The Development of a Probabilistic Dose-Response for a Burn Injury Model.
The objective was to augment a burn injury model, BURNSIM, with probabilistic dose-response risk curves. To develop the dose-response, we drew on a considerable amount of historical porcine burn injury data collected by U.S. Army Aeromedical Research Laboratory in the 1970s. The experimental parameters of each usable data point served as inputs to BURNSIM to calculate the burn damage integral (i.e., the internal dose) for 4 severities (mild, intermediate, deep second- and third-degree burns). The binary probability response was constructed and logistic regression was applied to generate the respective dose-response. Historic data collected at the University of Rochester in the 1950s were used for validation. Four dose-response curves were generated, ranging from mild to third degree, with tight 95% confidence bands for mild to deep second degree, and slightly wider bands for third degree. Parametric sensitivity analysis revealed that epidermal and whole skin thicknesses, skin temperature, and blood flow rate have a large effect on predicted outcomes. Addition of dose-response curves provides a critical augmentation to BURNSIM to improve operational risk assessments of burn hazard. Future recommendations for BURNSIM include the use of body location- and gender-specific parameters with coupling to a thermoregulatory model.


Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis.
Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy. PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated. A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors. PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.


Theoretical study of the spectroscopy and radiative transition probabilities of Si2 from visible to infrared.
High level ab initio calculations on the electronic states of a silicon dimer (Si2) have been carried out by employing a multi-reference configuration interaction plus Davidson correction (MRCI + Q) approach with the aug-cc-pVQZ basis set. The scalar relativistic correction is taken into consideration by the second-order Douglas-Kroll-Hess approximation. In the present work, the transition properties (oscillator strength, Einstein spontaneous emission coefficient and radiative lifetime) of the singlet-singlet, triplet-triplet, and quintet-quintet transitions of Si2 are discussed. We emphasize the triplet-triplet emission bands H3Σ-u-X3Σ-g, K3Σ-u-X3Σ-g and D3Πu-L3Πg which are dominant for 0-11 (18 822 cm-1), 0-0 (30 672 cm-1), and 0-0 (28 881 cm-1) transitions, respectively. In addition, the strong experimentally observed b1Πu-d1Σ+g band around 4184 cm-1 corresponds to the second 1Σ+g-b1Πu combination in the infrared region. The calculated oscillator strengths of the singlet-singlet transitions (f1Πg-e1Σ-u, 21Πg-b1Πu, b1Πu-d1Σ+g and g1Δu-a1Δg) are in the order of 10-3. From a theoretical point of view, the 0-0 sub-band for the f1Πg-e1Σ-u transition, 0-7 for 21Πg-b1Πu, 0-0 for b1Πu-d1Σ+g and the 0-7 vibronic bands for the g1Δu-a1Δg transition may be observed experimentally. It is expected that the present results could provide theoretical support for a deeper understanding of the experimental Si2 spectra providing further applications in astrophysics.


Treadmill exercise with bone marrow stromal cells transplantation potentiates recovery of locomotor function after spinal cord injury in rats.
Transplantation of bone marrow stromal cells (BMSCs) is regarded as a promising candidate for the spinal cord injury (SCI). In the present study, we investigated whether treadmill exercise potentiate the effect of BM-SCs transplantation on the functional recovery in the SCI rats. The spinal cord contusion injury applied at the T9-T10 level using the impactor. Cultured BMSCs were transplanted into the lesion at 1 week after SCI induction. Treadmill exercise was conducted for 6 weeks. Basso-Beattie-Bresnahan (BBB) scale for locomotor function was determined. Sprouting axons in the lesion cavity were detected by immunofluorescence staining for neurofilament-200. Brain-derived neurotrophic factor (BDNF) and synapsin-I expressions were analyzed using western blotting. BMSCs transplantation improved BBB score and increased expressions of neurofilament-200, BDNF, and synapsin-I in the SCI rats. Treadmill exercise potentiated the improving effect of BMSCs transplantation on BBB score in the SCI rats. This potentiating effect of treadmill exercise could be ascribed to the enhancement of BDNF expression in the SCI rats.


Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study.
Metabolic syndrome (MetS) is associated with increased risk for both vascular and chronic kidney disease. Whether statins ameliorate these risks is not established. This post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD). Evaluation (GREACE) examines the effect of statins on estimated glomerular filtration rate (e-GFR) and serum uric acid (SUA) levels and their relation to vascular events in CHD patients with MetS. MetS patients were divided into two groups: Group A (n = 365) received lifestyle advice, target-driven treatment with statins (mainly atorvastatin) and treatment for hypertension and elevated glucose. Group B (n = 347) received the same except for statins. Patients without MetS were divided into those who received treatment similar to Group A and Group B [Groups C (n = 504) and D (n = 384), respectively]. All patients were followed for 3 years. A total of 12.1% of patients in Group A experienced a vascular event vs 28% in Group B; risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20-0.64, P < 0.0001, while in those without MetS (Group C vs Group D), the respective RR was 0.59, 95% CI 0.41-0.79, P < 0.0001. In Group A, e-GFR increased by 13.7% and SUA levels fell by 8.9%, while in Group B e-GFR was reduced by 5.8% and SUA increased by 4.3% (P < 0.005). Stepwise regression analysis showed that these changes were independently related to vascular events. Among CHD patients, those with MetS benefited more from statin treatment than those without MetS. This benefit could be partially attributed to favourable changes in e-GFR and SUA levels probably induced by statin treatment.


A case report of onset of tinnitus following discontinuation of antidepressant and a review of the literature.
This case report describes a 46-year-old woman with long-standing episodic severe depression (ICD-10 code F33) who discontinued venlafaxine over a 4-week taper after taking the antidepressant for 8 years. Severe discontinuation syndrome was experienced. Panic and relapse of depression occurred 2 months after achieving discontinuation, and the development of tinnitus took place concurrently to the discontinuation. The experience of the tinnitus as a side effect of discontinuation is different from cases reported in the literature in which the tinnitus was experienced when the antidepressant was started and ceased when the antidepressant was stopped. Here, the patient experienced the tinnitus as a discontinuation symptom, and it persisted even after the antidepressant was reintroduced. A review of the literature on antidepressant discontinuation syndrome is also provided.


ACER2 forms a cold tumor microenvironment and predicts the molecular subtype in bladder cancer: Results from real-world cohorts.
Background: ACER2 is a critical gene regulating cancer cell growth and migration, whereas the immunological role of ACER2 in the tumor microenvironment (TME) is scarcely reported. Thus, we lucubrate the potential performance of ACER2 in bladder cancer (BLCA). Methods: We initially compared ACER2 expressions in BLCA with normal urothelium tissues based on data gathered from the Cancer Genome Atlas (TCGA) and our Xiangya cohort. Subsequently, we systematically explored correlations between ACER2 with immunomodulators, anti-cancer immune cycles, tumor-infiltrating immune cells, immune checkpoints and the T-cell inflamed score (TIS) to further confirm its immunological role in BLCA TME. In addition, we performed ROC analysis to illustrate the accuracy of ACER2 in predicting BLCA molecular subtypes and explored the response to several cancer-related treatments. Finally, we validated results in an immunotherapy cohort and Xiangya cohort to ensure the stability of our study. Results: Compared with normal urinary epithelium, ACER2 was significantly overexpressed in several cell lines and the tumor tissue of BLCA. ACER2 can contribute to the formation of non-inflamed BLCA TME supported by its negative correlations with immunomodulators, anti-cancer immune cycles, tumor-infiltrating immune cells, immune checkpoints and the TIS. Moreover, BLCA patients with high ACER2 expression were inclined to the luminal subtype, which were characterized by insensitivity to neoadjuvant chemotherapy, chemotherapy and radiotherapy but not to immunotherapy. Results in the IMvigor210 and Xiangya cohort were consistent. Conclusion: ACER2 could accurately predict the TME and clinical outcomes for BLCA. It would be served as a promising target for precision treatment in the future.


Diabetes risk factors in children: a partnership between nurse practitioner and high school students.
This project was a 4-year university/community collaboration to (1) screen for diabetes risk factors in children from in an inner-city community; (2) assess children's knowledge of nutrition and measure their physical endurance; and (3) survey parents about barriers to healthy living. Descriptive cross-sectional study utilizing a community participatory-based research approach. For a 4-week period each year, nurse practitioner students and high school students partnered in an evaluation of elementary school children that included assessment of (1) height, weight, waist circumference, BMI, and acanthosis nigricans; (2) scores on a nutrition knowledge test; and (3) recovery heart rate after a dance activity. Parents of the children were surveyed regarding barriers to healthy eating and activity. A total of 240 African American children were evaluated: 25% were obese, 24% had a waist circumference >95th percentile, and 14% had acanthosis nigricans. The mean score of a nutrition knowledge test was 65%, and recovery heart rates were significantly higher than preexercise heart rates. Of 48 parents surveyed, the most common barrier to eating healthy reported was the children's picky eating (62%), and most common barrier to activity was lack of access to safe places to play (54%). Nurses working with children from inner-city communities should be especially aware of the children's many risk factors for diabetes. Clinicians who hope to make a difference in altering these risks should collaborate with the community to target high-risk populations for diabetes screening, promote good nutrition and exercise, and address barriers to healthy living. When developing plans of care for children, regardless of setting, it is critical to understand the community and incorporate the families as partners in developing culturally relevant interventions.


