An approximation of herd effect due to vaccinating children against seasonal influenza - a potential solution to the incorporation of indirect effects into static models.
Indirect herd effect from vaccination of children offers potential for improving the effectiveness of influenza prevention in the remaining unvaccinated population. Static models used in cost-effectiveness analyses cannot dynamically capture herd effects. The objective of this study was to develop a methodology to allow herd effect associated with vaccinating children against seasonal influenza to be incorporated into static models evaluating the cost-effectiveness of influenza vaccination. Two previously published linear equations for approximation of herd effects in general were compared with the results of a structured literature review undertaken using PubMed searches to identify data on herd effects specific to influenza vaccination. A linear function was fitted to point estimates from the literature using the sum of squared residuals. The literature review identified 21 publications on 20 studies for inclusion. Six studies provided data on a mathematical relationship between effective vaccine coverage in subgroups and reduction of influenza infection in a larger unvaccinated population. These supported a linear relationship when effective vaccine coverage in a subgroup population was between 20% and 80%. Three studies evaluating herd effect at a community level, specifically induced by vaccinating children, provided point estimates for fitting linear equations. The fitted linear equation for herd protection in the target population for vaccination (children) was slightly less conservative than a previously published equation for herd effects in general. The fitted linear equation for herd protection in the non-target population was considerably less conservative than the previously published equation. This method of approximating herd effect requires simple adjustments to the annual baseline risk of influenza in static models: (1) for the age group targeted by the childhood vaccination strategy (i.e. children); and (2) for other age groups not targeted (e.g. adults and/or elderly). Two approximations provide a linear relationship between effective coverage and reduction in the risk of infection. The first is a conservative approximation, recommended as a base-case for cost-effectiveness evaluations. The second, fitted to data extracted from a structured literature review, provides a less conservative estimate of herd effect, recommended for sensitivity analyses.


Association between BRCA Gene Variants and the Response to Modified FOLFIRINOX in Patients with Unresectable Pancreatic Cancer.
We investigated the effect of modified FOLFIRINOX (mFFX) in unresectable pancreatic cancer by retrospectively analyzing the cases of 43 patients who underwent BRCA testing (germline, n=11; somatic, n=26; both germline and somatic, n=6). The association between BRCA mutations and therapeutic effect was clarified. Six patients tested positive for germline pathogenic variants. Familial pancreatic cancer (33% vs. 3%, p=0.006) and peritoneal disseminated lesions (66% vs. 8%, p<0.001) were significantly more common in patients with germline pathogenic variants. The partial response (PR) rate was 100% in the germline BRCA-positive patients, and 27% in the germline BRCA-negative patients (p<0.001). The median progression-free survival (PFS) was not reached for any germline BRCA-positive patients but was 9.0 months for the germline BRCA-negative patients (p=0.042). Patients with stage IV BRCA-associated pancreatic cancer had better overall survival than those with non-BRCA-associated pancreatic cancer, although the difference was nonsignificant (not reached vs. 655 days, p=0.061). Our results demonstrate that a PR and prolonged PFS can be expected in germline BRCA-positive patients after treatment with mFFX. Our findings also suggest that germline BRCA pathogenic variants may be useful as biomarkers for the therapeutic effect of mFFX in patients with pancreatic cancer.


Treatment of idiopathic pulmonary fibrosis with losartan: a pilot project.
Idiopathic pulmonary fibrosis is a progressive interstitial lung disease with no current effective therapies. Treatment has focused on antifibrotic agents to stop proliferation of fibroblasts and collagen deposition in the lung. We present the first clinical trial data on the use of losartan, an antifibrotic agent, to treat idiopathic pulmonary fibrosis. The primary objective was to evaluate the effect of losartan on progression of idiopathic pulmonary fibrosis measured by the change in percentage of predicted forced vital capacity (%FVC) after 12 months. Secondary outcomes included the change in forced expiratory volume at 1 second, diffusing capacity of carbon monoxide, 6-minute walk test distance, and baseline/transition dyspnea index. Patients with idiopathic pulmonary fibrosis and a baseline %FVC of ≥50 % were treated with losartan 50 mg by mouth daily for 12 months. Pulmonary function testing, 6-minute walk, and breathlessness indices were measured every 3 months. Twenty participants with idiopathic pulmonary fibrosis were enrolled and 17 patients were evaluable for response. Twelve patients had a stable or improved %FVC at study month 12. Similar findings were observed in secondary end-point measures, including 58, 71, and 65 % of patients with stable or improved forced expiratory volume at 1 second, diffusing capacity for carbon monoxide, and 6-minute walk test distance, respectively. No treatment-related adverse events that resulted in early study discontinuation were reported. Losartan stabilized lung function in patients with idiopathic pulmonary fibrosis over 12 months. Losartan is a promising agent for the treatment of idiopathic pulmonary fibrosis and has a low toxicity profile.


20-year Clinical Outcomes of Cervical Disk Arthroplasty: A Prospective, Randomized, Controlled Trial.
Prospective, randomized, controlled trial. To compare clinical outcomes of anterior cervical discectomy and fusion (ACDF) and cervical disk arthroplasty (CDA) at 20 years. Concern for adjacent-level disease after ACDF prompted the development of CDA. Forty-seven patients with single-level cervical radiculopathy were randomized to either BRYAN CDA or ACDF for a Food and Drug Administration Investigational Device Exemption trial. At 20 years, patient-reported outcomes, including visual analog scales (VAS) for neck and arm pain, neck disability index (NDI), and reoperation rates, were analyzed. Follow-up rate was 91.3%. Both groups showed significantly better NDI, VAS arm pain, and VAS neck pain scores at 20 years versus preoperative scores. Comparing CDA versus ACDF, there was no difference at 20 years in mean scores for NDI [11.1 (SD 14.1) vs. 19.9 (SD 17.2), P =0.087], mean VAS arm pain [0.9 (SD 2.4) vs. 2.3 (SD 2.8), P =0.095], or mean VAS neck pain [1.2 (SD 2.5) vs. 2.9 (3.3), P =0.073]. There was a significant difference between CDA versus ACDF groups in the change in VAS neck pain score between 10 and 20 years [respectively, -0.4 (SD 2.5) vs. 1.5 (SD 2.5), P =0.030]. Reoperations were reported in 41.7% of ACDF patients and 10.0% of CDA patients ( P =0.039). Both CDA and ACDF are effective in treating cervical radiculopathy with sustained improvement in NDI, VAS neck and VAS arm pain at 20 years. CDA demonstrates lower reoperation rates than ACDF. There were no failures of the arthroplasty device requiring reoperation at the index level. The symptomatic nonunion rate of ACDF was 4.2% at 20 years. Despite a higher reoperation rate in the CDA group versus ACDF group, there was no difference in the 20-year NDI, VAS Neck, and VAS arm pain scores.


Preparation and characterization of nicotine-magnesium aluminum silicate complex-loaded sodium alginate matrix tablets for buccal delivery.
Nicotine (NCT) buccal tablets consisting of sodium alginate (SA) and nicotine-magnesium aluminum silicate (NCT-MAS) complexes acting as drug carriers were prepared using the direct compression method. The effects of the preparation pH levels of the NCT-MAS complexes and the complex/SA ratios on NCT release, permeation across mucosa, and mucoadhesive properties of the tablets were investigated. The NCT-MAS complex-loaded SA tablets had good physical properties and zero-order release kinetics of NCT, which indicate a swelling/erosion-controlled release mechanism. Measurement of unidirectional NCT release and permeation across porcine esophageal mucosa using a modified USP dissolution apparatus 2 showed that NCT delivery was controlled by the swollen gel matrix of the tablets. This matrix, which controlled drug diffusion, resulted from the molecular interactions of SA and MAS. Tablets containing the NCT-MAS complexes prepared at pH 9 showed remarkably higher NCT permeation rates than those containing the complexes prepared at acidic and neutral pH levels. Larger amounts of SA in the tablets decreased NCT release and permeation rates. Additionally, the presence of SA could enhance the mucoadhesive properties of the tablets. These findings suggest that SA plays the important role not only in controlling release and permeation of NCT but also for enhancing the mucoadhesive properties of the NCT-MAS complex-loaded SA tablets, and these tablets demonstrate a promising buccal delivery system for NCT.


A deep matrix factorization framework for identifying underlying tissue-specific patterns of DCE-MRI: applications for molecular subtype classification in breast cancer.
Objective.Breast cancer is heterogeneous in that different angiogenesis and blood flow characteristics could be present within a tumor. The pixel kinetics of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assume several distinct signal patterns related to specific tissue characteristics. Identification of the latent, tissue-specific dynamic patterns of intratumor heterogeneity can shed light on the biological mechanisms underlying the heterogeneity of tumors.Approach.To mine this information, we propose a deep matrix factorization-based dynamic decomposition (DMFDE) model specifically designed according to DCE-MRI characteristics. The time-series imaging data were decomposed into tissue-specific dynamic patterns and their corresponding proportion maps. The image pixel matrix and the reference matrix of population-level kinetics obtained by clustering the dynamic signals were used as the inputs. Two multilayer neural network branches were designed to collaboratively project the input matrix into a latent dynamic pattern and a dynamic proportion matrix, which was justified using simulated data. Clinical implications of DMFDE were assessed by radiomics analysis of proportion maps obtained from the tumor/parenchyma region for classifying the luminal A subtype.Main results.The decomposition performance of DMFDE was evaluated by the root mean square error and was shown to be better than that of the conventional convex analysis of mixtures (CAM) method. The predictive model withK = 3, 4, and 5 dynamic proportion maps generated AUC values of 0.780, 0.786 and 0.790, respectively, in distinguishing between luminal A and nonluminal A tumors, which are better than the CAM method (AUC = 0.726). The combination of statistical features from images with different proportion maps has the highest prediction value (AUC = 0.813), which is significantly higher than that based on CAM.Conclusion.This proposed method identified the latent dynamic patterns associated with different molecular subtypes, and radiomics analysis based on the pixel compositions of the uncovered dynamic patterns was able to determine molecular subtypes of breast cancer.


