Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies.
We examined the rates of malignancy at 2 yr after transplantation in renal allograft patients receiving sirolimus (SRL) in continuous combination with cyclosporine (CsA), SRL as base therapy or SRL maintenance therapy after early withdrawal of CsA. A total of 1295 patients were enrolled in two double-blind studies comparing SRL with azathioprine (AZA) or placebo administered in continuous regimens with CsA. In two other trials (n = 161), SRL given as base therapy was compared with CsA. In the fifth trial, patients were randomly assigned at 3 months to either remain on CsA + SRL therapy (n = 215) or to have CsA eliminated with SRL being continued in concentration-controlled doses (n = 215). At 2 yr after transplantation, patients receiving SRL in continuous combination with CsA had a significantly lower incidence of skin cancer compared with patients receiving placebo. Patients receiving SRL as base therapy had no malignancies compared with a 5% incidence in those receiving CsA. The incidence of malignancy was significantly lower in patients receiving concentration-controlled SRL with elimination of CsA compared with those who remained on CsA + SRL. Based on the currently available data, patients receiving SRL-based therapy without CsA or SRL maintenance therapy after early CsA withdrawal have lower rates of malignancy in the first 2 yr after renal transplantation. SRL immunotherapy may be beneficial in protecting renal transplant patients from skin cancer even when given in combination with CsA.


Preventative strategies for low anterior resection syndrome.
A common and debilitating complication of low anterior resection for rectal cancer is low anterior resection syndrome (LARS). As a multifactorial entity, LARS is poorly understood and challenging to treat. Despite this, prevention strategies are commonly overlooked. Our aim was to review the pathophysiology of LARS and explore current evidence on the efficacy and feasibility of prophylactic techniques. A literature review was performed between [1st January 2000 to 1st October 2023] for studies which investigated preventative interventions for LARS. Mechanisms by which LARS develop are described, followed by a review of prophylactic strategies to prevent LARS. Medline, Cochrane, and PubMed databases were searched, 189 articles screened, 8 duplicates removed and 18 studies reviewed. Colonic dysmotility, anal sphincter dysfunction and neorectal dysfunction all contribute to the development of LARS, with the complex mechanism of defecation interrupted by surgery. Transanal irrigation (TAI) and pelvic floor rehabilitation (PFR) have shown benefits in preventing LARS, but may be limited by patient compliance. Intraoperative nerve monitoring (IONM) and robotic-assisted surgery have shown some promise in surgically preventing LARS. Nerve stimulation and other novel strategies currently used in treatment of LARS have yet to be investigated in their roles prophylactically. To date, there is a limited evidence base for all preventative strategies including IONM, RAS, PFP and TAI. These strategies are limited by either access (IONM, RAS and PFP) or acceptability (PFP and TAI), which are both key to the success of any intervention. The results of ongoing trials will serve to assess acceptability, while technological advancement may improve access to some of the aforementioned strategies.


Identification and Characterization of the Interaction Between the Methyl-7-Guanosine Cap Maturation Enzyme RNMT and the Cap-Binding Protein eIF4E.
The control of RNA metabolism is an important aspect of molecular biology with wide-ranging impacts on cells. Central to processing of coding RNAs is the addition of the methyl-7 guanosine (m7G) "cap" on their 5' end. The eukaryotic translation initiation factor eIF4E directly binds the m7G cap and through this interaction plays key roles in many steps of RNA metabolism including nuclear RNA export and translation. eIF4E also stimulates capping of many transcripts through its ability to drive the production of the enzyme RNMT which methylates the G-cap to form the mature m7G cap. Here, we found that eIF4E also physically associated with RNMT in human cells. Moreover, eIF4E directly interacted with RNMT in vitro. eIF4E is only the second protein reported to directly bind the methyltransferase domain of RNMT, the first being its co-factor RAM. We combined high-resolution NMR methods with biochemical studies to define the binding interfaces for the RNMT-eIF4E complex. Further, we found that eIF4E competes for RAM binding to RNMT and conversely, RNMT competes for binding of well-established eIF4E-binding partners such as the 4E-BPs. RNMT uses novel structural means to engage eIF4E. Finally, we observed that m7G cap-eIF4E-RNMT trimeric complexes form, and thus RNMT-eIF4E complexes may be employed so that eIF4E captures newly capped RNA. In all, we show for the first time that the cap-binding protein eIF4E directly binds to the cap-maturation enzyme RNMT.


The N-terminal region of the murine coronavirus spike glycoprotein is associated with the extended host range of viruses from persistently infected murine cells.
Although murine coronaviruses naturally infect only mice, several virus variants derived from persistently infected murine cell cultures have an extended host range. The mouse hepatitis virus (MHV) variant MHV/BHK can infect hamster, rat, cat, dog, monkey, and human cell lines but not the swine testis (ST) porcine cell line (J. H. Schickli, B. D. Zelus, D. E. Wentworth, S. G. Sawicki, and K. V. Holmes, J. Virol. 71:9499-9507, 1997). The spike (S) gene of MHV/BHK had 63 point mutations and a 21-bp insert that encoded 56 amino acid substitutions and a 7-amino-acid insert compared to the parental MHV strain A59. Recombinant viruses between MHV-A59 and MHV/BHK were selected in hamster cells. All of the recombinants retained 21 amino acid substitutions and a 7-amino-acid insert found in the N-terminal region of S of MHV/BHK, suggesting that these residues were responsible for the extended host range of MHV/BHK. Flow cytometry showed that MHV-A59 bound only to cells that expressed the murine glycoprotein receptor CEACAM1a. In contrast, MHV/BHK and a recombinant virus, k6c, with the 21 amino acid substitutions and 7-amino-acid insert in S bound to hamster (BHK) and ST cells as well as murine cells. Thus, 21 amino acid substitutions and a 7-amino-acid insert in the N-terminal region of the S glycoprotein of MHV/BHK confer the ability to bind and in some cases infect cells of nonmurine species.


Structure and properties of metallic glasses.
Recent experience has shown that certain metal alloys can be put into glass form by rapid melt-quenching or by various condensation processes. Models for the nature and structure of these glasses are surveyed and shown to be quite parallel to those already developed for the more common nonmetallic glasses. The rather unique magnetic, superconducting, and mechanical properties and the technical potential of metallic glasses are also discussed.


Midwives' work and attitudes towards contraceptive counselling and contraception among women with intellectual disability: focus group interviews in Sweden.
Family planning counselling is an essential part of sexual and reproductive health care; however, health care professionals often fail to offer sexual and reproductive health services to women with intellectual disability (ID), based on a misconception of inactive sexuality. The aims of this study were to gain a deeper understanding of midwives' perceptions of sexual health and contraceptive use of women with ID, and of midwives' practices in providing contraceptive counselling to women with ID. Five focus group interviews were conducted with 19 midwives at five antenatal/family planning clinics in central Sweden between December 2016 and February 2017. The findings are presented in a paradigm model comprising the following components: context, causal conditions for women with ID needing contraception, intervening conditions, action and interaction strategies based on the midwives' approach and performance during the consultation, and finally consequences. Midwives strived to enhance informed choice, whenever possible, and tried to maintain a neutral attitude during counselling. They wanted to provide the most suitable contraceptive method balanced against any risk of long-term use and possible side effects. Midwives raised the need for teamwork and inter-professional support to improve health care, security and access to other related services for women with ID. Few women with ID request contraceptive counselling, which limits midwives' knowledge, experience and competence. Midwives, therefore, plan consultations carefully and strive to enable women with ID to make informed contraceptive choices. Increased teamwork could be a way to strengthen the role of midwives and thereby improve counselling.


[Method for determining scan timing based on analysis of formation process of the time-density curve].
A strict determination of scan timing is needed for dynamic multi-phase scanning and 3D-CT angiography (3D-CTA) by multi-detector row CT (MDCT) . In the present study, contrast media arrival time (T(AR)) was measured in the abdominal aorta at the bifurcation of the celiac artery for confirmation of circulatory differences in patients. In addition, we analyzed the process of formation of the time-density curve (TDC) and examined factors that affect the time to peak aortic enhancement (T(PA)). Mean T(AR) was 15.57+/-3.75 s. TDCs were plotted for each duration of injection. The rising portions of TDCs were superimposed on one another. TDCs with longer injection durations were piled up upon one another. Rise angle was approximately constant in response to each flow rate. Rise time (T(R)) showed a good correlation with injection duration (T(ID)). T(R) was 1.01 TID (R(2)=0.994) in the phantom study and 0.94 T(ID)-0.60 (R(2)=0.988) in the clinical study. In conclusion, for the selection of optimal scan timing it is useful to determine T(R) at a given point and to determine the time from T(AR).


A naturalistic evaluation of psychosocial interventions for cancer patients in a community setting.
We used a naturalistic methodology to examine associations between change in cancer patients' emotional functioning and their use of interventions in a community organization. One-hundred ninety-two patients completed measures at baseline and 6 months later. During this time, they utilized the organization's various interventions as they wished. Attendance at educational events was associated with decreased well-being. Use of art therapy groups was not associated with decreases in negative emotion but was consistently associated with increases in positive emotion. Improved functioning on some measures was associated with use of psychoeducational groups, expressive/supportive groups, movement classes, healing arts, and a buddy-matching service.


Semiconductor Epitaxy in Superconducting Templates.
Integration of high-quality semiconductor-superconductor devices into scalable and complementary metal-oxide-semiconductor compatible architectures remains an outstanding challenge, currently hindering their practical implementation. Here, we demonstrate growth of InAs nanowires monolithically integrated on Si inside lateral cavities containing superconducting TiN elements. This technique allows growth of hybrid devices characterized by sharp semiconductor-superconductor interfaces and with alignment along arbitrary crystallographic directions. Electrical characterization at low temperature reveals proximity induced superconductivity in InAs via a transparent interface.


