Penetrating stab wounds to the brain: the timing of angiography in patients presenting with the weapon already removed.
Angiography is always necessary in patients with penetrating stab wounds to the head, to exclude unexpected vascular lesions. The most important, since they are seldom clinically evident, are traumatic aneurysms and arteriovenous fistulae. It has previously been proposed that carotid angiography should be delayed until the start of the second week, to allow for better visualization of these complications. However, traumatic aneurysms can rupture at any time after the injury, and the mortality resulting from a second hemorrhage is unacceptably high. A prospective study was undertaken in which 330 patients with penetrating stab wounds to the head underwent angiography as soon as possible after admission. In 250 of these patients (76%), the weapon had already been removed by the assailant, and there was radiological evidence of penetration of the dura. Of these 250, 130 patients underwent angiography within 7 days of the injury. Another 51 patients, who presented late, underwent angiography more than 7 days after the injury. The timing of angiography did not affect the identification of traumatic aneurysms, the incidence of which was 12% in both groups. Of the patients with cranial stabs and who required urgent evacuation of intracerebral hematomas, 10% had traumatic aneurysms that could be dealt with simultaneously. No patient in this series suffered a secondary hemorrhage. We conclude that it is neither necessary nor safe to delay angiography. In some patients, either because of vasospasm or "cut-off" of a vessel, a second angiogram may be necessary to further elucidate a vascular abnormality that might not have been evident originally.


Determinants of insulin responsiveness in young women: Impact of polycystic ovarian syndrome, nitric oxide, and vitamin D.
Polycystic ovary syndrome (PCOS) is associated with incremental risk of atherosclerosis and possibly of cardiovascular events. Insulin resistance (IR) occurs frequently in PCOS subjects, which might be one of the mechanisms involved in engendering such risk. We sought to evaluate whether the impact of other factors potentially associated both with PCOS and with IR might differentially modulate degree of IR in women with and without PCOS. We measured body mass index (BMI), hs-CRP, plasma concentrations of asymmetric dimethylarginine (ADMA), vitamin D (25(OH)D3) levels and platelet responsiveness to nitric oxide donor sodium nitroprusside (NO responsiveness) in 47 young women (n=27 with PCOS and n=20 weight-matched controls) without metabolic syndrome, hypertension or overt cardiovascular disease. We performed univariate and multivariate regression analyses to establish correlates of the quantitative insulin-sensitivity check index (QUICKI), as a marker of IR. On univariate analysis, plasma 25(OH)D3 levels and low NO responsiveness tended to be direct correlates with QUICKI in the entire subject group. BMI, hs-CRP, and ADMA levels were significant inverse correlates of QUICKI in PCOS subjects, but not in subjects without PCOS. On multivariate analysis, NO responsiveness, and 25(OH)D3 levels, but not PCOS per se were significant correlates of QUICKI. In the entire cohort of young women, low NO responsiveness and vitamin D deficiency are associated with low QUICKI, while elevated ADMA, inflammatory activation and obesity are selectively associated with low QUICKI in PCOS subjects; this may contribute to the increased cardiovascular risk associated with this syndrome.


Leader Affective Presence and Feedback in Teams.
Affective Presence refers to the consistent and stable feelings that an individual tends to leave in their interaction partners. Expanding previous research on the application of affective presence to individuals in the role of leaders in teams, in this study, I examine whether leaders' feedback behavior is related to the emergence of their affective presence. Using a multisource survey design with a sample of employees from a technology organization, as expected, results indicated that leader feedback behavior directed to the characteristics that team members should ideally have to perform well (ought self feedback) is positively related to leaders' positive affective presence. In contrast, feedback directed to compare team members' performance with other team members' performance (normative cues feedback) is positively associated with leaders' negative affective presence. As such, the study contributes to having an understanding of the etiology of affective presence in the context of teams, also informing organizational practitioners about how to manage leader influences on team members.


Using the theoretical domains framework to determine the barriers and facilitators to medication adherence in Parkinson's disease.
Patient medication adherence in Parkinson's Disease (PD) is often suboptimal. This may lead to poor symptom management, greater disease burden, decreased quality of life and increased healthcare costs. Use of psychological theory such as the Theoretical Domains Framework (TDF) has effectively captured barriers and facilitators to medication adherence in other long-term conditions. Applying this framework to medication adherence in PD could provide a better understanding of the challenges to inform the development of effective interventions. The aim of the study was to apply the TDF to determine the barriers and facilitators to medication adherence in people with PD. This qualitative study employed online interviews to explore medication adherence in a small group of people with PD recruited via Parkinson's UK and social media. A semi-structured interview schedule was designed informed by the 14 TDF domains. All interviews were audio-recorded, transcribed verbatim and mapped to the TDF using Framework Analysis. Twelve participants diagnosed with PD were interviewed, 11 of whom were currently taking prescribed medication plus another self-medicating with Vitamin B1. All TDF domains were evident in the data. Predominant facilitators were Domains 1 - Knowledge, 6 - Social Influence, and 12 - Beliefs about Consequences and barriers were 7 - Reinforcement, 10 - Memory, Attention and Decision Processes, and 11 - Environmental Context and Resources. Other themes were not related to medication adherence. In this small group, all data relating to the barriers and facilitators for medication adherence in PD were successfully mapped onto the TDF. This indicates the utility of the framework for determining and structuring the factors to consider when providing medication support for this patient population in an accessible and coherent way. Further quantitative studies are needed to determine the extent to which these factors can be generalised to other PD patients.


Rapid Growth of Large Forest Fires Drives the Exponential Response of Annual Forest-Fire Area to Aridity in the Western United States.
Annual forest area burned (AFAB) in the western United States (US) has increased as a positive exponential function of rising aridity in recent decades. This non-linear response has important implications for AFAB in a changing climate, yet the cause of the exponential AFAB-aridity relationship has not been given rigorous attention. We investigated the exponential AFAB-aridity relationship in western US forests using a new 1984-2019 database of fire events and 2001-2020 satellite-based records of daily fire growth. While forest-fire frequency and duration grow linearly with aridity, the exponential AFAB-aridity relationship results from the exponential growth rates of individual fires. Larger fires generally have more potential for growth due to more extensive firelines. Thus, forces that promote fire growth, such as aridification, have more potent effects on larger fires. As aridity increases linearly, the potential for growth of large fires accelerates, leading to exponential increases in AFAB.


Developing anti-racist undergraduate nursing education: themes and action.
The impact of racism on health is undeniable. However, undergraduate nurse education in the UK is not adequately addressing the racism within the profession. Literature on anti-racist nursing education was reviewed to uncover the most effective strategies for nurse educators to develop this approach. The literature describes a climate of denial and defensiveness among nurse educators. It urges nurse educators to develop racial literacy, and explores nursing curricula, recommending intersectionality as a way to teach about health disparities, with a move away from a culturalist perspective. There is growing recognition that institutions need to address issues around the retention of Black students, and robust reporting systems are required to respond to allegations of racism. Institutions also need to provide evidence-based anti-racist training for staff. The conclusion here is that, without institutional support, there is little nurse educators can do alone to change the culture of racism in nurse education. Thus, this review is a starting point for nurse educators interested in anti-racist nursing education.


A comparison of the maternal levels of serum proprotein convertase subtilisin/kexin type 9 in pregnant women with the complication of fetal open neural tube defects.
It was aimed to evaluate the levels of maternal serum proprotein convertase subtilisin/kexin type 9 (PCSK9) in pregnant women with a fetus diagnosed with open neural tube defects (NTDs). This case-control study included 38 pregnant women carrying fetuses with open NTDs and 44 age-matched, pregnant women with no specified risk factors. Comparisons were made of the groups in respect of demographic and clinical data and PCSK9 levels. To examine the performance of PCSK9 levels in the prediction of fetal open NTDs, receiver operating characteristic (ROC) curve analysis was used. In the first and second trimesters, PCSK9 levels were determined to be lower in the NTD group than in the control group (p = 0.010 and p = 0.015, respectively). In the first trimester, the lower PCSK9 levels in the NTD group were not statistically significant (p = 0.575). In the second trimester, the ROC curve value with the best balance of sensitivity/specificity for PCSK9 was 71.9 ng/ml (84.6% sensitivity, 51.7% specificity) and in the first and second trimester combined, 74.4 ng/ml (81.6% sensitivity, 45.5% specificity) (p = 0.015, p = 0.036, respectively). PCSK9 may be involved in the etiopathogenesis of open NTDs at the critical steps of fetal neuronal differentiation. Although it has limitations, PCSK9 may be used as an additional biomarker for the screening of NTDs.


Initiation of protein synthesis at an unusual position in an immunoglobulin gene?
The amino acid sequence of urinary beta(2)-microglobulin has been partially determined and found to be related to the constant region of IgG immunoglobulin heavy chain. beta(2)-Microglobulin is present in normal individuals. Its gene may have evolved from an immunoglobulin gene by the use of an unusually located start signal for initiating synthesis of the polypeptide.


Tubercular prosthetic knee joint infection.
This article reports a rare case of late-onset tubercular infection following total knee arthroplasty in a 60-year-old woman who had been treated with a full course of antitubercular therapy for latent tuberculosis almost 25 years ago. Because no clear guidelines exist for optimal management of disease reactivation in the prosthetic knee joint, the authors performed a literature review and attempted to provide a treatment algorithm based on the time of presentation. Two modes of presentation were identified for unsuspected tubercular prosthetic joint infections based on the onset of symptoms and time to diagnosis: an early-onset presentation that occurs within the first 6 to 8 weeks postoperatively and a late-onset presentation that usually manifests after 8 weeks. Early-onset presentations often can be treated with standard antitubercular chemotherapy alone, whereas late-onset presentation may require 2-stage reimplantation under cover of antitubercular medications. This report also highlights the fact that despite adequate treatment of latent tuberculosis, patients may remain at risk of prosthetic joint infection following total knee arthroplasty.