2D Raman-THz Spectroscopy of Binary CHBr3-MeOH Solvent Mixture.
Hybrid 2D Raman-terahertz (THz) spectroscopy is used to measure the interactions between two solvents paired in the binary CHBr3-MeOH mixture in the frequency range of 1-7 THz. Changes in the cross peak signature are monitored, originating from the coupling of an intramolecular bending mode of CHBr3 to the collective intermolecular degrees of freedom of the mixture. The appearance of a new cross peak in the 2D spectrum measured for solvent mixture with MeOH molar fraction of 0.3 indicates a coupling to a new set of low-frequency modes formed due to the hydrogen bond interactions between the two solvents. This interpretation is supported by the measurement of the CHBr3-CS2 binary solvent mixture as well as by 1D absorption measurements of neat MeOH.


Evidence for the presence of a large keratan sulphate proteoglycan in the human uterine cervix.
Profound changes occur in the uterine cervix during pregnancy. In particular, the extracellular matrix of the connective tissue is remodelled extensively. To elucidate the mechanisms involved in this process, we have analysed the proteoglycan pattern in the human cervix from pregnant and non-pregnant women. Proteoglycans of the cervix tissue specimen were extracted with 4 M guanidine hydrochloride and precipitated with 80% ethanol. Purification of proteoglycans was performed by several chromatographic steps. Characterization of proteoglycans was done by SDS/PAGE before and after digestion with glycosaminoglycan-specific enzymes. Proteoglycans were detected by combined Alcian Blue/silver staining or, after blotting of biotin-labelled proteoglycans on to poly(vinylidene difluoride) membrane, with peroxidase-conjugated avidin or by the use of keratan sulphate- or decorin-specific monoclonal antibodies. In contrast with previous reports, where only chondroitin/dermatan sulphate proteoglycans have been found in the uterine cervix, we have shown in the present study the existence of a large keratan sulphate proteoglycan with an M(r) > 220,000 in cervix samples from non-pregnant and pregnant women. This proteoglycan showed a strong reaction with the keratan sulphate-specific monoclonal antibody 5D4 and could be degraded by keratanases. The size of the core protein of this keratan sulphate proteoglycan was estimated to be about M(r) 220,000.


Machine perfusion in liver transplantation.
Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box). To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation. We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023. We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms. We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence. We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies. In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.


Cellular origin of pro-coagulant and (anti)-fibrinolytic factors in bleomycin-injured lungs.
Excessive pro-coagulant and decreased fibrinolytic activities in the alveolar compartment have been repeatedly documented for inflammatory and fibrotic lung diseases. The current authors determined the contribution of different resident lung cells to the altered local production of coagulation- and fibrinolysis-system components in bleomycin-injured mouse lungs via cell-specific and quantitative assessment of mRNA levels of various pro-coagulant and (anti)-fibrinolytic factors. Laser-assisted microdissection technology was used to sample specific cell populations in combination with subsequent mRNA analysis by real-time quantitative reverse transcriptase-PCR. Additionally, western blot analysis, immunohistochemistry and activity assays were performed. Following bleomycin challenge, the strongest induction of tissue factor and plasminogen activator inhibitor (PAI)-1 mRNA expression was observed in alveolar macrophages (approximately 250- and 60-fold induction, respectively). These factors were also upregulated in alveolar type II cells, but to an approximately six-fold lesser extent. In contrast, PAI-2 expression was induced exclusively in alveolar macrophages. A slight increase of urokinase-type plasminogen activator (uPA) expression was also observed in alveolar macrophages (two-fold induction), but uPA activity was reduced due to a disproportionate increase of PAI production. Alveolar macrophages and, to a lesser extent, alveolar type II cells are the main sources of locally produced pro-coagulant and anti-fibrinolytic factors in bleomycin-injured lungs.


Stress-induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service.
Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC-vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre- and post-exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symptoms post-exposure). We found that soldiers with decreased HC volume following military service (i.e., post-exposure) displayed more PTSD-related symptoms post-exposure as well as reduced HC-vmPFC functional and structural connectivity post-exposure, compared to soldiers with increased HC volume following military service. In contrast, initial smaller HC volume pre-exposure did not have an effect on any of these factors. Our results therefore suggest that reduction in HC volume and connectivity with the vmPFC together mark a maladaptive response to stressful military service. As stress-induced HC volume reductions were previously shown to be reversible, these localized biological markers may carry valuable therapeutic potential.


Stemming out of a new PML era?
The promyelocytic leukaemia protein PML is a growth and tumour suppressor inactivated in acute promyelocytic leukaemia (APL). Recent evidence indicates that PML plays a tumour-suppressive role in cancer of multiple histological origins. However, it is only very recently that PML growth-suppressive functions have been implicated in regulating physiological processes and tissue homoeostasis. In particular, it has been shown that PML is one of the key cell-cycle regulators controlling stem cell function in multiple tissues, from the blood to the brain. As a consequence, PML loss has an impact on tissue development and maintenance of stem cell pools. In addition, new data suggest that PML regulates self-renewal in cancer stem cells. Finally, the oncogenic fusion protein PML/RARalpha, contrary to the conventional view, appears to hijack growth-suppressive pathways to promote transformation of haematopoietic stem cells and to maintain the APL stem cell niche. Overall, these findings not only represent a change in paradigm in the field of PML/APL research, but also contribute to the understanding of fundamental mechanisms underlying stem cell function in vivo. The main objective of this review is to critically discuss the very recent literature on the role of PML in stem cells and tumour-initiating cells. Ultimately, it aims to propose new avenues of investigation.


Stachydrine Ameliorates Cardiac Fibrosis Through Inhibition of Angiotensin II/Transformation Growth Factor β1 Fibrogenic Axis.
Cardiovascular diseases, the leading cause of death worldwide, are tightly associated with the pathological myocardial fibrosis. Stachydrine (Sta), a major active compound in Chinese motherwort Leonurus heterophyllus, was reported to effectively attenuate cardiac fibrosis, but the cellular and molecular mechanism remains unclear. In this study, the anti-fibrotic effect of Sta and mechanism underlying were explored in a mouse model of pressure overload and AngII stimulated cardiac fibroblasts (CFs). Mice were randomly divided into sham, transverse aorta constriction with saline (TAC+Sal), TAC with telmisartan (TAC+Tel), and TAC with Sta (TAC+Sta) groups. Cardiac morphological and functional changes were evaluated by echocardiography and histological methods, and the molecular alterations were detected by western blotting. Primary cultured neonatal mouse CFs were treated with or without angiotensin II (AngII, 10-7 M), transformation growth factor β1 (TGFβ1, 10 ng/mL), and different dosage of Sta (10-6-10-4 M) for up to 96 h, and cell proliferation, cytotoxicity, morphology and related signals were also detected. The in vivo results revealed that TAC prominently induced cardiac dysfunction, left ventricular dilation, myocardial hypertrophy, and elevated myocardial collagen deposition, accompanied with increased fibrotic markers including α-smooth muscle actin (α-SMA) and periostin. However, Sta treatment partially reversed cardiac morphological and functional deteriorations, and significantly blunted cardiac fibrosis as well as Tel. Increments of myocardial angiotensinogen (AGT), angiotensin converting enzyme (ACE), AngII type 1 receptor (AT1R), and TGFβ1 transcripts, together with increased protein levels of ACE and AngII, after TAC were dramatically down-regulated by Sta treatment. Coincidently, in vitro experiments demonstrated that AngII stimulation in CFs led to up-regulation of AT1R and TGFβ1, and therefore promoted CFs trans-differentiating into hyper-activated myocardial fibroblasts (MFs) as evidenced by increased cell proliferation, collagen and fibrotic makers. On the contrary, Sta potently down-regulated but not directly inhibited AT1R, suppressed TGFβ1 production, and the pro-fibrotic effect of AngII in CFs. Moreover, activation of TGFβ1/Smads signal in the fibrotic process were observed both TAC model and in AngII stimulated CFs, which were also notably blunted by Sta. However, Sta failed to abolish the activation of CFs triggered by TGFβ1. Taken together, it was demonstrated in this study that Sta suppressed ACE/AngII/AT1R-TGFβ1 profibrotic axis, especially on the de novo production of AngII via down-regulating AGT/ACE and AT1R, and therefore inactivated CFs and blunted MFs transition, which ultimately prevented cardiac fibrosis.


