[Prevalence of anemia, calcium-phosphorus abnormalities and metabolic acidosis in different stages of chronic renal failure].
Chronic kidney disease (CKD) is associated with the reduction of haemoglobin concentration and a variety of biochemical abnormalities including changes in serum concentration of sodium, potassium, calcium, phosphate, bicarbonate, and hydrogen ions. However, data concerning epidemiology of these abnormalities are rare and incomplete, especially among subjects with mild to moderate CKD. Patients with a serum creatinine concentration > 110 micromol/l hospitalized in the Department of Nephrology, Endocrinology and Metabolic Diseases Medical University of Silesia from 1998 to 2002 were analyzed. Patients with acute renal failure or chronic renal failure treated with renal replacement therapy were excluded from this study. A total of 653 patients (262F and 391M) were divided into 9 subgroups differing from each other by progressive decline of glomerular filtration rate (GFR). A statistically significant decrease in haemoglobin concentration and increase in the prevalence of anaemia were found in patients with GFR < 50 ml/min. In a large number of patients with a GFR < 80 but > 50 ml/min, Hb concentration <11 g/dl was observed. Mean MCV, MCH and serum iron concentration were similar in all studied subgroups. A progressive increase in serum phosphorus concentration and decrease of calcaemia was found in patients with GFR < 30 ml/min. The elevated Ca x P product (> 4.44 mmol2/12) was noticed almost exclusively in patients with GFR< 30 ml/min. A decompensated metabolic acidosis was observed in 29.8% of patients with GFR <30 ml/min. Anaemia is an early symptom of chronic kidney disease preceding disturbances of calcium, phosphate and hydrogen ions metabolism. These abnormalities seem to be of therapeutic relevance.


The potential impacts of micro-and-nano plastics on various organ systems in humans.
Humans are exposed to micro-and-nano plastics (MNPs) through various routes, but the adverse health effects of MNPs on different organ systems are not yet fully understood. This review aims to provide an overview of the potential impacts of MNPs on various organ systems and identify knowledge gaps in current research. The summarized results suggest that exposure to MNPs can lead to health effects through oxidative stress, inflammation, immune dysfunction, altered biochemical and energy metabolism, impaired cell proliferation, disrupted microbial metabolic pathways, abnormal organ development, and carcinogenicity. There is limited human data on the health effects of MNPs, despite evidence from animal and cellular studies. Most of the published research has focused on specific types of MNPs to assess their toxicity, while other types of plastic particles commonly found in the environment remain unstudied. Future studies should investigate MNPs exposure by considering realistic concentrations, dose-dependent effects, individual susceptibility, and confounding factors.


[Directed cortico-cortical functional connectivity at the earlier stages of serial learning in adults and children of 7-8 years old].
The serial learning at its earlier stages that presumably involve working memory was studied in adults and children of 7-8 who were reproducing a sequences of discrete movements following the order given by a sequence of visual stimuli. In both age groups, the learning curves (latent time vs. trial number) were qualitatively similar in shape. The overall shape of the learning curve depended on the relative share of fast vs. slow phases of latent time reduction. Comparison of cortico-cortical functional connectivity at the prestimulus period in the sequence reproduction task vs. the simple visuo-motor reaction task showed an overall tendency for an increase in influence of postcentral cortical areas accompanied by a reduction in influence exerted by the prefrontal and the central cortical areas. In particular, it was typical for adults to show an increase in directed influence of TPO cortical areas while in children, an increase of directed influence of parietal cortex was also observed. Comparing subgroups with different shapes of learning curves showed a difference in the directed functional connectivity in those subgroups. The results are discussed with a particular focus on the role of working memory retaining the internal representations of sequences being learned.


Interactions of amelogenin with phospholipids.
Amelogenin protein has the potential to interact with other enamel matrix proteins, mineral, and cell surfaces. We investigated the interactions of recombinant amelogenin rP172 with small unilamellar vesicles as model membranes, toward the goal of understanding the mechanisms of amelogenin-cell interactions during amelogenesis. Dynamic light scattering (DLS), fluorescence spectroscopy, circular dichroism (CD), and nuclear magnetic resonance (NMR) were used. In the presence of phospholipid vesicles, a blue shift in the Trp fluorescence emission maxima of rP172 was observed (∼334 nm) and the Trp residues of rP172 were inaccessible to the aqueous quencher acrylamide. DLS studies indicated complexation of rP172 and phospholipids, although the possibility of fusion of phospholipids following amelogenin addition cannot be ruled out. NMR and CD studies revealed a disorder-order transition of rP172 in a model membrane environment. Strong fluorescence resonance energy transfer from Trp in rP172 to DNS-bound-phospholipid was observed, and fluorescence polarization studies indicated that rP172 interacted with the hydrophobic core region of model membranes. Our data suggest that amelogenin has ability to interact with phospholipids and that such interactions may play key roles in enamel biomineralization as well as reported amelogenin signaling activities.


Pervasive and persistent redundancy among duplicated genes in yeast.
The loss of functional redundancy is the key process in the evolution of duplicated genes. Here we systematically assess the extent of functional redundancy among a large set of duplicated genes in Saccharomyces cerevisiae. We quantify growth rate in rich medium for a large number of S. cerevisiae strains that carry single and double deletions of duplicated and singleton genes. We demonstrate that duplicated genes can maintain substantial redundancy for extensive periods of time following duplication ( approximately 100 million years). We find high levels of redundancy among genes duplicated both via the whole genome duplication and via smaller scale duplications. Further, we see no evidence that two duplicated genes together contribute to fitness in rich medium substantially beyond that of their ancestral progenitor gene. We argue that duplicate genes do not often evolve to behave like singleton genes even after very long periods of time.


C-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia.
In the adult liver, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of the constitutive androstane receptor (CAR, NR1I3), produces rapid hepatomegaly in the absence of injury. In this study, we identify c-Myc as a gene induced by CAR and demonstrate that TCPOBOP-induced proliferation of hepatocytes depends on c-Myc function. Moreover, the TCPOBOP-induced cell cycle program (Cdc2, cyclins, MCM proteins, Cdc20, and genes implicated in the spindle assembly checkpoint) is severely impaired in c-Myc mutant livers. Strikingly, many of these genes overlap with a program controlled by the forkhead transcription factor FoxM1, known to control progression through S-phase and mitosis. Indeed, FoxM1 is also induced by TCPOBOP. Moreover, we show that c-Myc binds to the FoxM1 promoter in a TCPOBOP-dependent manner, suggesting a CAR --> c-Myc --> FoxM1 pathway downstream of TCPOBOP. Collectively, this study identifies c-Myc and FoxM1 mediated proliferative programs as key mediators of TCPOBOP-CAR induced direct liver hyperplasia.


Dietary Flavonoids in p53-Mediated Immune Dysfunctions Linking to Cancer Prevention.
The p53 protein plays a central role in mediating immune functioning and determines the fate of the cells. Its role as a tumor suppressor, and in transcriptional regulation and cytokine activity under stress conditions, is well defined. The wild type (WT) p53 functions as a guardian for the genome, while the mutant p53 has oncogenic roles. One of the ways that p53 combats carcinogenesis is by reducing inflammation. WT p53 functions as an anti-inflammatory molecule via cross-talk activity with multiple immunological pathways, such as the major histocompatibility complex I (MHCI) associated pathway, toll-like receptors (TLRs), and immune checkpoints. Due to the multifarious roles of p53 in cancer, it is a potent target for cancer immunotherapy. Plant flavonoids have been gaining recognition over the last two decades to use as a potential therapeutic regimen in ameliorating diseases. Recent studies have shown the ability of flavonoids to suppress chronic inflammation, specifically by modulating p53 responses. Further, the anti-oxidant Keap1/Nrf2/ARE pathway could play a crucial role in mitigating oxidative stress, leading to a reduction of chronic inflammation linked to the prevention of cancer. This review aims to discuss the pharmacological properties of plant flavonoids in response to various oxidative stresses and immune dysfunctions and analyzes the cross-talk between flavonoid-rich dietary intake for potential disease prevention.


Resting state networks of the canine brain under sevoflurane anaesthesia.
Resting-state functional Magnetic Resonance Imaging (rs-fMRI) has become an established technique in humans and reliably determines several resting state networks (RSNs) simultaneously. Limited data exist about RSN in dogs. The aim of this study was to investigate the RSNs in 10 healthy beagle dogs using a 3 tesla MRI scanner and subsequently perform group-level independent component analysis (ICA) to identify functionally connected brain networks. Rs-fMRI sequences were performed under steady state sevoflurane inhalation anaesthesia. Anaesthetic depth was titrated to the minimum level needed for immobilisation and mechanical ventilation of the patient. This required a sevoflurane MAC between 0.8 to 1.2. Group-level ICA dimensionality of 20 components revealed distributed sensory, motor and higher-order networks in the dogs' brain. We identified in total 7 RSNs (default mode, primary and higher order visual, auditory, two putative motor-somatosensory and one putative somatosensory), which are common to other mammals including humans. Identified RSN are remarkably similar to those identified in awake dogs. This study proves the feasibility of rs-fMRI in anesthetized dogs and describes several RSNs, which may set the basis for investigating pathophysiological characteristics of various canine brain diseases.


Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes.
Spontaneous glucose uptake by brown adipose tissue (BAT) is lower in overweight or obese individuals and in diabetes. However, BAT metabolism has not been previously investigated in patients with type 2 diabetes during controlled cold exposure. Using positron emission tomography with (11)C-acetate, (18)F-fluoro-deoxyglucose ((18)FDG), and (18)F-fluoro-thiaheptadecanoic acid ((18)FTHA), a fatty acid tracer, BAT oxidative metabolism and perfusion and glucose and nonesterified fatty acid (NEFA) turnover were determined in men with well-controlled type 2 diabetes and age-matched control subjects under experimental cold exposure designed to minimize shivering. Despite smaller volumes of (18)FDG-positive BAT and lower glucose uptake per volume of BAT compared with young healthy control subjects, cold-induced oxidative metabolism and NEFA uptake per BAT volume and an increase in total body energy expenditure did not differ in patients with type 2 diabetes or their age-matched control subjects. The reduction in (18)FDG-positive BAT volume and BAT glucose clearance were associated with a reduction in BAT radiodensity and perfusion. (18)FDG-positive BAT volume and the cold-induced increase in BAT radiodensity were associated with an increase in systemic NEFA turnover. These results show that cold-induced NEFA uptake and oxidative metabolism are not defective in type 2 diabetes despite reduced glucose uptake per BAT volume and BAT "whitening."