Induction of rat WT1 gene expression correlates with human chromosome 11p11.2-p12-mediated suppression of tumorigenicity in rat liver epithelial tumor cell lines.
We have previously identified and mapped a locus within human chromosome 11p11.2-p12 that suppresses the tumorigenic potential of some rat liver tumor cell lines. In the present study, possible molecular mechanisms of human 11p11.2-p12-mediated liver tumor suppression were investigated by examining gene expression patterns in suppressed and non-suppressed microcell hybrid (MCH) cell lines. The parental rat liver tumor cell lines (GN6TF and GP7TB) express moderate levels of p53 mRNA and protein, overexpress mRNAs for c-H-ras, c-myc, and TGFá, and do not express detectable levels of WT1 mRNA or protein. Suppression of tumorigenicity by human chromosome 11p11.2-p12 was not accompanied by significant alterations in the levels of expression of p53, c-myc, or TGFá. Expression of c-H-ras was decreased significantly in both suppressed and non-suppressed MCH cell lines, suggesting that down-regulation of c-H-ras is not directly responsible for tumor suppression. In contrast, the level of expression of WT1 correlated precisely with tumor suppression in this model system. All suppressed MCH cell lines expressed WT1 mRNA and protein at levels comparable to that of untransformed rat liver epithelial cells (WB-F344), whereas only trace WT1 mRNA and protein were detected in a non-suppressed MCH cell line. PCR analysis demonstrated that two suppressed MCH cell lines do not carry the human WT1 gene, indicating that WT1 expression in these lines originates from the rat locus. Furthermore, RT-PCR analysis showed that each of the four known splice variants of the WT1 mRNA are expressed in these suppressed MCH cell lines, recapitulating the expression pattern observed in the untransformed rat liver epithelial cells. Re-expression of tumorigenicity by suppressed MCH cell lines was accompanied by the coordinate loss of human chromosome 11p11.2-p12 and of WT1 gene expression, suggesting that one or more human 11p11.2-p12 genes are required for sustained expression of WT1 in these cell lines. Together, these results suggest that the molecular mechanism governing human chromosome 11p11.2-p12-mediated liver tumor suppression may involve induction of rat WT1 gene expression under the direct or indirect transcriptional regulation of a genetic locus (or loci) on human 11p11.2-p12.


Update for nurse anesthetists. Part 6. Full-body patient simulation technology: gaining experience using a malignant hyperthermia model.
Simulation technology is extremely useful for training workers in a variety of industries. Simulation concepts have been developed and refined in full-body patient simulators. Contemporary full-body patient simulators can be used to teach the essential concepts of many healthcare professions, and they offer practice dealing with critical events, concentrating on the thought and decision-making processes related to favorable patient outcomes. Full-body patient simulators provide practitioners the opportunity to manage realistic and advanced physical findings in a variety of areas and are capable of responding to a large number of pharmacologic agents and a host of clinical interventions. The ability to combine high-fidelity educational tools with both classroom lecture and clinical experience provides nurse anesthetists the opportunity for a unique experience in a highly controlled and safe environment. Numerous technological and educational advantages and the chance for hands-on assessment and treatment of some of anesthesia's rarest and most life-threatening events provide a one-of-a-kind educational session for CRNAs.


Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung.
Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro . AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro .


[Morphometric analysis of colorectal carcinoma and its clinical significance].
The clinical value of 5 parameters (DNAP, DNAS, NAS, NCR, CEAD) in colorectal carcinoma was studied in 80 cases with a 5-year follow-up history. Four of the parameters (DNAP, NAS, NCR, CEAD) were significantly higher in colorectal carcinoma than those in normal mucosa (P less than 0.01). This result seemed valuable for the quantitative pathologic diagnosis of colorectal carcinoma. Comparing with the group surviving for 5 years or longer, the group surviving for less than 5 years had a significantly higher DNAP and NCR (P less than or equal to 0.01). No clear correlation was found between DNAP and NCR or between these two parameters and clinicopathologic data including clinical stage, histopathologic grade and pathologic classification. This fact indicates that DNAP and NCR of colorectal carcinoma reflect the malignant level of the tumor. It is considered that DNAP and NCR are valuable, objective and predictive parameters for prognosis. As higher DNAP and NCR indicated higher malignancy.


Indoor ultrafine particles of outdoor origin: importance of window opening area and fan operation condition.
Inhalation exposure to ambient ultrafine particles (UFP) has been shown to induce adverse health effects such as respiratory and cardiovascular mortality. Human exposure to particles of outdoor origin often occurs indoors due to entry of UFP into buildings. The objective of the present study is to investigate entry of UFP into a building considering building operational characteristics and their size-dependent effects on UFP concentrations. Indoor and outdoor UFP concentrations along with air change rates were continuously measured in a full-scale test building. Estimates of infiltration factor, penetration coefficient, and deposition rate have been made for a range of particle sizes from 4 to 100 nm. The results show that UFP infiltration factor varies with particle diameter, window position, air change rate, and central fan operation. When the central fan was on continuously, the average infiltration factor ranged from 0.26 (particles <10 nm) to 0.82 (particles >90 nm) for two large window openings, and from 0.07 to 0.60 for two small window openings. Under the central fan-off condition, the average infiltration factor ranged from 0.25 (particles <10 nm) to 0.72 (particles >90 nm) for two small window openings, while it ranged from 0.01 to 0.48 with all windows closed. Larger window openings led to higher infiltration factors due to the larger extent of particle penetration into the building. The fan operation mode (on vs off) also has a strong impact, as the infiltration factor was consistently lower (up to 40%) when the fan was on due to additional particle deposition loss to the furnace filter and duct surfaces.


Encore: Genetic Association Interaction Network centrality pipeline and application to SLE exome data.
Open source tools are needed to facilitate the construction, analysis, and visualization of gene-gene interaction networks for sequencing data. To address this need, we present Encore, an open source network analysis pipeline for genome-wide association studies and rare variant data. Encore constructs Genetic Association Interaction Networks or epistasis networks using two optional approaches: our previous information-theory method or a generalized linear model approach. Additionally, Encore includes multiple data filtering options, including Random Forest/Random Jungle for main effect enrichment and Evaporative Cooling and Relief-F filters for enrichment of interaction effects. Encore implements SNPrank network centrality for identifying susceptibility hubs (nodes containing a large amount of disease susceptibility information through the combination of multivariate main effects and multiple gene-gene interactions in the network), and it provides appropriate files for interactive visualization of a network using tools from our online Galaxy instance. We implemented these algorithms in C++ using OpenMP for shared-memory parallel analysis on a server or desktop. To demonstrate Encore's utility in analysis of genetic sequencing data, we present an analysis of exome resequencing data from healthy individuals and those with Systemic Lupus Erythematous (SLE). Our results verify the importance of the previously associated SLE genes HLA-DRB and NCF2, and these two genes had the highest gene-gene interaction degrees among the susceptibility hubs. An additional 14 genes previously associated with SLE emerged in our epistasis network model of the exome data, and three novel candidate genes, ST8SIA4, CMTM4, and C2CD4B, were implicated in the model. In summary, we present a comprehensive tool for epistasis network analysis and the first such analysis of exome data from a genetic study of SLE.


Diagnostic accuracy of peritoneal lavage in patients with pelvic fractures.
To determine the accuracy of diagnostic peritoneal lavage (DPL) for the evaluation of intraabdominal injury in patients with a pelvic fracture as a result of blunt trauma. Retrospective cohort analysis. Level I trauma center in metropolitan Seattle, Wash. Four hundred ninety-seven consecutive patients admitted with pelvic fractures following blunt trauma during a 60-month period. Positive results of DPL, defined by one of the following: an immediate aspiration of more than 10 mL of gross blood; a red blood cell count of more than 0.0001 x 10(12)/L; a white blood cell count greater than 0.0005 x 10(9)/L; an elevated amylase, bilirubin, or creatinine level; or organic particles or bacteria in the effluent returned after installation of 1 L of crystalloid fluid lavaged in the peritoneal cavity. Two hundred eighty-six patients underwent DPL. For 80 patients (28.0%), results of DPL were positive and for 194 patients (67.8%) the results of DPL were negative. For two patients (0.7%), results of DPL were false positive for a sensitivity of 94%. For another two patients (0.7%), the results of DPL were false negative for a specificity of 99%. As a diagnostic modality, DPL has a positive predictive value of 98% and a negative predictive value of 97%. Diagnostic peritoneal lavage is a reliable method for the evaluation of intra-abdominal injury and should remain a standard component in the evaluation of patients following blunt injury with or without pelvic fractures.


Muscarinic modulation of spike backpropagation in the apical dendrites of hippocampal CA1 pyramidal neurons.
In pyramidal neurons from the CA1 region of the rat hippocampus, Na+-dependent action potentials backpropagate over the dendrites in an activity-dependent manner. Consequently, later spikes in a train have smaller amplitudes when recorded in the apical arbors. We studied the effect of the cholinergic agonist carbachol (CCh) on this pattern of activity when spikes were evoked synaptically or antidromically in the transverse slice preparation. Concentrations as low as 1 microM were effective in reversing the modulation, making the amplitude of all spikes in a train equal and independent of the frequency of spike firing. CCh did not change the propagation of the first spike in a train. These effects of CCh were blocked by 1 microM atropine, showing that only muscarinic receptors were involved. The effects of CCh on the pattern of spike propagation were observed in the proximal and middle dendrites, but recordings in the distal dendrites (>300 micron from the soma) showed that CCh did not boost the amplitude in this region. Intracellular BAPTA (10 mM) or EGTA (10 mM) had no effect on activity-dependent backpropagation but blocked the effect of CCh. Backpropagating spikes caused increases in [Ca2+]i at all dendritic locations. In the middle and distal dendrites these increases normally peaked at the time of the first few large action potentials. In association with the enhancement of spike backpropagation, CCh increased the amplitude and duration of the train-evoked [Ca2+]i changes. These effects of CCh on dendritic spike potentials and associated [Ca2+]i changes may be important in modulating synaptic integration and plasticity in these neurons.