Small tube-nosed seabirds fledge on the full moon and throughout the lunar cycle.
Many seabirds are attracted to anthropogenic light, and the risk is greater for recent fledglings. Moon phase predicts the probability of stranding (fewer birds strand on the full moon), but it remains uncertain whether moon phase is associated with when young seabirds fledge. Fledging behaviour of nocturnal, burrowing seabirds can be difficult to monitor using traditional methods but can provide insight into environmental factors that influence the risk of stranding. We used passive integrated transponder tags to monitor the fledging dates and times of Leach's storm-petrel (Hydrobates leucorhous) chicks across four breeding seasons (2017, 2018, 2021, 2022) at a major colony in Newfoundland and Labrador, Canada. We also assessed whether moon phase and incident illumination related to fledging date and time. The median fledge time was 1.6 h after sunset (0.6-11.7 h). The median fledge date was 10 October, and fledging dates ranged from 13 September to 13 November. Most importantly, moon phase was not associated with the time and date that Leach's storm-petrel chicks fledged. These results suggest that recently fledged storm-petrels are less attracted to anthropogenic light during high levels of natural illumination, which could indicate periods of higher stranding risk and help concentrate conservation efforts.


Microcomputer as patient educator.
A computer-assisted lesson on general drug knowledge as a patient education tool is described. A drug I.Q. quiz is one of seven microcomputer lessons available to patients in the waiting room of an ambulatory-care clinic. The drug quiz consists of 19 multiple-choice and six true or false questions. After each question, the computer responds with a brief paragraph keyed to the answer selected by the user. If the answer for a multiple-choice question is incorrect, the user can reanswer the question before proceeding. At the end of the lesson, a score is graphically displayed and the user is asked to evaluate the lesson. The computer stores the total number of lessons completed, total scores, number of times each question was answered incorrectly on first and second attempts, number of times each question was answered a second time, and each user's responses to the quiz and evaluation questions. Based on 313 completions of the drug quiz from September 1981 through May 1982, 86% of the users stated that they learned at least something useful, and 72% liked the quiz. The mean (+/- S.D.) number of correct answers on the first attempt was 16 +/- 5; scores improved by an average of 2.5 +/- 2 by reanswering questions. Of 2421 multiple-choice questions answered incorrectly, 62% were reanswered. Of these second attempts, 52% were correct. Item validity scores indicated that the drug quiz serves as a realistic appraisal of drug knowledge. The microcomputer can be an effective medium for patient education.


True energy-minimal and finite-size biplanar gradient coil design for MRI.
Finite-sized high-performance planar magnetic field gradient coils in today's open configuration magnetic resonance imaging (MRI) systems have always been desirable for ever demanding imaging applications. We present a Lagrange multiplier technique for designing a minimum-energy gradient coil under a finite-size planar geometry constraint in addition to a set of magnetic field constraints. In this new design methodology, the surface current density on a finite size plane is represented by a two-dimensional (2-D) Fourier series expansion. Following the standard approach, we construct a functional F in terms of the stored magnetic energy and a set of field constraint points which are chosen over the desired imaging volume. Minimizing F, we obtain the continuous current density distribution for the finite-size planar gradient coil. Applying the stream function technique to the resulting continuous current distribution, the discrete current pattern can be generated. Employing the Biot-Savart law to the discrete current loops, the gradient magnetic field has been re-evaluated in order to validate the theory. Using this approach, we have been able to design a finite-size biplanar z-gradient coil which is capable of generating a gradient field of 40 mT/m @ 266 A. The excellent agreement between the analytical and numerical results has been achieved.


20-Iodo-14,15-epoxyeicosa-8(Z)-enoyl-3-azidophenylsulfonamide: photoaffinity labeling of a 14,15-epoxyeicosatrienoic acid receptor.
Endothelium-derived epoxyeicosatrienoic acids (EETs) relax vascular smooth muscle by activating potassium channels and causing membrane hyperpolarization. Recent evidence suggests that EETs act via a membrane binding site or receptor. To further characterize this binding site or receptor, we synthesized 20-iodo-14,15-epoxyeicosa-8(Z)-enoyl-3-azidophenylsulfonamide (20-I-14,15-EE8ZE-APSA), an EET analogue with a photoactive azido group. 20-I-14,15-EE8ZE-APSA and 14,15-EET displaced 20-(125)I-14,15-epoxyeicosa-5(Z)-enoic acid binding to U937 cell membranes with K(i) values of 3.60 and 2.73 nM, respectively. The EET analogue relaxed preconstricted bovine coronary arteries with an ED(50) comparable to that of 14,15-EET. Using electrophoresis, 20-(125)I-14,15-EE8ZE-APSA labeled a single 47 kDa band in U937 cell membranes, smooth muscle and endothelial cells, and bovine coronary arteries. In U937 cell membranes, the 47 kDa radiolabeling was inhibited in a concentration-dependent manner by 8,9-EET, 11,12-EET, and 14,15-EET (IC(50) values of 444, 11.7, and 8.28 nM, respectively). The structurally unrelated EET ligands miconazole, MS-PPOH, and ketoconazole also inhibited the 47 kDa labeling. In contrast, radiolabeling was not inhibited by 8,9-dihydroxyeicosatrienoic acid, 5-oxoeicosatetraenoic acid, a biologically inactive thiirane analogue of 14,15-EET, the opioid antagonist naloxone, the thromboxane mimetic U46619, or the cannabinoid antagonist AM251. Radiolabeling was not detected in membranes from HEK293T cells expressing 79 orphan receptors. These studies indicate that vascular smooth muscle, endothelial cells, and U937 cell membranes contain a high-affinity EET binding protein that may represent an EET receptor. This EET photoaffinity labeling method with a high signal-to-noise ratio may lead to new insights into the expression and regulation of the EET receptor.


Adiponectin and marine n-3 fatty acids in patients referred for coronary angiography.
Marine n-3 polyunsaturated fatty acids (n-3 PUFAs) in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may reduce the risk of coronary heart disease (CHD) and have anti-inflammatory effects. We examined whether levels of serum adiponectin were related to the occurrence and extent of CHD, and whether intake of n-3 PUFAs was associated to high levels of adiponectin. Serum adiponectin and the content of n-3 PUFAs in subcutaneous adipose tissue, platelets and granulocytes were measured in 291 patients referred to elective coronary angiography. Significantly lower levels of serum adiponectin were observed in patients with coronary stenoses compared to patients without stenoses (7336+/-3598 ng/ml vs 10,203+/-8396 ng/ml; p=0.003), but no significant correlation was seen between serum adiponectin and the extent of CHD. In men, serum adiponectin correlated to levels of the content of EPA in platelets (r=0.26; p<0.01) and in granulocytes (r=0.23; p<0.01) and to the content of DHA in subcutaneous adipose tissue (r=0.15; p<0.05) and granulocytes (r=0.17; p<0.05). After regression analysis EPA in platelets (p=0.017) and granulocytes (p=0.030) remained an independent correlate of adiponectin levels, while DHA was no longer an independent correlate. In conclusion, serum levels of adiponectin were lower in patients with angiographically documented coronary artery disease. Also, intake of EPA may increase serum adiponectin and through this exert a protective effect on CHD.


Two-dimensional coherent spectroscopy of a THz quantum cascade laser: observation of multiple harmonics.
Two-dimensional spectroscopy is performed on a terahertz (THz) frequency quantum cascade laser (QCL) with two broadband THz pulses. Gain switching is used to amplify the first THz pulse and the second THz pulse is used to probe the system. Fourier transforms are taken with respect to the delay time between the two THz pulses and the sampling time of the THz probe pulse. The two-dimensional spectrum consists of three peaks at (ωτ = 0, ωt = ω0), (ωτ = ω0, ωt = ω0), and (ωτ = 2ω0, ωt = ω0) where ω0 denotes the lasing frequency. The peak at ωτ = 0 represents the response of the probe to the zero-frequency (rectified) component of the instantaneous intensity and can be used to measure the gain recovery.


Whole genome and transcriptome sequencing of post-mortem cardiac tissues from sudden cardiac death victims identifies a gene regulatory variant in NEXN.
Sudden cardiac death (SCD) is a major public health problem and constitutes a diagnostic and preventive challenge in forensic pathology, especially for cases with structural normal hearts at autopsy, so-called sudden arrhythmic death syndrome (SADS). The identification of new genetic risk factors that predispose to SADS is important, because they may contribute to establish the diagnosis and increase the understanding of disease pathways underlying SADS. Pathogenic mutations in the protein coding regions of cardiac genes were found in relation to SADS. However, much remains unknown about variants in non-coding regions of the genome. In this study, we explored the potential of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to find DNA variants in SCD victims with structural normal hearts. With focus on the non-coding regulatory regions, we re-examined a cohort of 13 SADS and sudden unexplained death in infancy (SUDI) victims without disease causing DNA variants in recognized cardiac genes. The genetic re-examination of DNA was carried out using frozen tissue samples and WTS was carried out using five distinct formalin fixed and paraffin embedded (FFPE) cardiac tissue samples from each individual, including anterior and posterior walls of the left ventricle, ventricular papillary muscle, septum, and the right ventricle. We identified 23 candidate variants in regulatory sequences of cardiac genes, including a variant in the promotor region of NEXN, c.-194A>G, that was found to be statistically significantly (p < 0.05) associated with decreased expression of NEXN and cardiac hypertrophy. With the use of post-mortem FFPE tissues, we highlight the potential of using WTS investigations and compare gene expression levels with DNA variation in regulatory non-coding regions of the genome for a better understanding of the genetics of cardiac diseases leading to SCD.


Syntaxin1A-mediated Resistance and Hypersensitivity to Isoflurane in Drosophila melanogaster.
Recent evidence suggests that general anesthetics activate endogenous sleep pathways, yet this mechanism cannot explain the entirety of general anesthesia. General anesthetics could disrupt synaptic release processes, as previous work in Caenorhabditis elegans and in vitro cell preparations suggested a role for the soluble NSF attachment protein receptor protein, syntaxin1A, in mediating resistance to several general anesthetics. The authors questioned whether the syntaxin1A-mediated effects found in these reductionist systems reflected a common anesthetic mechanism distinct from sleep-related processes. Using the fruit fly model, Drosophila melanogaster, the authors investigated the relevance of syntaxin1A manipulations to general anesthesia. The authors used different behavioral and electrophysiological endpoints to test the effect of syntaxin1A mutations on sensitivity to isoflurane. The authors found two syntaxin1A mutations that confer opposite general anesthesia phenotypes: syxH3-C, a 14-amino acid deletion mutant, is resistant to isoflurane (n = 40 flies), and syxKARRAA, a strain with two amino acid substitutions, is hypersensitive to the drug (n = 40 flies). Crucially, these opposing effects are maintained across different behavioral endpoints and life stages. The authors determined the isoflurane sensitivity of syxH3-C at the larval neuromuscular junction to assess effects on synaptic release. The authors find that although isoflurane slightly attenuates synaptic release in wild-type animals (n = 8), syxH3-C preserves synaptic release in the presence of isoflurane (n = 8). The study results are evidence that volatile general anesthetics target synaptic release mechanisms; in addition to first activating sleep pathways, a major consequence of these drugs may be to decrease the efficacy of neurotransmission.