Diphenyleneiodonium inhibits both potassium and calcium currents in isolated pulmonary artery smooth muscle cells.
Diphenyleneiodonium (DPI) blocks hypoxic vasoconstriction in the pulmonary vasculature. Because one of the actions of DPI is the inhibition of NADPH oxidase, this has led to the suggestion that NADPH oxidase acts as an oxygen tension sensor in pulmonary smooth muscle cells. We investigated the effects of DPI on potassium and calcium currents in freshly isolated pulmonary artery smooth muscle cells by using whole cell patch-clamp recordings, since these ionic currents are known to be involved in hypoxic pulmonary vasoconstriction. DPI (3 and 10 microM) reversibly inhibited potassium currents, and in its presence, residual currents appeared markedly more transient than under control conditions. The actions of DPI could not be reversed by 4.4 mM hydrogen peroxide, the product of NADPH oxidase. Calcium channel currents were also reversibly inhibited by 3 microM DPI. Thus DPI is a nonselective blocker of ionic channels in pulmonary smooth muscle cells, and its mechanism of action does not appear to involve inhibition of hydrogen peroxide formation. The ability of DPI to block calcium currents can explain its inhibition of hypoxic pulmonary vasoconstriction.


Primary Mouse Invariant Natural Killer T (iNKT) Cell Purification and Transduction.
Invariant natural killer T (iNKT) cells are a non-conventional T-cell population expressing a conserved semi-invariant T-cell receptor (TCR) that reacts to lipid antigens, such as α-galactosyl ceramide (α-GalCer), presented by the monomorphic molecule CD1d. iNKT cells play a central role in tumor immunosurveillance and represent a powerful tool for anti-cancer treatment, notably because they can be efficiently redirected against hematological or solid malignancies by engineering with tumor-specific chimeric antigen receptors (CARs) or TCRs. However, iNKT cells are rare and require specific ex vivo pre-selection and substantial in vitro expansion to be exploited for adoptive cell therapy (ACT). This protocol describes a robust method to obtain a large number of mouse iNKT cells that can be effectually engineered by retroviral (RV) transduction. A major advantage of this protocol is that it requires neither particular instrumentation nor a high number of mice. iNKT cells are enriched from the spleens of iVα14-Jα18 transgenic mice; the rapid purification protocol yields a highly enriched iNKT cell population that is activated by anti-CD3/CD28 beads, which is more reproducible and less time consuming than using bone marrow-derived dendritic cells loaded with α-GalCer, without risks of expanding contaminant T cells. Forty-eight hours after activation, iNKT cells are transduced with the selected RV by spin inoculation. This protocol allows to obtain, in 15 days, millions of ready-to-use, highly pure, and stably transduced iNKT cells that might be exploited for in vitro assays and ACT experiments in preclinical studies.


Effect of Picture Archiving and Communication System Image Manipulation on the Agreement of Chest Radiograph Interpretation in the Neonatal Intensive Care Unit.
Variability in image interpretation has been attributed to differences in the interpreters' knowledge base, experience level, and access to the clinical scenario. Picture archiving and communication system (PACS) has allowed the user to manipulate the images while developing their impression of the radiograph. The aim of this study was to determine the agreement of chest radiograph (CXR) impressions among radiologists and neonatologists and help determine the effect of image manipulation with PACS on report impression. Prospective cohort study included 60 patients from the Neonatal Intensive Care Unit undergoing CXRs. Three radiologists and three neonatologists reviewed two consecutive frontal CXRs of each patient. Each physician was allowed manipulation of images as needed to provide a decision of "improved," "unchanged," or "disease progression" lung disease for each patient. Each physician repeated the process once more; this time, they were not allowed to individually manipulate the images, but an independent radiologist presets the image brightness and contrast to best optimize the CXR appearance. Percent agreement and opposing reporting views were calculated between all six physicians for each of the two methods (allowing and not allowing image manipulation). One hundred percent agreement in image impression between all six observers was only seen in 5% of cases when allowing image manipulation; 100% agreement was seen in 13% of the cases when there was no manipulation of the images. Agreement in CXR interpretation is poor; the ability to manipulate the images on PACS results in a decrease in agreement in the interpretation of these studies. New methods to standardize image appearance and allow improved comparison with previous studies should be sought to improve clinician agreement in interpretation consistency and advance patient care.


Selection of Rattus norvegicus cumulus-oocyte complex for vitrification by brilliant cresyl blue.
The influence of the method of evaluating developmentally competent oocytes on their viability after cryopreservation still needs to be better understood. The objective of this study was to determine the cleavage and embryo developmental rates after parthenogenetic activation of cumulus-oocyte complexes (COCs) selected by different concentrations of brilliant cresyl blue (BCB) and cryopreservation. In the first experiment, COCs were separated into groups and incubated for 1 h in medium containing BCB (13 μM, 16 μM, or 20 μM). The control group was not exposed to BCB staining. In the second experiment, COCs were divided into four groups: 13 μM BCB(+), 13 μM BCB(-), fresh control (selected by morphologic observation and immediately in vitro matured) and vitrified control (selected by morphologic evaluation, vitrified, and in vitro matured). In the first experiment, the 13 μM BCB group displayed greater development rates at the morula stage (65.45%, 36/55) when compared with the other groups. In the second experiment, cleavage (47.05%, 72/153) and morula development (33.55%, 51/153) of the control group of fresh COCs were increased compared with the other groups. However, when comparing morula rates between vitrified COC control and BCB(+) groups, the BCB(+) group had better results (19.23%, 5/26 and 64.7%, 11/17, respectively). Our best result in rat COC selection by BCB staining was obtained using a concentration of 13 μM. This selection could be a valuable tool to improve vitrification outcomes, as observed by the BCB(+) group that demonstrated better results compared with the vitrified COC control.


Cystathioninuria: nature of the defect.
A homogenate of liver obtained by biopsy from two patients with cystathioninuria, an inborn error of metabolism, cleaved radioactive cystathionine only slightly until an excess of pyridoxal phosphate was added. The apoenzyme failed to bind the coenzyme normally. Pyridoxine therapy of familial cystathioninuria thus has a sound basis.


Effects of anemia during the third trimester of pregnancy on postpartum depression and pregnancy outcomes in pregnant women older than 35 years: a retrospective cohort study.
There is no study on the impact of anemia on postpartum depression and outcomes in mothers older than 35 years, which makes the nursing of these pregnant women with anemia more difficult. We retrospectively collected the demographic and clinical characteristics of pregnant women older than 35 years at conception between August 2014 and December 2019. Hemoglobin less than 110 g/L was defined as anemia. Postpartum depression was assessed according to Edinburgh Postnatal Depression Scale. A subgroup analysis was performed by dividing anemia into mild anemia or moderate and severe anemia. All participants were followed up for at least 3 months postpartum and their pregnancy outcomes were recorded. The existence of postpartum depression was evaluated at 4 weeks postpartum. The risk factors of anemia during the third trimester of pregnancy and the impacts of anemia on postpartum depression and pregnancy outcomes were analyzed using multivariable logistic regression analysis. A total of 519 pregnant older than 35 years women were included in this study, including 281 without anemia and 238 with anemia. No significant difference was found in the incidence of postpartum depression between anemia and non-anemia groups (18.9% vs. 12.8%, P=0.057), while the anemia group had significantly higher incidence of preterm delivery, prolonged labor, and caesarean section. The subgroup analysis found that significantly pregnant women with older age in the moderate or severe anemia subgroup had postpartum depression than those in the mild anemia subgroup (23.2% vs. 12.5%, P=0.038). A higher rate of preterm delivery, prolonged labor, and caesarean section was recorded in the moderate or severe anemia subgroup (8.3% vs. 20.4%, P=0.012; 30.2% vs. 43.0%, P<0.001; 20.8% vs. 40.1%, P=0.002). Moderate or severe anemia, the presence of depression during the first trimester of pregnancy, unplanned pregnancy, and fewer parity were identified as risk factors of postpartum depression in pregnant women older than 35 years with anemia. Anemia has significant impacts on pregnancy outcomes in pregnant women older than 35 years. Furthermore, moderate and severe anemia will significantly increase the incidence of postpartum depression, which should be corrected at an early stage to minimize its negative effects.