Identification of mimotopes for the H4 minor histocompatibility antigen.
The H4 minor histocompatibility antigen (HA) of mice includes a single immunogenic peptide presented by H-2Kb molecules that stimulates skin allograft rejection and is immunodominant in the stimulation of cytolytic T lymphocytes (CTL) specific for multiple minor HA. We have identified H4 mimotopes that are recognized by the H4-specific M9 CTL clone through the use of a random peptide library comprised of bacterial clones expressing an inducible fusion protein tailed with the octamer sequence SXIXFXXL. Eight discrete mimotopes were identified that sensitized RMA-S cells for lysis by M9 CTL down to concentrations of 10(-11) M. Comparable reactivity was observed with a short-term, H4-specific CTL line indicating that the mimotopes were not solely specific for the selecting M9 clone. All mimotopes included Gly at p2 and either Val or Ile at p4, suggesting a requirement for a hydrophobic residue with specific conformation. All mimotopes included either Arg or His at p7, implicating a requirement for a specific positively charged amino acid at that position. The sixth position was more variable with four of eight mimotopes having a Val residue with single mimotopes including alternative amino acids, the majority of which were hydrophobic. Analysis of mimotopes for hydrophobicity and charge by reverse-phase HPLC and capillary electrophoresis respectively indicated that (i) mimotopes with Val at both p4 and p6 were hydrophobically similar (but not identical) to the natural H4 peptide, and (ii) a S --> E substitution at p1 resulted in a peptide (EGIVFVRL) with charge characteristics equivalent to those of the natural H4 peptide.


Radiographic comparison of cervical spine motion using LMA Fastrach, LMA CTrach, and the Macintosh laryngoscope
The optimal technique for airway management in patients with cervical pathology remains unclear. Intubating laryngeal mask airway devices such as LMA CTrach and LMA Fastrach have not been compared for cervical spine (C-spine) movements in the context of cervical pathology. The present study aimed to determine upper C-spine movements by radiography during intubation with different devices as well as comparing the duration and success of intubation in cervical surgery. Sixty patients scheduled for elective cervical surgery were registered in this prospective, randomized study. Patients with cervical trauma/injury, previous neck surgery, and body mass index (BMI) of >35 kg/m2 were excluded. Participants were randomized to one of the 3 groups: LMA CTrach, LMA Fastrach, or the Macintosh laryngoscope. C-spine motion was evaluated by measuring angles created by bordering vertebrae at cervical 1/2 and 2/3 (C1/2, C2/3) segments on 2 lateral cervical radiographs for each patient. Intubation time, ease of intubation, number of attempts, and success rate were also documented. Demographic data were similar in all the groups. The cervical movement with LMA CTrach and LMA Fastrach compared to the Macintosh laryngoscope were similar at C1/2. However, LMA CTrach significantly reduced extension compared to LMA Fastrach and Macintosh laryngoscopes at C2/3. Duration of intubation was significantly shorter with the Macintosh laryngoscope. The rate of successful intubation was 80% with LMA Fastrach and 100% with both LMA CTrach and the Macintosh laryngoscopes. The LMA CTrach laryngoscopy involves less upper C-spine movement than the LMA Fastrach and does not increase the duration of the intubation period.


Recent advances in the diagnosis and management of cirrhosis-associated cardiomyopathy in liver transplant candidates: advanced echo imaging, cardiac biomarkers, and advanced heart failure therapies.
Patients with end-stage liver disease in need of liver transplantation increasingly are older with a greater burden of cardiac disease and other co-morbidities, which may increase perioperative risk and adversely affect long-term prognosis. Cirrhosis of any etiology manifests hemodynamically as a state of low systemic vascular resistance, with high peripheral, but low central blood volume, leading to a state of neurohormonal activation and high cardiac output, which may adversely affect cardiac reserve under extreme perioperative stress, aptly termed cirrhosis-associated or cirrhotic cardiomyopathy. Evidence of asymptomatic cirrhotic cardiomyopathy may be found in subtle electrocardiographic and echocardiographic changes, but may progress to severe heart failure under the demands of bleeding and transfusions, vasopressors, rebounding peripheral vascular resistance, withdrawal of cardioprotective beta-blockers and mineralocorticoid antagonists, exacerbated by sepsis or systemic inflammatory response syndrome. This review will add to the current body of literature on cirrhotic cardiomyopathy by focusing on the role of advanced echocardiographic imaging techniques, cardiac biomarkers, and advanced heart failure therapies available to manage patients with cirrhotic cardiomyopathy while waiting for liver transplant and during the perioperative period.


Reorganization of polymerized actin: a possible trigger for induction of procollagenase in fibroblasts cultured in and on collagen gels.
Changes in cell shape are postulated to modulate gene expression during differentiation of a number of cell types, including rabbit synovial fibroblasts, which are inducible for expression of the zymogen form of the metalloendopeptidase, collagenase. In the work presented here, fibroblasts cultured on and within hydrated collagen gels were allowed to contract by release of the gels from the sides of the culture dish. Within 24 h of cell release, synthesis and secretion of procollagenase was initiated in the absence of any chemical manipulation. Fibroblasts grown in and on collagen also responded to 12-O-tetradecanoylphorbol-13-acetate and cytochalasin B with morphologic change and induced procollagenase. However, colchicine, which altered morphology to varying degrees in cells on plastic, on collagen, and within collagen gels, did not induce procollagenase expression. In all cases, the enzyme was induced only after reorganization of polymerized actin, rather than after a change in cellular morphology per se. As a first approach to identifying other aspects of the stimulated phenotype that could affect collagen turnover, the expression of collagen and endogenous metalloproteinase inhibitors in relation to procollagenase secretion was investigated. Collagen secretion by fibroblasts decreased when procollagenase secretion was induced by the pharmacologic agents, but not when cells were stimulated by contraction on or within collagen gels. The expression of two endogenous inhibitors was not coordinately regulated with induction of procollagenase. Therefore, the extracellular matrix and the cellular actin cytoskeleton may transduce signals that modulate the tissue remodeling phenotype of fibroblasts.


The INTERPHONE study: design, epidemiological methods, and description of the study population.
The very rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in the possible health effects of exposure to radio frequency (RF) fields. A multinational case-control study, INTERPHONE, was set-up to investigate whether mobile phone use increases the risk of cancer and, more specifically, whether the RF fields emitted by mobile phones are carcinogenic. The study focused on tumours arising in the tissues most exposed to RF fields from mobile phones: glioma, meningioma, acoustic neurinoma and parotid gland tumours. In addition to a detailed history of mobile phone use, information was collected on a number of known and potential risk factors for these tumours. The study was conducted in 13 countries. Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the UK using a common core protocol. This paper describes the study design and methods and the main characteristics of the study population. INTERPHONE is the largest case-control study to date investigating risks related to mobile phone use and to other potential risk factors for the tumours of interest and includes 2,765 glioma, 2,425 meningioma, 1,121 acoustic neurinoma, 109 malignant parotid gland tumour cases and 7,658 controls. Particular attention was paid to estimating the amount and direction of potential recall and participation biases and their impact on the study results.


A segmentation analysis of consumer uses of health information.
Public and private health data organizations are receiving increased pressure to produce consumer-level health information. In addition, the proposed health care reforms imply that health care networks will have to market their health plans. However, little attention has been given to what format the information should have and what the consumers' information needs are. This article discusses the health services marketing literature published to date on the subject, compares it to general marketing literature, and suggests some general guidelines for the effective publication and distribution of health information.


Vitamin K1 exerts antiproliferative effects and induces apoptosis in three differently graded human colon cancer cell lines.
Vitamin K1 has been demonstrated as having anticancer potentiality mainly in liver cancer cells. Beyond the reported mechanisms of cancer inhibition (cell cycle arrest and induction of apoptosis), a possible control by vitamin K1 on molecules affecting cell growth could be hypothesized. In the literature, few (if any) data are available on its antitumor effects on colon cancer cells. Therefore, the aims of the study were to investigate in three differently graded human colon cancer cell lines (Caco-2, HT-29, and SW480) the effects of increasing concentrations of vitamin K1 (from 10 μM to 200 μM) administered up to 72 h on (1) cell proliferation, (2) apoptosis with the possible involvement of the MAPK pathway, and (3) polyamine biosynthesis. Vitamin K1 treatment caused a significant antiproliferative effect and induced apoptosis in all the cell lines, with the involvement of the MAPK pathway. A concomitant and significant decrease in the polyamine biosynthesis occurred. This is the first study demonstrating a significant polyamine decrease in addition to the antiproliferative and proapoptotic effects following vitamin K1 administration to colon cancer cell lines. Therapeutically, combinations of vitamin K1 with polyamine inhibitors and/or analogues may represent a suitable option for chemoprevention and/or treatment in future strategies for colorectal cancer management.


