Novel bioactive and stable neurotensin peptide analogues capable of delivering radiopharmaceuticals and molecular beacons to tumors.
The prevalence of neurotensin receptor (NTR) in several human tumors makes it an attractive target for the delivery of cytotoxic drugs and imaging agents. Native neurotensin (NT) is a tridecapeptide that binds to NTR and induces tumor growth. Unfortunately, NT has a short plasma half-life, which hinders its use for in vivo biomedical applications. Numerous reports suggest that Arg(8)-Arg(9) and Tyr(11)-Ile(12) amide bonds are particularly susceptible to degradation by proteolytic enzymes. Predicated on this observation, we substituted Arg(8), Arg(9), and Ile(12) amino acids with the corresponding commercially available mimics. These surrogate amino acids are amenable to standard Fmoc peptide synthesis strategy, and the resulting compounds are stable in biological media for >4 h and bind to NTR with high affinity. Furthermore, conjugating DTPA to the new peptides and subsequent labeling with (111)In-DTPA for nuclear imaging or fluorescein for optical imaging did not diminish the NTR binding affinities of the peptides. In vivo biodistribution of a representative (111)In-DTPA-NT peptide analogue in SCID mice bearing NTR-positive human adenocarcinoma (HT29) xenograft shows that the compound was primarily retained in tumor tissue (2.2% ID/g) and the kidneys (4.8% ID/g) at 4 h postinjection. Coinjection of cold NT and the radiolabeled NT peptide analogue inhibited the tumor but not the kidney uptake, demonstrating that retention of the radiolabeled compound in tumor tissue was mediated by NTR specific uptake while it accumulates in the kidneys by a nonspecific mechanism. These findings show that the new NT peptide analogues are robust and can deliver imaging agents to NTR-positive tumors such as pancreatic cancer.


Application of O-RADS US combined with MV-Flow to diagnose ovarian-adnexal tumors.
This study aimed to explore the application of Ovarian-Adnexal Reporting and Data System Ultrasound (O-RADS US) combined with MV-Flow (Samsung Medison Co., Ltd.) to diagnose ovarian-adnexal masses. A total of 112 ovarian-adnexal masses (81 benign and 31 malignant) from 105 consecutive patients were analyzed. The O-RADS US and vascular index from MV-Flow (VIMV) were measured and compared with the reference standard. O-RADS US and MV-Flow were tested for consistency. Receiver operating characteristic curves were drawn for O-RADS US, MV-Flow, and their combination. The combined methods had the largest area under the curve (0.955), followed by O-RADS US (0.929) and MV-Flow (0.923). A mass was considered malignant when the O-RADS US classification was 5 and VIMV was ≥7.15. With this definition, MV-Flow had the highest sensitivity (87.10%), with consistent findings for the combined diagnostic methods and O-RADS US (83.87%). The specificity of the combined diagnostic methods (93.83%) was higher than that of MV-Flow (91.36%). O-RADS US had the lowest specificity (90.12%). The combined diagnostic methods had the highest coincidence rate (91.07%), and MV-Flow (90.18%) had a significantly higher coincidence rate than O-RADS US (88.39%). Both O-RADS US and MV-Flow showed good consistency among different physicians (former kappa, 0.974; latter intraclass correlation coefficient [ICC], 0.986). MV-Flow had a high consistency for the same physician (ICC, 1). O-RADS US and MV-Flow exhibited good diagnostic efficacy, and their combined diagnostic efficacy was higher than that of each individually. O-RADS US and MV-Flow can improve the diagnosis of benign and malignant ovarian-adnexal masses.


A brief review of the current breast cancer prevention trials and proposals for future trials.
The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed of which three have reported efficacy results. A fifth trial using raloxifene has also been published. The largest tamoxifen trial shows approximately a 50% reduction in breast cancer incidence in the short term, but the two smaller trials have not found any incidence reduction. Greater agreement exists for side-effects - thromboembolic disease and endometrial cancers are raised about 2 to 3-fold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 42% reduction in short-term incidence. Several important questions remain about the clinical implication of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow-up of these trials is crucial for resolving these issues.


Immune response to Japanese Encephalitis virus in mother mice and their congenitally infected offspring.
The immune response to Japanese encephalitis virus (JEV) was assessed in JEV-infected mice (mothers) and their offspring. The congenitally infected baby mice responded poorly in all assays for cell-mediated immunity. The total number of their splenic cells remained unaltered but the percentage of T cells was significantly reduced; a depressed delayed hypersensitivity response was seen against both homologous (JEV) and heterologous (sheep erythrocytes) antigens. In addition, significantly higher leukocyte migration inhibition (LMI) of spleen cells in the presence of specific antigen was observed. Adult mice infected during pregnancy demonstrated an impaired delayed hypersensitivity response to JEV antigen only. LMI was positive in mothers at 2 weeks post-partum, but not at later periods.


Urethral sphincteric responses to sacral root stimulation.
Deafferentation and stimulation of sacral nerves in patients with complete spinal cord lesions is a good model to study the parasympathetic influence on urethral behavior. During intradural sacral deafferentation from S2 to S4/S5 in preparation for implantation of the Finetech-Brindley anterior sacral root stimulator, sacral roots were stimulated with 3 and 30 Hz and 3 and 10 V and the bladder and urethral responses noted. Stimulation of the posterior roots at 3 Hz gives a urethral relaxation without bladder contraction. At this frequency, anterior sacral root stimulation has no effect on bladder nor urethral pressure. Stimulation of the anterior roots at 30 Hz produces simultaneous bladder contraction and urethral relaxation. These findings support the presence of an afferent parasympathetic inhibitory mechanism in the spinal micturition center in the human.


Innovation in practice: mobile phone technology in patient care.
Mobile phones are becoming increasingly important in everyday life and now in healthcare. There has been a steady growth of information and communication technologies in health communication and technology is used progressively in telemedicine, wireless monitoring of health outcomes in disease and in the delivery of health interventions. Mobile phones are becoming an important method of encouraging better nurse-patient communication and will undoubtedly increase in application over coming years. This article presents recent developments and applications of mobile technology for health promotion and patient-monitoring in chronic disease.


Heterosexual experience prevents the development of conditioned same-sex partner preference in male rats.
Sexual partner preferences can be strengthened, weakened or even drastically modified via Pavlovian conditioning. For example, conditioned same-sex partner preference develops in sexually-naïve male rats that undergo same-sex cohabitation under the effects of quinpirole (QNP, D2 agonist). Here, we assessed the effect of prior heterosexual experience on the probability to develop a conditioned same-sex preference. Naïve or Sexually-experienced males received either Saline or QNP and cohabited during 24h with a male partner that bore almond scent on the back as conditioned stimulus. This was repeated every 4days for a total of three trials and resulted in four groups (Saline-naïve, Saline-experienced, QNP-naïve, QNP-experienced). Social and sexual preference were assessed four days after the last conditioning trial in a drug-free test in which experimental males chose between the scented familiar male and a novel sexually receptive female. Results showed that Saline-naïve, Saline-experienced and QNP-experienced displayed a clear preference for the female (opposite-sex). By contrast, only QNP-naïve males displayed a same-sex preference. Accordingly, QNP-experienced males were not affected by the conditioning process and continued to prefer females. We discuss the effects of copulation and D2 agonists on the facilitation and/or disruption of conditioned partner preferences.


Modeling the causal effect of treatment initiation time on survival: Application to HIV/TB co-infection.
The timing of antiretroviral therapy (ART) initiation for HIV and tuberculosis (TB) co-infected patients needs to be considered carefully. CD4 cell count can be used to guide decision making about when to initiate ART. Evidence from recent randomized trials and observational studies generally supports early initiation but does not provide information about effects of initiation time on a continuous scale. In this article, we develop and apply a highly flexible structural proportional hazards model for characterizing the effect of treatment initiation time on a survival distribution. The model can be fitted using a weighted partial likelihood score function. Construction of both the score function and the weights must accommodate censoring of the treatment initiation time, the outcome, or both. The methods are applied to data on 4903 individuals with HIV/TB co-infection, derived from electronic health records in a large HIV care program in Kenya. We use a model formulation that flexibly captures the joint effects of ART initiation time and ART duration using natural cubic splines. The model is used to generate survival curves corresponding to specific treatment initiation times; and to identify optimal times for ART initiation for subgroups defined by CD4 count at time of TB diagnosis. Our findings potentially provide 'higher resolution' information about the relationship between ART timing and mortality, and about the differential effect of ART timing within CD4 subgroups.


[Relation of Ca2+ efflux from the heart to the concentration of Ca-channel blockers].
Dependence of calcium ion efflux from the heart ventricles on the concentration of verapamil, fenigidine and nicardipine was studied in frogs, using Ca-sensitive electrodes. The effect of sodium and potassium ions was also investigated. It was established that dependence of calcium ion efflux (delta Ca2+) on the concentration of Ca-antagonists (B) may be expressed by the following formula: (Formula: see text). With cellular membrane depolarization 50 mM KCl, none of the blockers (10(-5) M) caused Ca2+ efflux from ventricular cells. Analogous phenomenon was noted in low-sodium solution (60 mM).