Differences in the regulation of ochratoxin A by the HOG pathway in Penicillium and Aspergillus in response to high osmolar environments.
Penicillium verrucosum, P. nordicum and Aspergillus carbonarius are three important ochratoxin A producing species. P. verrucosum is in addition able to produce citrinin. It has been shown earlier that P. nordicum is adapted to NaCl rich environments like salt rich dry cured foods or even salines. In this organism, the biosynthesis of ochratoxin A plays an adaptive role in this habitat. P. verrucosum generally can be found on cereals, but occasionally also on salt rich dry cured foods. In contrast A. carbonarius usually cannot be found in NaCl rich environments, but it occurs in another environment with high concentration of solutes, e.g., in sugar rich substrates like grapes and grape juices. Usually osmotic challenging conditions activate the HOG MAP kinase signal cascade, which in turn activates various osmo-regulated genes. In the current analysis, it could be demonstrated that in case of P. nordicum and P. verrucosum the NaCl induced production of ochratoxin A is correlated to the phosphorylation status of the HOG MAP kinase. Just the opposite was true for A. carbonarius. In this case, also higher amounts of NaCl in the medium lead to an increased phosphorylation status of HOG, but no increase in ochratoxin biosynthesis was observed. In contrast to the Penicillia, higher NaCl concentrations lead to a rapid cessation of growth by A. carbonarius. High glucose concentrations have much less impact on growth and the phosphorylation of HOG.


[Heparin induced thrombocytopenia: case report with acute thrombotic complications and literature review].
Review of the frequency, clinical and biological features and treatment of type II heparin-induced thrombocyopenia. Case report and literature review. A 65 years old woman received as antithrombotic prophylaxis low molecular weight heparin (LMWH) after prosthetic knee replacement. Day 8, asymptomatic deep vein thrombosis was discovered after systematic echodoppler examination. Curative anticoagulation was started with LMWH. A fall in the platelet count (17 G/L) was noted day 12. Danaparoid was immediately introduced and heparin discontinued. However, day 16 a massive pulmonary embolism occurred which required transfer to an intensive care unit. Danaparoid was changed for lepirudin the same day. It took longer than three weeks for platelet count to return to normal value after heparin discontinuation. The suspicion of heparin-induced thrombocyopenia was confirmed by specific tests. HIT type II are rare but life-threatening and thrombosis events are the most frequent complications. The diagnosis is a high probability proved by both clinical and biological patterns. The treatment consists in alternative thrombin inhibitors such as danaparoid and lepirudin. The platelet count usually requires less than ten days to recover normal values after heparin withdrawal. Cases in which the delay to a normal platelet count exceeds 3 weeks have been reported specially after LMWH therapy. Type II HIT are rare but life-threatening events can occur. The platelet count check-up during heparin therapy must be systematic.


Detection of time-, frequency- and direction-resolved communication within brain networks.
Electroencephalography (EEG) records fast-changing neuronal signalling and communication and thus can offer a deep understanding of cognitive processes. However, traditional data analyses which employ the Fast-Fourier Transform (FFT) have been of limited use as they do not allow time- and frequency-resolved tracking of brain activity and detection of directional connectivity. Here, we applied advanced qEEG tools using autoregressive (AR) modelling, alongside traditional approaches, to murine data sets from common research scenarios: (a) the effect of age on resting EEG; (b) drug actions on non-rapid eye movement (NREM) sleep EEG (pharmaco-EEG); and (c) dynamic EEG profiles during correct vs incorrect spontaneous alternation responses in the Y-maze. AR analyses of short data strips reliably detected age- and drug-induced spectral EEG changes, while renormalized partial directed coherence (rPDC) reported direction- and time-resolved connectivity dynamics in mice. Our approach allows for the first time inference of behaviour- and stage-dependent data in a time- and frequency-resolved manner, and offers insights into brain networks that underlie working memory processing beyond what can be achieved with traditional methods.


Risk factors and prognosis of acute kidney injury in adult hospitalized patients: a two-year outcome.
Acute kidney injury (AKI) is becoming increasingly common in hospitalized patients. A few studies have defined epidemiological data concerning hospital-acquired AKI. The aim of this study was to determine the incidence and the risk factors of hospital-acquired AKI and its treatment and prevention. A dataset of 123,105 adults who were treated in the hospital from January 2010 to December 2011, excluding patients with chronic kidney disease (CKD) and community-acquired AKI patients, was evaluated. Clinical data of blood urea nitrogen (BUN) and serum creatinine (SCr) were collected and analyzed. AKI was defined and classified according to the Acute Kidney Injury Network (AKIN). Data were compared among patients with hospital-acquired and non-hospital-acquired AKI. Among a cohort of 123,105 hospitalized adult patients, 174 patients were identified with hospital-acquired AKI. The number of cases aged 18-39, 40-59, 60-79 and ≥80 years was, respectively, 15 (8.6%), 39 (22.4%), 82 (47.1%), and 38 (21.8%); the 60-79 years age group had the highest number. Univariate analysis showed that the unfavorable prognosis was correlated with >60 years of age, coronary heart disease, diabetes, hypotension, unconsciousness, mechanical ventilation, injuries and multiple organ dysfunction syndrome (MODS). Multivariate logistic regression analysis demonstrated that the coronary heart disease, diabetes, hypotension, mechanical ventilation and MODS were independent unfavorable prognostic factors for hospital-acquired AKI. Prerenal and renal factors are the major causes of the development of hospital-acquired AKI. Thus, focusing on the potential risk factors of hospital-acquired AKI may prove to be beneficial to the prognosis of patients.


Upregulation of CPNE3 suppresses invasion, migration and proliferation of glioblastoma cells through FAK pathway inactivation.
Glioblastoma (GBM) is a deadly brain tumor with a bleak prognosis. In recent years, the copine III (CPNE3) protein was discovered to be associated to metastasis across various types of malignancies. Nevertheless, its function has not been well documented in glioma. This study characterizes CPNE3 expression in GBM along with its impact and underlying molecular mechanism with regards to cellular migration, invasion and proliferation. Immunohistochemistry was used to characterizes CPNE3 expression in the glioma tissues. Then, knockdown of CPNE3 expression was used to analyze the role of CPNE3 in GBM cell viability, migration, invasion. Western blot analysis was performed to measure the protein levels of FAK signaling pathway. We found that GBM tissues had higher CPNE3 expressions as compared to those in normal brain tissues. CPNE3 silencing in GBM cells impaired the migratory, invasive and proliferative abilities of GBM cells that can be attributed to inactivation of the FAK signaling pathway. Collectively, these findings highlight the role of CPNE3 as a new biomarker, offering deeper insights into its carcinogenic role in GBM.


Precise co-registration of mass spectrometry imaging, histology, and laser microdissection-based omics.
Mass spectrometry imaging (MSI) is an analytical technique for the unlabeled and multiplex imaging of molecules in biological tissue sections. It therefore enables the spatial and molecular annotations of tissues complementary to histology. It has already been shown that MSI can guide subsequent material isolation technologies such as laser microdissection (LMD) to enable a more in-depth molecular characterization of MSI-highlighted tissue regions. However, with MSI now reaching spatial resolutions at the single-cell scale, there is a need for a precise co-registration between MSI and the LMD. As proof-of-principle, MSI of lipids was performed on a breast cancer tissue followed by a segmentation of the data to detect molecularly distinct segments within its tumor areas. After image processing of the segmentation results, the coordinates of the MSI-detected segments were passed to the LMD system by three co-registration steps. The errors of each co-registration step were quantified and the total error was found to be less than 13 μm. With this link established, MSI data can now accurately guide LMD to excise MSI-defined regions of interest for subsequent extract-based analyses. In our example, the excised tissue material was then subjected to ultrasensitive microproteomics in order to determine predominant molecular mechanisms in each of the MSI-highlighted intratumor segments. This work shows how the strengths of MSI, histology, and extract-based omics can be combined to enable a more comprehensive molecular characterization of in situ biological processes.


Application of classical models of chirality to optical rectification.
Classical models of chirality are used to investigate the optical rectification effect in chiral molecular media. Calculation of the zero frequency first hyperpolarizabilities of chiral molecules with different structures is performed and applied to the derivation of a dc electric-dipole polarization. The expression of second-order nonlinear static-electric-dipole susceptibilities is obtained by theoretical derivation in the isotropic chiral thin films. The microscopic mechanism producing optical rectification is analyzed in view of this calculation. We find that optical rectification is derived from interaction between the electric field gradient (spatial dispersion) and chiral molecules in optically active liquids and solution by our calculation, which is consistent with the result given by Wozniak and Wagniere [Opt. Commun. 114, 131 (1995)]: The optical rectification depends on the fourth-order electric-dipole susceptibilities.


CPAP Treatment Partly Normalizes Sleep Spindle Features in Obstructive Sleep Apnea.
Objective. Obstructive sleep apnea (OSA) decreases sleep spindle density and frequency. We evaluated the effects of continuous positive airway pressure (CPAP) treatment on different features of sleep spindles. Methods. Twenty OSA patients underwent two night polysomnographies in a diagnostic phase and one night polysomnography after 6 months of CPAP treatment. The control group comprised 20 healthy controls. Sleep spindles were analyzed by a previously developed automated method. Unilateral and bilateral spindles were identified in central and frontopolar brain locations. Spindle density and frequency were determined for the first and last half of the NREM time. Results. The density of bilateral central spindles, which did not change in the untreated OSA patients, increased towards the morning hours during CPAP treatment and in the controls. Central spindles did not become faster with sleep in OSA patients and the central spindles remained slow in the left hemisphere even with CPAP. Conclusion. CPAP treatment normalized spindle features only partially. The changes may be associated with deficits in thalamocortical spindle generating loops. Significance. This study shows that some sleep spindle changes persist after CPAP treatment in OSA patients. The association of these changes to daytime symptoms in OSA patients needs to be further evaluated.