Dopamine release from interplexiform cells in the retina: effects of GnRH, FMRFamide, bicuculline, and enkephalin on horizontal cell activity.
In teleost fish, dopaminergic interplexiform cells provide an intraretinal centrifugal pathway from the inner to the outer plexiform layer, where they make abundant synapses on cone-related horizontal cells. The interplexiform cells receive all their input in the inner plexiform layer from centrifugal fibers and amacrine cells. In fish, centrifugal fibers contain gonadotropin hormone-releasing hormone (GnRH)-like and FMRFamide-like peptides (Munz et al., 1982; Stell et al., 1984), whereas amacrine cells contain a variety of neuroactive substances, including a number of peptides. In this study, we examined the effects of GnRH, FMRFamide, bicuculline, and enkephalin on horizontal cell activity in the white perch retina in an attempt to understand the synaptic inputs to the interplexiform cells. When the retina was superfused with Ringer's solution containing GnRH, horizontal cells depolarized (approximately 10 mV), and their responses to small spots increased, whereas their responses to full-field lights decreased. Thus, GnRH closely mimicked the effects of dopamine on horizontal cells. The GnRH antagonist [D-Phe2, Pro3, D-Phe6]-GnRH blocked the effects of GnRH, as did haloperidol. GnRH also had no effect on horizontal cells in retinas treated with 6-hydroxydopamine. The results indicate that GnRH acts by stimulating the release of dopamine from interplexiform cells. FMRFamide alone produced no changes on either the membrane potential or light responses of horizontal cells, but it did suppress the effects of GnRH on horizontal cells in some experiments. FRMFamide also reversed the effects of prolonged darkness on horizontal cell responses. When bicuculline was applied to the retina, horizontal cells also depolarized (approximately 10 mV), responses to full-field illumination decreased, and responses to small spots increased. Most of the effects of bicuculline were suppressed by haloperidol, indicating that bicuculline also stimulates the release of dopamine from interplexiform cells. Similar results were obtained when [D-Ala2]-met-enkephalinamide was applied to the retina; horizontal cells depolarized (approximately 10 mV), responses to full-field stimuli decreased, and responses to the light spots increased. On the other hand, [D-Ala2]-leuenkephalinamide and [D-Ala2, D-Leu5]-enkephalin had no effects on horizontal cells. Both haloperidol and naloxone blocked the effects of [D-Ala2]-met-enkephalinamide on horizontal cells, indicating that [D-Ala2]-met-enkephalinamide stimulates dopamine release from interplexiform cells via specific opiate receptors.


The influence of potassium concentration on the inhibitory effect of amiodarone on guinea-pig microsomal Na(+)-K(+)-ATPase activity.
The effects of varying incubation K+ concentration on the inhibitory action of amiodarone on the Mg(2+)-dependent ATP hydrolysis by myocardial Na(+)-K(+)-ATPase (EC 18.104.22.168) were studied in guinea pig heart preparations. In the first part of the study, it was established that the activity of the enzyme increased with growing concentrations up to approximately 20 mM K+. The concentration-response relationships for amiodarone were investigated in incubation media containing 2.5, 5.0 and 10 mM K+ respectively. Amiodarone exhibited similar concentration-dependent inhibitory effects in the range of 0.01 nM-80 microM at 2.5 mM, 0.13-150 microM at 5.0 mM and 0.3-700 microM at 10.0 mM K+. The corresponding IC50 values were 10.4 +/- 3.2 microM, 28.3 +/- 7.6 microM at 5.0 mM and 33.3 +/- 9.2 microM at 10.0 mM K+, respectively. Thus, reduction in the K+ concentration from the "standard" 5.0 to 2.5 mM was accompanied by a significant right-to-left shift in the inhibitory potency of amiodarone, the effective concentrations being shifted from microM into nM ranges. Increasing K+ concentration to 10 mM on the other hand attained opposite but less remarkable effects. The results show that the in vitro inhibition of myocardial Na(+)-K(+)-ATPase activity by amiodarone is related to the K+ concentration of the incubation medium. These effects may be pertinent to the mechanism by which this drug interferes with the electrogenic Na+/K+ pump activity of the enzyme, thereby probably contributing to the mechanism(s) responsible for some of its cardiac actions.


Role of pyruvate carboxylase in facilitation of synthesis of glutamate and glutamine in cultured astrocytes.
CO2 fixation was measured in cultured astrocytes isolated from neonatal rat brain to test the hypothesis that the activity of pyruvate carboxylase influences the rate of de novo glutamate and glutamine synthesis in astrocytes. Astrocytes were incubated with 14CO2 and the incorporation of 14C into medium or cell extract products was determined. After chromatographic separation of 14C-labelled products, the fractions of 14C cycled back to pyruvate, incorporated into citric acid cycle intermediates, and converted to the amino acids glutamate and glutamine were determined as a function of increasing pyruvate carboxylase flux. The consequences of increasing pyruvate, bicarbonate, and ammonia were investigated. Increasing extracellular pyruvate from 0 to 5 mM increased pyruvate carboxylase flux as observed by increases in the 14C incorporated into pyruvate and citric acid cycle intermediates, but incorporation into glutamate and glutamine, although relatively high at low pyruvate levels, did not increase as pyruvate carboxylase flux increased. Increasing added bicarbonate from 15 to 25 mM almost doubled CO2 fixation. When 25 mM bicarbonate plus 0.5 mM pyruvate increased pyruvate carboxylase flux to approximately the same extent as 15 mM bicarbonate plus 5 mM pyruvate, the rate of appearance of [14C] glutamate and glutamine was higher with the lower level of pyruvate. The conclusion was drawn that, in addition to stimulating pyruvate carboxylase, added pyruvate (but not added bicarbonate) increases alanine aminotransferase flux in the direction of glutamate utilization, thereby decreasing glutamate as pyruvate + glutamate --> alpha-ketoglutarate + alanine. In contrast to previous in vivo studies, the addition of ammonia (0.1 and 5 mM) had no effect on net 14CO2 fixation, but did alter the distribution of 14C-labelled products by decreasing glutamate and increasing glutamine. Rather unexpectedly, ammonia did not increase the sum of glutamate plus glutamine (mass amounts or 14C incorporation). Low rates of conversion of alpha-[14C]ketoglutarate to [14C]glutamate, even in the presence of excess added ammonia, suggested that reductive amination of alpha-ketoglutarate is inactive under conditions studied in these cultured astrocytes. We conclude that pyruvate carboxylase is required for de novo synthesis of glutamate plus glutamine, but that conversion of alpha-ketoglutarate to glutamate may frequently be the rate-limiting step in this process of glutamate synthesis.


Classification of Proteus vulgaris biogroup 3 with recognition of Proteus hauseri sp. nov., nom. rev. and unnamed Proteus genomospecies 4, 5 and 6.
Strains traditionally identified as Proteus vulgaris formed three biogroups. Biogroup 1, characterized by negative reactions for indole production, salicin fermentation and aesculin hydrolysis, is now known as Proteus penneri. Biogroup 2, characterized by positive reactions for indole, salicin and aesculin, was shown by DNA hybridization (hydroxyapatite method) to be a genetic species separate from biogroup 1 and from biogroup 3 which is positive for indole production and negative for salicin and aesculin. In this study, 52 strains were examined, of which 36 strains were Proteus vulgaris biogroup 3, which included the current type strain of the species P. vulgaris (ATCC 29905T), and compared to seven strains of Proteus vulgaris biogroup 2 and nine type strains of other species in the genera Proteus, Providencia and Morganella. By DNA hybridization, these 36 strains were separated into four distinct groups, designated as Proteus genomospecies 3, 4, 5 and 6. DNAs within each separate Proteus genomospecies were 74-99% related to each other in 60 degrees C hybridization reactions with < or = 4.5% divergence between related sequences. Proteus genomospecies 3 contained the former P. vulgaris type strain and one other strain and was negative in reactions for salicin fermentation, aesculin hydrolysis and deoxyribonuclease, unlike the reactions associated with strains considered as typical P. vulgaris which are positive in reactions for salicin, aesculin and DNase. Genomospecies 3 can be distinguished from Proteus genomospecies 4, 5 and 6 because it is negative for Jordan's tartrate. Proteus genomospecies 4, containing five strains, was differentiated from Proteus penneri, genomospecies 3 and 6 and most, but not all, strains of genomospecies 5, by its ability to ferment L-rhamnose. Proteus genomospecies 5 and 6, containing 18 and 11 strains, respectively, could not be separated from each other by traditional biochemical tests, by carbon source utilization tests or SDS-PAGE of whole-cell proteins. In an earlier publication, a request was made to the Judicial Commission that the former type strain of P. vulgaris (ATCC 13315) be replaced by P. vulgaris biogroup 2 strain ATCC 29905T, a strain considered more biochemically typical of P. vulgaris strains. This would have the effect of assigning the name P. vulgaris to P. vulgaris biogroup 2. Since this request has been acceded to, the name Proteus hauseri is herein proposed for Proteus vulgaris genomospecies 3. Its type strain is ATCC 700826T. Proteus genomospecies 4, 5 and 6 will remain unnamed until better phenotypic differentiation can be accomplished. All Proteus genomospecies were similar in their antimicrobial susceptibility patterns. Nineteen strains were isolated from urine, four from faeces, two from wounds, nine from other human sources and two from animals.


Are We Over-Treating Insect Bite Related Periorbital Cellulitis in Children? The Experience of a Large, Tertiary Care Pediatric Hospital.
Preseptal (periorbital) and orbital cellulitis are potentially catastrophic infections near the eye. Preseptal cellulitis is far more common, and although classically reported to be associated with dacrocystitis, sinusitis/upper respiratory infection, trauma/surgery, or infection from contiguous areas, it can also be associated with insect bites. The objective of this study was to determine the prevalence of insect bite-associated preseptal cellulitis and to compare clinical findings and outcomes of these patients with those having other causes for the condition. Retrospective chart review of children with a final discharge diagnosis of periorbital cellulitis from January 2009 to December 2014 at a tertiary care children' hospital. 213 children were diagnosed with preseptal cellulitis during the 5-year study period, of whom 60 (28%) were associated with insect bites. Patients in the noninsect bite group more commonly had fever at presentation (P < 0.001), with increased white blood cell and C reactive protein values (both P < 0.001). No patient with insect bite-associated preseptal cellulitis presented with fever, and none underwent radiographic testing or computerized tomography; their mean age was also lower (P < 0.001) and length of stay was significantly shorter. This study suggests that children with preseptal cellulitis associated with insect bites could be candidates for oral antibiotic therapy with outpatient follow-up by.


Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?
Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.