Cholesterol sulfate alters astrocyte metabolism and provides protection against oxidative stress.
Cholesterol sulfate (CS) is one of the most important known sterol sulfates in human plasma and it is present as a normal constituent in a variety of human tissues. In both the brain and periphery, CS serves as a substrate for the synthesis of sulfonated adrenal steroids such as pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate and as a constituent of many biological membranes including red blood cells where it functions as a stabilizing agent. It also acts as an endogenous regulator of cholesterol synthesis. However, the role of CS in brain metabolism and neurological disorder is unclear. In the current study we investigated the neuroprotective action of CS as well as its role in brain energy metabolism. The neuroprotective effect of CS and its role on cell metabolism were determined in primary astrocyte prepared from the cortex of postnatal day 0-2 C57BL/6 pups and a hippocampal HT-22 cell line using Calcein AM and MTT cell viability assay, flow cytometry, Seahorse extracellular flux analysis, and metabolism assay kits. We found that CS attenuates glutamate and rotenone induced cell death in HT-22 cells, decrease glutamate induced mitochondria membrane potential collapse, and reactive oxygen species production. Additionally, CS activates the Akt/Bcl2 pathway. We observed that CS impacts astrocyte metabolism by increasing mitochondrial phosphorylation, ATP, and glycogen contents. Our study demonstrated that CS modulates brain energy metabolism and its neuroprotective effects might be due to the activation of Akt signaling or its ability to decrease reactive oxygen species production.


Intra/intermolecular direct allylic alkylation via Pd(II)-catalyzed allylic C-H activation.
The first catalytic direct alkylation of allylic C-H bonds via Pd(II)-catalysis is described in the absence of base. Polysubstituted cyclic compounds can also be constructed by the intramolecular direct allylic alkylation.


Gender-related differences in hypnosis-based treatments for smoking: a follow-up meta-analysis.
In an earlier meta-analysis of 12 studies using hypnosis-based treatments for smoking cessation, we provided preliminary evidence that males fare better than females when trying to quit smoking (Green, Lynn, & Montgomery, 2006). By excluding studies that reported no gender differences, but failed to report final outcome-statistics-by-gender, our previous conclusion may have overestimated the role of gender in hypnosis-based smoking cessation treatment. In the present analysis, we included 12 additional studies that reported no gender differences, but failed to report final outcome-by-gender statistics. Across each of these studies, we calculated identical success rates for male and female participants and then added these results to our database. Among all 24 groups of participants who completed hypnosis-based treatment for smoking, we found a small but significant effect for male participants being more successful in quitting smoking relative to females. Specific suggestions for tailoring hypnosis smoking cessation programs to take gender differences into account are discussed.


Absorption mechanism of 1,3-bis(2-ethoxycarbonylchromon-5-yloxy)-2-((S)-lysyloxy )propane dihydrochloride (N-556), a prodrug for the oral delivery of disodium cromoglycate.
To clarify the absorption mechanism of 1,3-bis(2-ethoxycarbonylchromon-5-yloxy)-2-((S)-lysyloxy+ ++)propane dihydrochloride (N-556), a prodrug for the oral delivery of disodium cromoglycate (DSCG), a study was made using rats. N-556 gave the highest plasma level of DSCG following its injection into the loop at the upper part of the small intestine. N-556 was stable in acidic washings of gastric contents, but rapidly hydrolyzed to M1 with twin ethyl residues on DSCG in the washings of the small intestinal contents. N-556 and M1 were hydrolyzed to DSCG via M2 having a mono ethyl residue in the homogenate of the small intestinal mucosa. The oral absorption of M1 following its administration in 50% (v/v) propylene glycol solution was essentially the same as that of N-556. That of M1 administered in aqueous suspension was low. After the oral administration of N-556, a small amount of M2 and a trace of M3 having L-lysyl residue were detected in the portal plasma, but no hydrolytic intermediate except DSCG could be found in the general plasma. The major absorption mechanism of N-556 may thus be concluded as follows: N-556 given orally is transferred to the small intestine in essentially intact form. N-556 is then rapidly diffused to an aqueous layer on the surface of the mucosal membrane and hydrolyzed to M1. The resultant M1 is transported to the mucosal membrane and hydrolyzed to DSCG via M2. DSCG generated in the mucosal membrane is used for general circulation through the portal blood and liver.(ABSTRACT TRUNCATED AT 250 WORDS)


Holistic Review in Medical School Admissions and Selection: A Strategic, Mission-Driven Response to Shifting Societal Needs.
Medical schools and residency programs have always sought excellence in the areas of education, research, and clinical care. However, these pursuits are not accomplished within a vacuum-rather, they are continually and necessarily influenced by social, cultural, political, legal, and economic forces. Persistent demographic inequalities coupled with rapidly evolving biomedical research and a complex legal landscape heighten our collective awareness and emphasize the continued need to consider medicine's social contract when selecting, educating, and developing physicians and physician-scientists.Selection-who gains access to a medical education and to a career as a physician, researcher, and/or faculty member-is as much art as science. Quantitative assessments of applicants yield valuable information but fail to convey the full story of an applicant and the paths they have taken. Human judgment and evidence-based practice remain critical parts of implementing selection processes that yield the desired outcomes. Holistic review, in promoting the use of strategically designed, evidence-driven, mission-based, diversity-aware processes, provides a conceptual and practical framework for marrying the art with the science without sacrificing the unique value that each brings.In this Commentary, the authors situate medical student selection as both responsive to and informed by broader social context, health and health care needs, educational research and evidence, and state and federal law and policy. They propose that holistic review is a strategic, mission-driven, evidence-based process that recognizes diversity as critical to excellence, offers a flexible framework for selecting future physicians, and facilitates achieving institutional mission and addressing societal needs.


Novel algorithm for real-time onset detection of surface electromyography in step-tracking wrist movements.
We present a novel algorithm for real-time detection of the onset of surface electromyography signal in step-tracking wrist movements. The method identifies abrupt increase of the quasi-tension signal calculated from sEMG resulting from the step-by-step recruitment of activated motor units. We assessed the performance of our proposed algorithm using both simulated and real sEMG signals, and compared with two existing detection methods. Evaluation with simulated sEMG showed that the detection accuracy of our method is robust to different signal-to-noise ratios, and that it outperforms the existing methods in terms of bias when the noise is large (low SNR). Evaluation with real sEMG analysis also indicated better detection performance compared to existing methods.


Multiscale modeling of insulin secretion.
Insulin secretion from pancreatic beta cells is a fundamental physiological process, and its impairment plays a pivotal role in the development of diabetes. Mathematical modeling of insulin secretion has a long history, both on the level of the entire body and on the cellular and subcellular scale. However, little direct communication between these disparate scales has been included in mathematical models so far. Recently, we have proposed a minimal model for the incretin effect by which the gut hormone glucagon-like peptide 1 (GLP-1) enhances insulin secretion. To understand how this model couples to cellular events, we use a previously published mechanistic model of insulin secretion, and show mathematically that induction of glucose competence in beta cells by GLP-1 can underlie derivative control by GLP-1.


Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis.
To elucidate the accuracy of abdominal ultrasonography (US) in the diagnosis of pancreatic tumors. In all patients referred for pancreatic US during 1988-1990, data on malignant disease and survival were analyzed by using the Swedish Death and Cancer Registries. Nine hundred nineteen patients were entered into the analysis. In 140 of them, a clinical diagnosis of tumor in the pancreatic area was confirmed within 1 year after US. These tumors were primary pancreatic tumors (n = 102), common bile duct and duodenal cancers (n = 17), and metastases in the pancreatic area (n = 21). The sensitivity of US in the detection of all tumors in the pancreatic area was 88.6% (124 of 140 patients), which was similar to that for the detection of exocrine pancreatic cancer, 90% (79 of 88 patients). There were nine false-positive US examinations, for a specificity of 98.8% (770 of 779 patients). Systematic sampling of 94 investigations confirmed an association between US accuracy and presence of clinical symptoms of pancreatic cancer. Significant differences in the sensitivity (P < .05) and accuracy (P < .01) of diagnosis were observed between three experienced investigators. Study results support the use of US as a first-line diagnostic examination in patients suspected of having pancreatic tumor. Dependency on the investigator's experience with US mandates continuous evaluation of its performance.


Human infections with Sarcocystis species.
Recurrent outbreaks of muscular sarcocystosis among tourists visiting islands in Malaysia have focused international attention on sarcocystosis, a disease once considered rare in humans. Sarcocystis species require two hosts, definitive and intermediate, to complete their life cycle. Humans can serve as definitive hosts, with intestinal sarcocystosis for two species acquired from eating undercooked meat: Sarcocystis hominis, from beef, and Sarcocystis suihominis, from pork. Symptoms such as nausea, stomachache, and diarrhea vary widely depending on the number of cysts ingested but appear more severe with pork than with beef. Humans serve as intermediate hosts for Sarcocystis nesbitti, a species with a reptilian definitive host, and possibly other unidentified species, acquired by ingesting sporocysts from feces-contaminated food or water and the environment; infections have an early phase of development in vascular endothelium, with illness that is difficult to diagnose; clinical signs include fever, headache, and myalgia. Subsequent development of intramuscular cysts is characterized by myositis. Presumptive diagnosis based on travel history to tropical regions, elevated serum enzyme levels, and eosinophilia is confirmed by finding sarcocysts in muscle biopsy specimens. There is no vaccine or confirmed effective antiparasitic drug for muscular sarcocystosis, but anti-inflammatory drugs may reduce symptoms. Prevention strategies are also discussed.