Exercise training reduces arterial stiffness in women with high blood pressure: a systematic review and meta-analysis.
The acute and long-term benefits of exercise on cardiovascular health are well established, yet the optimal mode of exercise training that improves arterial stiffness in women with high blood pressure remains unclear. The aim of this systematic review and meta-analysis was to assess the influence of aerobic and resistance training on arterial stiffness in women with high blood pressure. After an extensive search of four online databases, six randomized controlled trials met the inclusion criteria and were included in meta-analyses. Data were extracted from six studies examining the influence of exercise on arterial stiffness assessed by pulse wave velocity (PWV) and were expressed as standardized mean difference (SMD). Whereas aerobic exercise significantly reduced arterial PWV in women with high blood pressure after long-term training [SMD -1.87, 95% confidence interval (CI) -2.34 to -1.40], resistance training had a more modest effect that was borderline statistically significant (SMD -0.31, 95% CI -0.65 to 0.03). These findings suggest regular long-term aerobic exercise training (i.e. 12-20 week interventions) reduces arterial stiffness in women with high blood pressure. Although not statistically significant, the modest number of included trials and lack of publication bias encourages further assessments on the efficacy of resistance exercise for improving arterial stiffness in women with high blood pressure. Given the unique benefits of aerobic and resistance training, particularly for postmenopausal women (e.g. bone health and muscular strength), both modes of training should be encouraged for women with high blood pressure to enhance arterial function and support favorable cardiovascular outcomes.


Oxybutynin extended-release: a review of its use in the management of overactive bladder.
The OROS-based oxybutynin extended-release (ER) formulation (Lyrinel XL; Ditropan XL) represents a new form of oral delivery for oxybutynin, a muscarinic receptor antagonist used in the treatment of overactive bladder (OAB). The release of oxybutynin from oxybutynin ER occurs in a sustained manner, resulting in a smoother plasma concentration-time profile and a lower maximum plasma concentration than those seen with oxybutynin immediate-release (IR). The ER formulation has been developed with the aim of improving the tolerability of oxybutynin therapy and facilitating once-daily administration. Moreover, oxybutynin ER offers greater flexibility in dosage (5-30 mg/day) than the other available treatment options. At dosages of 5-30 mg once daily, oxybutynin ER produced significant decreases from baseline in weekly urinary urge incontinence in patients with OAB. In addition, there were significant decreases in weekly total incontinence episodes and micturition frequency. In two randomised, double-blind studies in patients with OAB, the improvement in all the symptoms with once-daily oxybutynin ER 5-30 mg/day was similar to that produced by oxybutynin IR 5-20 mg/day given one to four times daily. Once-daily oxybutynin ER 10 mg was superior to tolterodine IR 4 mg/day given as two daily doses and as effective as once-daily tolterodine ER 4 mg/day in decreasing urinary incontinence; the decreases in micturition frequency with oxybutynin ER were significantly greater than those seen with either of tolterodine formulations. Oxybutynin ER was well tolerated in all the trials, with adverse events usually being mild to moderate and transient. In direct comparisons, the overall tolerability profile of oxybutynin ER was better than that of oxybutynin IR. Oxybutynin ER was similar to tolterodine (IR and ER) with respect to the incidence of clinically important dry mouth. A large 12-month tolerability study demonstrated no significant risks associated with the long-term use of oxybutynin ER. A few noncomparative studies have shown promising results with oxybutynin ER in the treatment of adult and paediatric patients with neurogenic bladder dysfunction secondary to neuronal injury. Long- and short-term studies have reported significant improvements in health-related quality of life with oxybutynin ER therapy. In addition, pharmacoeconomic studies have suggested that oxybutynin ER is more cost effective than oxybutynin IR and at least as cost effective as tolterodine IR. In conclusion, oxybutynin ER shows excellent efficacy in the treatment of symptoms associated with OAB in adults and the elderly with a good tolerability profile over a prolonged period of use (12 months). The ER formulation of oxybutynin provides a smooth plasma concentration profile over the 24-hour dosage interval, facilitating once-daily administration. Hence, given its overall efficacy/tolerability profile and dosage flexibility, oxybutynin ER provides an excellent treatment option in the first-line pharmacotherapy of OAB.


Relationship between operon preference and functional properties of persistent genes in bacterial genomes.
Genes in bacteria may be organised into operons, leading to strict co-expression of the genes that participate in the same operon. However, comparisons between different bacterial genomes have shown that much of the operon structure is dynamic on an evolutionary time scale. This indicates that there are opposing effects influencing the tendency for operon formation, and these effects may be reflected in properties like evolutionary rate, complex formation, metabolic pathways and gene fusion. We have used multi-species protein-protein comparisons to generate a high-quality set of genes that are persistent in bacterial genomes (i.e. they have close to universal distribution). We have analysed these genes with respect to operon participation and important functional properties, including evolutionary rate and protein-protein interactions. Genes for ribosomal proteins show a very slow rate of evolution. This is consistent with a strong tendency for the genes to participate in operons and for their proteins to be involved in essential and well defined complexes. Persistent genes for non-ribosomal proteins can be separated into two classes according to tendency to participate in operons. Those with a strong tendency for operon participation make proteins with fewer interaction partners that seem to participate in relatively static complexes and possibly linear pathways. Genes with a weak tendency for operon participation tend to produce proteins with more interaction partners, but possibly in more dynamic complexes and convergent pathways. Genes that are not regulated through operons are therefore more evolutionary constrained than the corresponding operon-associated genes and will on average evolve more slowly.


Nitroxoline suppresses metastasis in bladder cancer via EGR1/circNDRG1/miR-520h/smad7/EMT signaling pathway.
Bladder cancer is one of the most common and deadly cancer worldwide. Current chemotherapy has shown limited efficacy in improving outcomes for patients. Nitroxoline, an old and widely used oral antibiotic, which was known to treat for urinary tract infection for decades. Recent studies suggested that nitroxoline suppressed the tumor progression and metastasis, especially in bladder cancer. However, the underlying mechanism for anti-tumor activity of nitroxoline remains unclear. Methods: CircRNA microarray was used to explore the nitroxoline-mediated circRNA expression profile of bladder cancer lines. Transwell and wound-healing assay were applied to evaluate the capacity of metastasis. ChIP assay was chosen to prove the binding of promotor and transcription factor. RNA-pulldown assay was performed to explore the sponge of circRNA and microRNA. Results: We first identified the circNDRG1 (has_circ_0085656) as a novel candidate circRNA. Transwell and wound-healing assay demonstrated that circNDRG1 inhibited the metastasis of bladder cancer. ChIP assay showed that circNDRG1 was regulated by the transcription factor EGR1 by binding the promotor of host gene NDRG1. RNA-pulldown assay proved that circNDRG1 sponged miR-520h leading to the overexpression of smad7, which was a negative regulatory protein of EMT. Conclusions: Our research revealed that nitroxoline may suppress metastasis in bladder cancer via EGR1/circNDRG1/miR-520h/smad7/EMT signaling pathway.


The new classification method in ACEF score is more useful in patients with acute coronary syndrome without ST segment elevation.
Goal In this study, it was investigated whether the age, creatinine, and ejection fraction (ACEF) score [age (years) / ejection fraction (%) +1 (if creatinine >2 mg / dL)] could predict in-hospital mortality in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and its relationship with the Global Record of Acute Coronary Events (GRACE) risk score were investigated.Material and methods The study enrolled 658 NSTE-ACS patients from January 2016 to August 2020. The patients were divided into two groups according to the ACEF score with an optimum cut-off value of 1.283 who were divided into two groups according to the ACEF score: low ACEF (≤1.283, n:382) and high ACEF (>1.283, n: 276). The primary outcome of the study was in-hospital all-cause mortality. The primary outcome of the study was in-hospital all-cause mortality. Statistically accuracy was defined with area under the curve by receiver-operating characteristic curve analysis.Results In total, 13 (4.71 %) patients had in-hospital mortality. The ACEF score was significantly higher in the group with higher mortality than in the group with low mortality (2.1±0.53 vs. 1.34±0.56 p=0.001). The ACEF score was positively correlated with GRACE risk score (r=0.188 p<0.0001). In ROC curve analysis, the AUC of the ACEF score for predicting in-hospital mortality was 0.849 (95 % CI, 0.820 to 0.876; p<0.0001); sensitivity, 92.3 %; specificity, 59.2 %, and the optimum cut-off value was >1.283.Conclusion The ACEF score presented excellent discrimination in predicting in-hospital mortality. We obtained an easier and more useful result by dividing the ACEF score into two groups instead of three in NSTE-ACS patients. As a simple, useful, and easily applicable risk stratification in the evaluation of an emergency event such as the ACEF score, it can significantly contribute to the identification of patients at high risk.