Reliable detection of Bacillus anthracis, Francisella tularensis and Yersinia pestis by using multiplex qPCR including internal controls for nucleic acid extraction and amplification.
Several pathogens could seriously affect public health if not recognized timely. To reduce the impact of such highly pathogenic micro-organisms, rapid and accurate diagnostic tools are needed for their detection in various samples, including environmental samples. Multiplex real-time PCRs were designed for rapid and reliable detection of three major pathogens that have the potential to cause high morbidity and mortality in humans: B. anthracis, F. tularensis and Y. pestis. The developed assays detect three pathogen-specific targets, including at least one chromosomal target, and one target from B. thuringiensis which is used as an internal control for nucleic acid extraction from refractory spores as well as successful DNA amplification. Validation of the PCRs showed a high analytical sensitivity, specificity and coverage of diverse pathogen strains. The multiplex qPCR assays that were developed allow the rapid detection of 3 pathogen-specific targets simultaneously, without compromising sensitivity. The application of B. thuringiensis spores as internal controls further reduces false negative results. This ensures highly reliable detection, while template consumption and laboratory effort are kept at a minimum.


Solid Phase Peptide Synthesis on Chitosan Thin Films.
Stable chitosan thin films can be promising substrates for creating nanometric peptide-bound polyglucosamine layers. Those are of scientific interest since they can have certain structural similarities to bacterial peptidoglycans. Such films were deposited by spin coating from chitosan solutions and modified by acetylation and N-protected amino acids. The masses of deposited materials and their stability in aqueous solutions at different pH values and water interaction were determined with a quartz crystal microbalance with dissipation (QCM-D). The evolution of the surface composition was followed by X-ray photoelectron (XPS) and attenuated total reflectance infrared (ATR-IR) spectroscopy. Morphological changes were measured by atomic force microscopy (AFM), while the surface wettability was monitored by by static water contact angle measurements. The combination of the characterization techniques enabled an insight into the surface chemistry for each treatment step and confirmed the acetylation and coupling of N-protected glycine peptides. The developed procedures are seen as first steps toward preparing thin layers of acetylated chitin, potentially imitating the nanometric peptide substituted glycan layers found in bacterial cell walls.


Systemic Lupus Erythematous and Neuromyelitis Optica Causing Hypercapnic Respiratory Failure.
BACKGROUND Neuromyelitis optica (NMO) is a rare neurological disease characterized by attacks of transverse myelitis and optic neuritis, contiguous spinal cord lesions on more than 3 vertebral segments on magnetic resonance imaging (MRI), and seropositivity for AQP-4 Ab. The tissue destruction from NMO is immune mediated and results in demyelination and axonal damage. Optic and spinal nerve involvement can eventually lead to blindness, weakness, and altered consciousness, and bladder and bowel involvement in some cases. CASE REPORT A 54-year-old Black woman presented with chest pain, dysphagia, generalized weakness, diplopia, and paresthesias in her bilateral feet. A brain MRI revealed an area of hyperintensity in the cervical medullary junction. A diagnosis of NMO was made after the treatment response was poor for systemic lupus erythematous (SLE) myelitis. She eventually developed acute hypercapnic respiratory failure, became encephalopathic, and was emergently intubated. She was extubated but had poor recovery and was eventually discharged home. CONCLUSIONS NMO is a rare immune-mediated disease that is often delayed in diagnosis and treatment. Clinical suspicion is important since there is a tendency for the disease to overlap concomitant autoimmune diseases in 25% of cases. Progressive and permanent tissue damage can occur despite the use of high-dose steroids, long-term immunosuppressant agents, immunomodulators, exchange transfusions, and even autologous hematopoietic stem cell bone marrow transplantation.


Perception of speech rate of Dutch and Italian utterances.
The speech signal contains many linguistic and prosodic cues which determine the perception of speech rate. We investigated which cues could optimally explain rate judgements of short Dutch and Italian utterances. For this, the correlation between an objective measure of speech rate (linguistic syllables per second, phonetic syllables per second, or phonetic segments per second) and perceived speech rate has been evaluated for rate judgements of normal, monotone, and unintelligible utterances. The effect of language background on speech rate perception was also studied, by using Dutch and Italian listeners.


Mislocalization of stationary and flashed bars after saccadic inward and outward adaptation of reactive saccades.
Recent studies have shown that saccadic inward adaptation (i.e., the shortening of saccade amplitude) and saccadic outward adaptation (i.e., the lengthening of saccade amplitude) rely on partially different neuronal mechanisms. There is increasing evidence that these differences are based on differences at the target registration or planning stages since outward but not inward adaptation transfers to hand-pointing and perceptual localization of flashed targets. Furthermore, the transfer of reactive saccade adaptation to long-duration overlap and scanning saccades is stronger after saccadic outward adaptation than that after saccadic inward adaptation, suggesting that modulated target registration stages during outward adaptation are increasingly used in the execution of saccades when the saccade target is visually available for a longer time. The difference in target presentation duration between reactive and scanning saccades is also linked to a difference in perceptual localization of different targets. Flashed targets are mislocalized after inward adaptation of reactive and scanning saccades but targets that are presented for a longer time (stationary targets) are mislocalized stronger after scanning than after reactive saccades. This link between perceptual localization and adaptation specificity suggests that mislocalization of stationary bars should be higher after outward than that after inward adaptation of reactive saccades. In the present study we test this prediction. We show that the relative amount of mislocalization of stationary versus flashed bars is higher after outward than that after inward adaptation of reactive saccades. Furthermore, during fixation stationary and flashed bars were mislocalized after outward but not after inward adaptation. Thus, our results give further evidence for different adaptation mechanisms between inward and outward adaptation and harmonize some recent research.


Sensor Fusion of Cardiorespiratory Signals Using an Adaptive Kalman Filter.
For unobtrusive monitoring of vital signs, redundant sensors are beneficial to fuse several sensor measurements which can improve the estimation of, e.g. heart rate and respiratory rate. In this paper, an adaptive unscented Kalman filter is used to estimate respiratory rate and heart rate on a new simplified model for cardiorespiratory coupling. Additionally, the Kalman filter is tuned to incorporate the non-white system noise of the model. The Kalman filter is tested on synthesised data with variations regarding SNR, model mismatch and amount of sensors. For respiratory rate, a median squared error of as low as 0.02BPM2 and, for heart rate, a median squared error of as low as 0.2BPM2 for ideal assumptions is achieved.


Therapeutic targeting of endoplasmic reticulum stress in acute graft-versus-host disease.
Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), a potentially curative treatment for leukemia. Endoplasmic reticulum (ER) stress occurs when the protein folding capacity of the ER is oversaturated. How ER stress modulates tissue homeostasis in the context of alloimmunity is not well understood. We show that ER stress contributes to intestinal tissue injury during GvHD and can be targeted pharmacologically. We observed high levels of ER stress upon GvHD onset in a murine allo- HCT model and in human biopsies. These levels correlated with GvHD severity, underscoring a novel therapeutic potential. Elevated ER stress resulted in increased cell death of intestinal organoids. In a conditional knockout model, deletion of the ER stress regulator transcription factor Xbp1 in intestinal epithelial cells induced a general ER stress signaling disruption and aggravated GvHD lethality. This phenotype was mediated by changes in the production of antimicrobial peptides and the microbiome composition as well as activation of pro-apoptotic signaling. Inhibition of inositol-requiring enzyme 1α (IRE1α), the most conserved signaling branch in ER stress, reduced GvHD development in mice. IRE1α blockade by the small molecule inhibitor 4m8c improved intestinal cell viability, without impairing hematopoietic regeneration and T-cell activity against tumor cells. Our findings in patient samples and mice indicate that excessive ER stress propagates tissue injury during GvHD. Reducing ER stress could improve the outcome of patients suffering from GvHD.


Overall anatomical features and clinical value of the sacral nerve in high resolution computed tomography reconstruction.
Sacral nerve injury is a common complication of pelvic or sacral fractures. As the sacral nerve courser within the sacrum and has a complex relationship with the surrounding tissues, different parts of the sacral plexus injury have similar clinical symptoms and signs. Since lack of specific imaging technique in the diagnosis of sacral nerve injury, especially on multi-segment, multi-site, how to determine the preoperative location and extent of the sacral nerve injury accurately becomes a concern of the general orthopaedic and images practitioners. This study was conducted to gain an insight into the overall anatomical features of the sacral nerve (SN) on the same slice in high resolution computed tomography (HRCT) reconstruction and to determine the value of this information for the clinical diagnosis of related diseases. Fifty healthy volunteers and 30 patients (40 sides) with SN lesions confirmed by surgery were scanned using a 16-slice helical CT scanner (Light Speed, GE, USA). Among the patients, 6 with intervertebral disk hernia (6 sides), 8 with spinal stenosis (12 sides), 11 with pelvic trauma (14 sides), 4 with pelvic malignancies (6 sides), and 1 with sacral vertebral tuberculosis (2 sides). The SN multiplanar reconstruction was performed using a UNIX-based SCD4.1 workstation where the image was set on the same slice. All images were stored in the Digital Imaging and Communications in Medicine format. The display of nerves in different sections was analyzed using a five-graded scale with coordinate curves of each individual score. The overall anatomic features visible on the slice were analyzed and the abnormalities of the lesions were studied. The image of the same slice clearly revealed the shape, running direction, thickness, tension and adjacent anatomy of the S1-S4 nerves. The rank of display rates in different sections was: outward-rotated oblique sagittal > outward-rotated oblique coronal > oblique coronal plane > coronal > sagittal > transverse section. The S5 nerve was partially displayed from the starting point to the segment around the posterior sacral foramen. The overall anatomy of the triangular sacral plexus was only revealed in the oblique outward-rotated sagittal section, while 100% of its individual rami, as well as two or three of the adjacent rami, were displayed from their starting points to the anterior border of the piriformis. The abnormalities included 39 sides of morphological change (97.5%), 38 sides of compression (95.0%), 35 sides of adhesion (87.5%), 32 sides of displacement (80.0%), 34 sides of shrinkage (85.0%), 6 sides of thickening (15.0%), and 2 sides of abruption (5.0%). The 16-slice CT multiplanar reconstruction was able to reveal the overall anatomic features of the SN on the same slice. The section of reconstruction was a crucial factor in determining the display capability of various sacral nerves. This technology was valuable in the diagnosis and management of related diseases.


Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.
Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.


Insights into catalysis and regulation of non-canonical ubiquitination and deubiquitination by bacterial deamidase effectors.
The bacterial effector MavC catalyzes non-canonical ubiquitination of host E2 enzyme UBE2N without engaging any of the conventional ubiquitination machinery, thereby abolishing UBE2N's function in forming K63-linked ubiquitin (Ub) chains and dampening NF-кB signaling. We now report the structures of MavC in complex with conjugated UBE2N~Ub and an inhibitor protein Lpg2149, as well as the structure of its ortholog, MvcA, bound to Lpg2149. Recognition of UBE2N and Ub depends on several unique features of MavC, which explains the inability of MvcA to catalyze ubiquitination. Unexpectedly, MavC and MvcA also possess deubiquitinase activity against MavC-mediated ubiquitination, highlighting MavC as a unique enzyme possessing deamidation, ubiquitination, and deubiquitination activities. Further, Lpg2149 directly binds and inhibits both MavC and MvcA by disrupting the interactions between enzymes and Ub. These results provide detailed insights into catalysis and regulation of MavC-type enzymes and the molecular mechanisms of this non-canonical ubiquitination machinery.


Prospective validation of a decision rule for the use of radiography in acute knee injuries.
To validate a previously derived decision rule for the use of radiography in patients with acute knee injury. Prospectively administered survey. Emergency departments of two university hospitals serving adults. Convenience sample of 1096 of 1251 eligible adults with acute knee injuries; 124 patients were examined by two physicians. Attending emergency physicians assessed each patient for standardized clinical variables and determined the need for radiography according to the decision rule. Patients who did not have radiography underwent a structured telephone interview at day 14 to determine the possibility of a fracture. The rule was assessed for ability to correctly identify the criterion standard, fracture of the knee. An attempt was made to refine the rule by means of univariate and recursive partitioning analyses. The decision rule had a sensitivity of 1.0 (95% confidence interval [CI], 0.94 to 1.0) for identifying 63 clinically important fractures. Physicians correctly interpreted the rule in 96% of cases, and the k value for interpretation was 0.77 (95% CI, 0.65 to 0.89). The potential relative reduction in use of radiography was estimated to be 28%. The probability of fracture, if the decision rule were "negative," is estimated to be 0% (95% CI, 0% to 0.4%). Attempts to refine the rule led to a model with improved specificity but with an unacceptable loss of sensitivity. Prospective validation has shown this decision rule to be 100% sensitive for identifying fractures of the knee, to be reliable and acceptable, and to have the potential to allow physicians to reduce the use of radiography in patients with acute knee injury.


Therapy with Radiopharmaceuticals.
In an investigation by the Swedish Cancer Society, an expert group described the present status, critical issues and future aspects and potentials for each of nine major areas of radiation therapy research. The present report deals with therapy with radiopharmaceuticals.


Serological and virological evidence of non-sexual transmission of human herpesvirus type 8 (HHV8).
To evaluate whether or not human herpesvirus 8 (HHV8) can be transmitted through a non-sexual route a serological survey was carried out in a group of 51 catholic nuns. The seroprevalence rate and the geometrical mean antibody titre to anti-latent HHV8 antigen were similar in nuns and in a group of 60 women, matched by age, in the general population (27 vs. 24%; 1028 vs. 1575, respectively). Moreover, by using nested polymerase chain reaction (PCR), HHV8 DNA sequences were detected in 7 of 16 (43.8%) saliva and peripheral blood mononuclear cells (PBMC) from patients with classical Kaposi's sarcoma (KS) and in 3 out of 7 (42%) AIDS-KS patients. None of 5 HIV positive persons who did not have KS tested positive for HHV8 DNA. HHV8 DNA sequences were also detected in 2 of 12 (17%) saliva and 1 PBMC sample out of 12 healthy HHV8 positive individuals (age range: 30-80 years old). This paper suggests that non-sexual transmission of HHV8 is operating in our geographical setting and saliva may be a potential source of HHV8 spreading in the general population.


The combination of antagonists of LHRH with antagonists of GHRH improves inhibition of androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancers.
Antagonists of growth hormone-releasing hormone (GHRH) could extend the duration of response of androgen sensitive prostate cancers to androgen deprivation. We investigated the effect of new GHRH antagonists MZ-J-7-118 and MZ-J-7-138 and luteinizing hormone-releasing hormone (LHRH) antagonist Cetrorelix or castration on androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancer models xenografted into nude mice. Animals bearing androgen-independent LuCaP-35V prostatic cancer model were also treated with MZ-J-7-118. Receptors for LHRH and GHRH were present in MDA-PCA-2b, LuCaP-35, and LuCaP-35V tumors. GHRH antagonists increased the inhibitory effect of surgical castration and LHRH antagonists on androgen sensitive MDA-PCa-2b and LuCaP-35 tumors. The time to relapse of androgen-dependent LuCaP-35 tumors was extended by GHRH antagonists. Growth of androgen-independent LuCaP-35V xenografts was also significantly inhibited by MZ-J-7-118. In MDA-PCa-2b tumors treatment with MZ-J-7-118 caused a significant decrease of VEGF and Cetrorelix or its combination with MZ-J-7-118 reduced EGF. The B(max) of EGF receptors was significantly reduced by Cetrorelix, MZ-J-7-118 and their combination. Our findings suggest that the use of a combination of antagonists of GHRH and LHRH could improve the therapy for androgen sensitive prostate cancer. Antagonists of GHRH could be also considered for treatment of androgen-independent prostate cancers.


Priming, Replication, and the Hardest Science.
Concerns have been raised recently about the replicability of behavioral priming effects, and calls have been issued to identify priming methodologies with effects that can be obtained in any context and with any population. I argue that such expectations are misguided and inconsistent with evolutionary understandings of the brain as a computational organ. Rather, we should expect priming effects to be highly sensitive to variations in experimental features and subject populations. Such variation does not make priming effects frivolous or capricious but instead can be predicted a priori. However, absent theories specifying the precise contingencies that lead to such variation, failures to replicate another researcher's findings will necessarily be ambiguous with respect to the inferences that can be made. Priming research is not yet at the stage where such theories exist, and therefore failures are uninformative at the current time. Ultimately, priming researchers themselves must provide direct replications of their own effects; researchers have been deficient in meeting this responsibility and have contributed to the current state of confusion. The recommendations issued in this article reflect concerns both with the practice of priming researchers and with the inappropriate expectations of researchers who have failed to replicate others' priming effects.


Functional histology of the neuroendocrine thymus.
The primary role of the thymus lies in T-cell differentiation and self-education leading to the establishment of appropriate host immune defenses. However, the view of the thymus as a self-contained organ is no longer valid. It is now clear that intricate interactions of both a stimulatory and inhibitory nature exist between the neuroendocrine and immune system. A broad array of neuroendocrine circuits are networked with the thymus and neuroendocrine-thymic interactions are bidirectional. These interactions are thought to play an important immunomodulatory role during an active immune response, during T-cell ontogeny and in the aging process of the whole organism. The chemical messengers that transmit communicating signals in this network are secreted neuropeptides and their specific receptors. The objective of this review is to provide a comprehensive overview of the morphological substrates of these neuropeptides in the thymus.


Pitfalls in experimental designs for characterizing the transcriptional, methylational and copy number changes of oncogenes and tumor suppressor genes.
It is a common practice that researchers collect a set of samples without discriminating the mutants and their wild-type counterparts to characterize the transcriptional, methylational and/or copy number changes of pre-defined candidate oncogenes or tumor suppressor genes (TSGs), although some examples are known that carcinogenic mutants may express and function completely differently from their wild-type counterparts. Based on various high-throughput data without mutation information for typical cancer types, we surprisingly found that about half of known oncogenes (or TSGs) pre-defined by mutations were down-regulated (or up-regulated) and hypermethylated (or hypomethylated) in their corresponding cancer types. Therefore, the overall expression and/or methylation changes of genes detected in a set of samples without discriminating the mutants and their wild-type counterparts cannot indicate the carcinogenic roles of the mutants. We also found that about half of known oncogenes were located in deletion regions, whereas all known TSGs were located in deletion regions. Thus, both oncogenes and TSGs may be located in deletion regions and thus deletions can indicate TSGs only if the gene is found to be deleted as a whole. In contrast, amplifications are restricted to oncogenes and thus can be used to support either the dysregulated wild-type gene or its mutant as an oncogene. We demonstrated that using the transcriptional, methylational and/or copy number changes without mutation information to characterize oncogenes and TSGs, which is a currently still widely adopted strategy, will most often produce misleading results. Our analysis highlights the importance of evaluating expression, methylation and copy number changes together with gene mutation data in the same set of samples in order to determine the distinct roles of the mutants and their wild-type counterparts.


Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling.
Protein misfolding, accumulation, and aggregation characterize many aging-related diseases. Protein aggregates do not accumulate in unstressed cells primarily because of the existence of competent cellular "quality control" machinery. The endoplasmic reticulum (ER) is a major part of this quality control system. Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). The UPR limits protein load by upregulating ER chaperones such as Ig binding protein (BiP)/glucose-regulated protein 78 (GRP78) and by attenuating protein translation through eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation. Acute sleep deprivation (6 h) in young mice leads to induction of the UPR with upregulation of BiP/GRP78 and attenuation of protein translation. We demonstrate here that aging impairs this adaptive response to sleep deprivation. Aged mice do not display an increase in BiP expression with acute sleep deprivation. In addition, there is decreased basal expression of BiP/GRP78 in aged mice. There is a decline in eIF2alpha phosphorylation in aged mouse cerebral cortex that is associated with higher levels of GADD34 (growth arrest and DNA damage 34) and proapoptotic proteins such as CCAAT/enhancer-binding protein-homologous protein and activated caspase-12, suggesting that young animals possess an efficient ER adaptive response that declines with aging.


[Experience with rotation of basic antibiotics in intensive care unit of cardiosurgical hospital].
Clinical and microbiological efficacies of antibiotic rotation in the intensive care unit of the Hospital were evaluated. The results of the local microbiological monitoring of the profile of the acquired resistance of gramnegative nosocomial pathogens (n = 151) isolated from adult patients with artificial ventilation of the lungs for more than 3 days after the open heart operations (n = 150) were analysed. Three 6-month cycles of cephalosporins rotation in the following order were performed: cefoperazone--ceftazidime--cefepime. The procedure provided a significant decrease in the frequency of infectious complications (7.2 vs. 4.5%, p=0.015). The rotation did not require any increase of the use of reserve antibiotics such as vancomycin and carbapenems. The use of the drugs active against Pseudomonas aeruginosa promoted its eradication in the structure of the nosocomial pathogens in the intensive care unit.


The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria.
Several small trails looking at antibiotic therapy targeted at Helicobacter pylori for the treatment of chronic urticaria have been published and have had conflicting results. We conducted a systematic review of existing studies to help answer the clinical question of whether this therapy has a role in the treatment of chronic urticaria. We identified studies published in the English language with searches of MEDLINE, PREMEDLINE, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effectiveness, and Cochrane Libraries using the key words "Helicobacter pylori" and "urticaria." Relevant studies from bibliography reviews were also included. Studies included met the following criteria: (1) patients had urticaria for at least 6 weeks; (2) other known causes of urticaria were excluded by appropriate testing; (3) the initial diagnosis of H pylori infection was made by either serology, urea breath test, or upper endoscopy; and (4) an adequate trial of an antibiotic with known activity against H pylori was completed. In all, 10 studies met our inclusion criteria. The rate of remission of urticaria when H pylori was eradicated was 30.9% (59/191) compared with 21.7% (18/83) when H pylori was not eradicated; the background remission rate among control subjects without H pylori infection was 13.5% (10/74). When data from the 10 studies were combined, eradication of H pylori was both quantitatively and statistically associated with remission of urticaria (odds ratio 2.9; 95% confidence interval 1.4-6.8; P =.005). We found that resolution of urticaria was more likely when antibiotic therapy was successful in eradication of H pylori infection than when patients who were infected did not achieve eradication. These results suggest that clinicians, after considering other causes of urticaria, should constitute (1) testing for H pylori; (2) treating with appropriate antibiotics if H pylori is present; and (3) confirming successful eradication of infection.


Mitogenic response and probiotic characteristics of lactic acid bacteria isolated from indigenously pickled vegetables and fermented beverages.
Lactic acid bacteria from indigenous pickled vegetables and fermented beverages (fermented rice and Madhuca longifolia flowers) were isolated and investigated for their functional characteristics in vitro as potential new probiotic strains. Four isolates (all Lactobacillus spp.) selected on the basis of high tolerance to bile (0.2%) were identified by standard and molecular methods (16S rDNA) as L. helveticus, L. casei, L. delbrueckii and L. bulgaricus from pickled vegetables and fermented beverages respectively. These selected strains had antibiotic resistance, tolerance to artificial gastric juice and phenol (0.4%), enzymatic profile, and antagonistic activity against enteric pathogens (Enterobacter sakazakii, Salmonella typhimurium, Shigella flexneri 2a, Listeria monocytogenes, Yersinia enterocolitica and Aeromonas hydrophila). All strains survived well in artificial gastric juice at low pH (3.0) values for 4 h, possessed bile salt hydrolase activity and were susceptible to most antibiotics including vancomycin. Additionally, the isolates exhibited high tolerance to phenol, high cell surface hydrophobicity (>60%) and induced proliferation of murine splenocytes. All the four strains of present study suppressed the Con A-stimulated proliferation of the mouse spleen cells, although L. casei had the strongest suppressive effect. The results of this study suggest a potential application of the strains (following human clinical trials), for developing probiotic foods.


Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility.
Adding clomiphene citrate (CC) to FSH for controlled ovarian stimulation (COS) decreases FSH dose required for optimum stimulation. However, because of its anti-estrogenic effects, CC may be associated with lower pregnancy rates offsetting the FSH-dose reduction benefit. Previously, we reported the success of aromatase inhibition in inducing ovulation without antiestrogenic effects. A prospective pilot study that included women with unexplained infertility undergoing COS and intrauterine insemination. Thirty-six women received the aromatase inhibitor letrozole + FSH, 18 women received CC + FSH and 56 women received FSH only. Each woman received one treatment regimen in one treatment cycle. All patients were given recombinant or highly purified FSH (50-150 IU/day) starting on day 3 to 7 until day of hCG. The FSH dose needed was significantly lower in letrozole + FSH and CC + FSH groups compared with FSH-only without a difference in number of follicles >1.8 cm. Pregnancy rate was 19.1% in the letrozole + FSH group, 10.5% in the CC + FSH group and 18.7% in the FSH-only group. Both pregnancy rate and endometrial thickness were significantly lower in CC + FSH group compared with the other two groups. Estradiol (E2) levels were significantly lower in the letrozole + FSH group compared with the other two groups. Similar to CC, aromatase inhibition with letrozole reduces FSH dose required for COS without the undesirable antiestrogenic effects sometimes seen with CC.


Examining Social Vulnerability and the Association With COVID-19 Incidence in Harris County, Texas.
Studies have investigated the association between social vulnerability and SARS-CoV-2 incidence. However, few studies have examined small geographic units such as census tracts, examined geographic regions with large numbers of Hispanic and Black populations, controlled for testing rates, and incorporated stay-at-home measures into their analyses. Understanding the relationship between social vulnerability and SARS-CoV-2 incidence is critical to understanding the interplay between social determinants and implementing risk mitigation guidelines to curtail the spread of infectious diseases. The objective of this study was to examine the relationship between CDC's Social Vulnerability Index (SVI) and SARS-CoV-2 incidence while controlling for testing rates and the proportion of those who stayed completely at home among 783 Harris County, Texas census tracts. SARS-CoV-2 incidence data were collected between May 15 and October 1, 2020. The SVI and its themes were the primary exposures. Median percent time at home was used as a covariate to measure the effect of staying at home on the association between social vulnerability and SARS-CoV-2 incidence. Data were analyzed using Kruskal Wallis and negative binomial regressions (NBR) controlling for testing rates and staying at home. Results showed that a unit increase in the SVI score and the SVI themes were associated with significant increases in SARS-CoV-2 incidence. The incidence risk ratio (IRR) was 1.090 (95% CI, 1.082, 1.098) for the overall SVI; 1.107 (95% CI, 1.098, 1.115) for minority status/language; 1.090 (95% CI, 1.083, 1.098) for socioeconomic; 1.060 (95% CI, 1.050, 1.071) for household composition/disability, and 1.057 (95% CI, 1.047, 1.066) for housing type/transportation. When controlling for stay-at-home, the association between SVI themes and SARS-CoV-2 incidence remained significant. In the NBR model that included all four SVI themes, only the socioeconomic and minority status/language themes remained significantly associated with SARS-CoV-2 incidence. Community-level infections were not explained by a communities' inability to stay at home. These findings suggest that community-level social vulnerability, such as socioeconomic status, language barriers, use of public transportation, and housing density may play a role in the risk of SARS-CoV-2 infection regardless of the ability of some communities to stay at home because of the need to work or other reasons.


Ectoparasitic insects and mites on Yunnan red-backed voles (Eothenomys miletus) from a localized area in southwest China.
Ectoparasitic insects and mites on Yunnan red-backed voles (Eothenomys miletus) in Dali prefecture, Yunnan Province, southwest China, were studied between 2003 and 2004. In total, 34,389 individuals of 86 species of ectoparasitic insects (seven species of fleas and five species of sucking lice) and mites (23 species of gamasid mites and 51 species of chigger mites) were collected from 916 individual hosts. The diversity of ectoparasites on this single rodent species in such a small area was much higher than in previous reports, which concerned more host species and greater geographical areas. The majority of the ectoparasites were chigger mites, which accounted for 59.3% of the parasite species and 87.4% of the individual parasites. Most voles harbored parasites with an overall prevalence (P) of 82.5% and mean abundance (MA) of 37.5 parasites per host. The dispersion coefficient (C) and patchiness index (m*/m) were used to study the spatial patterns of the seven dominant parasite species, and all seven had aggregated distributions. The species abundance distribution of the ectoparasites on the vole was fitted by Preston's lognormal distribution (R (2) = 0.82), and the total expected parasite species was estimated from this plot as 167 species. Yunnan red-backed voles harbor many ectoparasites as revealed by examination of a large host population. Future field investigations should sample large numbers of host individuals to assess ectoparasite populations.