Biliary excretion of a glutathione conjugate of busulfan and 1,4-diiodobutane in the rat.
gamma-Glutamyl-beta-(S-tetrahydrothiophenium)alanyl-glycine, the glutathione-sulfonium conjugate of busulfan and 1,4-diiodobutane, was identified in the bile of rats following intravenous administration of equimolar doses of either compound. The glutathione-sulfonium conjugate was synthesized from 1-bromo-4-chlorobutane and characterized by 1H and 13C NMR and FAB/MS. An HPLC method was developed to identify the conjugate from rat bile by pre-column fluorescent derivatization with o-phthalaldehyde. The biliary excretion of cyclic sulfonium conjugates was quantitated indirectly by measuring the release of tetrahydrothiophene (THT) after treatment of the bile with base. THT release was quantitative and was measured by gas chromatography. With busulfan, peak biliary concentrations of THT-releasing metabolite(s) were reached after 90 min and 26% of the dose of busulfan was recovered in the bile after 8 hr. When diiodobutane was administered, 21% of the dose was recovered, and the peak concentration was reached in 30 min. The decline in THT releasing metabolite(s) was more rapid with 1,4-diiodobutane, and THT was no longer measurable after 3.5 hr compared to 7.5 hr after busulfan administration. These data confirm that busulfan and other 1,4-disubstituted butanes are conjugated with glutathione in vivo.


Mucosal Dehiscence After Alveolar Bone Graft in Cleft.
Cleft lip and palate patient represent a challenging experience for the surgeon. This kind of patients had to be followed by a multidisciplinary team from the beginning to the end to avoid the deformation sequelae. During the several surgical procedures, the bone graft represents a possible procedure that, through the new procedure, could be avoided. Unfortunately, patient treated following the previous procedure must be submitted to alveolar bone graft to coordinate the arch, to restore the maxillary integrity, to allow the correct dentition.


On the concept of model structural error.
A consideration of model structural error leads to some particularly interesting tensions in the model calibration/conditioning process. In applying models we can usually only assess the total error on some output variable for which we have observations. This total error may arise due to input and boundary condition errors, model structural errors and error on the output observation itself (not only measurement error but also as a result of differences in meaning between what is modelled and what is measured). Statistical approaches to model uncertainty generally assume that the errors can be treated as an additive term on the (possibly transformed) model output. This allows for compensation of all the sources of error, as if the model predictions are correct and the total error can be treated as "measurement error." Model structural error is not easily evaluated within this framework. An alternative approach to put more emphasis on model evaluation and rejection is suggested. It is recognised that model success or failure within this framework will depend heavily on an assessment of both input data errors (the "perfect" model will not produce acceptable results if driven with poor input data) and effective observation error (including a consideration of the meaning of observed variables relative to those predicted by a model).


MicroRNA-9 enhances invasion and migration of cervical carcinomas by directly targeting FOXO1.
Cervical carcinoma is the third frequently diagnosed cancer among women worldwide. Increasing evidence suggests that dysfunctions of miRNAs are involved in human cancers and could act as either tumor suppressors or oncogenes. The purpose of this study is to elucidate pathobiological functions of miR-9 expression by targeting FOXO1 in cervical carcinoma. Real-time-PCR was utilized to detect miR-9 and FOXO1 level in cervical carcinoma tissues and cells. Transwell assays were employed to check out the roles of miR-9 on cells invasive and migratory potency. Luciferase reporter and Western blot were applied to verify FOXO1 as a target gene of miR-9. The results showed that miR-9 was significantly high expressed in cervical carcinoma cell lines and clinical tissues. miR-9 enhanced the ability of migration and invasion of C33A and HeLa cells. FOXO1 was confirmed as the direct target of miR-9, and miR-9 over-expression down-regulated the expression level of FOXO1. Our data demonstrate that miR-9 enhances invasion and migration of cervical carcinomas by directly targeting FOXO1. This may lead to a modern therapeutic strategy for the treatment of cervical carcinomas.


Plasma carcinoembryonic antigen (CEA) as an indicator for radical or palliative radiotherapy in patients with rectal cancer.
A study of 59 patients referred for radiotherapy because of inoperable or recurrent rectal cancers is presented in which a correlation is made between the response to radiotherapy and the pretreatment serum CEA level. Patients were treated radically or palliatively on the basis of clinical presentation and routine laboratory tests, but without regard to the plasma CEA level prior to treatment. The pretreatment CEA level was assessed retrospectively as an indicator of the response to treatment. Patients with a plasma CEA level in excess of 75 ng/ml had a poor prognosis, even after radical radiotherapy, whereas patients with plasma CEA less than 75 ng/ml responded better to treatment. These results suggest that plasma CEA is of value, indicating the need for radical or palliative radiotherapy. In patients with high plasma CEA at referral, radical radiotherapy appears to confer little benefit. Those with a low plasma CEA appear to respond better to radical radiotherapy, and this should be the preferred treatment in this group unless the clinical presentation indicates otherwise.


Growth characteristics of poliovirus in HeLa cells: nucleic acid metabolism.
The RNA and DNA contents of the nucleus and cytoplasm of the HeLa cell were determined. The rates of incorporation of P(32) into the various nucleic acid fractions were established for the ordinary HeLa cell maintained under a set of standard conditions. The changes in the rates of incorporation of P(32) and in the amounts of RNA and DNA which occurred subsequent to infection with poliovirus were followed throughout the infectious cycle. These changes were correlated with the intracellular appearance of the newly formed virus. A net synthesis of RNA occurred in the cytoplasmic component of the cell. The increase was detectable 2 hours before the first appearance of demonstrable virus and reached a maximum (2.5 times normal) at 6 hours. Viral increase was not maximal before the 7th hour after infection.


A Boolean algorithm for reconstructing the structure of regulatory networks.
Advances in transcriptional analysis offer great opportunities to delineate the structure and hierarchy of regulatory networks in biochemical systems. We present an approach based on Boolean analysis to reconstruct a set of parsimonious networks from gene disruption and over expression data. Our algorithms, Causal Predictor (CP) and Relaxed Causal Predictor (RCP) distinguish the direct and indirect causality relations from the non-causal interactions, thus significantly reducing the number of miss-predicted edges. The algorithms also yield substantially fewer plausible networks. This greatly reduces the number of experiments required to deduce a unique network from the plausible network structures. Computational simulations are presented to substantiate these results. The algorithms are also applied to reconstruct the entire network of galactose utilization pathway in Saccharomyces cerevisiae. These algorithms will greatly facilitate the elucidation of regulatory networks using large scale gene expression profile data.


Influence of mycotoxins on protein and amino acid utilization.
The interrelationships between mycotoxins and the utilization of dietary protein are reviewed. Acute aflatoxicosis is characterized by reduced growth and fatty infiltration of the liver. Studies with poultry, swine, and monkeys have shown that supplements of dietary protein beyond normal requirements can overcome these conditions. High-protein diets, however, have been shown to promote hepatoma characteristic of chronic aflatoxicosis in rats. Aflatoxin interferes with utilization of dietary protein by inhibiting synthesis of DNA, RNA, and protein. High-protein diets promote the metabolism of aflatoxin by the hepatic microsomal drug-metabolizing enzyme system. The Fusarium mycotoxin zearalenone increases membrane permeability and promotes uterine synthesis of DNA, RNA, and protein. Supplements of dietary protein overcome growth reduction due to zearalenone and reduce the metabolic half-life of the toxin by promoting urinary excretion of free, unmetabolized zearalenone in the rat. The trichothecene mycotoxins disrupt normal protein metabolism by inactivating the ribosomal cycle. Protein supplements appear to have little effect on trichothecene mycotoxicoses. Most mycotoxins impair utilization of dietary protein. The effectiveness of protein supplements in overcoming mycotoxicoses will depend on the mycotoxin in question.


Free tissue transfer for trophic ulcer complicating leprosy.
Plantar ulceration is the commonest disability in leprosy and occurs in about 10 to 20% of leprosy patients. Various loco-regional flaps have been described for reconstruction of trophic ulcers; however, very large defects are not amenable to local flaps and free flaps form one of the important treatment options. We present a case of a post Hansen's trophic ulcer over the forefoot managed using a radial artery forearm free flap. Debridement of the osteomyelitic bone, removal of the bony prominences, coverage by a well-vascularised tissue, end-to-side arterial anastomosis, use of anterior tibial as the recipient vessel and good postoperative compliance in foot care on the part of the patient gave us good results.


The Effect of Dual Task on Attentional Performance in Children With ADHD.
Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder without validated objective markers. Oculomotor behavior and executive motor control could potentially be used to investigate attention disorders. The aim of this study was to explore an oculomotor and postural dual task in children with ADHD. Forty-two children were included in the study, gathering children with ADHD (n = 21) (mean 8.15 age ± years 0.36) and sex-, age-, and IQ-matched typically developing children (TD). Children performed two distinct fixation tasks in three different postural conditions. Eye movements and postural body sway were recorded simultaneously, using an eye tracker and a force platform. Results showed that children with ADHD had poor fixation capability and poor postural stability when compared to TD children. Both groups showed less postural control on the unstable platform and displayed more saccades during the fixation task. Surprisingly, in the dual unstable platform/fixation with distractor task, the instability of children with ADHD was similar to that observed in TD children. "Top-down" dys-regulation mediated by frontal-striatal dysfunction could be at the origin of both poor inhibitory oculomotor deficits and impaired body stability reported in children with ADHD. Finally, we could assume that the fact both groups of children focused their attention on a secondary task led to poor postural control. In the future it could be interesting to explore further this issue by developing new dual tasks in a more ecological situation in order to gain more insight on attentional processes in children with ADHD. HIGHLIGHTS - Children with ADHD showed poor fixation capability when compared to TD children. - "Top-down" dys-regulation mediated by frontal-striatal dysfunction could be at the origin of both poor inhibitory oculomotor deficits and impaired body stability reported in children with ADHD. - Both groups of children focused their attention on the visual fixation task leading to poor postural control. - In the future it could be interesting to develop new dual tasks in an ecological situation in order to gain more insight on attentional processes in children with ADHD.