Time-lapse single-cell transcriptomics reveals modulation of histone H3 for dormancy breaking in fission yeast.
How quiescent cells break dormancy is a key issue in eukaryotic cells including cancer. Fungal spores, for example, remain quiescent for long periods until nourished, although the mechanisms by which dormancy is broken remain enigmatic. Transcriptome analysis could provide a clue, but methods to synchronously germinate large numbers of spores are lacking, and thus it remains a challenge to analyse gene expression upon germination. Hence, we develop methods to assemble transcriptomes from individual, asynchronous spore cells of fission yeast undergoing germination to assess transcriptomic changes over time. The virtual time-lapse analyses highlights one of three copies of histone H3 genes whose transcription fluctuates during the initial stage of germination. Disruption of this temporal fluctuation causes defects in spore germination despite no visible defects in other stages of the life cycle. We conclude that modulation of histone H3 expression is a crucial 'wake-up' trigger at dormancy breaking.


Machine learning-based detection of adventitious microbes in T-cell therapy cultures using long-read sequencing.
Assuring that cell therapy products are safe before releasing them for use in patients is critical. Currently, compendial sterility testing for bacteria and fungi can take 7-14 days. The goal of this work was to develop a rapid untargeted approach for the sensitive detection of microbial contaminants at low abundance from low volume samples during the manufacturing process of cell therapies. We developed a long-read sequencing methodology using Oxford Nanopore Technologies MinION platform with 16S and 18S amplicon sequencing to detect USP <71> organisms and other microbial species. Reads are classified metagenomically to predict the microbial species. We used an extreme gradient boosting machine learning algorithm (XGBoost) to first assess if a sample is contaminated, and second, determine whether the predicted contaminant is correctly classified or misclassified. The model was used to make a final decision on the sterility status of the input sample. An optimized experimental and bioinformatics pipeline starting from spiked species through to sequenced reads allowed for the detection of microbial samples at 10 colony-forming units (CFU)/mL using metagenomic classification. Machine learning can be coupled with long-read sequencing to detect and identify sample sterility status and microbial species present in T-cell cultures, including the USP <71> organisms to 10 CFU/mL. IMPORTANCE This research presents a novel method for rapidly and accurately detecting microbial contaminants in cell therapy products, which is essential for ensuring patient safety. Traditional testing methods are time-consuming, taking 7-14 days, while our approach can significantly reduce this time. By combining advanced long-read nanopore sequencing techniques and machine learning, we can effectively identify the presence and types of microbial contaminants at low abundance levels. This breakthrough has the potential to improve the safety and efficiency of cell therapy manufacturing, leading to better patient outcomes and a more streamlined production process.


Self-omics: A Self-supervised Learning Framework for Multi-omics Cancer Data.
We have gained access to vast amounts of multi-omics data thanks to Next Generation Sequencing. However, it is challenging to analyse this data due to its high dimensionality and much of it not being annotated. Lack of annotated data is a significant problem in machine learning, and Self-Supervised Learning (SSL) methods are typically used to deal with limited labelled data. However, there is a lack of studies that use SSL methods to exploit inter-omics relationships on unlabelled multi-omics data. In this work, we develop a novel and efficient pre-training paradigm that consists of various SSL components, including but not limited to contrastive alignment, data recovery from corrupted samples, and using one type of omics data to recover other omic types. Our pre-training paradigm improves performance on downstream tasks with limited labelled data. We show that our approach outperforms the state-of-the-art method in cancer type classification on the TCGA pancancer dataset in semi-supervised setting. Moreover, we show that the encoders that are pre-trained using our approach can be used as powerful feature extractors even without fine-tuning. Our ablation study shows that the method is not overly dependent on any pretext task component. The network architectures in our approach are designed to handle missing omic types and multiple datasets for pre-training and downstream training. Our pre-training paradigm can be extended to perform zero-shot classification of rare cancers.


Efferent connections of the internal globus pallidus in the squirrel monkey: I. Topography and synaptic organization of the pallidothalamic projection.
The objectives of this study were, on one hand, to better understand how the segregated functional pathways from the cerebral cortex through the striatopallidal complex emerged in the projections to the thalamus and, on the other hand, to compare the ultrastructure and synaptic organization of the pallidal efferents to the ventrolateral (VL) and centromedian (CM) thalamic nuclei in primates. These aims were achieved by injections of the retrograde-anterograde tracer, biotinylated dextran amine (BDA), in different functional regions of the internal pallidum (GPi) in squirrel monkeys. The location of retrogradely labelled cells in the striatum was determined to ascertain the functional specificity of the injection sites. Injections in the ventrolateral two-thirds of the GPi (group 1) led to retrograde labelling in the postcommissural region of the putamen ("sensorimotor striatum") and plexuses of labelled fibers in the rostral one-third of the principal ventrolateral nucleus (VLp) and the central part of the CM. On the other hand, injections in the dorsal one-third (group 3) and the rostromedial pole (group 4) of the GPi led to retrogradely labelled cells in the body of the caudate nucleus ("associative striatum") and the ventral striatum ("limbic striatum"), respectively. After those injections, dense plexuses of anterogradely labelled varicosities were found in common thalamic nuclei, including the parvocellular ventral anterior nucleus (VApc), the dorsal VL (VLd), and the rostrodorsal part of the parafascicular nucleus (PF). In the caudal two-thirds of the CM/PF, the labelled fibers formed a band that lay along the dorsal border of the complex in a region called the dorsolateral PF (PFdl) in this study. The ventromedial nucleus (VM) was densely labelled only after injections in the rostromedial GPi, whereas the dorsal part of the zona incerta was labelled in both groups. At the electron microscopic level, the BDA-positive terminals in the VLp were larger and more elongated than those in the CM but, overall, displayed the same pattern of synaptic organization. Our findings indicate 1) that some associative and limbic cortical information, which is largely processed in segregated corticostriatopallidal channels, converges to common thalamic nuclei and 2) that the PF is a major target of associative and limbic GPi efferents in monkeys.


Ethical Guidance for Disaster Response, Specifically Around Crisis Standards of Care: A Systematic Review.
Terrorism, disease outbreaks, and other natural disasters and mass casualty events have pushed health care and public health systems to identify and refine emergency preparedness protocols for disaster response. Ethical guidance, alongside legal and medical frameworks, are increasingly common components of disaster response plans. To systematically review the prevalence and content of ethical guidance offered for disaster response, specifically around crisis standards of care (CSCs). We systematically indexed academic literature from PubMed, Google Scholar, and ISI Web of Science from 2012 to 2016. We searched for peer-reviewed articles that substantively engaged in discussion of ethical guidance for CSCs. Researchers screened potential articles for identification and discussion of ethical issues in CSC planning. We categorized and cataloged ethical concepts and principles. Of 580 peer-reviewed articles mentioning ethics and CSCs or disaster planning, 38 (6%) met selection criteria. The systematic review of the CSC ethics literature since 2012 showed that authors were primarily focused on the ethical justifications for CSC (n = 20) as well as a need for ethics guidelines for implementing CSCs; the ethical justifications for triage (n = 19), both as to which criteria to use and the appropriate processes by which to employ triage; and international issues (n = 17). In addition to these areas of focus, the scholarly literature included discussion of a number of other ethical issues, including duty to care (n = 11), concepts of a duty to plan (n = 8), utilitarianism (n = 5), moral distress (n = 4), professional norms (n = 3), reciprocity (n = 2), allocation criteria (n = 4), equity (n = 4), research ethics (n = 2), duty to steward resources (n = 2), social utility and social worth (n = 2), and a number of others (n = 20). Although public health preparedness efforts have paid increasing attention to CSCs in recent years, CSC plans have rarely been implemented within the United States to date, although some components are common (e.g., triage is used in US emergency departments regularly). Conversely, countries outside the United States more commonly implement CSCs within a natural disaster or humanitarian crisis response, and may offer significant insight into ethics and disaster response for US-based practitioners. This systematic review identifies the most oft-used and -discussed ethical concepts and principles used in disaster planning around CSCs. Although discussion of more nuanced issues (e.g., health equity) are present, the majority of items substantively engaging in ethical discussion around disaster planning do so regarding triage and why ethics is needed in disaster response generally. Public health implications. A significant evolution in disaster planning has occurred within the past decade; ethical theories and frameworks have been put to work. For ethical guidance to be useful, it must be practical and implementable. Although high-level, abstract frameworks were once prevalent in disaster planning-especially in the early days of pandemic planning-concerns about the ethically difficult concept of CSCs pervade scholarly articles. Ethical norms must be clearly stated and justified and practical guidelines ought to follow from them. Ethical frameworks should guide clinical protocols, but this requires that ethical analysis clarifies what strategies to use to honor ethical commitments and achieve ethical objectives. Such implementation issues must be considered well ahead of a disaster. As governments and health care systems plan for mass casualty events, ethical guidance that is theoretically sound and practically useful can-and should-form an important foundation from which to build practical guidance for responding to disasters with morally appropriate means.