Impact of uncontrolled blood pressure on diagnostic accuracy of coronary flow reserve for detecting significant coronary stenosis in hypertensive patients.
Impaired coronary flow reserve (CFR) in patients with hypertension may be caused by epicardial coronary stenosis or microvascular dysfunction. Antihypertensive treatment has been shown to improve coronary microvascular dysfunction. The aim of this study was to evaluate the impact of uncontrolled blood pressure (BP) on diagnostic accuracy of CFR for detecting significant coronary stenosis. A total of 98 hypertensive patients scheduled for coronary angiography (CAG) due to chest pain were studied. Of them, 45 patients had uncontrolled BP (defined as the office BP ≥ 140/90 mmHg (1 mmHg = 0.133 kPa) in general hypertensive patients, or ≥ 130/80 mmHg in hypertensive individuals with diabetes mellitus), and the remaining 53 patients had well-controlled BP. CFR was measured in the left anterior descending coronary artery (LAD) during adenosine triphosphate-induced hyperemia by non-invasive transthoracic Doppler echocardiography (TTDE) within 48 hours prior to CAG. Significant LAD stenosis was defined as > 70% luminal narrowing. Diagnostic accuracy of CFR for detecting significant coronary stenosis was analyzed with a receiver operating characteristic analysis. CFR was significantly lower in patients with uncontrolled BP than in those with well-controlled BP (2.1 ± 0.6 vs. 2.6 ± 0.9, P < 0.01). Multivariate linear regression analysis of the study showed that the value of CFR was independently associated with the angiographically determined degree of LAD stenosis (β = -0.445, P < 0.0001) and the presence of uncontrolled BP (β = -0.272, P = 0.014). With a receiver operating characteristic analysis, CFR < 2.2 was the optimal cut-off value for detecting LAD stenosis in all hypertensive patients (AUC 0.83, 95%CI 0.75 - 0.91) with a sensitivity of 75%, a specificity of 78%, and an accuracy of 77%. A significant reduction of diagnostic specificity was observed in patients with uncontrolled BP compared with those with well-controlled BP (67% vs. 93%, P = 0.031). CFR measurement by TTDE is valuable in the diagnosis of significant coronary stenosis in hypertensive patients. However, the diagnostic specificity is reduced in patients with uncontrolled BP.


Detection of Minute virus of mice strains in different cell lines: Implications for adventitious agent testing.
Minute virus of mice (MMV) has contaminated biotechnological processes in the past and specific MMV testing is therefore recommended, if the production cell line is known to be permissive for this virus. Testing is widely done using cell-culture-based adventitious virus assays, yet MMV strains may differ in their in vitro cell tropism. Here, we investigated the growth characteristics of different MMV strains on A9 and 324K cells and identified significant differences in susceptibility of these widely used indicator cell lines to infection by different strains of MMV, which has implications for MMV detectability during routine testing of biotechnology process harvests. An MMV-specific polymerase chain reaction was evaluated as a more encompassing method and was shown as suitable replacement for cell culture-based detection of the different MMV strains, with the additional benefit that detection is more rapid and can be extended to other rodent parvoviruses that might contaminate biotechnological processes. Although no MMV contamination event of human-derived cell lines has happened in the past, biotechnological processes that are based on these also need to consider MMV-specific testing, as, for example, HEK293, a human-derived cell line commonly used in biopharmaceutical manufacturing, was shown as susceptible to productive MMV infection in the current work.


Correlations between cerebellar cyclic GMP and motor effects induced by deltamethrin: independence of olivo-cerebellar tract.
The latencies and incidence of deltamethrin-induced motor symptoms were compared in rats pretreated with saline or 3-acetylpyridine (3-AP) (75 mg/kg i.p. 4 days before). 3-AP produced considerable degeneration of the inferior olive and hence the climbing fiber afferents to the cerebellar cortex. The times of onset of whole body tremor and spontaneous choreiform episodes were accelerated significantly in lesioned rats. Therefore the olivocerebellar tract is not important in mediating deltamethrin symptoms, but is necessary to compensate for the disruption of motor activity and coordination induced by deltamethrin at another site. Cerebellar cyclic guanosine monophosphate (cyclic GMP) levels were elevated significantly during the deltamethrin syndrome. The increase in cyclic GMP levels correlated directly with the duration of motor symptoms. This suggests that deltamethrin has an indirect effect on cerebellar cyclic GMP levels. Lesion of the olive-cerebellar tract did not abolish this rise in cerebellar cyclic GMP levels. The sequential development of the motor symptoms, whole body tremor followed by choreiform episodes was found to have an additive effect in raising cerebellar cyclic GMP levels. This suggests that both the nature and the general level of motor activity can influence cerebellar cyclic GMP levels.


Dilute ammonia pretreatment of sorghum and its effectiveness on enzyme hydrolysis and ethanol fermentation.
A new pretreatment technology using dilute ammonium hydroxide was evaluated for ethanol production on sorghum. Sorghum fibers, ammonia, and water at a ratio of 1:0.14:8 were heated to 160 degrees C and held for 1 h under 140-160 psi pressure. Approximately, 44% lignin and 35% hemicellulose were removed during the process. Hydrolysis of untreated and dilute ammonia pretreated fibers was carried out at 10% dry solids at an enzyme concentration of 60 FPU Spezyme CP and 64 CBU Novozyme 188/g glucan. Cellulose digestibility was higher (84%) for ammonia pretreated sorghum as compared to untreated sorghum (38%). Fermentations with Saccharomyces cerevisiae D(5)A resulted in 24 g ethanol /100 g dry biomass for dilute ammonia pretreated sorghum and 9 g ethanol /100 g dry biomass for untreated sorghum.


Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections.
Studies of beta-lactam pharmacodynamics in infected patients are sparse. In this study, classification and regression tree (CART) and logistic regression analyses were used to identify which pharmacodynamic indices and magnitudes were significant predictors of meropenem efficacy for 101 adult patients with lower respiratory tract infections (LRTI). Using demographic data, a validated population pharmacokinetic model was employed to predict pharmacokinetic parameters and free serum concentrations in the studied patients. Pharmacodynamic indices [percentage of the dosing interval that free drug concentrations remain above the MIC (% fT > MIC), f(maximum concentration of drug in serum) (fC(max))/MIC, fC(min)/MIC, and f(area under the concentration-time curve) (fAUC)/MIC] were calculated based on the baseline pathogen with the highest drug MIC for each patient. The median (range) of percent fT > MIC, fC(max)/MIC, fC(min)/MIC, and fAUC/MIC were 100% (0 to 100%), 728.8 (0.8 to 15,777), 19.9 (0.01 to 278), and 3,605.4 (2.7 to 60,865.9), respectively. CART identified the following breakpoints as significant predictors for microbiological response: >54% fT > MIC, a fC(max)/MIC > 383, and a fC(min)/MIC > 5; fC(min)/MIC > 5 was the only significant predictor of clinical response. Due to 100% fT > MIC achieved in the majority of LRTI patients, fC(min)/MIC was the statistically significant parameter associated with meropenem clinical and microbiological response in the adults with LRTI. The findings for LRTI patients can be applied to optimize meropenem dose regimens to achieve clinical success and microbiological eradication in clinical practice.


Erratum.
The article "Back to the energy crisis" by Mark Crawford (News & Comment, 6 Feb., p. 626) overstated American imports of petroleum and petroleum products for the years 1977 and 1985. Imports in 1977 averaged 8.8 million barrels per day as opposed to 8807 million barrels as stated. By 1985 imports had fallen to 5.07 (rounded) million barrels per day, not 5067 million barrels daily. The United States' use of petroleum-not foreign consumption as stated in the article-is projected to hit 17.7 million barrels per day in 1995. U.S. imports could then reach 9.8 million barrels a day.


Free radical protection: why vitamin E, not vitamin C, beta-carotene or glutathione?
There is increasing evidence that as a result of infection or the action of toxic chemicals or radiation, the body may be continuously exposed to the damaging action of free radicals. While previous results have suggested that zinc may be involved in limiting the formation of these highly reactive species, natural organic antioxidants such as vitamin E may also play an important role in reducing their effect. Recent results showing quantitative and qualitative differences in the free radical reactivity of vitamin E, vitamin C, beta-carotene and glutathione are reported. The possibility that in vivo these compounds may sometimes act synergistically is discussed in the light of recent information on hydrogen atom and electron transfer reactions and the long-established findings that vitamin C can augment the antioxidant action of vitamin E whereas iron salts can have a deleterious effect.


[Human peripheral neurolymphomatosis (reticuloendothelial polyradiculoneuritis)].
This is the clinico-pathological report of a case of reticulo-endotheliosis of the nervous system in a 53-year-old white female. She had a history of transient facial palsy followed 6 months later by progressive weakness, paresthesiae and severe pain in both lower limbs. Clinical examination revealed signs of sensory and motor polyradiculoneuritis with involvement of the oculomotor, facial and trigeminal cranial nerves. She died 10 months after the onset because of bronchopneumonia. Pathological findings in the nervous system were limited to the cranial and spinal roots and ganglia. Histopathological examination showed intense infiltration by lymphocytes, histiocytes, plasmocytes and macrophages and a large amount of reticulin. The left oculomotor nerve, both Gasserian ganglia, the right trigeminal nerve and the lumbosacral nerves and ganglia were particularly involved. The previous literature on human peripheral neurolymphomatosis is reviewed and its differential diagnosis from Marek's disease, sarcomas, leukaemic polyradiculoneuritis, sarcoidosis and Hodgkin's disease of the nervous system is discussed. The importance of recognizing this variety of polyradiculoneuritis, and methods of treating it are emphasized.


Late referral to palliative care services in Korea.
Although timely referral to palliative care services can help improve quality of life by minimizing patient and family suffering during a life-threatening illness, it remains unclear whether patients in Korea who suffer from advanced cancer are referred to palliative care services in a timely manner. We aimed to investigate the timeliness of patient referral to palliative care services in Korea by examining the duration of survival after enrollment and identify the factors contributing to earlier or later referral. Patient- and episode-level data were collected from 3867 terminal cancer patients, who were registered in 34 inpatient palliative care services designated by the Ministry of Health, Welfare, and Family Affairs. Cox proportional hazard models were used to determine factors associated with the duration of survival after enrollment in palliative care services. The median duration of survival after enrollment in palliative care services was 18 days. Male sex, liver cancer diagnosis, poor performance status, being covered by National Health Insurance, and being married were significantly associated with shorter duration of survival after enrollment, whereas a prostate cancer diagnosis was associated with longer survival. Korean terminal cancer patients are referred to palliative care very late, and the timing appears to be influenced by some socioeconomic and medical factors. Interventions, such as physician education and establishing palliative care teams, are required to promote earlier referrals in Korea.