[Choice of total knee arthroplasty: posterior cruciate ligament preserved or not].
Total knee arthroplasty is an effective method for the treatment of end-stage knee osteoarthrosis, which can effectively relieve joint pain and reconstruct the integrity of the joint. Whether the posterior cruciate ligament should be preserved during surgery or not, which is still in dispute. In recent years, posterior cruciate-retaining and substituting total knee prostheses are both applied in clinical practice. Both domestic and international studies have shown that there are no significant difference in patient satisfaction, knee flexion, survival rate of the prosthesis and the main clinical manifestations between two prostheses. However, posterior cruciate-retaining total knee prosthesis is more consistent with the normal physiology and biomechanics of the human body. The gait is more balanced and proprioceptive when walking up and down the stairs, but when the joints are buckling, the femur is abnormal to move back to the tibia, resulting in abnormal motion. While posterior cruciate-substituting total knee prosthesis can correct severe deformity of the knee, and keep better balance between flexion and extension of the knee joint, but there is a potential complication of patellar clunk syndrome. Therefore, under the same conditions, the younger patients may prefer to chose posterior cruciate-retaining total knee prosthesis, while elder patients may prefer to chose posterior cruciate-substituting total knee prosthesis. This paper reviews the function of posterior cruciate ligament, as well as the advantages and disadvantages of two prostheses, so as to provide some references for clinic.


Neutrophil-to-Lymphocyte Ratio Predicts Outcomes in Patients Implanted with Left Ventricular Assist Devices.
The neutrophil-to-lymphocyte ratio (NLR) has been used to predict mortality in a wide range of cardiovascular diseases including acute decompensated heart failure and non-ST-elevation myocardial infarction. We investigated the prognostic utility of the NLR in patients with advanced heart failure who received left ventricular assist devices (LVADs). Two hundred seventy-three patients implanted with LVADs at our institution were divided into tertiles based on their NLR and were retrospectively analyzed. Outcomes, including survival and right ventricular (RV) failure, were compared between tertiles. The NLR was found to be an independent predictor of postoperative mortality (odds ratio [OR] = 1.159, confidence interval [CI] = 1.022-1.314, p = 0.021) and of postoperative RV failure (OR = 1.117, CI = 1.039-1.201, p = 0.003). In addition, patients in the highest NLR tertile were found to have significantly increased postoperative length of stay (tertile 1 = 20.6 ± 10.7 days, tertile 2 = 24.2 ± 20.7 days, and tertile 3 = 28.8 ± 18.6 days, p = 0.001). In conclusion, the NLR is a simple and practical method for predicting adverse outcomes including all-cause mortality and RV failure after LVAD implantation.


Hygienic conditions in child-care facilities in North Carolina and South Carolina: an integrated microbial and observational study.
In the United States almost one-quarter (23%) of children younger than age 5 years participate in some form of out-of-home child care; these children are 2.3-3.5 times more likely to contract acute gastrointestinal illness. Observational investigations were done to understand the hygienic conditions and practices of 40 child-care facilities in North Carolina and South Carolina. These data were compared with microbiological indicator data (aerobic plate counts and coliform counts) collected from selected surfaces in each facility. Results from the two data sets were analyzed using nonparametric statistical methods to reveal potential risk factors for enteric disease transmission. Statistically significant differences (P ≤ .05) in surface microbial counts were observed when comparing family child-care homes versus centers and between facilities participating in the Child and Adult Care Food Program and those that do not participate. Facilities without written surface cleaning or food preparation policies had statistically significantly higher microbial counts on surfaces. Our unique study, which combined observational and microbiological data, provided revealing information about the relationship between hygiene indicators and sanitary practices in child-care facilities in the southeastern United States.


Theta-Burst Stimulation for Cognitive Enhancement in Parkinson's Disease With Mild Cognitive Impairment: A Randomized, Double-Blind, Sham-Controlled Trial.
Background: Mild cognitive impairment is a common non-motor symptom of Parkinson's disease (PD-MCI) and has minimal treatment options. Objective: In this double-blind, randomized, sham-controlled trial, we assessed the effect of repeated sessions of intermittent theta-burst stimulation over the left dorsolateral prefrontal cortex on cognition and brain connectivity in subjects with PD-MCI. Methods: Forty-one subjects were randomized to receive real (n = 21) or sham stimulation (n = 20). All subjects underwent neuropsychological assessments before, 1 day, and 1 month after stimulation. Subjects also underwent resting-state functional magnetic resonance imaging before and 48 h after stimulation. The primary outcome was the change in the cognitive domain (executive function, attention, memory, language, and visuospatial abilities) z-scores across time. Results: There was an insignificant effect on cognitive domain z-scores across time when comparing real with sham stimulation and correcting for multiple comparisons across cognitive domains (p > 0.05 Bonferroni correction). However, the real stimulation group demonstrated a trend toward improved executive functioning scores at the 1-month follow-up compared with sham (p < 0.05 uncorrected). After real stimulation, the connectivity of the stimulation site showed decreased connectivity to the left caudate head. There was no change in connectivity within or between the stimulation network (a network of cortical regions connected to the stimulation site) and the striatal network. However, higher baseline connectivity between the stimulation network and the striatal network was associated with improved executive function scores at 1 month. Conclusions: These results suggest that intermittent theta-burst stimulation over the dorsolateral prefrontal cortex in subjects with PD-MCI has minimal effect on cognition compared with sham, although there were trends toward improved executive function. This intervention may be more effective in subjects with higher baseline connectivity between the stimulation network and the striatal network. This trial supports further investigation focusing on executive function and incorporating connectivity-based targeting. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03243214.


Importin 13 mediates nuclear import of histone fold-containing chromatin accessibility complex heterodimers.
The histone fold is a structural element that facilitates heterodimerization, and histone fold heterodimers play crucial roles in gene regulation. Here, we investigated the nuclear import of two human histone fold pairs, which belong to the H2A/H2B family: CHRAC-15/CHRAC-17 and p12/CHRAC-17. Our results from in vitro nuclear import assays with permeabilized cells and in vivo cotransfection experiments reveal that importin 13 facilitates nuclear import of both histone fold heterodimers. Using glutathione S-transferase pulldown experiments, we provide evidence that heterodimers are required for efficient binding of importin 13 because the monomers alone do not significantly interact. Mutational analysis shows that stepwise substitution of basic amino acid residues conserved among the histone fold subunits leads to a progressive loss of importin 13 binding and nuclear accumulation of CHRAC-15/CHRAC-17 and p12/CHRAC-17. The distribution of basic amino acid residues among the histone fold subunits essential for nuclear uptake suggests that heterodimerization of the histone fold motif-containing proteins forms an importin 13-specific binding platform.


Preejection period as a sympathetic activity index: a role of confounding factors.
In previous studies, one of the systolic time intervals - preejection period (PEP) - was used as an index of sympathetic activity reflecting the cardiac contractility. However, PEP could be also influenced by several other cardiovascular variables including preload, afterload and diastolic blood pressure (DBP). The aim of this study was to assess the behavior of the PEP together with other potentially confounding cardiovascular system characteristics in healthy humans during mental and orthostatic stress (head-up tilt test - HUT). Forty-nine healthy volunteers (28 females, 21 males, mean age 18.6 years (SD=1.8 years)) participated in the study. We recorded finger arterial blood pressure by volume-clamp method (Finometer Pro, FMS, Netherlands), PEP, thoracic fluid content (TFC) - a measure of preload, and cardiac output (CO) by impedance cardiography (CardioScreen® 2000, Medis, Germany). Systemic vascular resistance (SVR) - a measure of afterload - was calculated as a ratio of mean arterial pressure and CO. We observed that during HUT, an expected decrease in TFC was accompanied by an increase of PEP, an increase of SVR and no significant change in DBP. During mental stress, we observed a decrease of PEP and an increase of TFC, SVR and DBP. Correlating a change in assessed measures (delta values) between mental stress and previous supine rest, we found that deltaPEP correlated negatively with deltaCO and positively with deltaSVR. In orthostasis, no significant correlation between deltaPEP and deltaDBP, deltaTFC, deltaCO, deltaMBP or deltaSVR was found. We conclude that despite an expected increase of sympathetic activity during both challenges, PEP behaved differently indicating an effect of other confounding factors. To interpret PEP values properly, we recommend simultaneously to measure other variables influencing this cardiovascular measure.


Evaluation of the diffusive gradient in a thin film technique for monitoring trace metal concentrations in estuarine waters.
Monitoring trace metal concentrations in dynamic estuarine waters is not straightforward. This study demonstrated that important information could be obtained from intensive sampling of physicochemical parameters and trace metal concentrations, in the Gold Coast Broadwater, Australia. A regular pattern of variation in Cu and Ni concentrations was related to the movement of water passed point sources with tidal flows, rather than due to conventional estuarine mixing of end-member waters. However, this approach was logistically demanding and expensive. The diffusive gradients in a thin film (DGT) technique was used as an alternative method due to its continual time-integrated response to changes in trace metal concentrations. Significant correlations were found between 24 h DGT-labile measurements and 0.45-microm filterable measurements, on time-averaged composite samples (grab samples combined every 4 h for 24 h), for Cu (n = 24, r = 0.965, p < 0.001), Pb (n = 24, r = 0.799, p < 0.001), Zn (n = 17, r = 0.909, p < 0.001), and Ni (n = 23, r = 0.916, p < 0.001). DGT-labile measurements as a fraction of 0.45 microm-filterable concentrations were 21 +/- 2% for Cu, 29 +/- 11% for Pb, 28 +/- 5% for Zn, and 27 +/- 12% for Ni, demonstrating the speciation capabilities of DGT. Although DGT measurements were confirmed as being highly operationally defined, DGT was still found to be very promising as a monitoring approach, particularly for dynamic estuarine waters.