Physiology of ageing.
Aging is a process of gradually reducing abilities and functional capacities of the organism. It is a universal process with a considerable degree of variability that is characteristic of all higher animals. Among the theories of ageing, the theory of damage accumulation, which integrates the mechanisms of ageing known to date, is currently widely accepted. This theory is based on pathophysiological processes, injurious changes can occur in the human body. These changes can be understood as damage. Due to the continuous accumulation of damage, the whole system is subsequently deteriorated. The aim of the present work is to characterize the basic pathophysiological mechanisms of aging (damage) in the light of current scientific knowledge and to show them in their hierarchical context.


Natural history of hepatic fibrosis progression in chronic hepatitis C virus infection in India.
The rate of fibrosis progression per year can predict the time for the development of cirrhosis in chronic hepatitis C (CHC). We assessed the rate of fibrosis progression and the predictors of disease severity in Indian CHC patients. Of the 355 treatment-naïve, histologically-proven CHC patients, the precise duration of infection (from the time of exposure to HCV until liver biopsy) could be determined in 213 patients (age = 41.6 +/- 14.7 years, male : female = 139 : 74, genotype 3 = 75%). The rate of fibrosis progression per year was calculated. The correlation of the advanced degree of fibrosis and age, duration of infection, age at the onset of infection, sex, mode of infection, hepatitis C virus (HCV) genotype, histological activity index (HAI), and the presence of diabetes mellitus were studied. The median rate of fibrosis progression per year was 0.25 (0.0-1.5) fibrosis units. The fibrosis progression rate was higher in patients who acquired infection at > 30 years of age, those < 30 years (0.33 vs 0.15; P < 0.001), and those who acquired HCV infection with a history of blood transfusion than with other modes of transmission (0.25 vs 0.19; P = 0.04). The median time to progress to cirrhosis was 16 years. The multivariate analysis found that the HAI score (odds ratio [OR]= 14.03; P < 0.001) and the duration of infection > 10 years (OR = 4.83; P < 0.001) correlated with severe liver disease (fibrosis > or = 3). The median rate of fibrosis progression per year in Indian CHC patients is 0.25 fibrosis units. A higher HAI and longer duration of infection are associated with a significant risk of advanced liver disease, and merit early therapeutic interventions.


Systematic statistical comparison of comparative molecular similarity indices analysis molecular fields for computer-aided lead optimization.
Comparative molecular similarity indices analysis (CoMSIA) is a 3D quantitative structure-activity relationship technique used to determine structural and electronic features influencing biological activity. This proves particularly useful for facilitating lead optimization projects. This study aimed to compare CoMSIA models produced using different subsets of the CoMSIA molecular fields (steric, electrostatic, hydrophobic, hydrogen-bond donor, and hydrogen-bond acceptor) in a systematic and statistically valid manner. A total of 23 data sets sourced from the literature were used to compare molecular field contribution and model predictivity using leave-one-out cross-validated R2 values. Predictive ability varied in a highly statistically significant manner depending on the set of CoMSIA molecular fields used. In general, the greater the number of CoMSIA molecular fields included in the analysis, the better the model predictivity was. There is great redundancy in the information contained in the different CoMSIA molecular fields. When all five CoMSIA molecular fields are included, the hydrophobic and electrostatic fields had the largest and the steric field the smallest contribution. Data sets were clustered into four groups on the basis of the utility of molecular field sets to generate predictive models.


Significant changes in integrase-associated HIV-1 replication capacity between early and late isolates.
During the human immunodeficiency virus type 1 (HIV-1) pandemic, continuous, extensive genetic diversification of the virus has been observed. To study the effect of HIV-1 diversification on integrase-associated viral replication capacity (RC), 94 HIV-1 subtype B integrase sequences from two groups of antiretroviral-naive viruses isolated 15 y apart were amplified and recombined with an HIV-1 infectious clone. Viral RC was determined by infecting a T cell line with a long terminal repeat-driven green fluorescent protein reporter. Significant differences in integrase-mediated RC were observed between recombinant viruses from early and late isolates (p=0.0286). Integrases from late isolates had significantly lower sequence conservation scores compared to an ancestral subtype B sequence (p<0.0001). Integrase amino acid polymorphisms S17N, I72V, S119P, and D256E were associated with a lower ex vivo viral RC. These results suggest that integrase sequence diversification has affected ex vivo HIV-1 RC.


Diurnal changes in murine spermatogenesis.
We analysed testicular samples of NMRI mice every 2 h of a day in order to determine whether there is a circadian rhythm in spermatogenetic activity. We used flow cytometry after staining the DNA with DAPI. The highest proportion of DNA synthesizing cells (mainly spermatogonia and preleptotene spermatocytes) was seen at 8 p.m. and especially at 10 p.m.; the lowest proportion was observed at 2 p.m. At 6 a.m., the percentage of round spermatids increased significantly, whereas the fraction of 4c-cells decreased at that time. Our results of a diurnal rhythm of spermatogenic DNA synthesis rate are in contrast to another publication of other authors (Oakberg and Crosswait, 1983).


Carbonic anhydrase activators: an activation study of the human mitochondrial isoforms VA and VB with amino acids and amines.
The mitochondrial isozymes of human carbonic anhydrase (hCA, EC 188.8.131.52), hCA VA and hCA VB, were investigated for activation with a series of amino acids and amines. D-His, L-DOPA, histamine, dopamine, and 4-(2-aminoethyl)morpholine were excellent hCA VA activators, with KAs in the range of 10-130 nM. Good hCA VB activating effects were identified for L-His, D-Phe, D-DOPA, L-Trp, L-Tyr, serotonin, and 2-(2-aminoethyl)-pyridine, with KAs in the range of 44-110 nM. All these activators enhanced kcat, having no effect on KM, favoring thus the rate-determining step in the catalytic cycle, the proton transfer reactions between the active site and environment. The activation pattern of the two mitochondrial isoforms is very different from each other and as compared to those of the cytosolic isoforms hCA I and II.


Ultrahigh-throughput proteomics using fast RPLC separations with ESI-MS/MS.
We describe approaches for proteomics analysis using electrospray ionization-tandem mass spectrometry coupled with fast reversed-phase liquid chromatography (RPLC) separations. The RPLC separations used 50-microm-i.d. fused-silica capillaries packed with submicrometer-sized C18-bonded porous silica particles and achieved peak capacities of 130-420 for analytes from proteome tryptic digests. When these separations were combined with linear ion trap tandem mass spectrometry measurements, approximately 1000 proteins could be identified in 50 min from approximately 4000 identified tryptic peptides; approximately 550 proteins in 20 min from approximately 1800 peptides; and approximately 250 proteins in 8 min from approximately 700 peptides for a S. oneidensis tryptic digest. The dynamic range for protein identification with the fast separations was determined to be approximately 3-4 orders of magnitude of relative protein abundance on the basis of known proteins in human blood plasma analyses. We found that 55% of the MS/MS spectra acquired during the entire analysis (and up to 100% of the MS/MS spectra acquired from the most data-rich zone) provided sufficient quality for identifying peptides. The results confirm that such analyses using very fast (minutes) RPLC separations based on columns packed with microsized porous particles are primarily limited by the MS/MS analysis speed.


[Waste of resources as a result of cancelled or delayed diagnostic imaging of hospitalized patients].
When diagnostic imaging is cancelled on short notice or an examination is delayed, the Imaging Department suffers a loss. Based on voluntary reporting of such events, we have estimated the total expenditure involved. For one year an orderly reported cases in which, when he arrived to fetch an inpatient, the latter was no longer in the ward or was not ready. From this study material we estimated the waste of time for the staff and the total price of cancelled or delayed examinations, spread over various categories. This sum is related to the estimated cost of one preventive measure: letting the orderly check in the hospital's electronic administrative system whether the patient is still in the ward indicated. A total of 436 cancelled or delayed examinations were reported in 2004. In 249 cases the examination was cancelled, and since the recorded total number of cancellations was 1,435, we estimate the total number of cancelled or delayed exams to be approximately 2,500 (1,435 x 436/249). The estimated total waste of time is 66 weeks (1(1/2) years' work). The estimated price of the cancelled or delayed examinations is 2.4 million Danish kroner. When we relate the savings if the problem is solved to the cost of prevention, we find that it would be clearly profitable to address fluoroscopy and CT scanning. Conversely, addressing bone X-rays would generate a loss. We conclude that there is a very large waste of resources caused by cancelled or delayed imaging examinations.