Descemet Membrane Endothelial Keratoplasty Using a Pull-Through Technique With Novel Infusion Forceps.
To describe a surgical technique of Descemet membrane endothelial keratoplasty (DMEK) using an endothelium-in pull-through technique with novel infusion forceps and report 6-month clinical outcomes. This is a retrospective case series of 33 cases with Fuchs endothelial corneal dystrophy who underwent either DMEK alone (n = 5), DMEK combined with phacoemulsification (n = 27), or DMEK combined with intraocular lens exchange (n = 1) performed by surgeons at the beginning of the DMEK learning curve. Best-corrected visual acuity (BCVA), manifest refraction, central corneal thickness, endothelial cell density, intraoperative and postoperative complications, and need for additional surgeries including rebubbling were evaluated through 6 months postoperatively. Preoperative BCVA was 0.37 ± 0.34 logarithm of the minimum angle of resolution and improved to 0.09 ± 0.10 logarithm of the minimum angle of resolution at 6 months (P < 0.001). Eighty-two percent of eyes obtained a BCVA of 20/25 or better. Central corneal thickness decreased significantly at 6 months (P < 0.001). Endothelial cell loss was 29.1% at 6 months (available for 20 of 33 eyes). All surgeries were uneventful. Six eyes required rebubbling for graft detachments. There were no primary or secondary graft failures at 6 months. DMEK with infusion microforceps is efficacious and safe in eyes with Fuchs endothelial corneal dystrophy and could offer a more controlled surgery, making it suitable for both novice and experienced DMEK surgeons.


Correlating clinical appearance of nasopharyngeal carcinoma with tumour staging.
Since there is a tendency for nasopharyngeal carcinoma (NPC) to exhibit sub-mucosal spread and endophytic growth, it would be useful to know if NPC remained inconspicuous in the post-nasal space (PNS) even in advanced stages of disease. The aim of this study was to find out if there was a correlation between tumour appearance in the PNS and tumour stage. One hundred and twenty-two consecutive patients with NPC were studied. The appearance of a tumour in the PNS was classified as to whether or not it was obviously malignant-looking (via naso-endoscopy). Tumour stagings were undertaken according to computerised tomography (CT) scan findings. Of the patients studied, 67 (54.9%) had obvious malignant-looking lesions. Tumour appearance was found to correlate with tumour-staging (p = 0.023, chi-squared test). There was, therefore, a tendency for early tumours to present as inconspicuous or innocuous-looking lesions, whereas advanced tumours tended to appear as obvious malignant-looking lesions in the PNS. The clinical significance of these findings is discussed.


Prediction of O-glycosylation of mammalian proteins: specificity patterns of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase.
The specificity of the enzyme(s) catalysing the covalent link between the hydroxyl side chains of serine or threonine and the sugar moiety N-acetylgalactosamine (GalNAc) is unknown. Pattern recognition by artificial neural networks and weight matrix algorithms was performed to determine the exact position of in vivo O-linked GalNAc-glycosylated serine and threonine residues from the primary sequence exclusively. The acceptor sequence context for O-glycosylation of serine was found to differ from that of threonine and the two types were therefore treated separately. The context of the sites showed a high abundance of proline, serine and threonine extending far beyond the previously reported region covering positions -4 through +4 relative to the glycosylated residue. The O-glycosylation sites were found to cluster and to have a high abundance in the N-terminal part of the protein. The sites were also found to have an increased preference for three different classes of beta-turns. No simple consensus-like rule could be deduced for the complex glycosylation sequence acceptor patterns. The neural networks were trained on the hitherto largest data material consisting of 48 carefully examined mammalian glycoproteins comprising 264 O-glycosylation sites. For detection neural network algorithms were much more reliable than weight matrices. The networks correctly found 60-95% of the O-glycosylated serine/threonine residues and 88-97% of the non-glycosylated residues in two independent test sets of known glycoproteins. A computer server using E-mail for prediction of O-glycosylation sites has been implemented and made publicly available. The Internet address is email@example.com.


Coclustering for cross-subject fiber tract analysis through diffusion tensor imaging.
One of the fundamental goals of computational neuroscience is the study of anatomical features that reflect the functional organization of the brain. The study of physical associations between neuronal structures and the examination of brain activity in vivo have given rise to the concept of anatomical and functional connectivity, which has been invaluable for our understanding of brain mechanisms and their plasticity during development. However, at present, there is no robust and accurate computational framework for the quantitative assessment of cortical connectivity patterns. In this paper, we present a quantitative analysis and modeling tool that is able to characterize anatomical connectivity patterns based on a newly developed coclustering algorithm, termed the business model-based coclustering algorithm (BCA). We apply BCA to diffusion tensor imaging (DTI) data in order to provide an automated and reproducible assessment of the connectivity patterns between different cortical areas in human brains. BCA not only partitions the cortical mantel into well-defined clusters, but also maximizes the connectivity strength between these clusters. Moreover, BCA is computationally robust and allows both outlier detection as well as parameter-independent determination of the number of clusters. Our coclustering results have showed good performance of BCA in identifying major white matter fiber bundles in human brains and facilitate the detection of abnormal connectivity patterns in patients suffering from various neurological diseases.


Persistent demographic differences in colorectal cancer screening utilization despite Medicare reimbursement.
Colorectal cancer screening is widely recommended, but often under-utilized. In addition, significant demographic differences in screening utilization exist. Insurance coverage may be one factor influencing utilization of colorectal cancer screening tests. We conducted a retrospective analysis of claims for outpatient services for Washington state Medicare beneficiaries in calendar year 2000. We determined the proportion of beneficiaries utilizing screening fecal occult blood tests, flexible sigmoidoscopy, colonoscopy, or double contrast barium enema in the overall population and various demographic subgroups. Multiple logistic regression analysis was used to determine the relative odds of screening in different demographic groups. Approximately 9.2% of beneficiaries had fecal occult blood tests, 7.2% had any colonoscopy, flexible sigmoidoscopy, or barium enema (invasive) colon tests, and 3.5% had invasive tests for screening indications. Colonoscopy accounted for 41% of all invasive tests for screening indications. Women were more likely to receive fecal occult blood test screening (OR 1.18; 95%CI 1.15, 1.21) and less likely to receive invasive tests for screening indications than men (OR 0.80, 95%CI 0.77, 0.83). Whites were more likely than other racial groups to receive any type of screening. Rural residents were more likely than urban residents to have fecal occult blood tests (OR 1.20, 95%CI 1.17, 1.23) but less likely to receive invasive tests for screening indications (OR 0.89; 95%CI 0.85, 0.93). Reported use of fecal occult blood testing remains modest. Overall use of the more invasive tests for screening indications remains essentially unchanged, but there has been a shift toward increased use of screening colonoscopy. Significant demographic differences in screening utilization persist despite consistent insurance coverage.


Global research trends of nanotechnology for pain management.
Background: Nanotechnology has been increasingly used in healthcare during recent years. However, the systematic evaluation of research on nanotechnology for pain management is lacking. In this study, we employed a bibliometric approach to examine the status of the research and global trends of nanotechnology in relation to pain management. Methods: We selected relevant papers published in the Web of Science Core Collection database between 2013 and 2022 using search terms related to nanotechnology and pain management. Subsequently, the following bibliographic information was collected: publication year, originating country/region, affiliated authors and institutions, published journal, references cited, citation frequency, and keywords. The bibliometric software programs VOSViewer and CiteSpace were employed to obtain bibliometric statistics and perform visual analysis. Results: A total of 2680 papers were retrieved. The number of publications in the field of nanotechnology for pain management has been increasing annually since 2013. China had the highest number of published papers, whereas the United States led in total citations. The Chinese Academy of Sciences was the most prolific institution, while the Tehran University of Medical Sciences had the highest overall citations. Furthermore, De Paula was the most prolific author. Papers associated with nanotechnology for pain management were mainly published in the International Journal of Pharmaceutics, Pharmaceutics, and the International Journal of Nanomedicine. Keyword analysis showed that "in-vitro" and "drug-delivery" appeared most frequently, with the top 10 common keywords comprising nanoparticles, pain, in-vitro, drug-delivery, delivery, release, inflammation, neuropathic pain, formulation, and expression. Lastly, the latest emerging keyword was "electrochemical sensor". Conclusion: Research on applying nanotechnology for pain management is growing steadily. China is the top country in terms of number of publications, with institutions under the Chinese Academy of Sciences making significant contributions to this field. "In-vitro" and "drug-delivery" are the current hotspots in this area, with "electrochemical sensor" as the latest topic at the research forefront. However, national and inter-institutional collaborations should be strengthened to enable patients with pain disorders to benefit from nanotechnology implementation in pain management.


Dermoscopic and Histopathologic Analysis of the Correlation between the Pigmentation of Basal Cell Carcinoma and Tumor Aggressiveness.
Basal cell carcinoma (BCC) is the most common type of skin cancer. In patients with darker skin, most BCCs are pigmented. Studies suggest that increased pigmentation in BCC may be inversely associated with tumor aggressiveness. This study analyzed the dermoscopic features and histopathologic patterns of BCCs to evaluate the correlation between BCC pigmentation and tumor aggressiveness. A total of 76 BCC lesions were included in this retrospective study. The Mohs micrographic surgery (MMS) stage and tumor depth were measured as indices of tumor aggressiveness. The Fontana-Masson stain was performed for the identification of melanin, and immunohistochemical analysis was performed using Melan-A and HMB-45 to identify melanocytes. In MMS stage 1, the dermoscopic pigmentation value was 34.48%±14.22% (mean±standard deviation). In MMS stages 2 and 3, dermoscopic pigmentations were 13.72%±7.54% and 15.50%±17.52%, respectively. In the logistic regression model, higher dermoscopic pigmentation (95% confidence interval [CI], 0.68~0.99), melanin (95% CI, 0.63~0.89), and melanocyte-stained areas (95% CI, 0.70~0.92) were associated with a lower possibility of BCC tumor infiltration over the middle and lower layers. We found an inverse correlation between the pigmentation and aggressiveness of BCCs. Clinicians can predict the subclinical infiltration depth of BCC on the basis of the pigmentation observed on dermoscopy. Pigmentation can be considered a favorable prognostic factor for BCC.