SDF-1 in Mammary Fibroblasts of Bovine with Mastitis Induces EMT and Inflammatory Response of Epithelial Cells.
Fibroblasts constitute the majority of the stromal cells within bovine mammary gland, yet the functional contributions of these cells to mastitis and fibrosis and the mechanism are poorly understood. In this study, we demonstrate that inflammation-associated fibroblasts (INFs) extracted from bovine mammary glands with clinical mastitis had different expression pattern regarding to several extracellular matrix (ECM) proteins, chemokines and cytokines compared to normal fibroblasts (NFs) from dairy cows during lactation. The INFs induced epithelial-mesenchymal transition (EMT) and inflammatory responses of mammary epithelial cells in a vitro co-culture model. These functional contributions of INFs to normal epithelial cells were mediated through their ability to secrete stromal cell-derived factor 1 (SDF-1). SDF-1 was highly secreted/expressed by INFs, lipopolysaccharide (LPS) -treated NFs, lipoteichoic acid (LTA) -treated NFs, as well as mastitic tissue compared to their counterparts. Exogenous SDF-1 promoted EMT on epithelial cells through activating NF-κB pathway, induced inflammation response and inhibited proliferation of epithelial cells. In addition, SDF-1 was able to induce mastitis and slight fibrosis of mouse mammary gland, which was attenuated by a specific inhibitor of the receptor of SDF-1. Our findings indicate that stromal fibroblasts within mammary glands with mastitis contribute to EMT and inflammatory responses of epithelial cells through the secretion of SDF-1, which could result in the inflammation spread and fibrosis within mammary gland.


[Clinically conditional variants of the immune response in viral hepatitis A and B in children].
The immunity characteristics of the T-, B- and A-systems have been studied on the basis of the data registered in the dynamics of the acute period of the disease and several times in catamnesis during 6-12 months of the convalescence period in 217 children with viral hepatitis A and 99 children with viral hepatitis B. The clinical course of viral hepatitis A and that of viral hepatitis B have been found to have certain parallels in their development, as well as specific features of immune response, which can be subdivided into 3 main groups: (a) immunological imbalance, (b) the phase of immunodepression and (c) secondary immunodeficiency. The distinguishing of the variants of immune response and their clinical interpretation are of practical importance for the early prognostication of the course and outcome of the processes and for the differentiated approach to the treatment of viral hepatitides in children.


[Environmental medicine in public health service--a social responsibility and its consequences].
The special committee for "Environmental Medicine" established by the Federal Association of Doctors in the German Public Health Service presents its paper entitled "Environmental Medicine in the Public Health Service--A Social Responsibility and its Consequences: Propositions with regard to the situation, aims, strategies, and opportunities for action". The paper includes core ideas and responsibilities in the public health service. It aims at providing a number of guidelines for implementing "Environment and Health" ("Umwelt und Gesundheit"), an action programme by the Federal Ministry of Environmental Protection and the Ministry of Health, as well as "Health 21" ("Gesundheit 21"), the framework concept "Health for all" for the WHO's European Region. The paper also aims at initiating and facilitating steps for joint action by the Public Health Service. These theses were passed on to Mrs. Andrea Fischer, the Federal Minister of Health, during a meeting with the Board of the Association. In Germany, environment-related public health protection is well established in the Public Health Departments and state institutes/departments within the scope of public health provision and disease prevention. Typical responsibilities include environmental hygiene and environment-related medical services which have increased in importance. The range of responsibilities and its current political importance are a result of environment-related public health risks, the social situation of the population, also with regard to health issues, and the scope of responsibilities and competencies by doctors and staff in the public health departments. With the people's demands for health, quality of life and life expectancy, this need for action increases. In this paper, judicial, professional, and personal consequence are presented which arise as public health authorities assume these responsibilities.


Role of the membrane localization domain of the Pseudomonas aeruginosa effector protein ExoU in cytotoxicity.
ExoU is a potent effector protein that causes rapid host cell death upon injection by the type III secretion system of Pseudomonas aeruginosa. The N-terminal half of ExoU contains a patatin-like phospholipase A(2) (PLA(2)) domain that requires the host cell cofactor superoxide dismutase 1 (SOD1) for activation, while the C-terminal 137 amino acids constitute a membrane localization domain (MLD). Previous studies had utilized insertion and deletion mutations to show that portions of the MLD are required for membrane localization and catalytic activity. Here we further characterize this domain by identifying six residues that are essential for ExoU activity. Substitutions at each of these positions resulted in abrogation of membrane targeting, decreased ExoU-mediated cytotoxicity, and reductions in PLA(2) activity. Likewise, each of the six MLD residues was necessary for full virulence in cell culture and murine models of acute pneumonia. Purified recombinant ExoU proteins with substitutions at five of the six residues were not activated by SOD1, suggesting that these five residues are critical for activation by this cofactor. Interestingly, these same five ExoU proteins were partially activated by HeLa cell extracts, suggesting that a host cell cofactor other than SOD1 is capable of modulating the activity of ExoU. These findings add to our understanding of the role of the MLD in ExoU-mediated virulence.


Biogenesis of matrix vesicles in cartilage growth plates.
Although the structure and function of cartilage matrix vesicles have been comprehensively documented in the literature, the method of vesicle production and export to the extra-cellular matrix is less well understood. The existing data are grouped into four general hypotheses of matrix vesicle biogenesis, with a consideration of the relative merits and weaknesses of each postulate. The hypotheses are: a) budding from cellular processes; b) extrusion of preformed structures; c) cellular degeneration and disintegration; and c)subunit secretion and extracellular assembly. Each of these possibilities offers conceptual advantages and disadvantages, so that it is difficult to adopt a monistic stance. Previous notions of vesicle biogenesis have derived from statis morphologic and analytical data, which are necessarily limiting when attempting to draw kinetic conclusions. Radiotracer studies of lipid synthesis and transport in cartilage lead to the conclusion that matrix vesicles in the growth plate are derived from chondrocytes; the present data favor the hypotheses of budding from cellular processes and/or subunit secretion with extracellular self-assembly.


Fibre type and concentration in the lungs of workers in an asbestos cement factory.
The predominant asbestos fibre type used in the production of asbestos cement is chrysotile. The use of asbestos in relation to fibre type in a Norwegian asbestos cement plant during 1942-80 was 91.7% chrysotile, 3.1% amosite, 4.1% crocidolite, and 1.1% anthophyllite respectively. Electron microscopy and x ray microanalysis of lung tissue samples of asbestos cement workers who had died of malignant pleural mesothelioma or bronchogenic carcinoma showed a completely inverse ratio with regard to fibre type. The percentage of chrysotile asbestos in lung tissue varied between 0% and 9% whereas the corresponding numbers for the amphiboles were 76% and 99%. These differences are discussed with respect to the behaviour of different fibre types in the human body and to the occurrence of malignant mesothelioma in this asbestos cement factory.


Contraceptive adherence among women Veterans with mental illness and substance use disorder.
Emerging data suggest that mental illness and substance use disorder (SUD) are important risk factors for inconsistent contraceptive use. We investigated whether mental illness without or with SUD is associated with contraceptive adherence and continuation of hormonal methods among women Veterans. We conducted a retrospective analysis of national Veteran's Administration data among women aged 18-45 with a hormonal contraceptive prescription (pill/patch/ring/injectable) during the first week of fiscal year 2013. We tested associations between mental illness diagnoses (depression, posttraumatic stress disorder, anxiety, bipolar disorder, schizophrenia, adjustment disorder) without or with SUD diagnoses (drug/alcohol abuse) and 12-month contraceptive adherence (number and length of gaps ≥7 days between refills and months of contraceptive coverage) using multivariable regression models. Among 9780 Veterans, 43.6% had mental illness alone, 9.4% comorbid mental illness and SUD, and 47.0% neither diagnosis. In adjusted analyses, compared to women with neither diagnosis, women with mental illness alone had a similar rate of gaps but increased odds of having gaps longer than 30 days [odds ratio (OR): 1.35, 95% confidence interval (CI): 1.10-1.52] and fewer months of contraceptive coverage (β_coefficient: -0.39, 95% CI: -0.56 to -0.23). Women with mental illness and SUD experienced more gaps (incidence rate ratio: 1.12, 95% CI: 1.03-1.21), increased odds of gaps longer than 30 days (OR: 1.46, 95% CI: 1.10-1.79), fewer months of contraceptive coverage (β_coefficient: -0.90, 95% CI: -1.20 to -0.62) and reduced odds of continuous 12-month coverage (adjusted OR: 0.76, 95% CI: 0.63-0.93). Mental illness, particularly with comorbid SUD, is associated with reduced contraceptive adherence and continuation among women Veterans. Women with these risk factors could potentially benefit from use of long-acting reversible methods. Women Veterans have a high burden of mental illness and SUD, which we found are associated with inconsistent contraceptive use. Efforts to improve adherence to hormonal contraceptives and to increase availability of long-acting reversible methods in this vulnerable population are warranted.


Bidirectional Association between Nonalcoholic Fatty Liver Disease and Gallstone Disease: A Cohort Study.
Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are often found to coexist but the sequential relationship of NAFLD and GD to each other remains controversial. We prospectively evaluated the bidirectional relationship of NAFLD with GD. A cohort study was performed on Korean adults who underwent a health checkup and were followed annually or biennially for a mean of 6.0 years. Fatty liver and gallstones were diagnosed by ultrasound. NAFLD was defined as hepatic steatosis on ultrasonography in the absence of excessive alcohol use or other identifiable causes. The NAFLD severity was determined by non-invasive fibrosis markers. Among 283,446 participants without either gallstones or cholecystectomy at baseline, 6440 participants developed gallstones. Among 219,641 participants without NAFLD at baseline, 49,301 participants developed NAFLD. The multivariable-adjusted hazard ratio (95% confidence interval) for incident gallstone comparing the NAFLD group vs. the non-NAFLD group was 1.26 (1.17⁻1.35). Increased non-invasive fibrosis markers of NAFLD were positively associated with an increased incidence of gallstones in a graded and dose-responsive manner (p-trend < 0.01). The multivariable-adjusted hazard ratios (95% confidence intervals) for incident NAFLD comparing gallstone and cholecystectomy to no GD were 1.14 (1.07⁻1.22) and 1.17 (1.03⁻1.33), respectively. This large-scale cohort study of young and middle-aged individuals demonstrated a bidirectional association between NAFLD and GD. NAFLD and its severity were independently associated with an increased incidence of gallstones, while GD and cholecystectomy were also associated with incident NAFLD. Our findings indicate that the conditions may affect each other, requiring further studies to elucidate the potential mechanisms underlying this association.