Enhanced heterogenous hydration of SO2 through immobilization of pyridinic-N on carbon materials.
Carbon materials doped with nitrogen have long been used for SO2 removal from flue gases for the benefits of the environment. The role of water is generally regarded as hydration of SO3 which is formed through the oxidization of SO2. However, the hydration of SO2, especially on the surface of N-doped carbon materials, was almost ignored. In this study, the hydration of SO2 was investigated in detail on the pyridinic nitrogen (PyN)-doped graphene (GP) surfaces. It is found that, compared with the homogeneous hydration of SO2 assisted with NH3 in gas phase, the heterogeneous hydration is much more thermodynamically and kinetically favourable. Specifically, when a single H2O molecule is involved, the energy barrier for SO2 hydration is as low as 0.15 eV, with 0.59 eV released, indicating the hydration of SO2 can occur at rather low water concentration and temperature. Thermodynamic integration molecular dynamics results show the feasibility of the hydrogenated substrate recovery and the immobilized N acting as a catalytic site for SO2 hydration. Our findings show that the heterogeneous hydration of SO2 should be universal and potentially uncover the puzzling reaction mechanism for SO2 catalytic oxidation at low temperature by N-doped carbon materials.


[Transamination in the mechanism of protection of mitochondria from Ca2+ overload].
A high sensitivity of the succinate-dependent uptake of Ca2+ by mitochondria to (1) the transamination (TA) substrates glutamate (GLU) and alpha-ketoglutarate (KGL) and (2) the inhibitor of TA aminooxyacetate (AOA) was revealed. The effect of the TA substrates on Ca2+ uptake depends on the ratio (1:10 mM) of their concentrations: 1 mM GLU activates and 10 mM KGL decreases this activation by 35-46%, whereas AOA suppresses the Ca2+ capacity by 60% and the inhibitor of succinate oxidation malonate, by 80-90%. A similarity in the limiting action of KGL and phosphoenolpyruvate (PEP), two sources of oxaloacetate (OAA) and GTP, on Ca2+ capacity was revealed. The differences in the effects of KGL and GLU and the similarity in the effects of KGL and PEP on succinate oxidation are explained by the effect of OAA and GTP on this oxidation. The alternating inflow of OAA in coupled processes of TA, pyruvate cycle, and tricarboxylic acids cycle provides the reciprocal activation and cyclic recurrence of Ca2+ uptake, i. e., protection from the chronic exhausting activation of Ca2+-regulated dehydrogenases, the overload of Ca2+-outgoing channels, and the excessive production of free radicals in mitochondria. The reciprocal regulation of Ca2+ uptake by TA is considered as a mechanism of the maintenance of Ca2+ homeostasis and protection of mitochondria against Ca2+ overload.


Sclerosing epithelioid fibrosarcoma of bone with hybrid features: clinicopathologic, radiologic, and molecular analysis of three cases.
Sclerosing epithelioid fibrosarcoma (SEF) occurring as a primary bone tumor is exceptionally uncommon. Even more rare are cases of SEF that show morphologic overlap with low-grade fibromyxoid sarcoma (LGFMS). Such hybrid lesions arising within the bone have only rarely been reported in the literature. Due to their variegated histomorphology and non-specific radiologic features, these tumors may pose diagnostic difficulties. Herein we describe three molecularly confirmed primary bone cases of sclerosing epithelioid fibrosarcoma that demonstrated prominent areas showing the features of LGFMS and with areas resembling so-called hyalinizing spindle cell tumor with giant rosettes (HSCTGR). Two patients were female and one was male aged 26, 47, and 16, respectively. The tumors occurred in the femoral head, clavicle, and temporal bone. Imaging studies demonstrated relatively well-circumscribed radiolucent bone lesions with enhancement on MRI. Cortical breakthrough and soft tissue extension were present in one case. Histologically the tumors all demonstrated hyalinized areas with SEF-like morphology as well as spindled and myxoid areas with LGFMS-like morphology. Two cases demonstrated focal areas with rosette-like architecture as seen in HSCTGR. The tumors were all positive for MUC4 by immunohistochemistry and cytogenetics, fluorescence in-situ hybridization, and next-generation sequencing studies identified EWSR1 gene rearrangements confirming the diagnosis in all three cases.Hybrid SEF is exceedingly rare as a primary bone tumor and can be difficult to distinguish from other low-grade spindled and epithelioid lesions of bone. MUC4 positivity and identification of underlying EWSR1 gene rearrangements help support this diagnosis and exclude other tumor types.


Mice lacking bi-1 gene show accelerated liver regeneration.
The liver has enormous regenerative capacity such that, after partial hepatectomy, hepatocytes rapidly replicate to restore liver mass, thus providing a context for studying in vivo mechanisms of cell growth regulation. Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death. Interestingly, the BI-1 protein has been shown to regulate Ca(2+) handling by the ER similar to antiapoptotic Bcl-2 family proteins. Effects on cell cycle entry by Bcl-2 family proteins have been described, prompting us to explore whether bi-1-deficient mice display alterations in the in vivo regulation of cell cycle entry using a model of liver regeneration. Accordingly, we compared bi-1(+/+) and bi-1(-/-) mice subjected to partial hepatectomy with respect to the kinetics of liver regeneration and molecular events associated with hepatocyte proliferation. We found that bi-1 deficiency accelerates liver regeneration after partial hepatectomy. Regenerating hepatocytes in bi-1(-/-) mice enter cell cycle faster, as documented by more rapid incorporation of deoxynucleotides, associated with earlier increases in cyclin D1, cyclin D3, cyclin-dependent kinase (Cdk) 2, and Cdk4 protein levels, more rapid hyperphosphorylation of retinoblastoma protein, and faster degradation of p27(Kip1). Dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1), a substrate of the Ca(2+)-sensitive phosphatase calcineurin, were also accelerated following partial hepatectomy in BI-1-deficient hepatocytes. These findings therefore reveal additional similarities between BI-1 and Bcl-2 family proteins, showing a role for BI-1 in regulating cell proliferation in vivo, in addition to its previously described actions as a regulator of cell survival.


A versatile technology for droplet-based microfluidics: thermomechanical actuation.
We report on a versatile technique for microfluidic droplet manipulation that proves effective at every step: from droplet generation to propulsion to sorting, rearrangement or break-up. Non-wetting droplets are thermomechanically actuated in a microfluidic chip using local heating resistors. Controlled temperature variation induces local dilation of the PDMS wall above the resistor, which drives the droplet away from the hot (i.e. constricted) region (B. Selva, I. Cantat and M.-C. Jullien, Phys. Fluids, 2011, 23, 052002). Adapted placing and actuation of such resistors thus allow us to push forward, stop, store and release, or even break up droplets, at the price of low electric power consumption (<150 mW). We believe this technically accessible method to provide a useful tool for droplet microfluidics.


Genomic resources for Xiphophorus research.
Xiphophorus fishes and interspecies hybrids are used in many areas of contemporary research. Due to their high degree of heterozygosity Xiphophorus interspecies hybrids are extremely valuable models for molecular genetic study of gene regulation in physiology and behavior. Historically, Xiphophorus fish have made a contribution to understanding the genetics underlying tumorigenesis but the role this experimental model system may play in contemporary comparative biology has only just begun to be realized. In spite of many advantages a genome-level Xiphophorus sequencing project has not yet been initiated. In order to set a stage for a genome-level initiative, many Xiphophorus resources have recently been, or are currently being developed. Recent completion of the Xiphophorus gene linkage map, construction of microsatellite marker and EST databases, and the accessibility of BAC library resources hallmark the progress in development of genomic capabilities for Xiphophorus investigations. Herein we review current Xiphophorus genomic resources and to provide the reader with information that will enable them to access these resources available to enhance their investigations.


Closing the gates to consciousness: distractors activate a central inhibition process.
The paradigm of distractor-induced blindness has previously been used to track the transition from unconscious to conscious visual processing. In a variation of this paradigm used in this study, participants (n = 13) had to detect an orientation change of tilted bars (target) embedded in a dynamic random pattern; the onset of the target was signaled by the presentation of a color cue. Occasional orientation changes preceding the cue served as distractors and severely impaired the target's detection. ERPs showed that a frontal negativity was cumulatively activated by the distractors, and early sensory components were not affected. In a control condition, the target was defined by a coherent motion of the bars. Orientation changes preceding the motion target did not affect its detection, and the frontal suppression process was not observed. However, we obtained a significant reduction of the sensory components. The data support the notion that distractors that share the target's features trigger a cumulative inhibition process preventing the conscious representation of the inhibited features. Explorative source modeling suggests that this process originates in the pFC. A top-down modulation of sensory processing could not be observed.


COVID-19 Vaccine Acceptance and Beliefs among Black and Hispanic Americans.
The introduction of COVID-19 vaccines is a major public health breakthrough. However, members of US Black and Hispanic communities, already disproportionately affected by the COVID-19 virus, may be less willing to receive the vaccine. We conducted a broad, representative survey of US adults (N = 1,950) in order to better understand vaccine beliefs and explore opportunities to increase vaccine acceptance among these groups. The survey results suggested that Black and Hispanic individuals were less willing than Whites to receive the vaccine. US Blacks and Hispanics also planned to delay receiving the COVID-19 vaccine for a longer time period than Whites, potentially further increasing the risk of contracting COVID-19 within populations that are already experiencing high disease prevalence. Black respondents were less likely to want the COVID-19 vaccine at all compared with Whites and Hispanics, and mistrust of the vaccine among Black respondents was significantly higher than other racial/ethnic groups. Encouragingly, many Black and Hispanic respondents reported that COVID-19 vaccine endorsements from same-race medical professionals would increase their willingness to receive it. These respondents said they would also be motivated by receiving more information on the experiences of vaccine study participants who are of their own race and ethnicity. The results have implications for improved messaging of culturally-tailored communications to help reduce COVID-19 vaccine hesitancy among communities disproportionately impacted by the pandemic.


Can the crowd judge truthfulness? A longitudinal study on recent misinformation about COVID-19.
Recently, the misinformation problem has been addressed with a crowdsourcing-based approach: to assess the truthfulness of a statement, instead of relying on a few experts, a crowd of non-expert is exploited. We study whether crowdsourcing is an effective and reliable method to assess truthfulness during a pandemic, targeting statements related to COVID-19, thus addressing (mis)information that is both related to a sensitive and personal issue and very recent as compared to when the judgment is done. In our experiments, crowd workers are asked to assess the truthfulness of statements, and to provide evidence for the assessments. Besides showing that the crowd is able to accurately judge the truthfulness of the statements, we report results on workers' behavior, agreement among workers, effect of aggregation functions, of scales transformations, and of workers background and bias. We perform a longitudinal study by re-launching the task multiple times with both novice and experienced workers, deriving important insights on how the behavior and quality change over time. Our results show that workers are able to detect and objectively categorize online (mis)information related to COVID-19; both crowdsourced and expert judgments can be transformed and aggregated to improve quality; worker background and other signals (e.g., source of information, behavior) impact the quality of the data. The longitudinal study demonstrates that the time-span has a major effect on the quality of the judgments, for both novice and experienced workers. Finally, we provide an extensive failure analysis of the statements misjudged by the crowd-workers.