The LhrC sRNAs control expression of T cell-stimulating antigen TcsA in Listeria monocytogenes by decreasing tcsA mRNA stability.
The bacterial pathogen Listeria monocytogenes encodes seven homologous small regulatory RNAs, named the LhrC family of sRNAs. The LhrCs are highly induced under infection-relevant conditions and are known to inhibit the expression of multiple target mRNAs encoding virulence-associated surface proteins. In all cases studied so far, the LhrCs use their CU-rich regions for base pairing to complementary AG-rich sequences of the ribosomal binding site (RBS) of specific target mRNAs. Consequently, LhrC-mRNA interaction results in inhibition of translation followed by mRNA degradation, corresponding to the canonical model for sRNA-mediated gene regulation in bacteria. Here, we demonstrate that the LhrC sRNAs employ a different regulatory mechanism when acting to down-regulate the expression of tcsA, encoding a T cell-stimulating antigen. In this case, LhrC base pairs to an AG-rich site located well upstream of the RBS in tcsA mRNA. Using an in vitro translation assay, we found that LhrC could not prevent the ribosome from translating the tcsA messenger. Rather, the LhrC sRNAs act to decrease the half-life of tcsA mRNA in vivo. Importantly, LhrC-mediated destabilization of tcsA mRNA relies on an intact LhrC binding site near the 5´-end of the tcsA mRNA and occurs independently of translation. Based on these findings, we propose an alternative mechanism for LhrC-mediated control in L. monocytogenes that relies solely on sRNA-induced degradation of a target mRNA.


T7 Polymerase Expression of Guide RNAs in vivo Allows Exportable CRISPR-Cas9 Editing in Multiple Yeast Hosts.
Efficient guide RNA expression often limits CRISPR-Cas9 implementation in new hosts. To address this limitation in fungal systems, we demonstrate the utility of a T7 polymerase system to effectively express sgRNAs. Initially, we developed a methodology in Saccharomyces cerevisiae using a modified version of the T7 P266L mutant polymerase with an SV40 nuclear localization signal to allow guide RNA expression immediately downstream of a T7 promoter. To improve targeting efficiency, guide RNA design was found to be tolerant to three mismatches or up to three additional bases appended to the 5' end. The addition of three guanines to a T7-based guide RNA improved guide RNA expression 80-fold and achieved transcriptional output similar to the strong Pol III snr52 promoter. Resulting gene editing and dCas9-guided gene regulation with a T7-based guide RNA was on par with the commonly used snr52 system in S. cerevisiae. Finally, 96% and 60% genome editing efficiencies were achieved in Kluyveromyces lactis and Yarrowia lipolytica respectively with minimal optimization of this system. Thus, T7-based expression of sgRNAs offers an orthogonal method for implementing CRISPR systems in fungal systems.


HLA-II Alleles Influence Physical and Behavioral Responses to a Whey Allergen in a Transgenic Mouse Model of Cow's Milk Allergy.
The symptoms of food allergies vary significantly between individuals, likely due to genetic determinants. In humans, allergy development is initiated by antigen-presenting cells via class II human leukocyte antigen (HLA-II). The HLA-II gene is highly polymorphic, and its allelic variance is thought to influence the susceptibility of individuals to a particular allergen. However, whether antigen presentation by different HLA-II variants contributes to symptom variation is not clear. We hypothesized that HLA-II allelic variance affects symptom phenotypes, including immediate physical reactions and delayed behavioral changes, in individuals with food hypersensitivity. To test our hypothesis, male and female mice of three transgenic strains expressing an HLA-II variant, DR3, DR15, or DQ8, were used to establish a cow's milk allergy model. Mice were sensitized to a bovine whey allergen, β-lactoglobulin (BLG; Bos d 5), weekly for 5 weeks, followed by an acute oral allergen challenge. At 30 min post-challenge, BLG-sensitized DR3 mice showed moderate to severe anaphylaxis resulting in perioral redness, swelling, and death. In contrast, DQ8 and DR15 mice were generally asymptomatic. The production of allergen-specific immunoglobulins was also HLA- and sex-dependent. Both male and female DR3 and female DR15 mice significantly increased BLG-specific IgE production, while robust elevation in BLG-specific IgG1 was observed in sensitized DQ8 mice of both sexes and, to a lesser extent, in DR15 males. Furthermore, BLG-sensitized DR15 mice showed sex-specific behavior changes, with males exhibiting mobility changes and anxiety-like behavior and females showing spatial memory impairment. When splenocytes from transgenic mice were stimulated in vitro with BLG, phenotypes of immune cells were HLA- and sex-specific, further underscoring the influence of HLA-II on immune responses. Our results support that HLA-II alleles influence behavioral responses in addition to immune and physical reactions of food allergy, suggesting that certain HLA-II variants may predispose individuals to food-allergy-associated behavioral changes.


Burn injury.
Burn injuries are under-appreciated injuries that are associated with substantial morbidity and mortality. Burn injuries, particularly severe burns, are accompanied by an immune and inflammatory response, metabolic changes and distributive shock that can be challenging to manage and can lead to multiple organ failure. Of great importance is that the injury affects not only the physical health, but also the mental health and quality of life of the patient. Accordingly, patients with burn injury cannot be considered recovered when the wounds have healed; instead, burn injury leads to long-term profound alterations that must be addressed to optimize quality of life. Burn care providers are, therefore, faced with a plethora of challenges including acute and critical care management, long-term care and rehabilitation. The aim of this Primer is not only to give an overview and update about burn care, but also to raise awareness of the ongoing challenges and stigmata associated with burn injuries.


Duration of Dialysis in Acute Kidney Injury Donors and Transplant Outcomes.
Acute kidney injury (AKI) kidneys, including those from donors on dialysis, are often underutilized, although there is increasing data available demonstrating good transplant outcomes. To date, data on the duration of donor dialysis and transplant outcomes are limited. This was a single-center study of deceased donor kidney transplants from 2010 to 2022. The study cohort consisted of recipients of deceased donor kidney transplants from donors with AKI and on dialysis. Three groups were identified based on the predetermined interquartile range of donor dialysis duration: 1 to 2 dialysis days, 3 to 4 dialysis days, and 5 or more dialysis days. During this period, 765 AKI deceased donor transplants were performed, of which 230 were from donors on dialysis. The median dialysis duration was 2 days with a maximum of 13 days. Across the 3 groups, there were no differences in recipient age (p = 0.23) or dialysis vintage (p = 0.70). Donor age (p = 0.86) and kidney donor profile index (p = 0.57) were comparable between the groups. Recipients of deceased donor kidney transplants from donors on dialysis 5 or more days had lower terminal creatinine levels (p = 0.003) and longer cold ischemia times (p = 0.04). Posttransplant, the median length of hospital stay was 3 days for all groups (p = 0.75). There were no differences in delayed graft function occurrence (94.4% vs 86.8% vs 92.1%, p = 0.19), duration of delayed graft function (p = 0.56), or readmissions (p = 0.99). At 1 year posttransplant, the estimated glomerular filtration rate (p = 0.76), patient survival (p = 0.82), or death-censored graft survival (p = 0.28) were comparable. Excellent outcomes have been observed in AKI deceased donor kidney transplants, including those coming from donors on dialysis. In this small cohort, the duration of donor dialysis did not adversely affect outcomes. Cautious expansion of the donor pool, including donors on dialysis, should be considered given the ongoing organ shortage.


Growth-regulating influence of nonactivated resident macrophages on transformed and tumor cells in the in vitro contact interactions.
Susceptibility to cytostatic activity of nonactivated macrophages (Mph) of Syrian hamster embryo fibroblasts (HEF) transformed in vitro by BAV-3, SV40, RSV-SR, or spontaneously and of their in vivo selected variants was studied in dynamics (5 days of co-incubation). With the use of 3H-TdR incorporation test it was demonstrated that HEF transformed by BAV-3 appeared to be able to overcome the cytostasis at 4-5 day of the co-incubation with Mph, in contrast to deeply suppressed spontaneously transformed cells of STHE strain. HEF transformed by SV40, or RSV-SR appeared to be resistant to growth-inhibiting activity of Mph during almost all the 5-day period. The in vivo selected malignant variants of STHE cells were able to recover from cytostasis after 4-5 days of the co-incubation with nonactivated Mph, in contrast to low-malignant variant and to parental cell strain.


Children in general practice: an exciting area for research. Reflections on the EGPRN meeting in Plovdiv, Bulgaria, May 2010.
The European General Practice Research Network organized an international research conference on 'Children in General Practice' in Plovdiv, Bulgaria, in May 2010. Two of the authors were keynote speakers at the workshop, tasked with summarizing the theme research presentations on each of the two days of the meeting. The theme of the meeting 'Children in General Practice' refers to the primary aim for timely and high quality health care for every child and the related general practitioners' activities. The meeting was an important event, especially for young doctors and investigators from different countries, because they were informed of good practices from other European countries in preventive work with children. All participants shared and learned a lot of good ideas beyond the standards and quality management. Examples of ideas for new research questions that emerged were to study differences in routine check-ups during childhood between European countries; to study the effectiveness of advices given by GPs to (parents of) obese children; and to study adverse events of medication in general practice. At a European level, the diversity of the ways health care systems deal with health problems in children is striking. We felt great enthusiasm to further develop this research area. Interested family doctors are invited to attend future conferences to develop collaborative research projects on this topic.