Accelerated Screening of Ternary Chalcogenides for Potential Photovoltaic Applications.
Chalcogenides, which refer to chalcogen anions, have attracted considerable attention in multiple fields of applications, such as optoelectronics, thermoelectrics, transparent contacts, and thin-film transistors. In comparison to oxide counterparts, chalcogenides have demonstrated higher mobility and p-type dopability, owing to larger orbital overlaps between metal-X covalent chemical bondings and higher-energy valence bands derived by p-orbitals. Despite the potential of chalcogenides, the number of successfully synthesized compounds remains relatively low compared to that of oxides, suggesting the presence of numerous unexplored chalcogenides with fascinating physical characteristics. In this study, we implemented a systematic high-throughput screening process combined with first-principles calculations on ternary chalcogenides using 34 crystal structure prototypes. We generated a computational material database containing over 400,000 compounds by exploiting the ion-substitution approach at different atomic sites with elements in the periodic table. The thermodynamic stabilities of the candidates were validated using the chalcogenides included in the Open Quantum Materials Database. Moreover, we trained a model based on crystal graph convolutional neural networks to predict the thermodynamic stability of novel materials. Furthermore, we theoretically evaluated the electronic structures of the stable candidates using accurate hybrid functionals. A series of in-depth characteristics, including the carrier effective masses, electronic configuration, and photovoltaic conversion efficiency, was also investigated. Our work provides useful guidance for further experimental research in the synthesis and characterization of such chalcogenides as promising candidates, as well as charting the stability and optoelectronic performance of ternary chalcogenides.


Cyclin G2: A novel independent prognostic marker in pancreatic cancer.
Unlike other cyclins that positively regulate the cell cycle, cyclin G2 (CCNG2) regulates cell proliferation as a tumor suppressor gene. A decreased CCNG2 expression serves as a marker for poor prognosis in several types of cancer. The aim of the present study was to clarify the correlation of CCNG2 expression with overall survival and histopathological factors in pancreatic cancer patients. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. The association between prognoses and the expression of CCNG2 was assessed using immunohistochemical staining. Multivariate analysis identified that the expression of CCNG2 is an independent prognostic factor. In addition, the Kaplan-Meier curve for overall survival revealed that decreased expression of CCNG2 was a consistent indicator of poor prognosis in pancreatic cancer patients (P=0.0198). A decreased CCNG2 expression significantly correlated with venous invasion in tumor specimens and the tumor invasion depth. In conclusion, CCNG2 expression inversely reflected cancer progression and may be a novel, independent prognostic marker in pancreatic cancer.


Is the 2,3-carbon-carbon bond of indole really inert to oxidative cleavage by Oxone?--synthesis of isatoic anhydrides from indoles.
A recent report has indicated that the oxidizing agent Oxone does not possess the ability to cleave the 2,3-carbon-carbon bond of indole. Work in our laboratory shows that this is not the case. Indole and a variety of aryl ring substituted derivatives readily react to form synthetically important isatoic anhydrides.


Effects of Pb-EDTA and EDTA on oxidative stress reactions and mineral uptake in Phaseolus vulgaris.
Sequestration of Pb by synthetic chelates has been reported to increase bioavailability, uptake, and translocation of this metal in plants. In this work the potential phytotoxic effects of Pb-EDTA were investigated in Phaseolus vulgaris L. cv. Limburgse vroege plants grown on hydroponics. Addition of 50 microM Pb-EDTA to the nutrient solution caused a significant induction of syringaldazine peroxidase (SPOD; EC 22.214.171.124) in roots and primary leaves and guaiacol peroxidase (GPOD; EC 126.96.36.199) in leaves. Addition of 100 microM Pb-EDTA further exacerbated ascorbate peroxidase (APOD; EC 188.8.131.52), GPOD, dehydroascorbate reductase (DHAR; EC 126.96.36.199), glutathione reductase (GR; EC 22.214.171.124) and malic enzyme (ME; EC 220.127.116.11) in roots and APOD and ME in primary leaves. Addition of 200 microM Pb-EDTA also induced DHAR in leaves. This induction of peroxidases (SPOD, GPOD, APOD), enzymes of the ascorbate-glutathione cycle (DHAR, GR in roots) and of an NADP+ reducing enzyme in roots and primary leaves indicates that oxidative stress has been initiated. At 200 microM Pb-EDTA, chlorophyll a and b content in leaves was significantly reduced while visible effects on root morphology and shoot length were observed, while no significant morphological effects were found in the leaves, confirming the sensitive character of the measured enzymes as plant stress indicators. Elevation of the Pb-EDTA concentration in the growth medium significantly reduced the content of Ca, Fe, Mn and Zn taken up by plants, probably due to ion leakage as a result of observed toxicity. Addition of up to 200 microM EDTA increased chelation of divalent cations in nutrient solution resulting in reduced plant uptake of Zn, Cu, Fe and Mn. This did not result in phytotoxicity.


Comparison of multimodal attract-and-kill formulations for managing Drosophila suzukii: Behavioral and lethal effects.
Attract-and-kill (A&K) is a potential alternative control tactic for managing the invasive spotted-wing drosophila, Drosophila suzukii Matsumura. Here, we compared the efficacy of two novel A&K formulations based on proprietary blends-ACTTRA SWD OR1 (henceforth OR1) and ACTTRA SWD TD (henceforth TD)-in managing D. suzukii. Using two-choice bioassays, we compared OR1 and TD for their relative attractiveness to adult D. suzukii. Additionally, we tested how the addition of (1) a red dye (visual cue) and (2) the insecticide spinosad (Entrust™) to the OR1 and TD formulations influenced the attraction of adult D. suzukii in the presence of blueberry fruits. Finally, complementary laboratory efficacy (no-choice) bioassays were conducted to assess the mortality of adult D. suzukii exposed to OR1 and TD. A direct comparison between TD and OR1 formulations indicated the TD formulation was ~8 times more attractive than OR1. Adding a red dye to the TD or OR1 formulation did not significantly alter the attraction or mortality of adult D. suzukii compared to the formulation without a dye. Similarly, irrespective of dye status, adding spinosad to either the TD or OR1 formulation did not alter the adult D. suzukii behavioral response to these formulations but resulted in significantly higher D. suzukii mortality. Overall, the TD formulations resulted in significantly higher, or at least comparable, mortality to the OR1 formulations. In summary, our laboratory results demonstrated the higher efficacy of a TD-based A&K product in managing D. suzukii over its well-tested predecessor, the OR1 formulation, confirming its potential as a new behavioral tactic against this pest.


Severely injured geriatric population: morbidity, mortality, and risk factors.
With an increasing life expectancy and more active elderly population, management of geriatric trauma patients continues to evolve. The aim was to describe the mechanism and injuries of severely injured geriatric patients and to identify risk factors associated with mortality. The Trauma Registry at a Canadian Level I trauma center was queried for all trauma patients older than 65 years and injury severity score >15 from 2004 to 2006, resulting in a retrospective chart review of 276 patients. The data were subsequently analyzed using univariate and multivariate analysis. Average age was 81.5 years (mean injury severity score of 25). Most common comorbid illness was hypertension (57.3%) and most frequent mechanism of injury was falls (72.3%). The overall mortality was comparable with the US National Trauma Data Bank (26.8% vs. 32.0%, confidence interval, 0.00-0.10). Geriatric patients requiring intubation, blood transfusions, or suffering from head, C-spine, or chest trauma had an increased likelihood of death. In-hospital respiratory, gastrointestinal, or infectious complications also had higher likelihood of death. Falls continue to be the most frequent mechanism of injury in severely injured geriatric patients. Risk factors associated with a higher likelihood of death are identified. More research is needed to better understand this important and increasing group of trauma patients.


Evaluation of a partial genome screening of two asthma susceptibility regions using bayesian network based bayesian multilevel analysis of relevance.
Genetic studies indicate high number of potential factors related to asthma. Based on earlier linkage analyses we selected the 11q13 and 14q22 asthma susceptibility regions, for which we designed a partial genome screening study using 145 SNPs in 1201 individuals (436 asthmatic children and 765 controls). The results were evaluated with traditional frequentist methods and we applied a new statistical method, called bayesian network based bayesian multilevel analysis of relevance (BN-BMLA). This method uses bayesian network representation to provide detailed characterization of the relevance of factors, such as joint significance, the type of dependency, and multi-target aspects. We estimated posteriors for these relations within the bayesian statistical framework, in order to estimate the posteriors whether a variable is directly relevant or its association is only mediated.With frequentist methods one SNP (rs3751464 in the FRMD6 gene) provided evidence for an association with asthma (OR = 1.43(1.2-1.8); p = 3×10(-4)). The possible role of the FRMD6 gene in asthma was also confirmed in an animal model and human asthmatics.In the BN-BMLA analysis altogether 5 SNPs in 4 genes were found relevant in connection with asthma phenotype: PRPF19 on chromosome 11, and FRMD6, PTGER2 and PTGDR on chromosome 14. In a subsequent step a partial dataset containing rhinitis and further clinical parameters was used, which allowed the analysis of relevance of SNPs for asthma and multiple targets. These analyses suggested that SNPs in the AHNAK and MS4A2 genes were indirectly associated with asthma. This paper indicates that BN-BMLA explores the relevant factors more comprehensively than traditional statistical methods and extends the scope of strong relevance based methods to include partial relevance, global characterization of relevance and multi-target relevance.


Green space and physical activity: an observational study using Health Survey for England data.
Past studies have suggested that a link between health outcomes and green space is due to increased levels of physical activity of individuals living in areas with more green space. We found a positive association between green space and physical activity levels. The odds of achieving the recommended amount of physical activity was 1.27 (95% CI: 1.13-1.44) for people living in the greenest quintile in England compared to those living in the least green quintile, after controlling for individual and environmental factors. However, no association was found between green space and types of physical activity normally associated with green space. An association was found with other types of physical activity (gardening and do-it-yourself, and occupational physical activity). These findings suggest that although there is a positive association between physical activity and green space it may not be explained by individuals using green space for recreation.