[Active drainage of the abdominal cavity in diffuse purulent peritonitis].
The method of active drainage of the abdominal cavity and of the gastrointestinal tract lumen for acute peritonitis described by the author is based on the intraabdominal cyclic compression-decompression method of action on the organs and tissues of the abdominal cavity using 2-4 hermetically sealed rubber gloves distended with the help of a respiratory system in the uninterrupted regimen of work during 2-3 days. The method was used in 24 patients. Six patients died. No complications due to the method of treatment were observed.


Urogenital Symptoms in Neurologic Patients.
Lower urinary tract and sexual dysfunction are commonly reported sequelae of neurologic disease and have a significant impact on quality of life. This article presents an up-to-date summary of the clinical presentation, investigations, and treatment options for urogenital dysfunction in patients with neurologic disease. The pattern of lower urinary tract dysfunction is influenced by the site of the neurologic lesion. The risk for developing upper urinary tract damage is considerably less in patients with slowly progressive nontraumatic neurologic disorders, as compared to those with spinal cord injury or spina bifida. Investigations such as urinalysis, ultrasonography, and urodynamics provide further information about the cause and nature of lower urinary tract dysfunction. Antimuscarinic agents are the first-line management of urinary incontinence; however, side effect profile and anticholinergic burden should be considered when prescribing medications. β3-Adrenergic receptor agonists are a promising alternative oral medication. Tibial and sacral neuromodulation have been shown to be effective for managing incontinence, as well as urinary retention due to Fowler syndrome. Intradetrusor injections of onabotulinumtoxinA have revolutionized the management of neurogenic detrusor overactivity. Neurologic patients reporting urogenital symptoms require a comprehensive evaluation for planning a patient-tailored approach to management. Neurologists are increasingly inquiring about lower urinary tract and sexual functions and becoming involved in the management of these disorders.


Effect of communication skill training using group psychoeducation method on the stress level of psychiatry ward nurses.
Nursing is a dynamic and supportive job, with the main role of taking care of patients. Maintaining appropriate communication of the nurse with the patients is particularly known as the main core of care in mental health. However, in spite of the importance of providing communication, one of the main sources of stress in nurses of psychiatry wards is communication with the patients. Some important reasons for inappropriate relationship between the nurse and patient can be lack of necessary skills to communicate with patients because of insufficient training. Although training communication skills is an important part of the education of medical and paramedical students, in recent studies it has been demonstrated that the communication skills learned in theoretical courses would not necessarily be transferred to clinical settings, and proving training in clinical settings is a must. The present study was carried out to determine the effect of training communication skills using psychoeducation method on the stress level of nurses of psychiatry wards in 2010. This is a quasi-experimental study. The participants were 45 nurses; 23 and 22 in the experiment and control groups, respectively, working in psychiatry wards of Noor and Farabi hospitals, Isfahan, Iran. The sampling was carried out by the census method, and then the participants were randomly assigned to the two groups of experiment and control, using random number table. The two groups filled out the demographic data form and also the questionnaire on nurses' occupational stress, designed by the researcher. The questionnaire was filled out three times; before, immediately after, and one month after the training. Training of communication skills was carried out using group psychoeducation method, in six sessions, each lasted for 1.5 hours. The training sessions of the experiment group were held in Farabi Hospital. The findings indicated that before the intervention, the members of the two groups had a high level of occupational stress. Immediately after the training, the stress level of the experiment group decreased significantly, and the decrease was sustained for the following one month. Training communicative skills using group psychoeducation method can decrease the occupational stress of psychiatry ward nurses.


Insular and hippocampal gray matter volume reductions in patients with major depressive disorder.
Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder. For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes. Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala. The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.


POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in head and neck cancer.
HOX genes are master regulators of organ morphogenesis and cell differentiation during embryonic development, and continue to be expressed throughout post-natal life. To test the hypothesis that HOX genes are dysregulated in head and neck squamous cell carcinoma (HNSCC) we defined their expression profile, and investigated the function, transcriptional regulation and clinical relevance of a subset of highly expressed HOXD genes. Two HOXD genes, D10 and D11, showed strikingly high levels in HNSCC cell lines, patient tumor samples and publicly available datasets. Knockdown of HOXD10 in HNSCC cells caused decreased proliferation and invasion, whereas knockdown of HOXD11 reduced only invasion. POU2F1 consensus sequences were identified in the 5' DNA of HOXD10 and D11. Knockdown of POU2F1 significantly reduced expression of HOXD10 and D11 and inhibited HNSCC proliferation. Luciferase reporter constructs of the HOXD10 and D11 promoters confirmed that POU2F1 consensus binding sites are required for optimal promoter activity. Utilizing patient tumor samples a significant association was found between immunohistochemical staining of HOXD10 and both the overall and the disease-specific survival, adding further support that HOXD10 is dysregulated in head and neck cancer. Additional studies are now warranted to fully evaluate HOXD10 as a prognostic tool in head and neck cancers.


Microplastics: addressing ecological risk through lessons learned.
Plastic litter is an environmental problem of great concern. Despite the magnitude of the plastic pollution in our water bodies, only limited scientific understanding is available about the risk to the environment, particularly for microplastics. The apparent magnitude of the problem calls for quickly developing sound scientific guidance on the ecological risks of microplastics. The authors suggest that future research into microplastics risks should be guided by lessons learned from the more advanced and better understood areas of (eco) toxicology of engineered nanoparticles and mixture toxicity. Relevant examples of advances in these two fields are provided to help accelerate the scientific learning curve within the relatively unexplored area of microplastics risk assessment. Finally, the authors advocate an expansion of the "vector effect" hypothesis with regard to microplastics risk to help focus research of microplastics environmental risk at different levels of biological and environmental organization.


CA9 gene: single nucleotide polymorphism predicts metastatic renal cell carcinoma prognosis.
We assessed CA9 single nucleotide polymorphisms and mutations, and their association with CAIX protein expression, overall survival and response to interleukin-2 in white patients with metastatic clear cell renal cell carcinoma. Genomic DNA was extracted from frozen tumor samples of 54 metastatic clear cell renal cell carcinomas. The CA9 gene exons and flanking regions were amplified by polymerase chain reaction and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression in the primary tumor by immunohistochemistry. CA9 reference single nucleotide polymorphisms rs2071676, rs12553173, rs3829078 and rs1048638 were found in 59%, 15%, 11% and 33% of patients, respectively. The deletion c.376del393 was observed in 2 patients. CAIX expression was greater than 85% in 65% of patients. No single nucleotide polymorphisms were significantly associated with CAIX expression. Patients with the C allele variant of rs12553173 had improved median survival (27.3 vs 13.6 months, p = 0.0431) and a greater likelihood of an interleukin-2 response (57% vs 22%, p = 0.081) Likewise high CAIX expression was associated with longer median survival (25.5 vs 8.5 months, p <0.0001) and a greater interleukin-2 response rate (37% vs 8%, p = 0.070). In a multivariate Cox model the C allele variant of CA9 single nucleotide polymorphism rs12553173 and CAIX expression were retained as independent prognostic factors. CA9 single nucleotide polymorphisms are common in patients with metastatic clear cell renal cell carcinoma. The synonymous C allele variant of rs12553173 may be associated with improved overall survival and a greater likelihood of a response to interleukin-2. CA9 rs12553173 and CAIX are independent prognostic factors of overall survival and complementary for predicting the prognosis of metastatic clear cell renal cell carcinoma.


The impact of specialized enemies on the dimensionality of host dynamics.
Although individual species persist within a web of interactions with other species, data are usually gathered only from the focal species itself. We ask whether evidence of a species' interactions be detected and understood from patterns in the dynamics of that species alone. Theory predicts that strong coupling between a prey and a specialist predator/parasite should lead to an increase in the dimensionality of the prey's dynamics, whereas weak coupling should not. Here we describe a rare test of this prediction. Two natural enemies were added separately to replicate populations of a moth. For biological reasons that we identify here, the prediction of increased dimensionality was confirmed when a parasitoid wasp was added (although this increase had subtleties not previously appreciated), but the prediction failed for an added virus. Thus, an imprint of the interactions may be discerned within time-series data from component species of a system.


Validation of Four Smartwatches in Energy Expenditure and Heart Rate Assessment During Exergaming.
Objective: Validated the Apple Watch (AW), Fitbit Surge HR (FS), TomTom Multisport Cardio Watch (TT), and Microsoft Band (MB) in energy expenditure (EE), average heart rate (HR), and peak HR assessment during exergaming. Materials and Methods: Twenty-one college students participated in this study in Spring 2016. A 20-minute boxing session was completed on the Nintendo® Wii™. The AW and TT were placed on the left wrist and the FS and MB on the right. Each smartwatches' EE and HR data were compared with identical data provided by ActiGraph GT3X+-Bluetooth accelerometers and an associated ActiGraph HR strap. Results: Initial agreement was observed between the ActiGraph and: FS and TT EE (r = 0.62-0.69); AW, FS, and TT average HR (r = 0.47-0.74); and all smartwatches' peak HR (r = 0.59-0.65). However, post hoc comparisons indicated differences between the ActiGraph and: FS and TT EE measurements (P < 0.01) and MB average/peak HR measurements (P < 0.01). Low measurement bias/adequate precision observed for most smartwatches versus ActiGraph. Conclusions: Observations indicated smartwatch average/peak HR measurements as moderately valid. Smartwatch EE measurements were less valid.