Effects of carbohydrate quality and amount on plasma lactate: results from the OmniCarb trial.
Plasma lactate is a marker of non-oxidative glucose metabolism associated with progression to diabetes. We examined the effect of carbohydrate quality (glycemic index (GI)) and amount (%kcal) on plasma lactate. We hypothesized that low GI (≤45 (g)) versus high (≥65 (G)) and low %kcal from carbohydrate (40% kcal (c)) versus high (58% kcal (C)) each would reduce lactate levels. We measured lactate in OmniCarb, a randomized, cross-over trial of four diets in overweight/obese adults without diabetes or cardiovascular disease (N=163). The four diets were high carbohydrate+high GI (CG, reference), high carbohydrate+low GI (Cg), low carbohydrate+high GI (cG), and low carbohydrate+low GI (cg). Participants (N=163) consumed each of the four diets over a 5-week period, separated by 2-week washout periods. Plasma lactate levels were measured at baseline, during which the participants consumed their own diets, and after each 5-week period. Baseline plasma lactate was 1.2 mmol/L. In the setting of high carbohydrate amount, reducing GI lowered plasma lactate non-significantly by 0.08 mmol/L (Cg vs CG: 95% CI -0.16 to 0.00; p=0.06). In the setting of high GI, reducing carbohydrate amount lowered plasma lactate by 0.10 mmol/L (cG vs CG: 95% CI -0.19 to -0.02; p=0.02). The combined effect of reducing GI and carbohydrate proportion in the diet (cg vs CG) was similar (cg vs CG: -0.08; 95% CI -0.16 to 0.00; p=0.04). All four diets reduced plasma lactate compared with baseline. Compared with a diet with high GI and high carbohydrate amount, diets with low GI and/or low carbohydrate amount reduced plasma lactate. Whether this change in lactate leads to long-term change in glucose metabolism needs to be examined. NCT00608049.


Aneurysm growth, survival, and quality of life in untreated thoracic aortic aneurysms: the effective treatments for thoracic aortic aneurysms study.
To observe, describe, and evaluate management and timing of intervention for patients with untreated thoracic aortic aneurysms. Prospective study of UK National Health Service (NHS) patients aged ≥18 years, with new/existing arch or descending thoracic aortic aneurysms of ≥4 cm diameter, followed up until death, intervention, withdrawal, or July 2019. Outcomes were aneurysm growth, survival, quality of life (using the EQ-5D-5L utility index), and hospital admissions. Between 2014 and 2018, 886 patients were recruited from 30 NHS vascular/cardiothoracic units. Maximum aneurysm diameter was in the descending aorta in 725 (82%) patients, growing at 0.2 cm (0.17-0.24) per year. Aneurysms of ≥4 cm in the arch increased by 0.07 cm (0.02-0.12) per year. Baseline diameter was related to age and comorbidities, and no clinical correlates of growth were found. During follow-up, 129 patients died, 64 from aneurysm-related events. Adjusting for age, sex, and New York Heart Association dyspnoea index, risk of death increased with aneurysm size at baseline [hazard ratio (HR): 1.88 (95% confidence interval: 1.64-2.16) per cm, P < 0.001] and with growth [HR: 2.02 (1.70-2.41) per cm, P < 0.001]. Hospital admissions increased with aneurysm size [relative risk: 1.21 (1.05-1.38) per cm, P = 0.008]. Quality of life decreased annually for each 10-year increase in age [-0.013 (-0.019 to -0.007), P < 0.001] and for current smoking [-0.043 (-0.064 to -0.023), P = 0.004]. Aneurysm size was not associated with change in quality of life. International guidelines should consider increasing monitoring intervals to 12 months for small aneurysms and increasing intervention thresholds. Individualized decisions about surveillance/intervention should consider age, sex, size, growth, patient characteristics, and surgical risk.


Metallothionein cDNA, promoter, and genomic sequences of the tropical green mussel, Perna viridis.
The primary structure of the cDNA and metallothionein (MT) genomic sequences of the tropical green mussel (Perna viridis) was determined. The complete cDNA sequences were obtained using degenerate primers designed from known metallothionein consensus amino acid sequences from the temperate species Mytilus edulis. The amino acid sequences of P. viridis metallothionein deduced from the coding region consisted of 72 amino acids with 21 cysteine residues and 9 Cys-X-Cys motifs corresponding to Type I MT class of other species. Two different genomic sequences coding for the same mRNA were obtained. Each putative gene contained a unique 5'UTR and two unique introns located at the same splice sites. The promoters for both genes were different in length and both contained metal responsive elements and active protein-binding sites. The structures of the genomic clones were compared with those of other species. J. Exp. Zool. 284:445-453, 1999.


Suppression of the non-linear background in a multimode fibre CARS endoscope.
Multimode fibres show great potential for use as miniature endoscopes for imaging deep in tissue with minimal damage. When used for coherent anti-Stokes Raman scattering (CARS) microscopy with femtosecond excitation sources, a high band-width probe is required to efficiently focus the broadband laser pulses at the sample plane. Although graded-index (GRIN) fibres have a large bandwidth, it is accompanied by a strong background signal from four-wave mixing and other non-linear processes occurring inside the fibre. We demonstrate that using a composite probe consisting of a GRIN fibre with a spliced on step-index fibre reduces the intensity of the non-linear background by more than one order of magnitude without significantly decreasing the focusing performance of the probe. Using this composite probe we acquire CARS images of biologically relevant tissue such as myelinated axons in the brain with good contrast.


Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice.
Although previous studies have attempted to create "electronics-free" insulin delivery systems using glucose oxidase and sugar-binding lectins as a glucose-sensing mechanism, no successful clinical translation has hitherto been made. These protein-based materials are intolerant of long-term use and storage because of their denaturing and/or cytotoxic properties. We provide a solution by designing a protein-free and totally synthetic material-based approach. Capitalizing on the sugar-responsive properties of boronic acid, we have established a synthetic polymer gel-based insulin delivery device confined within a single catheter, which exhibits an artificial pancreas-like function in vivo. Subcutaneous implantation of the device in healthy and diabetic mice establishes a closed-loop system composed of "continuous glucose sensing" and "skin layer"-regulated insulin release. As a result, glucose metabolism was controlled in response to interstitial glucose fluctuation under both insulin-deficient and insulin-resistant conditions with at least 3-week durability. Our "smart gel" technology could offer a user-friendly and remarkably economic (disposable) alternative to the current state of the art, thereby facilitating availability of effective insulin treatment not only to diabetic patients in developing countries but also to those patients who otherwise may not be strongly motivated, such as the elderly, infants, and patients in need of nursing care.


Strengthening public health practice content in public health training.
U.S. schools of public health have recognized the imperative to strengthen the public health practice content of training for future public health practitioners. Five strategies to develop administrative and curriculum programs within schools of public health to address this need are described: (1) institution of centers for public health program evaluation; (2) creation of automated field placement and apprenticeship programs; (3) formalization of linkages with professional management training programs to create a track for future senior managers of community health agencies; (4) establishment of cross-departmental applied public health faculty tracks; and (5) offering applied public health evaluation scholarships for students. These initiatives may provide incentives for the institution of a public health practice focus within schools of public health.


External anions relieve DIDS inhibition of SO4 efflux from placental membrane vesicles.
Sulphate efflux from human placental microvillus membrane vesicles was inhibited by external DIDS (KI congruent to 10(-6) M). This inhibition was partially reversed on addition of the translocated substrates sulphate or selenate to the external medium: selenite which is not translocated does not protect against DIDS inhibition. These findings show that the mechanism responsible for sulphate efflux can be modified by substrate in the external medium.


Mesenchymal hamartoma of liver in a man: comparison with cases in infants.
A 53 year old man with a large mesenchymal hamartoma is reported. Only a few bile ducts could be found in the periphery of the lesion and no hepatocytes were identified within the lesion. As far as is known, this is the only adult male patient reported to date. On the basis of the reported findings of mesenchymal hamartoma in other adults, it is suggested that there could be changes in the morphology of this lesion with age: progressive loss of hepatocytes; degeneration of bile duct epithelium; and cystic change of the mesenchymal component. The haematopoietic element is considered to be part of the fetal hepatic haematopoiesis that occurs in the hamartoma.


Alzheimer's Disease, Oligomers, and Inflammation.
The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer's disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient's inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD.


Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites.
The purpose of the present study was to elucidate the expression of human organic anion transporter 1 (hOAT1) and hOAT3 in the choroid plexus of the human brain and their interactions with neurotransmitter metabolites using stable cell lines. Immunohistochemical analysis revealed that hOAT1 and hOAT3 are expressed in the cytoplasmic membrane and cytoplasm of human choroid plexus. Neurotransmitter metabolites, namely, 5-methoxyindole-3-acetic acid (5-MI-3-AA), homovanillic acid (HVA), vanilmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindole-3-acetic acid (5-HI-3-AA), N-acetyl-5-hydroxytryptamine (NA-5-HTT), melatonin, 5-methoxytryptamine (5-MTT), 3,4-dihidroxymandelic acid (DHMA), 5-hydroxytryptophol, and 5-methoxytryptophol (5-MTP), but not methanephrine (MN), normethanephrine (NMN), and 3-methyltyramine (3-MT), at 2 mM, inhibited para-aminohippuric acid uptake mediated by hOAT1. On the other hand, melatonin, 5-MI-3-AA, NA-5-HTT, 5-MTT, 5-MTP, HVA, 5-HI-3-AA, VMA, DOPAC, 5-hydroxytryptophol, and MN, but not 3-MT, DHMA, and NMN, at 2 mM, inhibited estrone sulfate uptake mediated by hOAT3. Differences in the IC(50) values between hOAT1 and hOAT3 were observed for DHMA, DOPAC, HVA, 5-HI-3-AA, melatonin, 5-MI-3-AA, 5-MTP, 5-MTT, and VMA. HOAT1 and hOAT3 mediated the transport of VMA but not HVA and melatonin. These results suggest that hOAT1 and hOAT3 are involved in the efflux of various neurotransmitter metabolites from the cerebrospinal fluid to the blood across the choroid plexus.