Identification of environmental chemicals targeting miscarriage genes and pathways using the comparative toxicogenomics database.
Miscarriage is a prevalent public health issue and many events occur before women are aware of their pregnancy, complicating research design. Thus, risk factors for miscarriage are critically understudied. Our goal was to identify environmental chemicals with a high number of interactions with miscarriage genes, based on known toxicogenomic responses. We used miscarriage (MeSH: D000022) and chemical gene lists from the Comparative Toxicogenomics Database in human, mouse, and rat. We assessed enrichment for gene ontology biological processes among the miscarriage genes. We prioritized chemicals (n = 25) found at Superfund sites or in the blood or urine pregnant women. For chemical-disease gene sets of sufficient size (n = 13 chemicals, n = 20 comparisons), chi-squared enrichment tests and proportional reporting ratios (PRR) were calculated. We cross-validated enrichment results. Miscarriage was annotated with 121 genes and overrepresented in inflammatory response (q = 0.001), collagen metabolic process (q = 1 × 10-13), cell death (q = 0.02), and vasculature development (q = 0.005) pathways. The number of unique genes annotated to a chemical ranged from 2 (bromacil) to 5607 (atrazine). In humans, all chemicals tested were highly enriched for miscarriage gene overlap (all p < 0.001; parathion PRR = 7, cadmium PRR = 6.5, lead PRR = 3.9, arsenic PRR = 3.5, atrazine PRR = 2.8). In mice, highest enrichment (p < 0.001) was observed for naphthalene (PRR = 16.1), cadmium (PRR = 12.8), arsenic (PRR = 11.6), and carbon tetrachloride (PRR = 7.7). In rats, we observed highest enrichment (p < 0.001) for cadmium (PRR = 8.7), carbon tetrachloride (PRR = 8.3), and dieldrin (PRR = 5.3). Our findings were robust to 1000 permutations each of variable gene set sizes. We observed chemical gene sets (parathion, cadmium, naphthalene, carbon tetrachloride, arsenic, lead, dieldrin, and atrazine) were highly enriched for miscarriage genes. Exposures to chemicals linked to miscarriage, and thus linked to decreased probability of live birth, may limit the inclusion of fetuses susceptible to adverse birth outcomes in epidemiology studies. Our findings have critical public health implications for successful pregnancies and the interpretation of adverse impacts of environmental chemical exposures on pregnancy.


Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins.
Meckel syndrome (MKS) is a ciliopathy characterized by encephalocele, cystic renal disease, liver fibrosis and polydactyly. An identifying feature of MKS1, one of six MKS-associated proteins, is the presence of a B9 domain of unknown function. Using phylogenetic analyses, we show that this domain occurs exclusively within a family of three proteins distributed widely in ciliated organisms. Consistent with a ciliary role, all Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia. Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins. This localization is evolutionarily conserved, because the human orthologues also localize to basal bodies, as well as cilia. As reported for MKS1, disrupting human MKSR1 or MKSR2 causes ciliogenesis defects. By contrast, single, double and triple C. elegans mks/mksr mutants do not display overt defects in ciliary structure, intraflagellar transport or chemosensation. However, we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling. Our findings therefore demonstrate functional interactions between a novel family of proteins associated with basal bodies or cilia, providing new insights into the molecular etiology of a pleiotropic human disorder.


Predictors of family risk for celiac disease: a population-based study.
There is an elevated prevalence of celiac disease (CD) in family members (FMs) of CD patients, but most prior studies have been done on selected populations. Our aim was to determine the clinical, serologic, and genetic predictors of CD in FMs of a population-based cohort of index cases. Index cases from southeast Minnesota provided contact information for their first-degree relatives. FMs were examined for endomysial antibodies (EMAs), tissue transglutaminase antibodies (tTGAs), and HLA-DQ genotyping. Two questionnaires were applied, Bowel Disease Questionnaire and Short Form Health Survey. Intestinal biopsies were offered if there were any positive autoantibody or seronegative FMs with gastrointestinal symptoms and HLA-DQ at risk for CD. We recruited 111 index cases that had 579 FMs, of whom 344 (59%) were investigated. The average screening rate among families was 65%. A positive tTGA test was found in 47 (14%), 33 with a positive EMA test. CD was diagnosed in 39 (21 males), with an estimated prevalence of 11% (lambda(R) = 16.1). All affected FMs carried the at-risk genotypes. Twenty-one (54%) had "silent" disease, most with severe intestinal villous atrophy. Carrying HLA-DQ2 (odds ratio, 16.1; 95% confidence interval, 2.1-123) and being a sibling (odds ratio, 2.5; 95% confidence interval, 1.1-5.8) are high-risk factors for CD. CD is more common in first-degree relatives than previously reported in the United States, with siblings having the greatest risk. There is male preponderance of new cases, and many had silent disease despite severe histologic injury. A more proactive case-finding strategy in FMs might improve the diagnostic rate of CD in North America.


Pseudomonas spp. associated vegetative endocarditis in two horses.
This paper describes the case histories of two Thoroughbred horses, a 2-year-old colt in training and a 7-year-old broodmare, that were presented with histories of weight loss, exercise intolerance, intermittent fever, limb oedema and anaemia. Vegetative endocarditis of the mitral and tricuspid valves was diagnosed in the colt by means of echocardiography. Pseudomonas sp. endocarditis of the mitral valve was diagnosed in the mare using echocardiography and bacterial culture. The colt had secondary congestive heart failure and was euthanased on humane grounds. Pseudomonas cepacia was isolated from the vegetative lesions following the post mortem examination. The mare was sent home and treated with gentamicin at a dosage of 3.3 mg/kg intra-muscularly twice daily for ten days. Her condition improved and she returned to stud.


Characterization of the alpha-MSH-like immunoreactivity in blood and cerebrospinal fluid of the rat.
We have investigated the nature of the alpha-melanocyte stimulating hormone-like immunoreactivity (alpha-MSH-LI) in blood and cerebrospinal fluid (CSF) of the rat. Blood and CSF from intact animals were subjected to high pressure liquid chromatography (HPLC) followed by a radioimmunoassay (RIA) specific for the C-terminal part of the alpha-MSH molecule. It appeared that in both body fluids the predominant alpha-MSH-LI co-migrated with synthetic alpha-MSH and not with its des-acetyl or di-acetyl analogues. We conclude that alpha-MSH is the predominant form of alpha-MSH-LI circulating in plasma and CSF of rats from our Wistar strain.


Training and tailored outreach support to improve alcohol screening and brief intervention in Aboriginal Community Controlled Health Services.
Aboriginal Community Controlled Health Services (ACCHSs) are often the primary point of contact for Indigenous Australians experiencing alcohol-related harms. Screening and brief intervention (SBI) is a cost-effective treatment for reducing these harms. Factors influencing evidence-based alcohol SBI delivery in ACCHSs have been identified. Evaluations of strategies targeting these factors are required. The aim of this paper is to quantify the effect of training and tailored outreach support on the delivery of alcohol SBI in four Aboriginal Community Controlled Health Services (ACCHSs). A pre- post- assessment of alcohol information recorded in computerised patient information systems of four ACCHSs. For ACCHSs combined there was a statistically significant increase in the proportion of eligible clients with an electronic record of any alcohol information (3.2% to 7.5%, P < 0.0001) and a valid alcohol screen (1.6% to 6.5%, P < 0.0001), and brief intervention (25.75% to 47.7%, P < 0.0001). All four ACCHSs achieved statistically significant increases in the proportion of clients with a complete alcohol screen (10.3%; 7.4%; 2%, P < 0.0001 and 1.3%, P < 0.05), and two in the proportion with a heavy drinking screen (7% and 3.1%, P < 0.0001). Implementing evidence-based alcohol SBI in ACCHSs is likely to require multiple strategies tailored to the characteristics of specific services. Outreach support provided by local drug and alcohol practitioners and a one item heavy drinking screen offer considerable promise for increasing routine alcohol SBI delivery in ACCHSs. Training and outreach support appear to be effective for achieving modest improvements in alcohol SBI delivery in ACCHSs.


A modified efficient method for dental pulp stem cell isolation.
Dental pulp stem cells can be used in regenerative endodontic therapy. The aim of this study was to introduce an efficient method for dental pulp stem cells isolation. In this in-vitro study, 60 extracted human third molars were split and pulp tissue was extracted. Dental pulp stem cells were isolated by the following three different methods: (1) digestion of pulp by collagenase/dispase enzyme and culture of the released cells; (2) outgrowth of the cells by culture of undigested pulp pieces; (3) digestion of pulp tissue pieces and fixing them. The cells were cultured in minimum essential medium alpha modification (αMEM) medium supplemented with 20% fetal bovine serum(FBS) in humid 37°C incubator with 5% CO 2. The markers of stem cells were studied by reverse transcriptase polymerase chain reaction (PCR). The student t-test was used for comparing the means of independent groups. P <0.05 was considered as significant. The results indicated that by the first method a few cell colonies with homogenous morphology were detectable after 4 days, while in the outgrowth method more time was needed (10-12 days) to allow sufficient numbers of heterogeneous phenotype stem cells to migrate out of tissue. Interestingly, with the improved third method, we obtained stem cells successfully with about 60% efficiency after 2 days. The results of RT-PCR suggested the expression of Nanog, Oct-4, and Nucleostemin markers in the isolated cells from dental pulps. This study proposes a new method with high efficacy to obtain dental pulp stem cells in a short time.