Effective eradication of pinworms (Syphacia obvelata and Aspiculuris tetraptera) with Polygonum cognatum Meissn.
Polygonum cognatum Meissn. (Polygonaceae) is a wild edible plant known locally as "solucanotu, madimak" in Turkey and it has been used for various purposes, such as diuretic and antidiabetic, as well to treat oxyuris and worms internally in humans. The present study was carried out to investigate the anthelmintic activity of various extracts were obtained from the aerial parts of P. cognatum in order to justify its traditional usage in Turkish folk medicine. n-Hexane, ethyl acetate and methanol extracts were prepared from the aerial parts of the plant, successively. The anthelmintic potentials of these extracts were evaluated on mice naturally infected with Syphacia obvelata and Aspiculuris tetraptera. Cellophane perianal tape test and fecal flotation test were used for the activity screening. The results were compared with control and reference groups. In addition to all these experiments, the total amount of phenolic compounds and tannin contents thought to be responsible for the activity were evaluated for all extracts. According to the results, it has been found that the methanolic extract reduced the number of S. obvelata (66.8%) and A. tetraptera (73.4%) eggs. Moreover, the methanolic extract include higher amount of total phenolic compound (48.75 ± 0.82 mg of GA/g of extract) and tannin (30.04 ± 0.22 mg TA/g of extract) than n-Hexane (17.21 ± 0.75 mg of GA/g of extract; 6.82 ± 0.41 mg TA/g of extract) and ethyl acetate (25.06 ± 0.94 mg of GA/g of extract; 10.29 ± 0.34 mg TA/g of extract); therefore the anthelmintic activity could be related to these constituents. The present study explored the anthelmintic potential of P. cognatum. Further studies should be conducted into the mechanism of these compounds' against helminths. This study can be an important step in the discovery of new anthelmintic agents.


Proteomics in the study of female fertility: an update.
Female fertility has been a field of interest for the scientific community throughout the years. The contribution of proteomics in the study of female fertility as well as female infertility and in vitro fertilization (IVF) has been significant. Proteomics is a recently developed field, extensively applied to the identification and quantification of proteins, which could be used as potential biomarkers in a diagnostic, prognostic, or predictive manner in a variety of medical conditions. The present review focuses on proteomic studies of the oocyte and endometrial environment as well as on conditions related to infertility, such as polycystic ovarian syndrome, endometriosis, obesity, and unexplained infertility. Moreover, this review presents studies that have been done in an effort to search for fertility biomarkers in individuals following the IVF procedure. The comprehension of the molecular pathways behind female fertility and infertility could contribute to the diagnosis, prognosis, and prediction of infertility. Moreover, the identification of proteomic biomarkers for IVF cycles could predict the possible outcome of an IVF cycle, prevent an unsuccessful IVF, and monitor the IVF cycle in a personalized manner, leading to increased success rates. [Figure: see text].


Long-term follow-up study of patients with cavernous sinus aneurysm treated by proximal occlusion.
Proximal occlusion of the internal carotid artery (ICA) is still the treatment of choice for a large cavernous sinus aneurysm. Endovascular occlusion or trapping of the ICA with or without an extracranial-intracranial bypass is sometimes performed. We analyzed the results of the long-term follow up of 11 patients with a giant or large cavernous sinus aneurysm treated by only proximal occlusion between 1975 and 1989. Proximal occlusion of the carotid artery was performed by Selverstone clamping. The follow-up period ranged from 6 to 21 years (mean 13.9 years). Eight of the 11 patients showed improvement of cranial nerves paresis or headache, and four became asymptomatic. None of the original aneurysms ruptured. The final outcomes were nine good recovery, one moderately disabled, and one severely disabled by the Glasgow Outcome Scale. The causes of morbidity were early ischemia and subarachnoid hemorrhage from a newly formed aneurysm. Late complications included ischemia in two patients, and new formation and enlargement of aneurysms at a site other than the original aneurysm in two patients, 13 and 17 years later. Therapeutic carotid artery occlusion requires strict test ICA occlusion. In addition, long-term follow up by periodical cerebral angiography using magnetic resonance, computed tomography, or digital subtraction angiography is necessary, and postoperative medical treatment is important to reduce the risk of late complications.


Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis.
Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and the autoimmune process. Therefore, we performed a randomised, placebo-controlled prospective study to investigate the effects of Se treatment on patients with autoimmune thyroiditis (AIT). Sixty five patients aged 22-61 years (median age 48 years) with AIT were recruited into two groups. Group I (Gr I) (n=34) was treated with selenomethionine (Seme) 200 microg, plus L-thyroxine (LT(4)) to maintain TSH levels between 0.3-2.0 mU/l, whereas group II (Gr II) (n=31) received LT(4) plus placebo over a period of 6 months. Moreover, the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h, 4 h, 6 h and 24 h after oral administration of a 200 microg tablet of Seme. Finally, Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels. In the pharmacokinetics study, basal serum concentration of Se (75+/-6 microg/l) was within the reference range (70-125 microg/l), it promptly increased at 2 h, peaked at 4 h (147+/-17 microg/l; P<0.0001) and it was abundant in serum at 24 h. In Gr I, antibodies against thyroid peroxidase (anti-TPO) levels showed an overall decrease of 46% at 3 months (from 1875+/-1039 U/l to 1013+/-382 U/l; P<0.0001) and of 55.5% at 6 months. In Gr II the overall decrease of anti-TPO amounted to 21% at 3 months and to 27% at 6 months (from 1758+/-917 U/l to 1284+/-410 U/l; P<0.005). There were no significant changes of antibodies against thyroglobulin levels between the groups. At the end of this study Se levels were found to be statistically significantly increased in Gr I (n = 9/34) compared with Gr II (n=11/31) (97+/-8.4 vs 79+/-8; P<0.01) but no correlation with thyroid hormone was found. Seme is proven to be rapidly absorbed by the gastrointestinal tract. It appears to be useful as adjunctive therapy with LT(4) in the treatment of AIT. The exact mechanism(s) is not very well determined, it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress.


Mechanisms of resistance to immune checkpoint inhibitors and strategies to reverse drug resistance in lung cancer.
In recent years, the research of immune checkpoint inhibitors has made a great breakthrough in lung cancer treatment. Currently, a variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4, and so on. However, not all patients can benefit from the treatment. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the molecular mechanism of immune checkpoint inhibitor resistance and various combination strategies to overcome resistance, in order to expand the beneficial population and enable precision medicine.


Spatiotemporal Clustering of Mycobacterium tuberculosis Complex Genotypes in Florida: Genetic Diversity Segregated by Country of Birth.
Tuberculosis (TB) is caused by members of the Mycobacterium tuberculosis complex (MTBC). Although the MTBC is highly clonal, between-strain genetic diversity has been observed. In low TB incidence settings, immigration may facilitate the importation of MTBC strains with a potential to complicate TB control efforts. We investigated the genetic diversity and spatiotemporal clustering of 2,510 MTBC strains isolated in Florida, United States, between 2009 and 2013 and genotyped using spoligotyping and 24-locus MIRU-VNTR. We mapped the genetic diversity to the centroid of patient residential zip codes using a geographic information system (GIS). We assessed transmission dynamics and the influence of immigration on genotype clustering using space-time permutation models adjusted for foreign-born population density and county-level HIV risk and multinomial models stratified by country of birth and timing of immigration in SaTScan. Among the 2,510 strains, 1,245 were reported among foreign-born persons; including 408 recent immigrants (<5 years). Strain allelic diversity (h) ranged from low to medium in most locations and was most diverse in urban centers where foreign-born population density was also high. Overall, 21.5% of cases among U.S.-born persons and 4.6% among foreign-born persons clustered genotypically and spatiotemporally and involved strains of the Haarlem family. One Haarlem space-time cluster identified in the mostly rural northern region of Florida included US/Canada-born individuals incarcerated at the time of diagnosis; two clusters in the mostly urban southern region of Florida were composed predominantly of foreign-born persons. Both groups had HIV prevalence above twenty percent. Almost five percent of TB cases reported in Florida during 2009-2013 were potentially due to recent transmission. Improvements to TB screening practices among the prison population and recent immigrants are likely to impact TB control. Due to the monomorphic nature of available markers, whole genome sequencing is needed to conclusively delineate recent transmission events between U.S. and foreign-born persons.


Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression.
To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.


The psychological impact of a cancer diagnosed during pregnancy: determinants of long-term distress.
Cancer occurs during one in 1000-5000 of the approximately 6 million yearly US pregnancies identified by the American Pregnancy Association. Although a newly diagnosed cancer is associated with substantial distress, little is known about cancer's emotional impact on women when diagnosed during pregnancy, and no studies have been conducted on the subject. The Cancer and Pregnancy Registry was developed by Elyce H. Cardonick MD, specialist in Maternal and Fetal Medicine and Associate Professor of Obstetrics and Gynecology at Robert Wood Johnson Medical School, to examine the consequences of maternal cancer diagnosis and treatment during pregnancy on maternal, fetal, and neonatal outcomes, including the impact of in utero exposure to chemotherapy. Participants were asked to complete questionnaires, including measures of psychological distress, permitting the examination of variables associated with long-term psychological distress in women following a cancer diagnosis in pregnancy. Seventy-four women completed the Brief Symptom Inventory-18 and Impact of Event Scale on average 3.8 years (SD 2.5) following their cancer diagnosis. Potential variables related to distress included information on: sociodemographics, disease, pregnancy, birth, cancer treatment, and health status. Multiple regression analyses revealed that women were at higher risk of long-term distress if they had not received fertility assistance, had been advised to terminate the pregnancy, had had a preterm baby, had had a cesarean delivery, had not produced sufficient milk to breastfeed, had been experiencing a recurrence, and/or had undergone surgery post-pregnancy. Results are discussed in light of our current knowledge of the normal developmental phase of pregnancy and motherhood.