Persecutory ideation and anomalous perceptual experiences in the context of the COVID-19 outbreak in France: what's left one month later?
Beyond the effects of the coronavirus pandemic on the public's health, the length of lockdown and its possible psychological impacts on populations is heavily debated. However, the consequences of lockdown on psychotic symptoms have been poorly investigated. An online survey was run from April 13 to May 11, 2020; a total of 728 French subjects from the general population were included in the study. We assessed the perceived impact of the COVID-19 outbreak, length of isolation, diagnosis/symptoms/hospitalisation related to the COVID-19 (oneself and family). Paranoid ideations and hallucination-like experiences were assessed via the Paranoia Scale and the Cardiff Anomalous Perceptions Scale, respectively. Self-reported measures of negative affect, loneliness, sleep difficulties, jumping to conclusion bias, repetitive thoughts, among others, were also included. Final regression model for paranoia indicated that socio-demographic variables (age, sex and education), loneliness, cognitive bias, anxiety, experiential avoidance, repetitive thoughts and hallucinations were associated with paranoia (R2 = 0.43). For hallucinations, clinical variables as well as the quality of sleep, behavioural activation, repetitive thoughts, anxiety and paranoia were associated with hallucinations in our sample (R2 = 0.27). Neither length of isolation nor the perceived impact of the COVID-19 pandemic were associated with psychotic experiences in the final models. No evidence was found for the impact of isolation on psychotic symptoms in the general population in France one month after the lockdown. It nevertheless confirms the preeminent role of several factors previously described in the maintenance and development of psychotic symptoms in the context of a pandemic and lockdown measures.


Better Compression With Deep Pre-Editing.
Could we compress images via standard codecs while avoiding visible artifacts? The answer is obvious - this is doable as long as the bit budget is generous enough. What if the allocated bit-rate for compression is insufficient? Then unfortunately, artifacts are a fact of life. Many attempts were made over the years to fight this phenomenon, with various degrees of success. In this work we aim to break the unholy connection between bit-rate and image quality, and propose a way to circumvent compression artifacts by pre-editing the incoming image and modifying its content to fit the given bits. We design this editing operation as a learned convolutional neural network, and formulate an optimization problem for its training. Our loss takes into account a proximity between the original image and the edited one, a bit-budget penalty over the proposed image, and a no-reference image quality measure for forcing the outcome to be visually pleasing. The proposed approach is demonstrated on the popular JPEG compression, showing savings in bits and/or improvements in visual quality, obtained with intricate editing effects.


Polyolefin-supported recoverable/reusable Cr(III)-salen catalysts.
The design of functional soluble polyolefins for use as supports for salen ligands and metal complexes is described. Examples and applications that use both polyisobutylene (PIB)- and polyethylene (PE(Olig))-bound recoverable/recyclable salen ligands/metal complexes are detailed. In the case of using PIB as a support, the polymer-bound complexes can be recovered through the use of latent biphasic or a thermomorphic mixed solvent systems. In the case of PE(Olig)-supported complexes, the thermomorphic PE(Olig)-bound salen species can be dissolved in "hot" solvents and quantitatively recovered as solids upon cooling to room temperature. Both the PIB- and PE(Olig)-bound salen catalysts were shown to catalyze the ring-opening of epoxides with various nucleophiles. Both sorts of polyolefin-bound catalysts can be recycled and reused with no observed loss in activity. However, limitations of catalyst concentration make chiral versions of these complexes uncompetitive in comparison to conventional chiral salen catalysts that can be used in neat substrate at higher concentration to produce high enantioselectivity in the ring-opening products. The preparation of a PIB-bound "half-salen" catalyst was also briefly examined.


GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis.
The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1-/-), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1-/- The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.SIGNIFICANCE STATEMENT Genome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.


Post-traumatic stress disorder: the history of a recent concept.
This review describes the history of PTSD in relation to military psychiatry, physiology, and crisis theory. It appears that the consequences of psychic trauma are often underestimated and mental health services often fail to provide adequate care. PTSD may be explained as an initially adequate reaction to danger, which becomes pathological if it does not disappear after the danger is gone. The authors argue in favour of better psychiatric intervention after traumatic events and better care for trauma victims.


Evaluation of a screening interview for Briquet syndrome (hysteria) by the study of medically ill women.
A screening interview for Briquet syndrome consisting of 14 symptom questions was administered to a group of 50 medically ill women. No patient was found eligible for a diagnosis of Briquet syndrome, a frequency less than the estimated general population prevalence of 1% to 2%. When symptoms explainable by known organic disorder were considered positive, 14% of patients became eligible for the diagnosis. We consider this a low enough rate to allow screening by lay interviewers. A frequency distribution of symptoms comparing the medically ill women and a group of psychiatric clinic women with Briquet syndrome shows that the Briquet group had both more symptoms and distinctive patterns of symptoms.


In vitro and in situ caries-preventive effect of a new combined fluoride and calcium experimental nanocomposite solution.
To assess the in vitro and in situ effect of experimental combined fluoride and calcium nanocomposite solutions on dental caries prevention. Nanocompound mesoporous silica (MS) with calcium (Ca) and sodium fluoride (NaF) - (MSCaNaF); MS with NaF (MSNaF), NaF solution (positive control), and deionized water (negative control - CG) were studied. The specimens (n=130) were submitted in vitro to a multispecies biofilm in the presence of 2% sucrose. After 24 h and 48 h, the culture medium pH, the percent of surface mineral loss (%SML), and lesion depth (ΔZ) were analyzed. In the in situ study, 10 volunteers participated in four phases of 7-days each. The products were applied on the specimens (n=240) before 20% sucrose solution drips. The polysaccharides (SEPS and IEPS), %SML and roughness (Sa) were evaluated. There was an in vitro decrease in pH values in 24h and 48h, compared to baseline. The MSCaNaF and MSNaF groups obtained lower values of %SML and ΔZ (p < 0.05) than CG and NaF after 24h and were similar to NaF after 48h (p<0.05). In situ results showed similar SEPS and IEPS among all groups after 48h. An after 7-days, the nanocomposites had similar values (p>0.05), while NaF was similar to CG (p>0.05). After 48h, the MSCaNaF and MSNaF reduced the %SML (p<0.05). After 7-days, both experimental nanocomposites were similar to NaF (p>0.05). Regarding Sa, MSCaNaF was better than NaF for both periods (p<0.05). The nanocomposites controlled the in vitro and in situ enamel demineralization, mainly in the initial periods.


Pleural mesothelioma in New Caledonia: associations with environmental risk factors.
High incidences of malignant mesothelioma (MM) have been observed in New Caledonia. Previous work has shown an association between MM and soil containing serpentinite. We studied the spatial and temporal variation of MM and its association with environmental factors. We investigated the 109 MM cases recorded in the Cancer Registry of New Caledonia between 1984 and 2008 and performed spatial, temporal, and space-time cluster analyses. We conducted an ecological analysis involving 100 tribes over a large area including those with the highest incidence rates. Associations with environmental factors were assessed using logistic and Poisson regression analyses. The highest incidence was observed in the Houaïlou area with a world age-standardized rate of 128.7 per 100,000 person-years [95% confidence interval (CI), 70.41-137.84]. A significant spatial cluster grouped 18 tribes (31 observed cases vs. 8 expected cases; p = 0.001), but no significant temporal clusters were identified. The ecological analyses identified serpentinite on roads as the greatest environmental risk factor (odds ratio = 495.0; 95% CI, 46.2-4679.7; multivariate incidence rate ratio = 13.0; 95% CI, 10.2-16.6). The risk increased with serpentinite surface, proximity to serpentinite quarries and distance to the peridotite massif. The association with serpentines was stronger than with amphiboles. Living on a slope and close to dense vegetation appeared protective. The use of whitewash, previously suggested to be a risk factor, was not associated with MM incidence. Presence of serpentinite on roads is a major environmental risk factor for mesothelioma in New Caledonia.


Darwinian genomics and diversity in the tree of life.
Genomics encompasses the entire tree of life, both extinct and extant, and the evolutionary processes that shape this diversity. To date, genomic research has focused on humans, a small number of agricultural species, and established laboratory models. Fewer than 18,000 of ∼2,000,000 eukaryotic species (<1%) have a representative genome sequence in GenBank, and only a fraction of these have ancillary information on genome structure, genetic variation, gene expression, epigenetic modifications, and population diversity. This imbalance reflects a perception that human studies are paramount in disease research. Yet understanding how genomes work, and how genetic variation shapes phenotypes, requires a broad view that embraces the vast diversity of life. We have the technology to collect massive and exquisitely detailed datasets about the world, but expertise is siloed into distinct fields. A new approach, integrating comparative genomics with cell and evolutionary biology, ecology, archaeology, anthropology, and conservation biology, is essential for understanding and protecting ourselves and our world. Here, we describe potential for scientific discovery when comparative genomics works in close collaboration with a broad range of fields as well as the technical, scientific, and social constraints that must be addressed.