Still acting green: continued expression of photosynthetic genes in the heterotrophic Dinoflagellate Pfiesteria piscicida (Peridiniales, Alveolata).
The loss of photosynthetic function should lead to the cessation of expression and finally loss of photosynthetic genes in the new heterotroph. Dinoflagellates are known to have lost their photosynthetic ability several times. Dinoflagellates have also acquired photosynthesis from other organisms, either on a long-term basis or as "kleptoplastids" multiple times. The fate of photosynthetic gene expression in heterotrophs can be informative into evolution of gene expression patterns after functional loss, and the dinoflagellates ability to acquire new photosynthetic function through additional endosymbiosis. To explore this we analyzed a large-scale EST database consisting of 151,091 unique sequences (29,170 contigs, 120,921 singletons) obtained from 454 pyrosequencing of the heterotrophic dinoflagellate Pfiesteria piscicida. About 597 contigs from P. piscicida showed significant homology (E-value <e(-30)) with proteins associated with plastid and photosynthetic function. Most of the genes involved in the Calvin-Benson cycle were found, genes of the light-dependent reaction were also identified. Also genes of associated pathways including the chorismate pathway and genes involved in starch metabolism were discovered. BLAST searches and phylogenetic analysis suggest that these plastid-associated genes originated from several different photosynthetic ancestors. The Calvin-Benson cycle genes are mostly associated with genes derived from the secondary plastids of peridinin-containing dinoflagellates, while the light-harvesting genes are derived from diatoms, or diatoms that are tertiary plastids in other dinoflagellates. The continued expression of many genes involved in photosynthetic pathways indicates that the loss of transcriptional regulation may occur well after plastid loss and could explain the organism's ability to "capture" new plastids (i.e. different secondary endosymbiosis or tertiary symbioses) to renew photosynthetic function.


Vulnerability of the northern Mongolian steppe to climate change: insights from flower production and phenology.
The semiarid, northern Mongolian steppe, which still supports pastoral nomads who have used the steppe for millennia, has experienced an average 1.7 degrees C temperature rise over the past 40 years. Continuing climate change is likely to affect flowering phenology and flower numbers with potentially important consequences for plant community composition, ecosystem services, and herder livelihoods. Over the growing seasons of 2009 and 2010, we examined flowering responses to climate manipulation using open-top passive warming chambers (OTCs) at two locations on a south-facing slope: one on the moister, cooler lower slope and the other on the drier, warmer upper slope, where a watering treatment was added in a factorial design with warming. Canonical analysis of principal coordinates (CAP) revealed that OTCs reduced flower production and delayed peak flowering in graminoids as a whole but only affected forbs on the upper slope, where peak flowering was also delayed. OTCs affected flowering phenology in seven of eight species, which were examined individually, either by altering the time of peak flowering and/or the onset and/or cessation of flowering, as revealed by survival analysis. In 2010, which was the drier year, OTCs reduced flower production in two grasses but increased production in an annual forb found only on the upper slope. The particular effects of OTCs on phenology, and whether they caused an extension or contraction of the flowering season, differed among species, and often depended on year, or slope, or watering treatment; however, a relatively strong pattern emerged for 2010 when four species showed a contraction of the flowering season in OTCs. Watering increased flower production in two species in 2010, but slope location more often affected flowering phenology than did watering. Our results show the importance of taking landscape-scale variation into account in climate change studies and also contrasted with those of several studies set in cold, but wetter systems, where warming often causes greater or accelerated flower production. In cold, water-limited systems like the Mongolian steppe, warming may reduce flower numbers or the length of the flowering season by adding to water stress more than it relieves cold stress.


[Factors influencing quality of life in married immigrant women in Korea].
The purpose of this study was to identify the factors influencing quality of life of married immigrant women in Korea. The participants included 508 married immigrant women who met the eligibility criteria and agreed to participate in the study. Participants were evaluated for subjective assessment of married immigrant-related constructs using a self-report questionnaire, for self-esteem, self-efficacy, and quality of life (QOL). The analysis was done using SPSS for Windows, version 10.1, and included stepwise regression. The major findings were as follows; 1) There were significant relationships between marital satisfaction (r=.39, p=.001), violence by the husband during the couple's arguments (r= -.24, p<.001), satisfaction with life in Korea (r=.39, p<.001), self-esteem (r=.16, p<.001), self-efficacy (r=.51, p<.001) and quality of life. 2) Marital satisfaction, self-efficacy, education level and satisfaction life with in Korea were significant factors, which explained 53% of the variance in quality of life (F=43.97, p<.001). Multiple regression analysis revealed that a powerful predictor of QOL for married immigrant women was self-efficacy. Developing nursing interventions to enhance self-efficacy toward improvement of QOL among married immigrant women is recommended.


Apical root resorption due to orthodontic treatment detected by cone beam computed tomography.
To determine the frequency of apical root resorption (ARR) due to orthodontic treatment using cone beam computed tomography (CBCT) in a sample of 1256 roots from 30 patients. All patients had Class I malocclusion with crowding. Of the 30 patients evaluated, 11 were boys and 19 were girls; their mean age was 13 years (11 to 16 years). Orthodontic treatment followed the nonextraction treatment. CBCT images were obtained before and after orthodontic treatment, and ARR was determined using Axial Guided Navigation of CBCT images. All patients had ARR. No statistically significant association was found between resorption frequency, gender, and age. ARR was detected using CBCT in 46% of all roots that underwent orthodontic treatment. CBCT was effective for detecting in vivo even minimal degrees of ARR due to orthodontic treatment and allowed three-dimensional evaluation of dental roots and visualization of palatine roots of maxillary molars. The highest frequencies and the most significant ARR occurred in incisors and distal roots of first maxillary and mandibular molars.


A narrative review of anastomotic leak in the Ivor Lewis esophagectomy: expected, accepted, but preventable.
Anastomotic leak (AL) remains a common and highly morbid complication after Ivor Lewis Esophagectomy. Leak is associated with increased morbidity, mortality, strictures and even cancer recurrence. Unfortunately, despite advances in surgical technique and perioperative care, the reported frequency of AL has remained largely unchanged. A PubMed search for all English-language articles that discuss Ivor Lewis esophagectomy, AL, risk factors, and outcomes was conducted from 1901 to 2023 prioritizing research from randomized trials that evaluated outcomes from patients undergoing esophagectomy. This narrative review will discuss the prevailing literature on AL, risk factors and outcomes with a focus on its relationship to the Ivor Lewis esophagectomy (ILE). In particular, we emphasize that the gastric conduit, as commonly created for most esophagectomy procedures, is inherently vulnerable to ischemia. We will show trends in the literature that have contributed to the high rate of postoperative complications, with a focus on the AL. In addition, we propose that the traditional Ivor Lewis procedure itself is a risk factor for AL. We review a surgical alternative that increases blood supply of the conduit, and is associated with reduced leak, no strictures, and improved surgical outcomes. Multiple factors contribute to AL after esophagectomy; including several current surgical practices. We believe that some of them, especially the commonly accepted approach to the gastric conduit, can be modified to optimize tissue perfusion. With further investigation, we may reduce the incidence of short and long-term anastomotic complications and improve surgical outcomes.


Lateral Compartment Contact Pressures Do Not Increase After Lateral Extra-articular Tenodesis and Subsequent Subtotal Meniscectomy.
Modified Lemaire lateral extra-articular tenodesis (LET) has been proposed as a method of addressing persistent anterolateral rotatory laxity after anterior cruciate ligament (ACL) reconstruction (ACLR). However, concerns remain regarding the potential for increasing lateral compartment contact pressures. To investigate changes in tibiofemoral joint contact pressures after isolated ACLR and combined ACLR plus LET with varying states of a lateral meniscal injury. Controlled laboratory study. Eight fresh-frozen cadaveric knee specimens (mean age, 60.0 ± 3.4 years) were utilized for this study, with specimens potted and loaded on a materials testing machine. A pressure sensor was inserted into the lateral compartment of the tibiofemoral joint, and specimens were loaded at 0°, 30°, 60°, and 90° of flexion in the following states: (1) baseline (ACL- and anterolateral ligament-deficient), (2) ACLR, (3) ACLR with LET, (4) partial meniscectomy (removal of 50% of the posterior third of the lateral meniscus), (5) subtotal meniscectomy (removal of 100% of the posterior third of the lateral meniscus), and (6) LET release (LETR). Mean contact pressure, peak pressure, and center of pressure were analyzed using 1-way repeated-measures analysis of variance. Across all flexion angles, there was no statistically significant increase in the mean contact pressure or peak pressure after ACLR plus LET with and without lateral meniscectomy compared with isolated ACLR. There was a significant reduction in the mean contact pressure, from baseline, after subtotal meniscectomy (69.72% ± 19.27% baseline; P = .04) and LETR (65.81% ± 13.40% baseline; P = .003) at 0° and after the addition of LET to ACLR at 30° (61.20% ± 23.08% baseline; P = .031). The center of pressure was observed to be more anterior after partial (0°, 30°) and subtotal (0°, 60°) meniscectomy and LETR (0°, 30°, 60°). Under the loading conditions of this study, LET did not significantly alter lateral compartment contact pressures when performed in conjunction with ACLR in the setting of an intact or posterior horn-deficient lateral meniscus. This study should provide surgeons with the confidence that it is safe to perform LET in this manner in conjunction with ACLR without altering lateral compartment pressures, regardless of the status of the lateral meniscus.