Novel Clade C-I Clostridium difficile strains escape diagnostic tests, differ in pathogenicity potential and carry toxins on extrachromosomal elements.
The population structure of Clostridium difficile currently comprises eight major genomic clades. For the highly divergent C-I clade, only two toxigenic strains have been reported, which lack the tcdA and tcdC genes and carry a complete locus for the binary toxin (CDT) next to an atypical TcdB monotoxin pathogenicity locus (PaLoc). As part of a routine surveillance of C. difficile in stool samples from diarrheic human patients, we discovered three isolates that consistently gave negative results in a PCR-based screening for tcdC. Through phenotypic assays, whole-genome sequencing, experiments in cell cultures, and infection biomodels we show that these three isolates (i) escape common laboratory diagnostic procedures, (ii) represent new ribotypes, PFGE-types, and sequence types within the Clade C-I, (iii) carry chromosomal or plasmidal TcdBs that induce classical or variant cytopathic effects (CPE), and (iv) cause different levels of cytotoxicity and hamster mortality rates. These results show that new strains of C. difficile can be detected by more refined techniques and raise questions on the origin, evolution, and distribution of the toxin loci of C. difficile and the mechanisms by which this emerging pathogen causes disease.


Delirium assessed by Memorial Delirium Assessment Scale in advanced cancer patients admitted to an acute palliative/supportive care unit.
Delirium is often unrecognized in cancer patients. The aim of this study was to investigate the prevalence of delirium assessed by the Memorial Delirium Assessment Scale (MDAS) and possible associated factors on admission to an acute palliative/supportive care unit (APSCU). The secondary outcome was to assess changes in MDAS and symptom burden at time of discharge. A consecutive sample of advanced cancer patients who were admitted to an APSCU was prospectively assessed for a period of 10 months. Patient demographics, including age, gender, primary diagnosis, Karnofsky status, stage of disease, and educational level were collected. The Edmonton Symptom Assessment Scale (ESAS) and the MDAS were measured at hospital admission and discharge. A total of 314 patients were surveyed. Of 292 patients with MDAS available at T0, 74 (25.3%) and 24 (8.2%) had a MDAS of 7-12 and ≥13, respectively. At discharge, there was a significant decrease in the number of patients with a MDAS ≥7/30. Higher values of MDAS were associated with age (p = .028), a lower Karnofsky status (p < .0005), gender (male, p = .04), low level of education (p = .002), less awareness of disease (p < .0005), more indications for end-of-life care admission (p < .0005) or other symptoms (p = .026), hospital stay (p = .038) and death (p < .0005). Significant decreases in ESAS were observed in all patients independently of MDAS values (p < .0005). Delirium is highly prevalent in patients admitted to APSCU, characterized by a low mortality due to early referral. Comprehensive assessment and treatment may allow a decrease in the level of cognitive disorders and symptom burden.


Molecular Epidemiology of Carbapenem-Resistant Acinetobacter baumannii From Khartoum State, Sudan.
Carbapenem resistant Acinetobacter baumannii (CRAb) is an important global pathogen contributing to increased morbidity and mortality in hospitalized patients, due to limited alternative treatment options. Nine international clonal (IC) lineages have been identified in many countries worldwide, however, data still lacks from some parts of the world, particularly in Africa. We hereby present the molecular epidemiology of MDR A. baumannii from four hospitals in Khartoum, Sudan, collected from 2017 to 2018. Forty-two isolates were whole-genome sequenced, and subsequent molecular epidemiology was determined by core genome MLST (cgMLST), and their resistomes identified. All isolates had an array of diverse antibiotic resistance mechanisms conferring resistance to multiple classes of antibiotics. We found a predominance (88%) of IC2 (with the intrinsic OXA-66 and acquired OXA-23), and some with NDM-1. IC2 isolates were sub-divided into 4 STs separated by 5 to 431 allelic differences, and with evidence of seven transmission clusters. Isolates belonging to IC1, IC5, and IC9 were also identified. These data illustrate that MDR IC2 A. baumannii are widely distributed in Khartoum hospitals and are in possession of multiple antibiotic resistance determinants.


Molecular characterization of G6PD mutations reveals the high frequency of G6PD Aures in the Lao Theung population.
The prevalence and genotypes of G6PD deficiency vary worldwide, with higher prevalence in malaria endemic areas. The first-time assessment of G6PD deficiency prevalence and molecular characterization of G6PD mutations in the Lao Theung population were performed in this study. A total of 252 unrelated Lao Theung participants residing in the Lao People's Democratic Republic (PDR) were recruited. All participant samples were tested for G6PD enzyme activity and G6PD gene mutations. The amplification refractory mutation system (ARMS)-PCR for detecting G6PD Aures was developed. The G6PD mutations were detected in 11.51% (29/252) of the participants. Eight G6PD mutations were detected. The G6PD Aures was the most common mutation identified in this cohort, which represented 58.62% (17/29) of all mutation. The mutation pattern was homogenous, predominantly involving the G6PD Aures mutation (6.75%), followed by 1.19% G6PD Union and 0.79% each G6PD Jammu, G6PD Mahidol and G6PD Kaiping. One subject (0.4%) each carried G6PD Viangchan and G6PD Canton. Interestingly, one case of coinheritance of G6PD Aures and Quing Yan was detected in this cohort. Based on levels of G6PD enzyme activity, the prevalence of G6PD deficiency in the Lao Theung population was 9.13% (23/252). The prevalence of G6PD deficient males and females (activity < 30%) in the Lao Theung population was 6.41% (5/78) and 1.72% (3/174), respectively, and the prevalence of G6PD intermediate (activity 30-70%) was 5.95% (15/252). The G6PD Aures mutation is highly prevalent in the Lao Theung ethnic group. The common G6PD variants in continental Southeast Asian populations, G6PD Viangchan, Canton, Kaiping, Union and Mahidol, were not prevalent in this ethnic group. The technical simplicity of the developed ARMS-PCR will facilitate the final diagnosis of the G6PD Aures.


Colon carcinoma presenting with a synchronous oesophageal carcinoma and Basal cell carcinoma of the skin.
With advances in diagnostic techniques and treatment modalities, the number of patients identified with colorectal carcinoma who develop multiple primary malignancies during long-term followup has been increasing. We report a patient who developed three histologically distinct malignancies. Primary colon carcinoma treated radically followed by an 8-year disease-free period. The patient then presented with progressive dysphagia and was investigated and diagnosed to have a synchronous multicentric squamous cell carcinoma of the oesophagus and basal cell carcinoma of the skin. There was a simultaneous multicentric recurrence in the colon. This case is worth mentioning because the clustering of three primary malignancies (synchronous and metachronous) is of rare occurrence in a single patient, and, to our knowledge, this is the first report of this combination occurring in the same individual. In addition, the report emphasizes the importance of evaluating patients with known colonic primary neoplasms for synchronous colonic and extracolonic tumors.


Capillary microsampling in nonclinical safety assessment: practical sampling and bioanalysis from a CRO perspective.
Microsampling has the 3R benefits of refining blood collection techniques while reducing the number of animals required for rodent safety assessment studies. There are significant scientific benefits of correlating study findings with systemic exposure and consequently, there is an industry drive to utilize microsampling in regulatory toxicology studies. This article will focus on capillary microsampling and will discuss the initial considerations before using capillary microsampling, study design and some practicalities of sample collection. From a bioanalytical perspective, the impact of different sample collection and storage workflows on the design of method validation experiments, the suitability of using microsampling for unstable analytes and aspects supporting analysis of peptides, large molecules and for biomarker applications will be discussed.


Synergistic activity of bortezomib and HDACi in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT, and NF-κB.
Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients. Antiproliferative and proapoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from patients with ALL, and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation. We identified the proteasome inhibitor bortezomib as a promising combination partner for HDACi due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK, PI3K/AKT, p53, ubiquitin/proteasome, and NF-κB pathways. We observed an activation of NF-κB after bortezomib treatment and the induction of apoptosis-related NF-κB target genes such as TNFαRs after concomitant treatment, indicating a possible involvement of NF-κB as proapoptotic mediator. In this context, significantly lower NF-κB subunits gene expression was detected in leukemia cells from patients who developed a relapse during frontline chemotherapy, compared with those who relapsed after cessation of frontline therapy. These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols.


TRAF3 controls activation of the canonical and alternative NFkappaB by the lymphotoxin beta receptor.
Components of lymphotoxin beta receptor (LTBR)-associated signaling complexes, including TRAF2, TRAF3, NIK, IKK1, and IKK2 have been shown to participate in the coupling of LTBR to NFkappaB. Here, we report that TRAF3 functions as a negative regulator of LTBR signaling via both canonical and non-canonical NFkappaB pathways by two distinct mechanisms. Analysis of NFkappaB signaling in cell lines with functionally intact NFkappaB pathway but lacking LTBR-mediated induction of NFkappaB target genes revealed an inverse association of cellular TRAF3 levels with LTBR-specific defect in canonical NFkappaB activation. Increased expression of TRAF3 correlated with its increased recruitment to LTBR-induced signaling complexes, decreased recruitment of TRAF2, and attenuated phosphorylation of IkappaB alpha and RelA. In contrast, activation of NFkappaB by TNF did not depend on TRAF3 levels. siRNA-mediated depletion of TRAF3 promoted recruitment of TRAF2 and IKK1 to activated LTBR, enabling LTBR-inducible canonical NFkappaB signaling and NFkappaB target gene expression. TRAF3 knock-down also increased mRNA and protein expression of several non-canonical NFkappaB components, including NFkappaB2/p100, RelB, and NIK, accompanied by processing of NFkappaB2/p100 into p52. These effects of TRAF3 depletion did not require LTBR signaling and were consistent with autonomous activation of the non-canonical NFkappaB pathway. Our data illustrate the function of TRAF3 as a dual-mode repressor of LTBR signaling that controls activation of canonical NFkappaB, and de-repression of the intrinsic activity of non-canonical NFkappaB. Modulation of cellular TRAF3 levels may thus contribute to regulation of NFkappaB-dependent gene expression by LTBR by affecting the balance of LTBR-dependent activation of canonical and non-canonical NFkappaB pathways.