[Instability and sensitivity of the genome of healthy children in Magnitogorsk].
Problem of the influence of factors of the industrial city on the hereditary apparatus of its residents has not been fully resolved, because of traditionally in such studies only the pollution of environment components is taken into account. However the existence of a set of contributing socialfactors that modify the genotoxic effects ofpollution, requires the creation of a new methodology for genetic and toxicological studies. For this purpose, in Magnitogorsk, where one of Russia's largest steel plants is located, we conducted a comprehensive survey, whose tasks included the analysis of the influence of the complex of exogenous and endogenous factors on the genome of children. In this publication there are presented the results of the fifth fragment of this work - the analysis of instability and individual sensitivity of the genome of 166 children of 5-7 years, residing in two districts of Magnitogorsk: around the steel plant and on the opposite bank of Ural river, where there are no large-scale industrial enterprises. The study was conducted in the micronucleus test on peripheral blood lymphocytes cultured with cytochalasin B. For assessment of individual sensitivity of genome blood cultures were exposed to standard N-methyl-N-nitro-N-nitrosoguanidine (MNNG) mutagen. Cytogenetic analysis was performed in binucleated cells accordingly to international protocol, as well as with the use of an extended protocol including 32 indices. Average group frequency of binuclear cells with micronuclei (0.5-0.7%) were found not differ from the levels defined in children residing in Europe, and not differ between areas of the town. However the extended protocol of cytogenetic analysis discovered that the real frequency of dividing cells with lesions in blood cultures of children was 1,49-1,66%. Higher spontaneous proliferative activity of the cells and the frequency of dividing cells with injuries were found in blood cultures of children residing in settlements around the Magnitogorsk steel plant, while the individual sensitivity of the genome in these children was lower than that of their peers from the opposite bank of the Ural river A similar conclusion, but already in relation to the state of the systems for adaptation of entire body has been made from results of other fragments of the study, published earlier.


Coevolution of Synchronization and Cooperation in Costly Networked Interactions.
Despite the large number of studies on synchronization, the hypothesis that interactions bear a cost for involved individuals has seldom been considered. The introduction of costly interactions leads, instead, to the formulation of a dichotomous scenario in which an individual may decide to cooperate and pay the cost in order to get synchronized with the rest of the population. Alternatively, the same individual can decide to free ride, without incurring any cost, waiting for others to get synchronized to his or her state. Thus, the emergence of synchronization may be seen as the byproduct of an evolutionary game in which individuals decide their behavior according to the benefit-to-cost ratio they accrued in the past. We study the onset of cooperation and synchronization in networked populations of Kuramoto oscillators and report how topology is essential in order for cooperation to thrive. We also display how different classes of topology foster synchronization differently both at microscopic and macroscopic levels.


Transoral robotic submandibular sialadenectomy: how and when.
Traditional removal of the submandibular gland is done through a transcervical approach; new proposals have come into the scientific limelight such as endoscopy-assisted transcervical sialadenectomy or (robot-assisted) submandibular sialadenectomy through a postauricular facelift transcervical approach. Transoral submandibular sialadenectomy has been described in the past, but with the advent of transoral robotic surgery, the proposal of removing the submandibular gland from the oral floor is gaining strength. A transoral robotic submandibular sialadenectomy by the Si Da Vinci Surgical Robot was performed in a 68-years-old female patient under general anaesthesia. The transoral robotic procedure was successful with no major postoperative complications. A mild tingling of the tip of the tongue was described by the patient 3 months after. The surgical time took 110 minutes. No residual gland was observed at ultrasonography. The transoral robotic submandibular sialadenectomy seems to be, with selective indication based on clinical and radiological assessment, a viable and safe alternative to traditional management in patients who refuse a cervical scar and the risk of paralysis of the facial nerve.


Fluorescence characterization of VU-9 calmodulin, an engineered calmodulin with one tryptophan in calcium binding domain III.
Absorption and fluorescence properties of VU-9 calmodulin, an engineered calmodulin in which a tryptophan residue has been introduced in position 99, have been investigated. Tryptophan 99 fluoresces with a maximum around 348 nm and is easily quenched by fluorescence quenchers such as acrylamide, indicating that the chromophore is in a polar environment and well exposed to the solvent, a location which has been reported previously for tyrosine 99 in mammalian calmodulin [Kilhoffer, M. C., Demaille, J. G., & Gérard, D. (1981) Biochemistry 20, 4407-4414]. The quantum yields of tryptophan 99 were found to be 0.19 in the absence of calcium and 0.15 in its presence. These values indicate that the chromophore is in a particular microenvironment where it is protected from the quenching mechanisms normally occurring in proteins. Steady-state fluorescence polarization measurements indicate that the protein exhibits segmental mobility both in the absence and in the presence of calcium. Binding of calcium decreases the mobility of the chromophore, a good indication for a rigidification of the protein structure. A quite rigid structure of at least the carboxy-terminal part of VU-9 calmodulin in the presence of Ca2+ is also suggested by Förster energy-transfer measurements.


Determination of protein and amino acid requirements of lactating sows using a population-based factorial approach.
Determination of appropriate nutritional requirements is essential to optimize the productivity and longevity of lactating sows. The current recommendations for requirements do not consider the large variation between animals. Therefore, the aim of this study was to determine the amino acid recommendations for lactating sows using a stochastic modeling approach that integrates population variation and uncertainty of key parameters into establishing nutritional recommendations for lactating sows. The requirement for individual sows was calculated using a factorial approach by adding the requirement for maintenance and milk. The energy balance of the sows was either negative or zero depending on feed intake being a limiting factor. Some parameters in the model were sow-specific and others were population-specific, depending on state of knowledge. Each simulation was for 1000 sows repeated 100 times using Monte Carlo simulation techniques. BW, back fat thickness of the sow, litter size (LS), average litter gain (LG), dietary energy density and feed intake were inputs to the model. The model was tested using results from the literature, and the values were all within ±1 s.d. of the estimated requirements. Simulations were made for a group of low- (LS=10 (s.d.=1), LG=2 kg/day (s.d.=0.6)), medium- (LS=12 (s.d.=1), LG=2.5 kg/day (s.d.=0.6)) and high-producing (LS=14 (s.d.=1), LG=3.5 kg/day (s.d.=0.6)) sows, where the average requirement was the result. In another simulation, the requirements were estimated for each week of lactation. The results were given as the median and s.d. The average daily standardized ileal digestible (SID) protein and lysine requirements for low-, medium- and high-producing sows were 623 (CV=2.5%) and 45.1 (CV=4.8%); 765 (CV=4.9%) and 54.7 (CV=7.0%); and 996 (CV=8.5%) and 70.8 g/day (CV=9.6%), respectively. The SID protein and lysine requirements were lowest at week 1, intermediate at week 2 and 4 and the highest at week 3 of lactation. The model is a valuable tool to develop new feeding strategies by taking into account the variable requirement between groups of sows and changes during lactation. The inclusion of between-sow variation gives information on safety margins when developing new dietary recommendations of amino acids and protein for lactating sows.


Local structure of DNA toroids reveals curvature-dependent intermolecular forces.
In viruses and cells, DNA is closely packed and tightly curved thanks to polyvalent cations inducing an effective attraction between its negatively charged filaments. Our understanding of this effective attraction remains very incomplete, partly because experimental data is limited to bulk measurements on large samples of mostly uncurved DNA helices. Here we use cryo electron microscopy to shed light on the interaction between highly curved helices. We find that the spacing between DNA helices in spermine-induced DNA toroidal condensates depends on their location within the torus, consistent with a mathematical model based on the competition between electrostatic interactions and the bending rigidity of DNA. We use our model to infer the characteristics of the interaction potential, and find that its equilibrium spacing strongly depends on the curvature of the filaments. In addition, the interaction is much softer than previously reported in bulk samples using different salt conditions. Beyond viruses and cells, our characterization of the interactions governing DNA-based dense structures could help develop robust designs in DNA nanotechnologies.


[Mechanisms of the liver anti-endotoxin defence].
Current knowledge of immunocellular and lipoprotein mechanisms of the liver-induced anti-endotoxin tolerance has been summarized. The role of T regulatory cells, different macrophage phenotypes, high density lipoproteins, oxidized low density lipoproteins and their receptors as the key players in mechanism of tolerance to endotoxin has been discussed.


[Current trends on cholinergic effect on secretion and activity of renin and angiotensin-converting enzyme].
This article concerned to insufficiently studied subject on regulatory influence of cholinergic system on key parameters of renin-angiotensin system (renin and angiotensin converting enzyme activity and secretion). Literature data and author's investigations are considered. Influence of systemic and intrarenal infusions of acetylcholine, its analogues and antagonists, inhibition of vagal activity, denervation of kidney, increased and decreased parasympathetic tonus on renin and angiotensin converting enzyme secretion is discussed. Molecular mechanisms of acetylcholine influence on juxtaglomerular cells are considered. Regulatory significance of cholinergic influence on reninangiotensin system is discussed.


Development of an automatic ankle stretching device for lower limb monoplegia patients.
This paper describes a rehabilitation device developed to replace a conventional wooden wedge type ankle stretching device (ASD) and this new device consists of sensors and microcontroller-controlled electro-mechanical actuators. A conventional ASD has been used for lower limb rehabilitation treatment system for training of monoplegia (hemiplegia) patients for a long time. The new automatic ASD machine can control angle between foot and calf (AFC), holding time and the number of repetition, and has four training modes. The new ASD machine consists of an embedded controller unit (ECU), a display unit and an actuator unit. The ECU consists of two clinometers, a 12-bit serial ADC, microcontroller, RS-232 serial interface with the display unit and actuator unit consists with electro-mechanical actuators. It can reduce the workload of physical therapists and improve the effect of rehabilitation exercise for lower limb monoplegia patients.