[Traveling instructions for a voyage into the French scientific expeditions (1750-1830)].
At the turn of the eighteenth and nineteenth centuries, the literature of travel instructions increased greatly. This literature expresses the expectations of naturalists, the scientific community and government with respect to knowledge and use of natural products from exotic lands. As far as texts relating to natural history are concerned, the research priorities emphasized, the methodology proposed and the audience to which they were directed make it clear that expeditions were conceived as an essential but not final stage of scientific investigation. Indeed, the requirements voiced in these instructions show that the appraisal of the data gathered was to be carried out within French research institutions and botanical gardens.


Antihypertensive drugs and sodium restriction. Analysis of their interaction based on pressure-natriuresis relationship.
The hypotensive effects of some antihypertensive drugs are augmented under sodium restriction, while those of others are not. The mechanisms of these interactions were theoretically analyzed based on the arterial pressure-natriuresis relationship. Four-week studies were performed in 24 patients with essential hypertension who were given a regular sodium diet (12-15 g of NaCl/d) in the first and third weeks and a sodium-restricted diet (1-3 g/d) in the second and fourth weeks. One of three antihypertensive drugs, 60 mg/d of nicardipine (Ca-antagonist), 120 mg/d of propranolol (beta-blocker) or 150 mg/d of captopril (converting-enzyme inhibitor) was administered in the third and fourth weeks. The mean arterial pressure and urinary sodium excretion were measured on the last three days of each week. The degree of interaction between the antihypertensive drugs and sodium restriction was statistically compared. The hypotensive effect of nicardipine and propranolol did not differ with the change in sodium intake, whereas that of captopril was greater under sodium restriction than under the regular sodium diet. Urinary sodium excretion was plotted on the ordinate as a function of arterial pressure before and after administration of the antihypertensive drugs. The pressure-natriuresis curve was shifted left, without a change in the slope, by nicardipine and propranolol and also left, but with a decrease in the slope, by captopril. The hypotensive effect of nicardipine and propranolol, being independent of the amount of sodium intake, was based on the leftward shift of the pressure-natriuresis curve that was probably due to the decrease in renal vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)


Pathogenesis of cholesterol gallstones.
Symptomatic cholesterol gallstone disease occurs because of the combination of a number of biochemical and physiologic defects: formation of supersaturated bile, nucleation, crystal retention, stone growth, and gallbladder inflammation. There are several possible explanations for the high prevalence of supersaturated bile in the Western adult human as compared to other adult mammals. First, the human liver is defective in converting cholesterol to bile acids; the majority of cholesterol is eliminated as cholesterol. Second, the large flux of cholesterol in vesicular form is not matched by a large flux of recycling bile acids. Third, humans live sedentary lives and voluntarily reduce their caloric requirement to prevent obesity. Low caloric intake decreases the circulation of bile acids (including the flux through the hepatocyte). Fourth, the human species is a defective bile secretor in terms of biliary volume (microliter/kg-min) compared to other mammals. This is because human enterohepatic circulation of bile acids is "sluggish" and because bile acid-independent flow is also lower than in all other mammals. The accumulation of deoxycholic acid, a secondary bile acid formed in the colon, appears to cause secretion of bile that is supersaturated in cholesterol, and may also contribute. Five additional risk factors explain why cholesterol gallstone disease is so prevalent. First, the human species has a gallbladder, and the irregular meal pattern of humans may be responsible for prolonged storage of bile. Second, bile from cholesterol gallstone patients nucleates cholesterol more rapidly. Third, defective gallbladder contraction is associated with cholesterol gallstone disease in the majority of gallstone patients. Fourth, the healthy gallbladder absorbs cholesterol and desaturates bile--protective functions that may be lost with chronic cholecystitis. Finally, the presence of gallstones stimulates mucous secretion, which traps cholesterol crystals.


Structural Pharmacokinetics of Polymethoxylated Flavones in Rat Plasma Using HPLC-MS/MS.
The purpose of this study was to investigate the pharmacokinetics of the polymethoxylated flavonoids kumatakenin, pachypodol, and retusin, which contain two, three, or four methoxy substitutions, using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method in rats. The pharmacokinetic results demonstrated that the elimination half-lives for kumatakenin, pachypodol, and retusin were 30 ± 11.6, 39.4 ± 19.5, and 106.9 ± 26 min, respectively, for the low dose group and 54.5 ± 16.5, 33.8 ± 10, and 134.6 ± 34.7 min for the high dose group. The results suggested that the area under the curve values (AUC) for the analytes did not correlate with the number of methoxy groups. Pachypodol had the lowest AUC, which may have been correlated with lipophilicity, for both the low and high dose groups. In conclusion, the polymethoxylated flavonoid pachypodol is more hydrophilic than kumatakenin or retusin, which were correlated with the pharmacokinetic results.


Immunoglobulin M and G antibody response to type- and subtype-specific antigens after primary and secondary exposures of mice to influenza A viruses.
A mouse model of influenza infection was studied to help define parameters that may affect serodiagnosis of human infections by immunoassays. Antibodies to both type- and subtype-specific influenza A antigens were measured by a solid-phase immunofluorometric assay. Dilute mouse sera were added to purified influenza virus that had been covalently bound to polyaminostyrene microbeads, and the bound antibody was detected by fluorescein isothiocyanate-labeled isotype-specific antisera. Results were consistent in that upon exposure of mice by either infection alone or by vaccination after infection, both immunoglobulin M (IgM) and IgG antibodies reactive with newly encountered subtype specific viral antigens were measured. IgG antibody was usually detectable by the solid-phase immunofluorometric assay several days before it could be detected by a hemagglutination inhibition test. Increased levels of antibody of the IgG1, IgGa, IgG2b, and IgG3 subclasses were also measured during influenza infection. Surprisingly, response to type-specific viral antigens was of the IgG class in primary as well as in secondary exposure. The results suggest that for serodiagnosis of influenza infections by detection of specific IgM antibody, the assay should use subtype-specific antigens.


[Antioxidase activities and photosynthetic pigment contents in Larix principis-rupprechtii leaves along an altitudinal gradient].
To study the physiological mechanisms in environment adaptation of alpine trees, the antioxidase activities and photosynthetic pigment contents in Larix principis-rupprechtii leaves along an altitudinal gradient from 1 600 m to 2 800 m at Pangquangou National Nature Reserve were investigated. The results showed that the superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities in L. principis-rupprechtii leaves had the same change pattern along the altitudinal gradient, i. e. , relatively lower at middle altitude (1 900-2 400 m) and relatively higher at lower (1 600-1 800 m) and higher altitudes (2 500-2 800 m). Comparing with those at middle altitude, the SOD, POD and CAT activities were 62.79%, 42.13% and 7.87% higher at lower altitude and 75.20%, 14.49% and 63.38% higher at higher altitude, respectively, but decreased at the altitude near the upper limit of forest vertical distribution. At lower and higher altitudes, malondialdehyde (MDA) content was up to 9.27 and 14.06 micromol x g(-1) FM, respectively, while at middle altitude, it was 5.58 micromol x g(-1) FM on average. Chlorophyll and carotinoid contents tended to decrease with increasing altitude, while chlorophyll a/b ratio and relative carotinoid content (Car/ Chl) were in adverse, with the relative coefficients being -0.969 and -0.986, and 0.962 and 0.877, respectively.


A stage is a stage is a stage: a direct comparison of two scoring systems.
L. Kohlberg (1969) argued that his moral stages captured a developmental sequence specific to the moral domain. To explore that contention, the author compared stage assignments obtained with the Standard Issue Scoring System (A. Colby & L. Kohlberg, 1987a, 1987b) and those obtained with a generalized content-independent stage-scoring system called the Hierarchical Complexity Scoring System (T. L. Dawson, 2002a), on 637 moral judgment interviews (participants' ages ranged from 5 to 86 years). The correlation between stage scores produced with the 2 systems was .88. Although standard issue scoring and hierarchical complexity scoring often awarded different scores up to Kohlberg's Moral Stage 2/3, from his Moral Stage 3 onward, scores awarded with the two systems predominantly agreed. The author explores the implications for developmental research.


Aerobic fungal cell immobilization in a dual hollow-fiber bioreactor: Continuous production of a citric acid.
Aspergillus niger B60 was immobilized in a dual hollow-fiber bioreactor (DHFBR) to produce citric acid continuously. The fungi proliferated well in the interstitial region formed by a parallel arrangement of three microporous polypropylene hollow fibers contained within a silicone tube. Long-term operation with nitrogen-enriched medium was not possible due to expansion of the silicone tubes by continual cell growth. The fungal growth could be controlled by supplying a nitrogen-deficient medium at the production stage. With pure oxygen aeration and nitrogen-deficient medium, volumetric productivity reached 1.62 g/L h at a residence time of 4.02 h, which corresponded to a 27-fold increase over that of shake-flask fermentation. When the residence time was increased to 20.1 h, citric acid at a concentration of 26 g/L was continuously produced, with a yield of 80-90% and a volumetric productivity of 1.3 g/L h. This represents a significant improvement in final concentration, yield, and the volumetric productivity over the equivalent values of the corresponding batch fermentation, which were 18 g/L, 40%, and 0.06 g/L h, respectively.


