Group Antigens Leading to Different Transmission Vector Dynamics in Pacific Oysters.
Noroviruses are the major cause of foodborne outbreaks of acute gastroenteritis, which are often linked to raw oyster consumption. Previous studies have suggested histo-blood group antigens (HBGA)-like structures in the oyster tissues as ligands for norovirus binding and persistence. To better understand how oysters function as vectors for the most common human noroviruses, we first tested the ability of the norovirus strains GI.1 West Chester, the pandemic GII.4 Sydney, and the epidemic GII.17 Kawasaki308 strains to interact with oyster tissues. Secondly, we explored how the HBGA preferences of these strains can affect their persistence in oyster tissues. We found limited HBGA expression in oyster tissues. HBGAs of A and H type 1 were present in the digestive tissues and palps of the Pacific oyster Crassostrea gigas, while the gills and mantle lacked any HBGA structures. By using Virus-like particles (VLPs), which are antigenically and morphologically similar to native virions, we were able to demonstrate that VLPs of GI.1 West Chester norovirus reacted with the digestive tissues and palps. Despite of the lack of HBGA expression in mantle, dominant GII.4 Sydney strain readily bound to all the oyster tissues, including the digestive tissues, gills, palps, and mantle. In contrast, no binding of the epidemic GII.17 Kawasaki308 VLPs to any of the investigated oyster tissues was observed. In synthetic HBGA and saliva-binding assays, GI.1 reacted with A type, H type, and Leb (Lewis b) HBGAs. GII.4 Sydney VLPs showed a broad binding pattern and interacted with various HBGA types. Compared to GI.1 and GII.4 VLPs, the GII.17 Kawasaki308 VLPs only weakly associated with long-chain saccharides containing A type, B type, H type, and Leb blood group epitopes. Our findings indicate that GI.1 and GII.4 noroviruses are likely to be concentrated in oysters, by binding to HBGA-like glycans, and therefore potentially leading to increased long term transmission. In regards to the GII.17 Kawasaki308 strain, we suggest that oysters can only function as short term transmission vector in periods of high environmental virus concentrations.


[Epidemiologic support of troops during the Great Patriotic War].
The article is dedicated to the analysis of experience of domestic military preventive medicine during the Great Patriotic War. It describes the methods used and the means of protection of troops, volume control activities carried out. The authors state that these measures had provided epidemiological welfare of troops, expressed in a relatively small proportion of infectious diseases among all diseases of the soldiers.


A review of Ireland's waterbirds, with emphasis on wintering migrants and reference to H5N1 avian influenza.
Ireland is characterised by its diversity and large abundance of wetlands, making it attractive to a wide variety of waterbirds throughout the year. This paper presents an overview of Ireland's waterbirds, including ecological factors relevant to the potential introduction, maintenance, transmission and spread of infectious agents, including the H5N1 avian influenza virus, in Ireland. Particular emphasis is placed on five groups of wintering migrants (dabbling and sieving wildfowl, grazing wildfowl, diving wildfowl, waders and gulls), noting that the H5N1 avian influenza virus has mainly been isolated from this subset of waterbirds. Ireland's wetlands are visited during the spring and summer months by hundreds of thousands of waterbirds which come to breed, predominantly from southern latitudes, and during the autumn and winter by waterbirds which come from a variety of origins (predominantly northern latitudes), and which are widely distributed and often congregate in mixed-species flocks. The distribution, feeding habits and social interactions of the five groups of wintering migrants are considered in detail. Throughout Ireland, there is interaction between different waterbird populations (breeding migrants, the wintering migrants and resident waterbird populations). There is also a regular and complex pattern of movement between feeding and roosting areas, and between wetlands and farmland. These interactions are likely to facilitate the rapid transmission and spread of the H5N1 avian influenza virus, if it were present in Ireland.


Tick-borne relapsing fever as a potential veterinary medical problem.
Tick-borne relapsing fever (TBRF) caused by the bacteria Borrelia, is poorly documented in veterinary medicine. Given the widespread presence of the soft tick vectors - Ornithodoros and the recently discovered hard tick vectors, as well as their close association with animal hosts, it is highly likely that infection occurs, but is rarely reported to be of veterinary importance. Sporadic reports of canine infection, some being fatal through to probable cause of abortion in horses have been published. Some of these pathogens exist in regions where there are limited diagnostic facilities, hence, they are likely to be missed and their impact on productivity may be unquantified. Here we review available literatures on cases of TBRF in domestic and wild animals in order to show their potential veterinary medical impact. Future efforts using field and laboratory surveys are needed to determine pathogenesis, vector competence and distribution in animals, their impact on animal health and productivity as well as to prevent further spill to the human population, where it is already a public health problem in some parts of the world.


Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020-2022).
(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1-56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment.


Role of neural retina and vitreous body during lens regeneration: transplantation and autoradiography.
The trophic influence of neural retina in regeneration of the lens from dorsal iris is well known. The first part of this study involved transplantation of dorsal iris pieces into various intra-ocular positions in order to determine the field of action of the neural retina. The most favorable location for lens regeneration was the pupillary space, closely followed by the vitreous chamber. Lens regeneration was retarded from implants lying in the anterior chamber; this was most evident when grafts were placed in front of the iris and not in contact with the swollen vitreous body. Incorporation of 3H-leucine in the neural retina and vitreous body was also investigated using autoradiography. No significant difference in labeling was seen between the control and lentectomized neural retina at all time intervals studied. However, increased labeling above that in the controls was observed over the vitreous body between 8 to 20 days after lentectomy. There was also an increase in the number of silver grains over the vitreous body with increasing time between injection of isotope and sacrifice of the animal. These results provide evidence that vitreous body plays an important role in the process of lens regeneration, perhaps serving as a preferential pathway for transfer of the neural retinal factor to the dorsal iris.


DNA-binding proteins.
The structures of three proteins that regulate gene expression have been determined recently and suggest how these proteins may bind to their specific recognition sites on the DNA. One protein (Cro) is a repressor of gene expression, the second (CAP) usually stimulates gene expression, and the third (lambda repressor) can act as either a repressor or an activator. The three proteins contain a substructure consisting of two consecutive alpha helices that is virtually identical in each case. Structural and amino acid sequence comparisons suggest that this bihelical fold occurs in a number of proteins that regulate gene expression, and is an intrinsic part of the DNA-protein recognition event. The modes of repression and activation by Cro and lambda repressor are understood reasonably well, but the mode of action of CAP is still unclear.


Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) has an annual worldwide incidence of 626 000 cases and causes 550 000 deaths per year. Although the mainstay of treatment is surgical resection, for inoperable or metastatic disease, chemotherapy may be offered. The primary agent used is doxorubicin, but response rates are poor (<20%). The unfolded protein response (UPR) is a cytoprotective cellular stress response that enables cells to survive periods of hypoxia and nutrient deprivation. The UPR may confer resistance to anticancer agents and contribute to treatment failure. This study has investigated whether the UPR is activated in HCC and whether this may contribute to doxorubicin resistance. Eighty-six human HCCs were immunohistochemically stained for glucose regulated protein 78, the key marker of UPR activation. An in-vitro model of UPR activation in HepG2 HCC cells was developed by glucose deprived culture. UPR activation was confirmed with western blotting and PCR to show overexpression of glucose regulated protein 78. The relative efficacy of doxorubicin chemotherapy on UPR-activated HepG2 cells was compared with normal HepG2 cells by use of an thiazolyl blue tetrazolium bromide colorimetric assay. Expression of glucose regulated protein 78 was shown in 100% of the HCC samples with 66% showing strong staining. In-vitro UPR activation was achieved with glucose deprivation. UPR activation induced significant resistance to doxorubicin: 34% survival under standard culture conditions versus 58% and 63% for UPR-activated cells in 0.5 and 1 mmol glucose respectively (P=0.00928). The UPR is activated in HCCs and confers resistance to chemotherapy in vitro. UPR activation may contribute to HCC chemoresistance.


[The place of ultrasonic diagnosis in radiotherapy].
1. Before starting radiotherapy ultrasonic investigation of the abdominal, retroperitoneal and pelvic area is mainly used to determine the stage of the disease, the tumour size and its relation to adjacent organs, as well as in the diagnosis of metastases. 2. During treatment, ultrasonography is useful in controlling the correct position of the treatment fields and the response of the tumour to treatment. 3. During follow up echography is helpful in controlling therapeutic results and in the early detection of tumour recurrence. At this point the procedure frequently replaces diagnostic X-ray control. 4. In regard to treatment planning, the outlines of the organs are directly transferred from the B-mode scan to the treatment plan. Hence, the position of the treatment fields and the isodose distribution can be exactly adjusted to e patient's anatomical requirements. Several examples are given to illustrate this procedure.


Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogues.
Intradermal injection of 0.1 pmole (52 pg.) of acetyl glyceryl ether phosphorylcholine (AGEPC) in guinea pigs induced increased vascular permeability as assessed by a skin-blueing model. Rabbits and rats showed increased vascular permeability with 1.0 pmole (520 pg.) of AGEPC. On a molar basis, from 1,000 to 10,000 times more histamine was required to induce skin blueing in the same animals. In rabbits and guinea pigs, the increased vascular permeability induced by AGEPC occurred as an early, transient phase and as a delayed, prolonged phase. The early, transient phase was not inhibited by chlorpheniramine doses which markedly reduced or abrogated histamine-induced blueing. AGEPC was 100 to 1000 times more potent than histamine on a molar basis for the induction of vasoconstriction in a blued skin assay in guinea pigs. These studies demonstrate that AGEPC has potent vasoactive properties and provide additional information that implicates this acetylated alkyl phosphoglyceride as a mediator of the acute inflammatory process.


Interpretation and management of INR results: a case history based survey in 13 countries.
Standardisation of treatment with vitamin K antagonists (VKAs) is still an issue after 60 years of use. The study aimed to explore aspects of VKA monitoring in primary and secondary care. Two case histories were distributed to physicians in 13 countries. Case history A focused on a patient with atrial fibrillation on stable anticoagulation (latest INR 2.3). Physicians were asked about frequency of INR measurement, when to change the VKA dose, and the patient's annual risk of ischemic stroke and bleeding. Case history B focused on a patient with an unexpected INR of 4.8, asking for the patient's 48-hour bleeding risk, the immediate dose reduction and time until a repeat INR. Altogether, 3016 physicians responded (response rate 8 - 38%), of which 82% were from primary care and 18% from secondary care. Answers varied substantially within and between countries regardless of level of care and VKA used. Median number of weeks between INR measurements was 4 - 6 weeks. Median threshold INR for increasing or decreasing the VKA dose was 1.9 and 3.1, respectively. Risk of ischemic stroke and bleeding were overestimated 2 - 3 times. In case history B, the median dose reduction the two first days was 75% for GPs and 55% for specialists, irrespective of estimates of bleeding risk; with one week to a repeat INR. Variation in VKA monitoring is substantial implying clinical consequences. Guidelines seem either unknown or may be considered impracticable. Further efforts towards standardisation of VKA management are needed.


Floating ideas on theta waves.
This special issue on the theta rhythm highlights recent experiments aimed at understanding the relationship between this slow, large amplitude oscillation and plasticity, fast oscillations, cellular activity and disease in both animals and humans. The articles in this issue of Behavioral Neuroscience use a number of approaches across different model systems and behavioral paradigms to provide an up-to-date account of recent progress in understanding how the theta rhythm coordinates neural activity in the service of cognition. Prominent themes that emerge are how theta is tightly related to movement in humans and rodents and how this rhythm could be leveraged as a biomarker for understanding and testing therapeutic approaches to treat psychiatric and neurological diseases. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Physical Characteristics of Elite Male Bandy Players.
Physical characteristics of elite male bandy players have not been studied for the last 30 years. Therefore, the purpose of this study was to evaluate the physical characteristics of elite male bandy players with respect to playing positions. A cross-sectional study was performed that included 25 male bandy players from one of the highest-ranked bandy leagues in the world. Body weight, length, isometric mid-thigh pull, countermovement jump, squat jump, unilateral long jump, bilateral long jump, 15- and 30-m sprint, 15-m flying sprint, and VO2max were tested. Players were divided into forwards, midfielders, and defenders. Forwards had significantly (p = 0.012) higher relative VO2max than defenders (59.8 ± 4.3 compared to 53.0 ± 5.6 mL/kg/min). No significant differences for any of the other measurements were observed between positions. This is the first study to present the physical characteristics between playing positions in off- and on-ice tests for male bandy players competing at the highest level. Today's bandy players are heavier and have lower relative VO2max compared with players in the early 1990s. However, their work capacities have increased since their absolute VO2max is higher. These results provide benchmark values that can serve as a foundation for strength and conditioning professionals when designing future training programs.