Genotypic characteristics of Mycobacterium tuberculosis isolated from household contacts of tuberculosis patients in the Philippines.
The Philippines has an extremely high rate of tuberculosis but little is known about M. tuberculosis genotypes and transmission dynamics in this country. The aim of this study was to determine the proportion of household contacts who develop active TB due to direct transmission from an index case in that household. Mycobacterium tuberculosis isolates from household contacts of tuberculosis patients in the Philippines were characterized using restriction-fragment-length polymorphism analysis, spoligotyping, and mycobacterial interspersed repetitive units - variable number tandem repeats typing (12-loci) to determine their utility in elucidating transmission in an area of high tuberculosis prevalence. Drug susceptibility patterns for these isolates were also determined. Spoligotyping and MIRU-VNTR typing results matched in 10 (62.5%) of 16 index patient-household contact pairs while IS6110 fingerprints matched in only six (37.5%) pairs. Only 3/16 (18.8%) index patient-household contact pairs had identical drug susceptibility results. Strain typing of M. tuberculosis isolates from household contacts in the Philippines indicates that transmission of strains does not necessarily occur directly from the index patient living in close proximity in the same household but rather that community-based transmission also frequently occurs. Accurate susceptibility testing of all isolates is necessary to insure optimal care of both the index patients and any culture-positive household contacts.


Rich internet application system for patient-centric healthcare data management using handheld devices.
Rich Internet Applications (RIAs) are an emerging software platform that blurs the line between web service and native application, and is a powerful tool for handheld device deployment. By democratizing health data management and widening its availability, this software platform has the potential to revolutionize telemedicine, clinical practice, medical education and information distribution, particularly in rural areas, and to make patient-centric medical computing a reality. In this paper, we propose a telemedicine application that leverages the ability of a mobile RIA platform to transcode, organise and present textual and multimedia data, which are sourced from medical database software. We adopted a web-based approach to communicate, in real-time, with an established hospital information system via a custom RIA. The proposed solution allows communication between handheld devices and a hospital information system for media streaming with support for real-time encryption, on any RIA enabled platform. We demonstrate our prototype's ability to securely and rapidly access, without installation requirements, medical data ranging from simple textual records to multi-slice PET-CT images and maximum intensity (MIP) projections.


MicroRNAs dysregulation in human malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a rare but aggressive asbestos-related cancer that develops by mesothelial cell transformation. At present, there are no effective therapies for MPM. Great efforts have been made in finding specific markers/mechanisms for MPM onset, including studies into microRNAs (miRNAs). Recent studies have shown the differential expression of mature miRNAs in several human cancers, suggesting their potential role as oncogenes or tumor suppressor genes. In this study, we investigated miRNAs profile in five human normal pleural mesothelial short-term cell cultures (HMCs) and five MPMs, with microarray approach. These results were confirmed by real-time quantitative reverse-transcriptase polymerase chain reaction and Western blotting. A comparative analysis of miRNA expression in MPM and HMCs was carried out. Microarray profiling showed different miRNA expression between MPM and HMCs. Specifically, members of the oncomiRNA miR 17-92 cluster and its paralogs, namely miR 17-5p, 18a, 19b, 20a, 20b, 25, 92, 106a, 106b, were markedly upregulated. Besides, in our investigation, additional miRNAs, such as miR-7, miR-182, miR-214, and miR-497 were found to be dysregulated in MPM. These data are in agreement with results that have previously been reported on dysregulated miRNAs for other solid human tumors. Moreover, in our investigation, additional miRNAs were found to be dysregulated in MPM. Interestingly, gene products that regulate the cell cycle are targets and predicted targets for these miRNAs. Our data suggest that specific miRNAs could be key players in MPM development/progression. In addition, some of these miRNAs may represent MPM markers and potential targets for new therapeutic approaches.


Remembering the Occam's Razor: Could Simple Electrocardiographic Findings Provide Relevant Predictions for Current Hemodynamic Criteria of Pulmonary Hypertension?
We evaluated the predictive value of electrocardiographic (ECG) findings for pulmonary hemodynamics assessed by right heart catheterization (RHC). Our study population comprised 562 retrospectively evaluated patients who underwent RHC between 2006 and 2022. Correlations between ECG measures and pulmonary arterial systolic and mean pressures (PASP and PAMP) and pulmonary vascular resistance (PVR) were investigated. Moreover, receiver operating characteristic (ROC) curve analysis assessed the predictive value of ECG for pulmonary hypertension (PH) and precapillary PH. The P-wave amplitude (Pwa) and R/S ratio (r) in V1 and V2, Ra in augmented voltage right (aVR), right or indeterminate axis, but not P wave duration (Pwd) or right bundle branch block (RBBB) significantly correlated with PASP, PAMP, and PVR (P <.001 for all). The partial R2 analysis revealed that amplitude of R wave (Ra) in aVR, R/Sr in V1 and V2, QRS axis, and Pwa added to the base model provided significant contributions to variance for PASP, PAMP, and PVR, respectively. The Pwa > 0.16 mV, Ra in aVR > 0.05 mV, QRS axis > 100° and R/Sr in V1 > 0.9 showed the highest area under curve (AUC) values for PAMP > 20 mm Hg. Using the same cutoff value, Ra in aVR, Pwa, QRS axis, and R/Sr in V1 showed highest predictions for PVR > 2 Wood Units (WU). In this study, Pwa, Ra in aVR, right or indeterminate axis deviations, and R/Sr in V1 and V2 showed statistically significant correlations with pulmonary hemodynamics, and Ra in aVR, R/Sr in V2 and V1, QRS axis, and Pwa contributed to variance for PASP, PAMP, and PVR, respectively. Moreover, Pwa, Ra in aVR, QRS axis, and R/Sr in V1 seem to provide relevant predictions for PH and precapillary PH.


Prefronto-cerebellar neuromodulation affects appetite in obesity.
Human neuroimaging studies have consistently reported changes in cerebellar function and integrity in association with obesity. To date, however, the nature of this link has not been studied directly. Emerging evidence suggests a role for the cerebellum in higher cognitive functions through reciprocal connections with the prefrontal cortex. The purpose of this exploratory study was to examine appetite changes associated with noninvasive prefronto-cerebellar neuromodulation in obesity. Totally, 12 subjects with class I obesity (mean body mass index 32.9 kg/m2) underwent a randomized, single-blinded, sham-controlled, crossover study, during which they received transcranial direct current stimulation ((tDCS); active/sham) aimed at simultaneously enhancing the activity of the prefrontal cortex and decreasing the activity of the cerebellum. Changes in appetite (state and food-cue-triggered) and performance in a food-modified working memory task were evaluated. We found that active tDCS caused an increase in hunger and desire to eat following food-cue exposure. In line with these data, subjects also tended to make more errors during the working memory task. No changes in basic motor performance occurred. This study represents the first demonstration that prefronto-cerebellar neuromodulation can influence appetite in individuals with obesity. While preliminary, our findings support a potential role for prefronto-cerebellar pathways in the behavioral manifestations of obesity.


BCNNM: A Framework for in silico Neural Tissue Development Modeling.
Cerebral ("brain") organoids are high-fidelity in vitro cellular models of the developing brain, which makes them one of the go-to methods to study isolated processes of tissue organization and its electrophysiological properties, allowing to collect invaluable data for in silico modeling neurodevelopmental processes. Complex computer models of biological systems supplement in vivo and in vitro experimentation and allow researchers to look at things that no laboratory study has access to, due to either technological or ethical limitations. In this paper, we present the Biological Cellular Neural Network Modeling (BCNNM) framework designed for building dynamic spatial models of neural tissue organization and basic stimulus dynamics. The BCNNM uses a convenient predicate description of sequences of biochemical reactions and can be used to run complex models of multi-layer neural network formation from a single initial stem cell. It involves processes such as proliferation of precursor cells and their differentiation into mature cell types, cell migration, axon and dendritic tree formation, axon pathfinding and synaptogenesis. The experiment described in this article demonstrates a creation of an in silico cerebral organoid-like structure, constituted of up to 1 million cells, which differentiate and self-organize into an interconnected system with four layers, where the spatial arrangement of layers and cells are consistent with the values of analogous parameters obtained from research on living tissues. Our in silico organoid contains axons and millions of synapses within and between the layers, and it comprises neurons with high density of connections (more than 10). In sum, the BCNNM is an easy-to-use and powerful framework for simulations of neural tissue development that provides a convenient way to design a variety of tractable in silico experiments.


Effect of 3-mercaptopyruvate Sulfurtransferase Deficiency on the Development of Multiorgan Failure, Inflammation, and Wound Healing in Mice Subjected to Burn Injury.
The gaseous transmitter hydrogen sulfide (H2S) has been implicated in various forms of critical illness. Here, we have compared the outcome of scald burn injury in wild-type mice and in mice deficient in 3-mercaptopyruvate sulfurtransferase (3-MST), a mammalian H2S-generating enzyme. Outcome variables included indices of organ injury, clinical chemistry parameters, and plasma levels of inflammatory mediators. Plasma levels of H2S significantly increased in response to burn in wild-type mice, but remained unchanged in 3-MST-/- mice. The capacity of tissue homogenates to produce H2S from 3-mercaptopyruvate was unaffected by burn injury. In 3-MST-/- mice, compared to wild-type controls, there was a significant enhancement in the accumulation of polymorphonuclear cells (as assessed by the quantification of myeloperoxidase) in the liver (but not heart, lung, or skin) at 7 days postburn. Oxidative tissue damage (as assessed by malon dialdehyde content) was comparable between wild-type and 3-MST-deficient mice in all tissues studied. 3-MST-/- and wild-type mice exhibited comparable burn-induced elevations in circulating plasma levels of hepatic injury; however, 3-MST-/- mice exhibited a higher degree of renal injury (as reflected by elevated blood urea nitrogen levels) at 7 days postburn. Inflammatory mediators (eg, TNF-α, IL-1β, IL-2, IL-6, IL-10, and IL-12) increased in burn injury, but without significant differences between the 3-MST-/- and wild-type groups. The healing of the burn wound was also unaffected by 3-MST deficiency. In conclusion, the absence of the H2S-producing enzyme 3-MST slightly exacerbates the development of multiorgan dysfunction but does not affect inflammatory mediator production or wound healing in a murine model of burn injury.