Metalloproteases with EGF, CUB, and thrombospondin-1 domains function in molting of Caenorhabditis elegans.
Functional analysis using RNAi was performed on eleven genes for metalloproteases of the M12A family in Caenorhabditis elegans and the interference of the C17G1.6 gene (nas-37) was found to cause incomplete molting. The RNAi of the C26C6.3 gene (nas-36) also caused a similar molting defect but not so severely as that of the nas-37 gene. Both the genes encode an astacin-like metalloprotease with an epidermal growth factor (EGF)-like domain, a CUB domain, and a thrombospondin-1 domain, in this order. The promoter-driven green fluorescent protein (GFP) expression analysis suggested that they are expressed in hypodermal cells throughout the larval stages and in the vulva of adult animals. In the genetic background of rde-1(ne219), where RNAi does not work, the molting defect caused by the nas-37 interference was observed when the transgenic wild-type rde-1 gene was expressed under the control of the dpy-7 promoter, known to be active in the hypodermal cells, but not under the control of the myo-3 promoter, active in the muscular cells. Therefore these proteases are thought to be secreted by the hypodermal cells and to participate in shedding of old cuticles.


Radiolabeled alpha-melanocyte-stimulating hormone analogs for receptor-mediated targeting of melanoma: from tritium to indium.
Following the first synthesis of tritiated alpha-melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin) in 1974 by Medzihradszky et al., several alpha-MSH analogs were designed containing between 2 and 12 tritium atoms, the latter of which displayed a specific radioactivity of 12.21 GBq/micromol (330 Ci/mmol). Similarly, radioiodinated alpha-MSH analogs of high purity, full biological activity and a specific radioactivity of approximately 140 GBq/micromol were obtained. Although tritiated and radioiodinated alpha-MSH became indispensable tools as tracer molecules for numerous in vitro and in vivo studies, above all for receptor identification and characterization as well as for structure-activity studies, they did not fulfill the criteria required for therapeutic in vivo targeting of metastatic melanoma. Therefore, we recently developed alpha-MSH analogs containing the universal metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in different positions of the molecule. As DOTA can equally well incorporate diagnostic (e.g. (111)In, (67,68)Ga) and therapeutic (e.g. (90)Y, (67)Cu) radionuclides, DOTA-MSH compounds may serve for both melanoma scintigraphy and therapy. The analog DOTA-[betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (DOTA-MSH(OCT)), which contains the metal chelator at its N-terminal end, displayed good in vitro MC1R affinity (IC(50) 9.21 nm). In vivo, [(111)In]DOTA-MSH(OCT) exhibited a favorable biodistribution profile after injection in B16-F1 tumor-bearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [(111)In]DOTA-MSH(OCT). A comparative study of [(111)In]DOTA-MSH(OCT) with [(111)In]DOTA-[Nle(4), D-Phe(7)]-alpha-MSH ([(111)In]DOTA-NDP-MSH) demonstrated the superiority of the DOTA-MSH(OCT) peptide, particularly with respect to the amount of radioactivity taken up by non-malignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [(111)In]DOTA-MSH(OCT) specifically targets melanoma metastases and represents a lead compound for the development of therapeutic DOTA-MSH analogs.


Transfer RNA is a substrate for RNase D in vivo.
RNase D is a 3'-exonuclease whose in vitro specificity has suggested a role in tRNA processing. However, since mutant Escherichia coli strains devoid of RNase D display a normal phenotype, it has not been possible to ascertain the enzyme's function or even to determine which RNA is its substrate in vivo. Here we show that transformation of strains devoid of tRNA nucleotidyltransferase with a multicopy plasmid carrying the rnd+ gene leads to extremely slow growth due to elevated levels of RNase D activity. Analysis of such a slow-growing strain revealed that less tRNA is present in the cell and that the tRNA that could be recovered is substantially damaged. These studies demonstrate that RNase D can act at the 3' terminus of tRNA in vivo, and they support the conclusion that RNase D participates in tRNA metabolism.


Fletcher factor deficiency, source of variations of the activated partial thromboplastin time test.
The activated partial thromboplastin time test measures the integrity of the intrinsic clotting system. The sensitivity of this test to Fletcher factor deficiency is dependent upon the particular protocol and reagents utilized in the test system. The case report presented here demonstrates conflicting laboratory results obtained for a patient who had Fletcher factor deficiency, the results depending on the laboratory choice of test reagents. This serves to emphasize the importance of physician awareness of the procedures utilized in laboratory testing.


Overweight & obese Australian adults and micronutrient deficiency.
Micronutrients have been implicated as an important factor in regulating various metabolic processes and thus playing a role in the aetiology of obesity. Many studies have been conducted worldwide that clearly show a direct link between obesity and micronutrient deficiencies. The aim of this study was to assess the nutritional status of overweight and obese Australian adults to see if there were any associations between BMI and serum micronutrient levels. Baseline serum micronutrient data of overweight and obese individuals with a body mass index (BMI) between 25 and 40 kg/m2 and aged between 18 and 65 years was compared to the clinical micronutrient reference ranges for associations between BMI and micronutrient status. There were significant negative associations between BMI and serum vitamin D (p = 0.044), folate (p = 0.025), magnesium (p = 0.010) and potassium (p = 0.023). Overweight and obesity appears to impact on the bioavailability and utilisation of micronutrients with absorption, excretion, storage/distribution (fat sequestering, tissue dispersion), metabolism (catabolic losses, possibly oxidative), increased physiologic requirements, and lower absolute total dietary intake being the current theory for observed differences. While vitamins D, folate, magnesium and potassium showed a negative relationship to BMI, other micronutrients did not. This may be explained by the fortification of certain processed foods, or the possibility of overweight and obese people eating more to satisfy their nutritional requirements.


The microstructural, melting, rheological, and sensorial properties of high-overrun frozen desserts.
Air incorporated during dynamic freezing influences the development of the microstructure and the final texture of frozen desserts. Frozen desserts were manufactured with 100-175% overrun from a constant ice cream mix formulation. Microstructural elements (fat, air, and ice phases) of the frozen desserts were then investigated and related to the melting, rheological, and sensory properties of the product. Mean ice crystal and air cell size were found to decrease with increasing overrun, and the extent of fat destabilization increased. Frozen desserts manufactured with higher overrun had slower drip-through rate and better shape retention after melting at ambient conditions, demonstrating that fat destabilization and the interplay of fat, air, and serum phases affect the melting behavior. Structural elements also influenced the rheological behavior, as measured by oscillatory thermo-rheometry. Frozen desserts had similar rheological properties at temperatures below the freezing point due to the presence of ice, and the values of G' and G″ (solid-like and viscous-like character, respectively) increased with increasing overrun above the freezing point, corresponding to a more solid-like structure. Slight differences in sensory denseness and breakdown were detected, but sensory texture was not significantly different for the frozen desserts studied. This study provided insights into the role of air in ice cream and frozen desserts, and its influence on product texture.


Uniquely women's issues in colorectal cancer screening.
Colorectal cancer (CRC) is the third most common cause of cancer in women. Screening has been shown to increase detection and decrease morbidity from this disease, but compliance is poor. This paper reviews special considerations for determining screening intervals in women, factors making screening more difficult in women, and studies reviewing preventative strategies in addition to screening that may reduce CRC.


A novel principled method for the measurement of vascular robustness uncovers hidden risk for premature CVD death.
The detection of high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor scores is a major challenge. Systems biology suggests that the vasculature's functional robustness against risk factor challenges may serve as a novel discriminator of mortality risk under similar risk factor loads. However, principled methods to measure vascular robustness are not available. To develop a score for the vasculature's functional robustness we used a recently presented method that applies computational physiological modeling to the quantitation of vascular function. We hypothesized that the expected inverse robustness-mortality association is verifiable as a significant robustness-calendar age trend in a cross-sectional investigation of a population cohort of risk factor-challenged individuals. Using only functional parameters of the cardiovascular system we applied multivariate linear regression to derive from our study population of 372 adults gender-specific multivariate robustness scoring algorithms. For any individual, the deviation of his/her robustness score from the value of the regression function characterizes the deviation of the individual's fatal CVD event probability from its age-appropriate fatal CVD event probability. Robustness correlated linearly with calendar age in our risk factor-challenged but not in our unchallenged cohorts. This observation supports the hypothesis of preferential elimination of less robust individuals along the aging trajectory under risk factor challenges. We conclude that physiologically principled scoring for vascular robustness may serve as a biomarker of vulnerability to CVD risk factor challenges, prognosticating otherwise undetectable elevated risk for premature CVD mortality. NEW & NOTEWORTHY We developed a principled method for the derivation of a vascular robustness score that we translated into a correction factor for calendar age. We demonstrated the score's potential to uncover risk for premature cardiovascular death in apparently healthy young adults whose risk elevation remains hidden in conventional risk factor models.