A Fetal Rat Model of Ventricular Non-compaction Caused by Intrauterine Hyperglycemia.
This study aims to develop a fetal rat model of ventricular non-compaction (NVM) using streptozotocin (STZ)-induced gestational hyperglycemia and compare it with a retinoic acid (RA) model. Female SD rats were categorized into STZ, RA, and normal control (NC) groups. The STZ group was given a high-fat diet pre-pregnancy and 35 mg/kg of 2% STZ post-pregnancy. The RA group received a 90 mg/kg dose of RA on day 13 post-pregnancy. Embryonic myocardial morphology was analyzed through HE staining, and embryonic cardiomyocyte ultrastructures were studied using electron microscopy. Diagnoses of NVM were based on a ratio of non-compact myocardium (N) to compact myocardium (C) >1.4, accompanied by thick myocardial trabeculae and a thin myocardial compaction layer. Kruskal-Wallis test determined N/C ratio differences among groups. Both STZ and RA groups displayed significant NVM characteristics. The left ventricular (LV) N/C in the STZ, RA, and NC groups were 1.983 (1.423-3.527), 1.640 (1.197-2.895), and 0.927 (0.806-1.087), respectively, with a statistically significant difference (P<0.001). The right ventricular (RV) N/C in the STZ, RA, and NC groups were 2.097 (1.364-3.081), 1.897 (1.337-2.662), and 0.869 (0.732-1.022), respectively, with a significant difference (P<0.001). Electron microscopy highlighted marked endoplasmic reticulum swelling in embryonic cardiomyocytes from both STZ and RA groups. Our model underscores the pivotal role of an adverse intrauterine developmental environment in the onset of NVM. This insight holds significant implications for future studies exploring the pathogenesis of NVM.


[Indices based on entropy for measuring social inequalities in health].
As described in the scientific literature, indices used to measure social inequalities in health have positive features, but they also have shortcomings, depending on how they are applied. The objective of this article is to put forward and to demonstrate, in both theoretical and practical terms, the advantages of measurements of inequality based on the notion of entropy, which is well known in physics and in information theory. The article defines and presents the main properties of indices based on the notions of entropy and redundancy. The application of the indices is illustrated with two fictitious data sets and also with real data derived from basic health indicators for the Americas, from the Pan American Health Organization. Indices based on the notion of entropy have properties that include: a) not varying with scale changes, b) being symmetrical, c) incorporating a socioeconomic dimension, and d) being easy to interpret thanks to the condition of equivalence between entropy and a system with two categories.


Segregating cognitive functions within hippocampal formation: a quantitative meta-analysis on spatial navigation and episodic memory.
The most important cognitive domains where hippocampal formation is crucially involved are navigation and memory. Some evidence suggests that different hippocampal subregions mediate these domains. However, a quantitative meta-analysis on neuroimaging studies of spatial navigation versus memory is lacking. By means of activation likelihood estimation (ALE), we investigate concurrence of brain regions activated during spatial navigation encoding and retrieval as well as during episodic memory encoding and retrieval tasks in humans. During encoding in spatial navigation, activity was located in more posterior regions of the hippocampal formation, whereas episodic memory encoding was located in more anterior regions. Retrieval in spatial navigation was more strongly lateralized to the right compared to episodic memory retrieval. Within studies on spatial navigation retrieval, immediate recall was located more posterior and delayed recall more anterior. Overlap between concurrence of activation in spatial navigation and episodic memory was rather limited in comparison to uniquely involved regions. This argues in favor of two distinct networks, one for spatial navigation the other for episodic memory within the hippocampal formation.


An ultrafast rechargeable aluminium-ion battery.
The development of new rechargeable battery systems could fuel various energy applications, from personal electronics to grid storage. Rechargeable aluminium-based batteries offer the possibilities of low cost and low flammability, together with three-electron-redox properties leading to high capacity. However, research efforts over the past 30 years have encountered numerous problems, such as cathode material disintegration, low cell discharge voltage (about 0.55 volts; ref. 5), capacitive behaviour without discharge voltage plateaus (1.1-0.2 volts or 1.8-0.8 volts) and insufficient cycle life (less than 100 cycles) with rapid capacity decay (by 26-85 per cent over 100 cycles). Here we present a rechargeable aluminium battery with high-rate capability that uses an aluminium metal anode and a three-dimensional graphitic-foam cathode. The battery operates through the electrochemical deposition and dissolution of aluminium at the anode, and intercalation/de-intercalation of chloroaluminate anions in the graphite, using a non-flammable ionic liquid electrolyte. The cell exhibits well-defined discharge voltage plateaus near 2 volts, a specific capacity of about 70 mA h g(-1) and a Coulombic efficiency of approximately 98 per cent. The cathode was found to enable fast anion diffusion and intercalation, affording charging times of around one minute with a current density of ~4,000 mA g(-1) (equivalent to ~3,000 W kg(-1)), and to withstand more than 7,500 cycles without capacity decay.


[Use of microfiltration and gel filtration technics for purifying and concentrating the Venezuelan equine encephalomyelitis virus].
A system for purification and concentration of Venezuelan equine encephalomyelitis (VEE) virus omitting large-scale ultracentrifugation was developed. The first step consists in prefiltration through large pore nuclear filters (NF) to remove large particle admixtures from the virus-containing fluid. In the second step, the resulting filtrage undergoes concentrating microfiltration through small pore NF. In this way the virus, but not total protein, is concentrated approximately 30-fold without any loss of biological activity. For VEE virus purification the next step uses gel filtration chromatography in a column with chemically modified macropore silica. In this stage, the purification factor by protein is approximately 100-fold and virus yield reaches 40%. It is suggested that the procedure used be applied for purification and concentration of a wide range of enveloped viruses.


Manifestation of carrier relaxation through the manifold of localized states in PCDTBT:PC60BM bulk heterojunction material: the role of PC84BM traps on the carrier transport.
The transport and relaxation of photogenerated carriers in a bulk heterojunction (BHJ) material made of a blend of PCDTBT and PC(60) BM are studied as a function of the concentration of PC(84)BM impurities. For low concentrations of PC(84)BM, the increasing activation energy with delay time indicates transport dominated by trap-limited carrier drift while the photocarriers relax through a manifold of disorder-induced localized states near the band edge. In the BHJ material with high concentration of PC(84)BM, transport is dominated by carrier hopping within the PC(84)BM impurity band.


Nontypeable Haemophilus influenzae: pathogenesis and prevention.
In this paper, we describe the ability of nontypeable Haemophilus influenzae (NTHi) to coexist with the human host and the devastating results associated with disruption of the delicate state of balanced pathogenesis, resulting in both acute and chronic respiratory tract infections. It has been seen that the strains of NTHi causing disease show a marked genetic and phenotypic diversity but that changes in the lipooligosaccharide (LOS) and protein size and antigenicity in chronically infected individuals indicate that individual strains of NTHi can remain and adapt themselves to avoid expulsion from their infective niche. The lack of reliance of NTHi on a single mechanism of attachment and its ability to interact with the host with rapid responses to its environment confirmed the success of this organism as both a colonizer and a pathogen. In vitro experiments on cell and organ cultures, combined with otitis media and pulmonary models in chinchillas, rats, and mice, have allowed investigations into individual interactions between NTHi and the mammalian host. The host-organism interaction appears to be a two-way process, with NTHi using cell surface structures to directly interact with the mammalian host and using secreted proteins and LOS to change the mammalian host in order to pave the way for colonization and invasion. Many experiments have also noted that immune system evasion through antigenic variation, secretion of enzymes and epithelial cell invasion allowed NTHi to survive for longer periods despite a specific immune response being mounted to infection. Several outer membrane proteins and LOS derivatives are discussed in relation to their efficacy in preventing pulmonary infections and otitis media in animals. General host responses with respect to age, genetic makeup, and vaccine delivery routes are considered, and a mucosal vaccine strategy is suggested.


Point: uses of carotid plaque measurement as a predictor of cardiovascular events.
Vascular prevention is most cost-effective in high-risk patients, but secondary prevention misses many opportunities. The high-risk strategy- identifying patients with high levels of risk factors-is problematic because traditional risk factors predict only half of vascular events. In multiple regression, traditional risk factors explained only half of carotid atherosclerosis. New strategies are being explored, such as electron-beam computerized tomographic measurement of coronary calcification, to identify high-risk patients. Carotid plaque is a powerful tool for identifying and managing high-risk vascular patients, as it explains twice as much of unexplained vascular risk as coronary calcium by electron beam computerized tomography, and it has significant advantages compared with intimal-medial thickness. After adjustment for risk factors, patients in the highest quartile of baseline plaque area have 3.5 times the risk of stroke, death, or myocardial infarction compared with those in the lowest quartile. Those with regression or stable plaque have half the risk of those with progression after adjustment for the same panel of risk factors. The therapeutic target is plaque regression or stabilization, not just control of traditional risk factors. Trying to treat arteries without measuring plaque is like trying to treat hypertension without measuring the pressure, or hyperlipidemia without measuring the lipids.


Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes.
Recent large clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, with the aim of verifying cardiovascular safety, have revealed that these medications have a preventative advantage on adverse cardiovascular outcomes, including worsening of heart failure and deterioration of nephropathy, in patients with type 2 diabetes (T2D). These observed benefits do not seem to correlate with the glucose-lowering effect, and the underlying mechanism is being intensively investigated. Given the results from recent studies, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that patients with T2D and clinical cardiovascular disease (CVD) with inadequate glucose control despite treatment with metformin should receive an SGLT2 inhibitor or GLP-1 receptor agonist. In this review we summarize the results of recent cardiovascular outcome trials and discuss the potential clinical advantage of SGLT2 inhibitors and GLP-1 receptor agonists. We also present practical implications of these glucose-lowering agents for reducing the risk of adverse cardiovascular events and progressive renal comorbidity in patients with T2D and CVD.


[Menetrier's hypertrophic gastritis associated with polyarteritis nodosa].
Case presentation of a 61 year old male who presented with a 3 months' history of anorexia, weight loss, prolonged febrile syndrome, myalgias, peripheral polyneuropathy, abdominal pain, anemia, renal insufficiency, sonographically detected splenomegaly, elevated alkaline phosphatase, hypoproteinemia, sudden drops of the hematocrit, gastric ulcer with negative biopsies for malignancy and where the histological study of the surgical specimen confirmed the diagnosis of Ménétrier's disease or hypertrophic gastritis associated with nodose polyarteritis. The first explains the hypoproteinemia, edema; whereas the second explains the renal insufficiency, peripheral polyneuropathy, fever, skeletal muscle, spleen and liver involvements. The gastric ulcer, blood loss, anorexia, weight loss and abdominal pain can be justified by both diseases. We have been unable to find in the literature any other case of a similar association.


Inhibitors of human indoleamine 2,3-dioxygenase identified with a target-based screen in yeast.
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan degradation enzyme that is emerging as an important drug target. IDO is expressed by many human tumors to help them escape immune detection, and it has been implicated in depression and in the formation of senile nuclear cataracts. There is a need for potent and selective IDO inhibitors for use in research and as lead compounds for drug development. We show that expression of human IDO in a Saccharomyces cerevisiae tryptophan auxotroph restricts yeast growth in the presence of low tryptophan concentrations and that inhibition of IDO activity can restore growth. We use this assay to screen for IDO inhibitors in collections of pure chemicals and crude natural extracts. We identify NSC 401366 (imidodicarbonimidic diamide, N-methyl-N'-9-phenanthrenyl-, monohydrochloride) as a potent nonindolic IDO inhibitor (Ki=1.5 +/- 0.2 microM) that is competitive with respect to tryptophan. We also use this assay to identify the active compound caulerpin from a crude algal extract. The yeast growth restoration assay is simple and inexpensive. It combines desirable attributes of cell- and target-based screens and is an attractive tool for chemical biology and drug screening.


The Wildland Firefighter Exposure and Health Effect (WFFEHE) Study: Rationale, Design, and Methods of a Repeated-Measures Study.
The wildland firefighter exposure and health effect (WFFEHE) study was a 2-year repeated-measures study to investigate occupational exposures and acute and subacute health effects among wildland firefighters. This manuscript describes the study rationale, design, methods, limitations, challenges, and lessons learned. The WFFEHE cohort included fire personnel ages 18-57 from six federal wildland firefighting crews in Colorado and Idaho during the 2018 and 2019 fire seasons. All wildland firefighters employed by the recruited crews were invited to participate in the study at preseason and postseason study intervals. In 2019, one of the crews also participated in a 3-day midseason study interval where workplace exposures and pre/postshift measurements were collected while at a wildland fire incident. Study components assessed cardiovascular health, pulmonary function and inflammation, kidney function, workplace exposures, and noise-induced hearing loss. Measurements included self-reported risk factors and symptoms collected through questionnaires; serum and urine biomarkers of exposure, effect, and inflammation; pulmonary function; platelet function and arterial stiffness; and audiometric testing. Throughout the study, 154 wildland firefighters participated in at least one study interval, while 144 participated in two or more study interval. This study was completed by the Centers for Disease Control and Prevention's National Institute for Occupational Safety and Health through a collaborative effort with the U.S. Department of Agriculture Forest Service, Department of the Interior National Park Service, and Skidmore College. Conducting research in the wildfire environment came with many challenges including collecting study data with study participants with changing work schedules and conducting study protocols safely and operating laboratory equipment in remote field locations. Forthcoming WFFEHE study results will contribute to the scientific evidence regarding occupational risk factors and exposures that can impact wildland firefighter health over a season and across two wildland fire seasons. This research is anticipated to lead to the development of preventive measures and policies aimed at reducing risk for wildland firefighters and aid in identifying future research needs for the wildland fire community.


Biodegradation of three different collagen membranes in the rat calvarium: a comparative study.
Collagen barrier membranes are commonly applied in periodontal and bone-regenerative procedures. Membranes differ in their resorption pattern following implantation, thus influencing clinical outcome. The purpose of this study was to quantitatively evaluate the biodegradation of three different commercially available collagen membranes. Collagen membranes were cut into 5-mm-diameter disks and labeled with aminohexanoyl-biotin-N-hydroxy-succinimide ester. One membrane disk of each type (non-cross-linked [NCL], glutaraldehyde cross-linked [GCL], and ribose cross-linked [RCL]) was implanted on the calvaria of 20 Wistar rats. Block sections were retrieved after 2 days (baseline, two animals), 14 days (10 animals), or 28 days (eight animals). Decalcified histologic sections were stained with streptavidin horseradish peroxidase. Residual membrane thickness and area were measured. Statistical analysis consisted of analysis of variance (ANOVA) with repeated measures. Statistically significant differences in the amount of residual membrane material were recorded within each membrane (among different time points) and among different membranes at the same time points (P <0.001). At 28 days, the least amount of residual collagen area, expressed as the percentage of baseline, was observed in the NCL group (13.9% +/- 10.25%), followed by the GCL (24.7% +/- 35.11%) and RCL (91.3% +/- 10.35%) groups. Residual membrane thickness, expressed as the percentage of baseline thickness, presented a similar pattern (31% +/- 16.55%, 37% +/- 41.90%, and 94.1% +/- 12.22%, respectively). ANOVA with repeated measures showed a significant interaction between membranes and time (P <0.001). The tested membranes differed in their degradation patterns and collagen contents. Membranes should be chosen for each clinical case according to the desired biodegradation characteristics.


Concordance of genetic divergence among sockeye salmon populations at allozyme, nuclear DNA, and mitochondrial DNA markers.
We examined genetic variation at 21 polymorphic allozyme loci, 15 nuclear DNA loci, and mitochondrial DNA in four spawning populations of sockeye salmon (Oncorhynchus nerka) from Cook Inlet, Alaska, to test for differences in the patterns of divergence among different types of markers. We were specifically interested in testing the suggestion that natural selection at allozyme loci compromises the effectiveness of these markers for describing the amount and patterns of gene flow among populations. We found concordance among markers in the amount of genetic variation within and among populations, with the striking exception of one allozyme locus (sAH), which exhibited more than three times the amount of among-population differentiation as other loci. A consideration of reports of discordance between allozymes and other loci indicates that these differences usually result from one or two exceptional loci. We conclude that it is important to examine many loci when estimating genetic differentiation to infer historical amounts of gene flow and patterns of genetic exchange among populations. It is less important whether those loci are allozymes or nuclear DNA markers.


Racial and ethnic disparities in early treatment with immunotherapy for advanced HCC in the United States.
Immunotherapy has emerged as an effective treatment for patients with advanced-stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. We used the US National Cancer Database to identify patients with tumor-node-metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65-0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46-0.83) and Black patients (aOR: 0.71, 95% CI: 0.54-0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race-ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial-ethnic disparities in the management of advanced HCC is urgently needed.


Spaceflight Activates Lipotoxic Pathways in Mouse Liver.
Spaceflight affects numerous organ systems in the body, leading to metabolic dysfunction that may have long-term consequences. Microgravity-induced alterations in liver metabolism, particularly with respect to lipids, remain largely unexplored. Here we utilize a novel systems biology approach, combining metabolomics and transcriptomics with advanced Raman microscopy, to investigate altered hepatic lipid metabolism in mice following short duration spaceflight. Mice flown aboard Space Transportation System -135, the last Shuttle mission, lose weight but redistribute lipids, particularly to the liver. Intriguingly, spaceflight mice lose retinol from lipid droplets. Both mRNA and metabolite changes suggest the retinol loss is linked to activation of PPARα-mediated pathways and potentially to hepatic stellate cell activation, both of which may be coincident with increased bile acids and early signs of liver injury. Although the 13-day flight duration is too short for frank fibrosis to develop, the retinol loss plus changes in markers of extracellular matrix remodeling raise the concern that longer duration exposure to the space environment may result in progressive liver damage, increasing the risk for nonalcoholic fatty liver disease.


Global case studies for chronic kidney disease/end-stage kidney disease care.
The prevalence of chronic kidney disease and its risk factors is increasing worldwide, and the rapid rise in global need for end-stage kidney disease care is a major challenge for health systems, particularly in low- and middle-income countries. Countries are responding to the challenge of end-stage kidney disease in different ways, with variable provision of the components of a kidney care strategy, including effective prevention, detection, conservative care, kidney transplantation, and an appropriate mix of dialysis modalities. This collection of case studies is from 15 countries from around the world and offers valuable learning examples from a variety of contexts. The variability in approaches may be explained by country differences in burden of disease, available human or financial resources, income status, and cost structures. In addition, cultural considerations, political context, and competing interests from other stakeholders must be considered. Although the approaches taken have often varied substantially, a common theme is the potential benefits of multistakeholder engagement aimed at improving the availability and scope of integrated kidney care.