Understanding other cultures: the need for training.
People from ethnic minorities from a substantial group treated in the renal unit, some 10% or more. Because of the language, dietary and cultural differences, there are special problems for the multi-disciplinary team in communication, understanding and sensitivity to the particular needs that may arise. Three case studies and their implications will be discussed. In all these situations staff felt helpless and de-skilled, having no knowledge of the cultural implications. Questionnaires show that the majority of staff from all disciplines receive very little, if any, training in the faiths and cultural traditions of those from other countries--a situation that needs urgent attention.


[Content of cyclic nucleotides in blood plasma of patients with bronchial asthma].
The ratio of cAMP and cGMP in blood plasma of patients with bronchial asthma was altered depending on the severity of the disease. There was noted a decrease in cAMP content and an increase--in cGMP. Distinct alterations in the cAMP content were not observed in infectious and atopic forms of the asthma. Content of cGMP was higher in blood plasma of patients with infectious form of the asthma as compared with the atopic one. Dynamics of improvement in the patients with the severe type of bronchial asthma was accompanied by the increased in the ratio cAMP/cGMP due to an increase in the cAMP content, while the content of cGMP remained elevated.


Differences in risk factors for coronary heart disease among diabetic and nondiabetic individuals from a population with high rates of diabetes: the Strong Heart Study.
Coronary heart disease (CHD) is the leading cause of death in the United States. This study compares differences in risk factors for CHD in diabetic vs. nondiabetic Strong Heart Study participants. This was an observational study. The study was conducted at three centers in Arizona, Oklahoma, and North and South Dakota. Data were obtained from 3563 of 4549 American Indians free of cardiovascular disease at baseline. CHD events were ascertained during follow-up. CHD events were classified using standardized criteria. In diabetic and nondiabetic participants, 545 and 216 CHD events, respectively, were ascertained during follow-up (21,194 and 22,990 person-years); age- and sex-adjusted incidence rates of CHD were higher for the diabetic group (27.5 vs. 12.1 per 1,000 person-years). Risk factors for incident CHD common to both groups included older age, male sex, prehypertension or hypertension, and elevated low-density lipoprotein cholesterol. Risk factors specific to the diabetic group were lower high-density lipoprotein cholesterol, current smoking, macroalbuminuria, lower estimated glomerular filtration rate, use of diabetes medication, and longer duration of diabetes. Higher body mass index was a risk factor only for the nondiabetic group. The association of male sex and CHD was greater in those without diabetes than in those with diabetes. In addition to higher incidence rates of CHD events in persons with diabetes compared with those without, the two groups differed in CHD risk factors. These differences must be recognized in estimating CHD risk and managing risk factors.


Nutrient transport and the blood-brain barrier in developing animals.
Structural alterations in the development of the blood-brain barrier (BBB) can be seen in capillary profiles from the rat cortex. The neonatal luminal membrane is amplified with irregular folds, a possible adaptation to reduced cerebral blood flow rates. By 21 days the capillaries have resolved to a smooth-surfaced, adult-like appearance. Developmental alterations in the basement membrane, tight junctions, capillary seams, Golgi, pinocytotic vesicles, and cytoplasmic thickness are observed. Two studies have addressed developmental modulations in BBB polarity; both indicate that brain-to-blood transport mechanisms that were inoperative in the early neonatal rat become functional in weanlings. Six of the seven major independent BBB nutrient transport systems that regulate plasma-to-brain uptake have been kinetically characterized in the newborn rabbit, and comparisons have been made in the weanling (28-day-old) rabbit. All of these saturable transport systems are operative at birth, which suggests that the immature rabbit has a mature BBB with respect to regulation of nutrients. Purine base permeability, affinity, and uptake velocities are virtually unchanged during postnatal development. Subtle alterations in amino acid and amine transport were suggested by the lower-affinity (high-capacity) transport mechanisms characterized in the newborn as compared to the 28-day-old BBB. Under conditions of elevated plasma levels (typical of the neonate), these higher-capacity mechanisms would facilitate a relative increase in metabolite influx to the developing brain. Significant differences in kinetics were also observed for the monocarboxylic acid and hexose transport systems in the absence of developmental changes in permeability times surface area products. A low-affinity, high-capacity monocarboxylic acid transport system operates at birth. It supplies the developing brain with increased quantities of ketone bodies, but is seen as a high-affinity, low-capacity mechanism in the 28-day-old rabbit. Concomitantly, the higher-affinity glucose carrier defined in newborn rabbits modulates, and by 28 days becomes a lower-affinity, high-capacity mechanism capable of delivering about 2 mumol X min-1 X g-1 of glucose to the (anesthetized) brain.


Preliminary validation of a UK-modified version of the BASIS-32.
The authors examined the reliability and validity of a UK-modified version of the Behavioral and Symptom Identification Scale (BASIS-32). Data from two samples of patients from acute psychiatric inpatient settings were used in the analyses ( n =303, n =92). The factor structure of the scale differed from that of the original BASIS-32. Five factors emerged: (i) depression and anxiety, (ii) lability, (iii) psychosis, (iv) substance misuse and (v) functioning. The full scale of the modified BASIS demonstrated high internal consistency (Cronbach's alpha=0.93). Internal consistency for the subscales ranged from 0.86 to 0.45. The depression and anxiety subscale discriminated patients with a diagnosis of unipolar depression from those with other diagnoses (median score=3.11 (Inter quartile range (IQR)=2.67,3.33) versus median score=2.44 (1.67,3.11), P < 0.001). The substance misuse subscale discriminated patients with a diagnosis of alcohol or opiate dependence from those with other diagnoses (median score=2.33 (2, 3) versus median score=1.33 (0.67, 2), P < 0.001). However, the psychosis subscale did not differentiate patients with a psychotic illness from those with a nonpsychotic diagnosis (median score=1.4 (0.6,2.4) versus median score=1.2, (0.6,2), P = 0.16). The total scale appeared to be at least as good as the Brief Symptom Inventory (BSI) in its responsiveness to change. The effect size for the BASIS=1.17 versus 0.91 for the BSI. Convergent validity was partially demonstrated between the modified BASIS and the BSI. ( Int J Psych Clin Pract 2001; 5:41-48).


Perinatal characteristics and parents' perspective of health status of NICU graduates born at term.
Long-term outcomes of preterm infants have been extensively studied, but few studies have examined long-term outcomes of term infants who require neonatal intensive care unit (NICU). Our objectives were to assess perinatal characteristics and health status of preschool age term babies using data from a population-based study of NICU graduates. Retrospective cross-sectional survey. All babies were born in 1996 to 1997 in BC (Canada). The Health Status Classification System Preschool (HSCS-PS) questionnaire was completed by parents at 42 months of age. HSCS-PS was grouped in four categories (neurosensory, learning, motor and quality of life). Logistic regression was used to identify perinatal risk factors associated with moderate/severe problems at 42 months of age. Completed surveys were received for 261 term NICU survivors and 393 control children. Term infants represent 32% of all NICU admissions. Mean birth weight of NICU graduates was 3458 g (s.d.=600 g). Median length-of-stay in NICU was 5 days. At 42 months, the NICU group had significantly more problems on the HSCS-PS as compared to the full-term healthy infants in neurosensory, motor and learning/remembering. Moderate/severe health status problems were associated with congenital anomalies (odds ratio (OR), 3.2; confidence interval (CI): 1.3 to 7.8); smoking status (OR, 2.7, CI: 1.1 to 6.6) and SNAP score (OR, 1.04; CI: 1.0 to 1.1). Term babies admitted to NICUs may have significant health issues in childhood. Greater attention needs to be paid to long-term outcomes of term NICU graduates. Further study is warranted to address which NICU term survivors warrant secondary and/or tertiary-level neurodevelopmental follow-up.


Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects.
Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A-related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies.


L-tryptophan-kynurenine pathway metabolites regulate type I IFNs of acute viral myocarditis in mice.
The activity of IDO that catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn) increases after diseases caused by different infectious agents. Previously, we demonstrated that IDO has an important immunomodulatory function in immune-related diseases. However, the pathophysiological role of IDO following acute viral infection is not fully understood. To investigate the role of IDO in the l-Trp-Kyn pathway during acute viral myocarditis, mice were infected with encephalomyocarditis virus, which induces acute myocarditis. We used IDO-deficient (IDO(-/-)) mice and mice treated with 1-methyl-d,l-Trp (1-MT), an inhibitor of IDO, to study the importance of Trp-Kyn pathway metabolites. Postinfection with encephalomyocarditis virus infection, the serum levels of Kyn increased, whereas those of Trp decreased, and IDO activity increased in the spleen and heart. The survival rate of IDO(-/-) or 1-MT-treated mice was significantly greater than that of IDO(+/+) mice. Indeed, the viral load was suppressed in the IDO(-/-) or 1-MT-treated mice. Furthermore, the levels of type I IFNs in IDO(-/-) mice and IDO(-/-) bone marrow-transplanted IDO(+/+) mice were significantly higher than those in IDO(+/+) mice, and treatment of IDO(-/-) mice with Kyn metabolites eliminated the effects of IDO(-/-) on the improved survival rates. These results suggest that IDO has an important role in acute viral myocarditis. Specifically, IDO increases the accumulation of Kyn pathway metabolites, which suppress type I IFNs production and enhance viral replication. We concluded that inhibition of the Trp-Kyn pathway ameliorates acute viral myocarditis.