Carbon dioxide laser absorption spectra of toxic industrial compounds.
CO(2) laser absorption cross-section data are reported for acrolein, styrene, ethyl acrylate, trichloroethylene, vinyl bromide, and vinylidene chloride. These data indicate that sub parts per billion level, interference-free detection limits should be possible for these compounds by the CO(2) laser photoacoustic technique. Photoacoustic detectabilities below 40 ppb should be possible for these compounds in the presence of ambient air concentrations of water vapor and other anticipated interferences. These compounds are also found not to be important interferences in the detection of toxic hydrazine-based rocket fuels by CO(2) laser spectroscopic techniques.


Assessment of miR-103a-3p in leukocytes-No diagnostic benefit in combination with the blood-based biomarkers mesothelin and calretinin for malignant pleural mesothelioma diagnosis.
Malignant pleural mesothelioma (MPM) is a cancer associated with asbestos exposure and its diagnosis is challenging due to the moderate sensitivities of the available methods. In this regard, miR-103a-3p was considered to increase the sensitivity of established biomarkers to detect MPM. Its behavior and diagnostic value in the Mexican population has not been previously evaluated. In 108 confirmed MPM cases and 218 controls, almost all formerly exposed to asbestos, we quantified miR-103-3a-3p levels in leukocytes using quantitative Real-Time PCR, together with mesothelin and calretinin measured in plasma by ELISA. Sensitivity and specificity of miR-103-3a-3p alone and in combination with mesothelin and calretinin were determined. Bivariate analysis was performed using Mann-Whitney U test and Spearman correlation. Non-conditional logistic regression models were used to calculate the area under curve (AUC), sensitivity, and specificity for the combination of biomarkers. Mesothelin and calretinin levels were higher among cases, remaining as well among males and participants ≤60 years old (only mesothelin). Significant differences for miR-103a-3p were observed between male cases and controls, whereas significant differences between cases and controls for mesothelin and calretinin were observed in men and women. At 95.5% specificity the individual sensitivity of miR-103a-3p was 4.4% in men, whereas the sensitivity of mesothelin and calretinin was 72.2% and 80.9%, respectively. Positive correlations for miR-103a-3p were observed with age, environmental asbestos exposure, years with diabetes mellitus, and glucose levels, while negative correlations were observed with years of occupational asbestos exposure, creatinine, erythrocytes, direct bilirubin, and leukocytes. The addition of miR-103a-3p to mesothelin and calretinin did not increase the diagnostic performance for MPM diagnosis. However, miR-103a-3p levels were correlated with several characteristics in the Mexican population.


Reconstruction of the Near-Field Electric Field by SNOM Measurement.
Scanning near-field optical microscope (SNOM) with nanoscale spatial resolution has been a powerful tool in studying the plasmonic properties of nano materials/structures. However, the quantification of the SNOM measurement remains a major challenge in the field due to the lack of reliable methodologies. We employed the point-dipole model to describe the tip-surface interaction upon laser illumination and theoretically derived the quantitative relationship between the measured results and the actual near-field electric field strength. Thus, we can experimentally reconstruct the near-field electric field through this theoretically calculated relationship. We also developed an experimental technique together with FEM simulation to get the above relationship experimentally and reconstruct the near-field electric field from the measurement by SNOM.


Gravitational Redshift Test Using Eccentric Galileo Satellites.
We report on a new test of the gravitational redshift and thus of local position invariance, an integral part of the Einstein equivalence principle, which is the foundation of general relativity and all metric theories of gravitation. We use data spanning 1008 days from two satellites of Galileo, Europe's global satellite navigation system, which were launched in 2014, but accidentally delivered on elliptic rather than circular orbits. The resulting modulation of the gravitational redshift of the onboard atomic clocks allows the redshift determination with high accuracy. Additionally, specific laser ranging campaigns to the two satellites have enabled a good estimation of systematic effects related to orbit uncertainties. Together with a careful conservative modeling and control of other systematic effects we measure the fractional deviation of the gravitational redshift from the prediction by general relativity to be (0.19±2.48)×10^{-5} at 1 sigma, improving the best previous test by a factor 5.6. To our knowledge, this represents the first reported improvement on one of the longest standing results in experimental gravitation, the Gravity Probe A hydrogen maser rocket experiment back in 1976.


ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice.
ClC-3 channel/antiporter plays a critical role in a variety of cellular activities. ClC-3 has been detected in the ileum and colon. To determine the functions of ClC-3 in the gastrointestinal tract. After administration of dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), intestines from ClC-3-/- and wild-type mice were examined by histological, cellular, molecular and biochemical approaches. ClC-3 expression was determined by western blot and immunostaining. ClC-3 expression was reduced in intestinal tissues from patients with UC or Crohn's disease and from mice treated with DSS. Genetic deletion of ClC-3 increased the susceptibility of mice to DSS- or TNBS-induced experimental colitis and prevented intestinal recovery. ClC-3 deficiency promoted DSS-induced apoptosis of intestinal epithelial cells through the mitochondria pathway. ClC-3 interacts with voltage-dependent anion channel 1, a key player in regulation of mitochondria cytochrome c release, but DSS treatment decreased this interaction. In addition, lack of ClC-3 reduced the numbers of Paneth cells and impaired the expression of antimicrobial peptides. These alterations led to dysfunction of the epithelial barrier and invasion of commensal bacteria into the mucosa. A defect in ClC-3 may contribute to the pathogenesis of IBD by promoting intestinal epithelial cell apoptosis and Paneth cell loss, suggesting that modulation of ClC-3 expression might be a new strategy for the treatment of IBD.


Natural history of coarctation of the aorta.
With the increasing number of subjects with coarctation of the aorta having operations, its natural history becomes more difficult to determine. The expectation of life has been calculated by two quite independent methods: (1) from 304 reported necropsies, and (2) from 22 deaths among 161 subjects followed for 716 patient-years. These were mostly patients rather than unselected school-children, but many were quite free from symptoms and were sent only because a murmur was heard on examination. Knowing how long they had been under observation, mortality rates could be calculated for each decade. They rise gradually but not very regularly, from 1.6 per cent in the first two decades to 6.7 per cent per annum in the sixth and later decades. The two methods give results in close agreement, closer than could be expected considering the relatively small numbers of patients and patient-years. The percentages of deaths at the end of each decade found by the two methods never differ by more than +/-4 per cent and are often much closer. Of those surviving the serious hazards of the first one or two years, 25 per cent die before they reach 20, 50 per cent by 32, 75 per cent by 46, and 90 per cent by 58 years. The arithmetical mean of the ages of death is 34 years instead of 71 years as normally. These means, however, hide a very wide range, with standard deviations of at least +/-15 per cent. For coarctation the median is 31 years and the mode is widely spread through the second to fifth decades rather than closely clustered round a point. This poor outlook makes an operative mortality in the region of 5 per cent a small price to pay for the greatly increased security afterwards. We do not yet know how much the risk of bacterial endocarditis or of intracranial haemorrhage will be reduced in the long run because there may be bicuspid aortic valves or intracranial berry aneurysms. The exact incidence of subacute bacterial endocarditis is uncertain, somewhere between 0.6 (from necropsy series) and 1.3 per cent per annum in clinical series. The range was similar for persistent ductus arteriosus, but paradoxically 1.5 for the necropsy series and 0.5 for the clinical series. Clearly the incidence is high in all the four malformations shown in Table 5, about 0.9+/-0.4 per cent per annum.


Implementation of Electronic Health Record Integration and Clinical Decision Support to Improve Emergency Department Prescription Drug Monitoring Program Use.
To evaluate the implementation of 3 electronic health record (EHR)-based interventions to increase prescription drug monitoring program (PDMP) use in the emergency department (ED): EHR-PDMP integration, addition of a PDMP risk score, and addition of EHR-based clinical decision support alert to review the PDMP when prescribing an opioid. Three intervention stages were implemented using a prospective stepped-wedge design at 5 university-affiliated EDs split into 3 practice groups. The PDMP use and prescribing rates during the 3 stages were compared with baseline before EHR integration and a sustainability stage where the clinical decision support alert was removed, but EHR integration and risk score remained. Generalized linear mixed model with logit link function and a random intercept for clinicians was analyzed. The ED provider PDMP review before opioid prescribing was low in all stages. The highest review rate occurred during interruptive clinical decision support alerts, 23.8% (interquartile range 10.6 to 37.5). Overall, opioid prescribing declined, and PDMP review was not associated with a decrease in opioid prescribing. PDMP review was associated with a reduction in the probability of prescribing an opioid as the number of prior opioid prescriptions increased (odds ratio: 0.92 [95% confidence interval: 0.91 to 0.94] for every additional prescription). The EHR-PDMP integration did not increase PDMP use in the ED, but a PDMP risk score and a clinical decision support alert were associated with modest increases in the probability of PDMP review. When the PDMP is reviewed, ED clinicians are less likely to prescribe opioids to patients with a high number of prior opioid prescriptions.