Can Crohn's disease be diagnosed at laparotomy?
The typical macroscopic features of Crohn's disease have been well described and are widely regarded as sufficient to diagnose the disease at laparotomy. We report six patients undergoing laparotomy for symptomatic Crohn's disease, shown radiologically, who were found to have macroscopically normal small bowel despite careful examination of the bowel by an experienced surgeon. In four cases resection was deferred, but all subsequently deteriorated and required further surgery. Minor abnormalities found by balloon examination of the terminal ileum prompted resection in two further patients. Histology showed an unusually superficial distribution of inflammation, which could explain the negative findings at laparotomy. We conclude that normal laparotomy findings alone do not exclude a diagnosis of clinically important small bowel Crohn's disease. Crohn's disease should be considered in patients with persisting symptoms after negative laparotomy.


Lipopolysaccharide impairs the in vitro growth, steroidogenesis, and maturation of oocyte-cumulus-granulosa cell complexes derived from bovine early antral follicles.
In postpartum dairy cows, lipopolysaccharide (LPS) derived from gram-negative bacteria causes uterine or mammary inflammation, resulting in low fertility. The present study aimed to investigate the effect of LPS on the in vitro growth (IVG), steroidogenesis, and maturation of oocyte-cumulus-granulosa cell complexes (OCGCs) derived from bovine early antral follicles. OCGCs were isolated from bovine early antral follicles (0.5-1 mm in diameter) and cultured in vitro for 12 days using media containing 0 (control), 0.01, or 1 μg/mL of LPS. The viability, cavity formation, and oocyte diameter of the OCGCs, as well as the concentrations of estradiol (E2) and progesterone (P4) in the IVG culture media, were determined. After IVG culture, oocytes collected from viable OCGCs were matured in vitro (IVM) in a medium without LPS. The nuclear maturation rate and the mitochondrial membrane potential of oocytes were determined. Bovine oocytes and cumulus-granulosa complexes derived from early antral follicles expressed genes encoding LPS receptor complex, such as toll-like receptor 4 (TLR4). Immunohistochemistry analysis further localized TLR4 expression predominantly in follicular granulosa and theca cells of early antral follicles. The viability of OCGCs and cavity formation in OCGCs were lower in the 0.01 and 1 μg/mL LPS groups than in the control group. No significant difference in oocyte diameter was observed between the treatment groups throughout the culture period. Moreover, E2 production was suppressed in the 0.01 and 1 μg/mL LPS groups from Days 4-8, whereas P4 production increased in the 1 μg/mL LPS group from Days 0-8. The nuclear maturation rate after IVM was lower in the 0.01 and 1 μg/mL LPS groups than in the control group. The mitochondrial membrane potential of post-IVM oocytes was lower in the 0.01 and 1 μg/mL LPS groups than in the control group. Taken together, these results indicate that LPS inhibited the growth and steroidogenesis of OCGCs and the meiosis and mitochondrial function of oocytes derived from early antral follicles. This study suggests that the detrimental effects of LPS on developing oocytes may contribute to long-term decreased fertility in postpartum dairy cows.


Inhibition of retrovirus RNA-dependent DNA polymerase by novobiocin and nalidixic acid.
Inhibitors of bacterial DNA gyrase and eukaryotic DNA topoisomerase (novobiocin and nalidixic acid) were investigated with respect to their effect on the activity of RNA-dependent DNA polymerases from murine and avian retroviruses. Purified RNA-dependent DNA polymerase from AKR virus was inhibited more than 90% by 0.3 mg/ml and almost completely by 1 mg/ml of the drugs when poly(A) X oligo(dT)12-18 was used as a template-primer. In contrast to the enzyme from AKR virus, purified enzyme from avian myeloblastosis virus was less sensitive, i.e. nearly 50% activity remained even in the presence of 1 mg/ml of the drugs with the same template-primer. RNA-dependent DNA polymerase activity in AKR virus particles was inhibited, but was resistant to low concentrations of the drugs. The inhibition was not due to specific interaction between drugs and the template-primer or labelled precursor, since RNA-dependent DNA polymerase was inhibited by the drugs with activated calf thymus DNA or poly(C) X oligo(dG)12-18 as the template. Endogenous DNA synthesis by AKR virus particles was inhibited by novobiocin to the same extent.


Carbenium ion-mediated oligomerization of methylglyoxal for secondary organic aerosol formation.
Secondary organic aerosol (SOA) represents a major constituent of tropospheric fine particulate matter, with profound implications for human health and climate. However, the chemical mechanisms leading to SOA formation remain uncertain, and atmospheric models consistently underpredict the global SOA budget. Small α-dicarbonyls, such as methylglyoxal, are ubiquitous in the atmosphere because of their significant production from photooxidation of aromatic hydrocarbons from traffic and industrial sources as well as from biogenic isoprene. Current experimental and theoretical results on the roles of methylglyoxal in SOA formation are conflicting. Using quantum chemical calculations, we show cationic oligomerization of methylglyoxal in aqueous media. Initial protonation and hydration of methylglyoxal lead to formation of diols/tetrol, and subsequent protonation and dehydration of diols/tetrol yield carbenium ions, which represent the key intermediates for formation and propagation of oligomerization. On the other hand, our results reveal that the previously proposed oligomerization via hydration for methylglyoxal is kinetically and thermodynamically implausible. The carbenium ion-mediated mechanism occurs barrierlessly on weakly acidic aerosols and cloud/fog droplets and likely provides a key pathway for SOA formation from biogenic and anthropogenic emissions.


Being a grump only makes things worse: a transactional account of acute stress on mind wandering.
The current work investigates the influence of acute stress on mind wandering. Participants completed the Positive and Negative Affect Schedule as a measure of baseline negative mood, and were randomly assigned to either the high-stress or low-stress version of the Trier Social Stress Test. Participants then completed the Sustained Attention to Response Task as a measure of mind-wandering behavior. In Experiment 1, participants reporting a high degree of negative mood that were exposed to the high-stress condition were more likely to engage in a variable response time, make more errors, and were more likely to report thinking about the stressor relative to participants that report a low level of negative mood. These effects diminished throughout task performance, suggesting that acute stress induces a temporary mind-wandering state in participants with a negative mood. The temporary affect-dependent deficits observed in Experiment 1 were replicated in Experiment 2, with the high negative mood participants demonstrating limited resource availability (indicated by pupil diameter) immediately following stress induction. These experiments provide novel evidence to suggest that acute psychosocial stress briefly suppresses the availability of cognitive resources and promotes an internally oriented focus of attention in participants with a negative mood.


Bottom-up priority setting revised. A second evaluation of an institutional intervention in a Swedish health care organisation.
Transparent priority setting in health care based on specific ethical principles is requested by the Swedish Parliament since 1997. Implementation has been limited. In this case, transparent priority setting was performed for a second time round and engaged an entire health care organisation. Objectives were to refine a bottom-up priority setting process, reach a political decision on service limits to make reallocation towards higher prioritised services possible, and raise systems knowledge. An action research approach was chosen. The national model for priority setting was used with addition of dimensions costs, volumes, gender distribution and feasibility. The intervention included a three step process and specific procedures for each step which were created, revised and evaluated regarding factual and functional aspects. Evaluations methods included analyses of documents, recordings and surveys. Vertical and horizontal priority setting occurred and resources were reallocated. Participants' attitudes remained positive, however less so than in the first priority setting round. Identifying low-priority services was perceived difficult, causing resentment and strategic behaviour. The horizontal stage served to raise quality of the knowledge base, level out differences in ranking of services and raise systems knowledge. Existing health care management systems do not meet institutional requirements for transparent priority setting. Introducing transparent priority setting constitutes a complex institutional reform, which needs to be driven by management/administration. Strong managerial commitment is required.


The optimal training load for the development of muscular power.
Muscular power is considered one of the main determinants of athletic performance that require the explosive production of force such as throwing and jumping. Various training methods have been suggested to improve muscular power and dynamic athletic performance. Although various acute training valuables (e.g., sets, repetitions, rest intervals) could be manipulated, the training loads used are some of the most important factors that determine the training stimuli and the consequent training adaptations. Many research results showed that the use of different training loads elicits the different training adaptations and further indicated the load- and velocity-specific adaptations in muscular-power development. Using the optimal loads at which mechanical power output occurs has been recommended, especially to enhance maximum muscular power. Additionally, introducing periodization and combined training approach into resistance-training programs may further facilitate muscular-power development and enhance a wide variety of athletic performances.


Patients' existential situation prior to colorectal surgery.
The aim of this paper is to present a hermeneutic phenomenological study illuminating patients' existential situation prior to colorectal surgery. The intention was also to explore the value of the encounter between patient and nurse. Patients waiting for major surgery experience multifarious reactions. Emotions of anxiety, fears of the unknown, anaesthesia, cancer diagnosis and death can arise. Several earlier studies have reported the importance of information, coping strategies and the need to reduce anxiety and stress in relation to surgery. However, there is a lack of studies focusing on patients' existential situation in the preoperative phase. Conversational interviews were conducted with 28 patients 1 week before their surgery during autumn 2002. Analysis of the data was influenced by van Manen's existential themes: lived space/spatiality, lived body/corporeality, lived time/temporality and lived relation/relationality. Participants expressed either hope of increased spatiality or fear of restricted spatiality, according to whether they had a benign or malign diagnosis. Statements about lived time were also related to the diagnosis. Patients waiting for surgery for a benign diagnosis could use the time to relax and gather energy, while malignancy gave them high levels of anxiety and stress. Lived body experiences showed the ambivalence felt in entrusting one's body to professionals. Statements about lived relations drew attention to the need for considerate caregivers to enhance feelings of security and continuity. The existential situation of patients in a preoperative context was shown to be a state of uncertainty with regard to lived space, body, time and relation. The significance of meeting and talking to the nurse did not appear in the statements. The nurse was invisible. If nurses were to employ the existential themes proposed by van Manen in preoperative encounter with patients, their need for care might be more clearly identified and affirmed.