Insufficient reduction in heart rate during hospitalization despite beta-blocker treatment in acute decompensated heart failure: insights from the ASCEND-HF trial.
Heart failure (HF) can be associated with a higher resting heart rate (HR), and an elevated HR is associated with adverse long-term events. However, the mechanistic and causal role of HR in HF is unclear. This study aimed to investigate changes in HR during hospitalization, and the association between discharge HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with acute decompensated HF (ADHF). We studied 2906 patients with an LVEF ≤35%, without AF, who were enrolled in the ASCEND-HF trial. A total of 2492 (85.8%) patients had a HR ≥70 b.p.m. at baseline and 1580 (54.4%) patients were on beta-blocker treatment. Although HR was gradually reduced from baseline to discharge (85.5 ± 15.9 b.p.m. at baseline, 81.7 ± 14.1 b.p.m. at 24 h from treatment initiation, and 79.1 ± 12.2 b.p.m. at discharge), 80.2% of the patients still had a HR ≥70 b.p.m. at discharge. Patients with a HR ≥70 b.p.m. at discharge had significantly lower survival rates than those with a HR <70 b.p.m. (adjusted hazard ratio 1.02, 95% confidence interval 1.01-1.04, P = 0.002). Moreover, HR at discharge had a curvilinear association with mortality, and had no significant interaction effect with beta-blocker therapy at discharge (P = 0.82). Despite current beta-blocker therapy, many patients with hospitalized ADHF with reduced LVEF have relatively high discharge HR, and discharge HR is associated with higher mortality. Further studies are warranted to determine the optimal strategy for HR control to improve outcomes.


A Phase II Trial of Sorafenib and Dacarbazine for Leiomyosarcoma, Synovial Sarcoma, and Malignant Peripheral Nerve Sheath Tumors.
Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. The study included 37 patients (19 female); median age was 55 years (range 26-87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction. This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity.


Peptidoglycan from Bacillus cereus mediates commensalism with rhizosphere bacteria from the Cytophaga-Flavobacterium group.
Previous research in our laboratory revealed that the introduction of Bacillus cereus UW85 can increase the populations of bacteria from the Cytophaga-Flavobacterium (CF) group of the Bacteroidetes phylum in the soybean rhizosphere, suggesting that these rhizosphere microorganisms have a beneficial relationship (G. S. Gilbert, J. L. Parke, M. K. Clayton, and J. Handelsman, Ecology 74:840-854, 1993). In the present study, we determined the frequency at which CF bacteria coisolated with B. cereus strains from the soybean rhizosphere and the mechanism by which B. cereus stimulates the growth of CF rhizosphere strains in root exudate media. In three consecutive years of sampling, CF strains predominated among coisolates obtained with B. cereus isolates from field-grown soybean roots. In root exudate media, the presence of B. cereus was required for CF coisolate strains to reach high population density. However, rhizosphere isolates from the phylum Proteobacteria grew equally well in the presence and absence of B. cereus, and the presence of CF coisolates did not affect the growth of B. cereus. Peptidoglycan isolated from B. cereus cultures stimulated growth of the CF rhizosphere bacterium Flavobacterium johnsoniae, although culture supernatant from B. cereus grown in root exudate media did not. These results suggest B. cereus and CF rhizosphere bacteria have a commensal relationship in which peptidoglycan produced by B. cereus stimulates the growth of CF bacteria.


The in-vitro activity of temafloxacin, against gram-positive bacteria.
Temafloxacin, a new fluoroquinolone with enhanced activity against Gram-positive bacteria, was compared with other antibiotics. A review of the literature on the in-vitro activity of temafloxacin was also done. The susceptibility of Gram-positive cocci isolated from blood cultures was determined using a broth microdilution method. Temafloxacin MIC90s for Staphylococcus aureus (oxacillin-sensitive and -resistant) and Streptococcus pneumoniae were less than 0.12, less than 0.12 and 0.76 mg/L respectively. Temafloxacin was more active than either ciprofloxacin or ofloxacin against these organisms. A review of the literature supported these findings. Temafloxacin was the most active of the quinolones tested against a small number of S. pneumoniae with decreased sensitivity to penicillin. Temafloxacin activity was not appreciably affected by changes in pH or the presence of serum, but activity was slightly reduced in urine at pH 6.5-7.2, and at high magnesium ion concentrations. With the exception of S. pneumoniae at high concentration, no significant inoculum effect was observed.


Xylose assimilation enhances the production of isobutanol in engineered Saccharomyces cerevisiae.
Bioconversion of xylose-the second most abundant sugar in nature-into high-value fuels and chemicals by engineered Saccharomyces cerevisiae has been a long-term goal of the metabolic engineering community. Although most efforts have heavily focused on the production of ethanol by engineered S. cerevisiae, yields and productivities of ethanol produced from xylose have remained inferior as compared with ethanol produced from glucose. However, this entrenched focus on ethanol has concealed the fact that many aspects of xylose metabolism favor the production of nonethanol products. Through reduced overall metabolic flux, a more respiratory nature of consumption, and evading glucose signaling pathways, the bioconversion of xylose can be more amenable to redirecting flux away from ethanol towards the desired target product. In this report, we show that coupling xylose consumption via the oxidoreductive pathway with a mitochondrially-targeted isobutanol biosynthesis pathway leads to enhanced product yields and titers as compared to cultures utilizing glucose or galactose as a carbon source. Through the optimization of culture conditions, we achieve 2.6 g/L of isobutanol in the fed-batch flask and bioreactor fermentations. These results suggest that there may be synergistic benefits of coupling xylose assimilation with the production of nonethanol value-added products.


Lifetime reproductive benefits of cooperative polygamy vary for males and females in the acorn woodpecker (Melanerpes formicivorus).
Cooperative breeding strategies lead to short-term direct fitness losses when individuals forfeit or share reproduction. The direct fitness benefits of cooperative strategies are often delayed and difficult to quantify, requiring data on lifetime reproduction. Here, we use a longitudinal dataset to examine the lifetime reproductive success of cooperative polygamy in acorn woodpeckers (Melanerpes formicivorus), which nest as lone pairs or share reproduction with same-sex cobreeders. We found that males and females produced fewer young per successful nesting attempt when sharing reproduction. However, males nesting in duos and trios had longer reproductive lifespans, more lifetime nesting attempts and higher lifetime reproductive success than those breeding alone. For females, cobreeding in duos increased reproductive lifespan so the lifetime reproductive success of females nesting in duos was comparable to those nesting alone and higher than those nesting in trios. These results suggest that for male duos and trios, reproductive success alone may provide sufficient fitness benefits to explain the presence of cooperative polygamy, and the benefits of cobreeding as a duo in females are higher than previously assumed. Lifetime individual fitness data are crucial to reveal the full costs and benefits of cooperative polygamy.


Early E-selectin, VCAM-1, ICAM-1, and late major histocompatibility complex antigen induction on human endothelial cells by flavivirus and comodulation of adhesion molecule expression by immune cytokines.
Expression of E-selectin (ELAM-1, CD62E) on human umbilical vein endothelial cells significantly increased 30 min postinfection with the flavivirus West Nile virus (WNV), was maximal by 2 h postinfection, and declined to baseline levels within 24 h. Expression of ICAM-1 (CD54) and VCAM-1 (CD106) was significantly increased by 2 h and maximal at 4 h after infection. P-selectin (CD62P) expression was unaffected by WNV. Upregulation occurred earlier than that caused by tumor necrosis factor alpha (TNF-alpha) or interleukin 1 (IL-1) and could not be inhibited by neutralizing TNF-alpha, IL-1alpha, or alpha/beta interferon (IFN-alpha/beta) antibodies, suggesting a direct, virus-mediated phenomenon. TNF-alpha significantly enhanced WNV-induced increases in E-selectin, P-selectin, ICAM-1, and VCAM-1 expression, while IFN-gamma enhanced WNV-induced ICAM-1 expression. In contrast, IL-4 abrogated WNV-induced E-selectin expression increases but acted in synergy with WNV to increase P-selectin and VCAM-1 expression. WNV increased the expression of class I and II major histocompatibility complex antigens (MHC-I and MHC-II, respectively) at 24 and 72 h, respectively. IFN-gamma, TNF-alpha, or IL-1 acted in synergy with WNV to produce greater increases in MHC-I expression than WNV or cytokines alone, while IFN-alpha/beta or IL-4 had no effect. MHC-II induction in cytokine-treated, WNV-infected cells was similar to that caused by cytokines alone. Neutralizing IFN-alpha/beta antibody inhibited WNV-induced MHC-I expression by 30% at 24 h and by 100% by 72 h. The differential kinetics of modulation suggest sequential adhesion of leukocyte subpopulations to infected endothelial cells, which may be important in initial viral spread in vivo.


Ring-breaking electron attachment to uracil: following bond dissociations via evolving resonances.
Calculations are carried out at various distinct energies to obtain both elastic cross sections and S-matrix resonance indicators (poles) from a quantum treatment of the electron scattering from gas-phase uracil. The low-energy region confirms the presence of pi(*) resonances as revealed by earlier calculations and experiments which are compared with the present findings. They turn out to be little affected by bond deformation, while the transient negative ions (TNIs) associated with sigma(*) resonances in the higher energy region ( approximately 8 eV) indeed show that ring deformations which allow vibrational redistribution of the excess electron energy into the molecular target strongly affect these shape resonances: They therefore evolve along different dissociative pathways and stabilize different fragment anions. The calculations further show that the occurrence of conical intersections between sigma(*) and pi(*)-type potential energy surfaces (real parts) is a very likely mechanism responsible for energy transfers between different TNIs. The excess electron wavefunctions for such scattering states, once mapped over the molecular space, provide nanoscopic reasons for the selective breaking of different bonds in the ring region.