Enteric viruses in Brazilian turkey flocks: single and multiple virus infection frequency according to age and clinical signs of intestinal disease.
Poult enteritis complex has been associated with enteritis and reduction in growth rates in commercial turkeys worldwide. Intestinal samples from 76 turkey flocks from different Brazilian states affected or not with intestinal disorders were evaluated for the presence of adenovirus groups 1 and 2 (TAV), astrovirus types 1 and 2 (TAstV-1 and TAstV-2), turkey coronavirus (TCoV), reovirus, rotavirus, and avian nephritis virus (ANV) using PCR. The percentage of positive samples was categorized according to the geographic origin, age of the flocks, and presence of clinical signs of intestinal disease. The percentage of samples that were positive for at least one virus was 93.4%, whereas the percentage of samples that were positive for more than one virus was 69.7%. An average of 3.20 viruses per sample was detected in turkeys in the growing phase of the production cycle (1 to 4 wk of age). The TAstV-1 and TCoV were the most frequently observed viruses in growing phase turkeys and occurred simultaneously in 85% of these samples. In turkeys in the finishing phase of development (5 to 18 wk), a lower average number of viruses was observed (2.41), and the most frequent viruses isolated in these turkeys were TAstV-1 (57.1%) and rotavirus (51.8%). Overall, every virus was detected more frequently in growing phase turkeys than in finishing phase turkeys with the exception of TAV. Samples from flocks exhibiting clinical signs of intestinal disease showed a higher rate of positivity, and TAstV-1, TAstV-2, and TCoV were the most frequently occurring viruses in this cohort. Birds without clinical signs most frequently harbored TAstV-1 and rotavirus. Future studies should focus on the description and elucidation of the role of each virus, as well as the pathogenic and immunological implications of the different combinations of viruses in turkeys.


The Efficacy of PowerPoint-based CBT Delivered Through Email: Breaking the Barriers to Treatment for Generalized Anxiety Disorder.
A lack of resources and cultural stigma associated with mental health treatment necessitate the development of innovative and economical individualized treatments. This study evaluated the efficacy of delivering computer-based cognitive behavioral therapy (e-CBT) presented through Microsoft PowerPoint and delivered via email in the treatment of generalized anxiety disorder (GAD) to Iranian patients, as a means of overcoming treatment barriers. Participants (N=80) of Iranian descent were recruited through announcements on psychology websites, Iranian organization websites, weblogs, and in flyers. Participants were randomly assigned to either an e-CBT or a control group. The e-CBT group received 12 weekly modules and homework assignments through email, presented using PowerPoint. The control group received no treatment (individuals in the control group were able to pursue another treatment, but would then be excluded from the study although they could continue with the program). All emails were sent by an attending or resident psychiatrist, who also provided feedback on weekly homework via email. The Beck Anxiety Inventory was used to measure levels of anxiety before study onset and changes in levels of anxiety upon completion of the program at 12 weeks, and at 6-month and 1-year follow-up in both groups. Beck Anxiety Inventory scores were significantly reduced in the group who received PowerPoint e-CBT modules delivered via email, compared with the control group, following 12 weeks of treatment, and the reductions were maintained at both follow-up points. Delivery of PowerPoint e-CBT modules via email was found to be a viable method for delivering CBT to individuals with GAD and a simple method for overcoming language, cultural, and travel barriers to accessing mental health resources. This simplified approach to the individualization and delivery of treatment modules has the potential to improve access to CBT as a treatment option throughout the world.


Interstitial cells of blood vessels.
Blood vessels are made up of several distinct cell types. Although it was originally thought that the tunica media of blood vessels was composed of a homogeneous population of fully differentiated smooth muscle cells, more recent data suggest the existence of multiple smooth muscle cell subpopulations in the vascular wall. One of the cell types contributing to this heterogeneity is the novel, irregularly shaped, noncontractile cell with thin processes, termed interstitial cell, found in the tunica media of both veins and arteries. While the principal role of interstitial cells in veins seems to be pacemaking, the role of arterial interstitial cells is less clear. This review summarises the knowledge of the functional and structural properties of vascular interstitial cells accumulated so far, offers hypotheses on their physiological role, and proposes directions for future research.


Early use of phonological codes in deaf readers: An ERP study.
Previous studies suggest that deaf readers use phonological information of words when it is explicitly demanded by the task itself. However, whether phonological encoding is automatic remains controversial. The present experiment examined whether adult congenitally deaf readers show evidence of automatic use of phonological information during visual word recognition. In an ERP masked priming lexical decision experiment, deaf participants responded to target words preceded by a pseudohomophone (koral - CORAL) or an orthographic control prime (toral - CORAL). Responses were faster for the pseudohomophone than for the orthographic control condition. The N250 and N400 amplitudes were reduced for the pseudohomophone when compared to the orthographic control condition. Furthermore, the magnitude of both the behavioral and the ERP pseudohomophone effects in deaf readers was similar to that of a group of well-matched hearing controls. These findings reveal that phonological encoding is available to deaf readers from the early stages of visual word recognition. Finally, the pattern of correlations of phonological priming with reading ability suggested that the amount of sub-lexical use of phonological information could be a main contributor to reading ability for hearing but not for deaf readers.


The Association of Estrogen Receptor-β Gene Variation With Salt-Sensitive Blood Pressure.
Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-β, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle. To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women. Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging. Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1. The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.


The Mechanism of Killing by the Proline-Rich Peptide Bac7(1-35) against Clinical Strains of Pseudomonas aeruginosa Differs from That against Other Gram-Negative Bacteria.
Pseudomonas aeruginosa infections represent a serious threat to worldwide health. Proline-rich antimicrobial peptides (PR-AMPs), a particular group of peptide antibiotics, have demonstrated in vitro activity against P. aeruginosa strains. Here we show that the mammalian PR-AMP Bac7(1-35) is active against some multidrug-resistant cystic fibrosis isolates of P. aeruginosa By confocal microscopy and cytometric analyses, we investigated the mechanism of killing against P. aeruginosa strain PAO1 and three selected isolates, and we observed that the peptide inactivated the target cells by disrupting their cellular membranes. This effect is deeply different from that previously described for PR-AMPs in Escherichia coli and Salmonella enterica serovar Typhimurium, where these peptides act intracellularly after having been internalized by means of the transporter SbmA without membranolytic effects. The heterologous expression of SbmA in PAO1 cells enhanced the internalization of Bac7(1-35) into the cytoplasm, making the bacteria more susceptible to the peptide but at the same time more resistant to the membrane lysis, similarly to what occurs in E. coli The results evidenced a new mechanism of action for PR-AMPs and indicate that Bac7 has multiple and variable modes of action that depend on the characteristics of the different target species and the possibility to be internalized by bacterial transporters. This feature broadens the spectrum of activity of the peptide and makes the development of peptide-resistant bacteria a more difficult process.


Radiographic evaluation of the skull base.
The anatomic complexities of the skull base and the variable clinical presentation of skull base tumors often precludes accurate determination of tumor boundaries by history and physical alone. Imaging, employing computed tomography (CT) and magnetic resonance imaging (MR) allows for accurate tumor mapping and planning of appropriate therapeutic intervention. Calvarium floor involvement and extracranial lesions are well delineated by CT. While multiplanar MR is unparalleled in demonstrating tumor boundaries and extension through the skull base. In order to employ these imaging modalities in an efficient way, it is important to understand the limitations and capabilities of these modalities as well as the imaging characteristics of common skull base lesions.


Magnetic resonance imaging of the middle and inner ear after intratympanic injection of a gadolinium-containing gel.
To investigate the distribution and elimination of a gadolinium containing high viscosity formulation of sodium hyaluronan (HYA gel) after injection to the middle ear. The T1 contrast agent gadolinium-diethylenetriamine pentaacetic acid-bis methylamine (Gd-DTPA-BMA) was added to HYA gel and delivered to the middle ear of 13 albino guinea pigs by 3 different ways of injection. Magnetic resonance imaging was performed with a 4.7 T MRI system using a T1-weighted 3-dimentional rapid acquisition with relaxation enhancement sequence. An injection technique where the Gd-DTPA-BMA-containing HYA gel was delivered to the middle ear through a percutaneous injection through the auditory bulla after a small incision had been made in the tympanic membrane gave the best filling of the middle ear, covering the cochlea and the region of the round window niche for 24 hours in a majority of the ears studied. Ears injected without an incision in the tympanic membrane showed an immediate uptake of Gd-DTPA-BMA in the inner ear as a sign of rupture of the round window membrane. A percutaneous injection of a HYA gel into the tympanic bulla is distributed in a predictable way and gives a good filling of the middle ear cavity. The HYA gel remains in close vicinity to the RWM for more than 24 hours. Injection should be performed after an incision of the tympanic membrane has been made to prevent rupture of the round window membrane.


Phenological responses to climate change based on a hundred years of herbarium collections of tropical Melastomataceae.
Changes in phenological events have been vastly documented in face of recent global climate change. These studies are concentrated on temperate plants, and the responses of tropical species are still little understood, likely due to the lack of long-term phenological records in the tropics. In this case, the use of herbarium specimens to gather phenological data over long periods and wide geographic areas has emerged as a powerful tool. Here, we used four Melastomataceae species endemic to the Brazilian Atlantic Forest to evaluate phenological patterns and alterations as responses to recent climate changes. Phenological data were gathered from Reflora Virtual Herbarium specimens collected between 1920 and 2018, and analyzed with circular statistics applied to the intervals 1920-1979, 1980-1999, and 2000-2018. The effects of temperature range, average temperature, precipitation, and photoperiod on flowering and fruiting of each species were tested using multiple linear regressions. Through circular statistics, we detected changes, mostly delays, in the flowering of Miconia quinquedentata, Pleroma clavatum and P. trichopodum, and in the fruiting of M. acutiflora, P. clavatum and P. trichopodum. We also found that flowering and fruiting occurrence were related to local climatic conditions from months prior to the collections. We found marked phenological variations over the decades and also that these variations are associated to global climate change, adding up to the large body of evidence from higher latitudes. Our results also support herbarium collections as an important source for long-term tropical phenological studies. The lack of consistent patterns of responses among the four species (e.g. fruiting delayed two months in P. clavatum and advanced one month in M. acutiflora) suggests that climate change has unequal effects across tropical forests. This highlights the urgent need for further research to understand and forecast the ecological implications of these changes in global ecosystems processes.