A double-blinded randomized controlled trial of silymarin for the prevention of antituberculosis drug-induced liver injury.
Hepatitis is a common adverse effect of antituberculosis drugs. Silymarin prevented drug-induced hepatoxicity in animals with anti-oxidative mechanisms but its effect in human has been unknown. We aimed to evaluate the efficacy of silymarin for preventing antituberculosis-drug induced liver injury (antiTB-DILI) in patients with tuberculosis. A double-blind randomized placebo-controlled trial was performed. Tuberculosis patients were randomly allocated to receive placebo or silymarin. The outcomes of interests were antiTB-DILI and the maximum liver enzymes at week 4. Antioxidative enzymes (i.e., superoxide dismutase (SOD), glutathione and malondialdehyde assays) were assessed. The risks of antiTB-DILI between the two groups were compared. A number need to treat was estimated. A total of 55 out of 70 expected numbers of patients were enrolled. There were 1/27 (3.7%) and 9/28 (32.1%) patients who developed antiTB-DILI in the silymarin and the placebo groups. Risk reduction was 0.28 (0.10, 0.47), i.e., receiving silymarin was 28% at lower risk for antiTB-DILI than placebo. This led to prevention of 28 patients from being antiTB-DILI among 100 treated patients. Median (IQR) of ALT levels at week 4 in the placebo and the silymarin group were 35.0 (15, 415) IU/L and 31.5 (20, 184) IU/L (p = 0.455). The decline of SOD level at week 4 in the silymarin group was less than the placebo group (p < 0.027). Silymarin reduced the incidence of antiTB-DILI. The benefit of silymarin may be explained from superoxide dismutase restoration. Larger clinical trials are required to confirm the result of our small study [Clinicaltrials.Gov Identifier Nct01800487].


Inability to remove an aspirated straight pin by flexible fiberoptic bronchoscopy.
The patient we have described had severe hemoptysis caused by an aspirated straight pin, with subsequent tissue reaction. Foreign bodies can be successfully removed with the flexible fiberoptic bronchoscope, and they should be removed even if the patient is asymptomatic.


Epineural optogenetic activation of nociceptors initiates and amplifies inflammation.
Activation of nociceptor sensory neurons by noxious stimuli both triggers pain and increases capillary permeability and blood flow to produce neurogenic inflammation1,2, but whether nociceptors also interact with the immune system remains poorly understood. Here we report a neurotechnology for selective epineural optogenetic neuromodulation of nociceptors and demonstrate that nociceptor activation drives both protective pain behavior and inflammation. The wireless optoelectronic system consists of sub-millimeter-scale light-emitting diodes embedded in a soft, circumneural sciatic nerve implant, powered and driven by a miniaturized head-mounted control unit. Photostimulation of axons in freely moving mice that express channelrhodopsin only in nociceptors resulted in behaviors characteristic of pain, reflecting orthodromic input to the spinal cord. It also led to immune reactions in the skin in the absence of inflammation and potentiation of established inflammation, a consequence of the antidromic activation of nociceptor peripheral terminals. These results reveal a link between nociceptors and immune cells, which might have implications for the treatment of inflammation.


A computational model of four regions of the cerebellum based on feedback-error learning.
We propose a computationally coherent model of cerebellar motor learning based on the feedback-error-learning scheme. We assume that climbing fiber responses represent motor-command errors generated by some of the premotor networks such as the feedback controllers at the spinal-, brain stem- and cerebral levels. Thus, in our model, climbing fiber responses are considered to convey motor errors in the motor-command coordinates rather than in the sensory coordinates. Based on the long-term depression in Purkinje cells each corticonuclear microcomplex in different regions of the cerebellum learns to execute predictive and coordinative control of different types of movements. Ultimately, it acquires an inverse model of a specific controlled object and complements crude control by the premotor networks. This general model is developed in detail as a specific neural circuit model for the lateral hemisphere. A new experiment is suggested to elucidate the coordinate frame in which climbing fiber responses are represented.


Premature contraction of the cricopharyngeus: a new sign of gastroesophageal reflux disease.
A cricopharyngeal bar seen on barium fluoroscopy has been shown to be related to the presence of gastroesophageal reflux (GER). We investigated premature contraction of the cricopharyngeus (PCC) muscle, which may be a precursor of a fixed cricopharyngeal bar, to assess its significance in GER. The prevalence of PCC on barium swallow was recorded in three groups: (1) 83 patients with non-cardiac chest pain who were investigated for possible GER; (2) 21 patients with severe GER undergoing fundoplication; and (3) 25 normal controls. Group 1: PCC was observed in 42 of 77 with documented GER (54.5%), and in two of six patients without GER. Group 2: PCC was present in 11 of 21 fundoplication subjects. Group 3: PCC was seen in five of 25 normal controls. The incidence of PCC in patients with GER was statistically significantly higher than in normal subjects (p = 0.002). The sensitivity of the presence of PCC as a predictor of GER is only 0.54, but the specificity is 0.774, with a positive predictive value of 0.883. We conclude that observing premature cricopharyngeal contraction during the first swallows of an upper gastrointestinal (GI) study should direct attention to the possibility of GER.


An overview of Compassionate Use Programs in the European Union member states.
The past decade witnessed rapid development of novel drugs and therapeutic biological agents. The marketing authorization for novel therapies is often time consuming and distressing for patients. Earlier clinical trials were the only way to access new drugs under development. However, not every patient meets the enrolment criteria, and participation is difficult for patients with life-threatening, long-lasting or seriously debilitating diseases like rare diseases. Early access programs like "Compassionate Use Program (CUP)" have generated alternative channels for such patients. The European Medical Agency provides regulations and recommendations for compassionate use, upon which every European Union (EU) member state has developed its own rules and regulations. Despite previous reviews and studies, the available information is limited and gaps exist. This literature review explores CUP in 28 EU member states. Data was collected through literature review and use of country-specific search terms from the healthcare domain. Data sources were not limited to databases and articles published in journals, but also included grey literature. The results implied that CUP was present in 20 EU member states (71%). Of 28 EU states, 18 (∼64%) had nationalized regulations and processes were well-defined. Overall, this review identified CUP and its current status and legislation in 28 EU member states. The established legislation for CUP in the EU member states suggest their willingness to adopt processes that facilitate earlier and better access to new medicines. Further research and periodic reviews are warranted to understand the contemporary and future regulatory trends in early access programs.


Identification of conditionally essential genes for Streptococcus suis infection in pigs.
Streptococcus suis is a Gram-positive bacterium and zoonotic pathogen that causes meningitis and sepsis in pigs and humans. The aim of this study was to identify genes required for S. suis infection. We created Tn-Seq libraries in a virulent S. suis strain 10, which was used to inoculate pigs in an intrathecal experimental infection. Comparative analysis of the relative abundance of mutants recovered from different sites of infection (blood, cerebrospinal fluid, and meninges of the brain) identified 361 conditionally essential genes, i.e. required for infection, which is about 18% of the genome. The conditionally essential genes were primarily involved in metabolic and transport processes, regulation, ribosomal structure and biogenesis, transcription, and cell wall membrane and envelope biogenesis, stress defenses, and immune evasion. Directed mutants were created in a set of 10 genes of different genetic ontologies and their role was determined in ex vivo models. Mutants showed different levels of sensitivity to survival in whole blood, serum, cerebrospinal fluid, thermic shock, and stress conditions, as compared to the wild type. Additionally, the role of three selected mutants was validated in co-infection experiments in which pigs were infected with both wild type and isogenic mutant strains. The genetic determinants of infection identified in this work contribute to novel insights in S. suis pathogenesis and could serve as targets for novel vaccines or antimicrobial drugs.


Taxonomic Affinities and Intra- and Interspecific Variation in Bursaphelenchus spp. as Determined by Polymerase Chain Reaction.
Identification of closely related nematode species or races can be very difficult when diagnostic characters are plastic and overlapping. In this study we describe the use of polymerase chain reaction technology and direct DNA sequencing on 19 populations of Bursaphelenchus spp. to help understand their taxonomic relationships. The 5' end of the heat shock 70A gene from Caenorhabditis elegans was used as the target DNA sequence because it contains both coding and non-coding regions. The results indicate that the 19 populations could be divided into five types within B. xylophilus and four types within B. mucronatus. On a larger scale, the data revealed three distinct groups, representing B. xylophilus from North America and Japan, B. mucronatus from Japan, and "B. mucronatus" from Europe. There is sufficient difference between the European and Japanese "B. mucronatus" groups to warrant their consideration as separate species.


Bowel function of healthy men consuming liquid diets with and without dietary fiber.
The importance of the level of dietary fiber intake on bowel function was measured in 16 healthy young males consuming self-selected and liquid enteral diets. Subjects consumed liquid Ensure as their sole nutrient source plus 0 (diet a), 30 (diet c), and 60 (diet d) g/day soy fiber, a fiber source high in hemicellulose that was added to the Ensure. Further, to examine whether heat processing affects the physiologic action of fiber, subjects consumed Enrich, an enteral formula similar to Ensure, which contains 30 g of the same soy fiber (diet b). The four diets were consumed in randomized order each for 10 days. Daily wet stool weight averaged 144.6 g on the self-selected diet and decreased significantly to 67.3 g when Ensure was consumed alone. Average stool weights on diets (b), (c), and (d) were 114.6, 100.2, and 150.3 g/day, respectively. Average fecal dry weights for the four diets were 19.1, 28.7, 25.0, and 30.3 g/day for (a-d), respectively. Gastrointestinal transit time, as measured with radiopaque pellets, was longest on the Ensure diet, 72.4 hr, and approximately 2 days on the fiber-supplemented diets and the self-selected diet. Thus, soy fiber's physiologic effect on laxation was not changed by heat processing. Also, although stool weights were larger on higher fiber intakes, transit rates were similar on all the fiber-containing diets.