Role of heme-hemopexin in human T-lymphocyte proliferation.
Heme-hemopexin supports and stimulates proliferation of human acute T-lymphoblastic (MOLT-3) cells, suggesting the participation of heme in cell growth and division. MOLT-3 cells express approximately 58,000 hemopexin receptors per cell (apparent Kd 20 nM), of which about 20% are on the cell surface. Binding is dose- and temperature-dependent, and growth in serum-free IMDM medium is stimulated by 100-1000 nM heme-hemopexin, consistent with the high affinity of the receptor for hemopexin, and maximal growth is seen in response to 500 nM complex. Growth was similar in defined minimal medium supplemented with either low concentrations of heme-hemopexin or iron-transferrin, and either of these complexes were about 80% as effective as a serum supplement. Heme-hemopexin, but not apo-hemopexin, reversed the growth inhibition caused by desferrioxamine showing that heme-iron derived from heme catabolism is used for cell growth. Cobalt-protoporphyrin (CoPP)-hemopexin, which binds to the receptor but is not transported intracellularly [Smith et al., (1993) J. Biol. Chem. 268, 7365], also stimulated cell proliferation in serum-free IMDM but did not "rescue" the cells from desferrioxamine. Furthermore, CoPP-hemopexin effectively competed for the hemopexin receptor with heme-hemopexin and diminished its growth stimulatory effects. In addition, protein kinase C (PKC) is translocated to the plasma membrane within 5 min after heme-hemopexin is added to the medium, reaches maximum activity within 5-10 min, and declines to unstimulated levels by 30 min. Heme-hemopexin and CoPP-hemopexin both augmented MOLT-3 cell growth stimulated by serum. Thus, heme-hemopexin not only functions as an iron source for T-cells but occupancy of the hemopexin receptor itself triggers signaling pathway(s) involved in the regulation of cell growth. The stimulation of growth of human T-lymphocytes by heme-hemopexin is likely to be a physiologically relevant mechanism at sites of injury, infection, and inflammation.


Basal Joint Arthroplasty and Radial-sided Carpal Tunnel Release Using a Single Incision.
The purpose of our study was to determine in vivo outcomes and consistency of relief of symptoms attributable to carpal tunnel syndrome in patients who underwent radial-sided carpal tunnel release in conjunction with basal joint arthroplasty through a single incision. A retrospective chart review identified all patients who had undergone radial-sided carpal tunnel release in combination with basal joint arthroplasty at 1 institution from February 2011 through April 2014. Both preoperative and postoperative symptoms attributable to carpal tunnel syndrome were documented. Patient outcomes were assessed using the QuickDASH (Disabilities of the Arm, Shoulder, and Hand) questionnaire. The mean length of follow-up was 16 months (range, 2 to 37 mo). Eight patients (7 women; 10 extremities) were available for follow-up. There was complete resolution of all symptoms attributable to carpal tunnel syndrome in 9 of 10 extremities. There was complete relief of paresthesias in the remaining extremity (and the patient reported complete relief of night waking), as well as improvement but not resolution of hypoesthesia and pain. Radial-sided carpal tunnel release performed with basal joint arthroplasty through a single incision provided reliable improvement or resolution of carpal tunnel syndrome symptoms.


Immunologic dysfunction in the myeloproliferative disorders.
Forty patients with various types of myeloproliferative disorders were evaluated immunologically. Serum immunoglobulin levels were within the normal range in most patients and no monoclonal gammopathies were detected. Serum C'3 levels were decreased in 19 of 40 (48%) patients. The response of peripheral blood lymphocytes to phytohemagglutinin was decreased in 26 of 40 (65%) and to pokeweed mitogen in 18 of 28 (64%) patients studied. Lymphocytes from patients with polycythemia vera were least affected. Unstimulated lymphocytes from some patients demonstrated markedly increased thymidine uptake activity. Despite the diminished mitogenic response, only 2 of 33 patients (6%) were anergic by intradermal skin testing. There was no association between depressed lymphocyte response and recent chemotherapy except in chronic myelogenous leukemia where 6 of 8 patients were receiving cytotoxic therapy when studied. These observations suggest that most of our patients with myeloproliferative disorders have abnormal cellular responses in vitro, but that delayed hypersensitivity and humoral responses are minimally affected.


Aggregation induced emission of diketopyrrolopyrrole (DPP) derivatives for highly fluorescent red films.
A large number of diketopyrrolopyrrole (DPP) compounds showing aggregation induced emission (AIE) have been reported in the past few years. However, although DPP compounds exhibited AIE and excellent luminescence properties, their luminescence properties in solid or film states were not much focused on. Here we synthesized and characterized a series of DPP compounds with triphenylamine (TPA) moieties to investigate the AIE properties in the solid film state depending on the functional groups (TPA, BTPA, and MTPA) attached to the TPA moieties. T2 and D2 thin films showed excellent fluorescence quantum yields of 31% and 26%, respectively, compared to an M2 thin film (9%). The restriction of an intramolecular rotation process could inhibit the aggregation induced quenching process and play a key role in achieving highly fluorescent molecules in the solid state.


The effect of concentrate supplement type on milk production, nutrient intake, and total-tract nutrient digestion in mid-lactation, spring-calving dairy cows grazing perennial ryegrass (Lolium perenne L.) pasture.
The objective of this study was to evaluate the effect of concentrate supplement type on milk production, nutrient intake, and total-tract nutrient digestion in lactating dairy cows grazing mid-season perennial ryegrass (Lolium perenne L.; PRG) pasture. Twelve primiparous (mean ± standard deviation; 95 ± 30 d in milk and 470 ± 43 kg of body weight) and 68 multiparous (99 ± 24 d in milk and 527 ± 64 kg of body weight) lactating dairy cows were blocked based on pre-study milk yield and parity and randomly assigned to 1 of 4 dietary treatments. The 4 dietary treatments were a non-supplemented PRG control (PRG); PRG supplemented with 4.4 kg of dry matter (DM) per cow per day of citrus pulp and 0.067 kg of DM/cow per day of urea (PRG+C); PRG supplemented with 0.8 kg of DM/cow per day of heat-treated soybean meal (PRG+PP); and PRG supplemented with 3.1 kg of DM/cow per day of a combination of heat-treated soybean meal and citrus pulp (PRG+C+PP). The study consisted of a 2-wk adaptation period and a 10-wk period of data collection. Weekly measurements of milk yield, body weight, body condition score, and feeding and rumination time were made. Nutrient intake and total-tract digestibility were measured during wk 6 of the study. A large soil moisture deficit was experienced during the study that probably reduced herbage growth rate and likely altered the chemical composition of the PRG offered when compared with typical mid-season PRG. Total dry matter intake was increased in cows fed PRG+C compared with cows fed PRG and PRG+PP and was similar to cows fed PRG+C+PP (18.0, 15.9, 16.4, and 17.2 ± 0.41 kg of DM/d, respectively). The apparent total-tract neutral detergent fiber digestibility of cows fed the PRG+C diet was lower compared with the PRG and PRG+PP diets and was similar to the PRG+C+PP diet (0.67, 0.70, 0.70, and 0.69 ± 0.01 g/g, respectively). The energy-corrected milk (ECM) yield of cows fed PRG+C+PP was highest (23.7 kg/d), PRG+C was intermediate (22.2 kg/d), and PRG was lowest (20.8 kg/d). Cows fed PRG+PP produced more ECM (22.9 kg/d) compared with cows fed PRG and produced similar ECM compared with cows fed PRG+C and PRG+C+PP diets. The PRG+PP diet increased milk protein yield compared with the PRG diet, tended to increase milk protein yield compared with the PRG+C diet, and was similar to the PRG+C+PP diet. Milk fat concentration and the composition of milk fat were not influenced by treatment. The results demonstrated that, for cows consuming pasture-based diets, increasing metabolizable protein supply allowed higher milk yield as metabolizable protein was more limiting than metabolizable energy. However, due to the large soil moisture deficit experienced during this experiment, caution is recommended when extrapolating these results to cows consuming typical mid-season PRG herbage.


Conducting polymer transistors making use of activated carbon gate electrodes.
The characteristics of the gate electrode have significant effects on the behavior of organic electrochemical transistors (OECTs), which are intensively investigated for applications in the booming field of organic bioelectronics. In this work, high specific surface area activated carbon (AC) was used as gate electrode material in OECTs based on the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(styrenesulfonate) (PSS). We found that the high specific capacitance of the AC gate electrodes leads to high drain-source current modulation in OECTs, while their intrinsic quasi-reference characteristics make unnecessary the presence of an additional reference electrode to monitor the OECT channel potential.


[Physical activity during pregnancy--facts and practical guidelines].
Physical activity during pregnancy is known to have a positive effect on both the mother and the fetus/newborn, as long as there are no specific contraindications relating to maternal pathology. Physical activity during pregnancy is known to be associated with reduced incidence of several gestational pathologies, as well as boosting physical and mental capabilities. Furthermore, a positive effect was found in newborns whose mothers continued their physical activity habits throughout pregnancy. Nevertheless, the intensity and duration, and specifically their efforts against resistance, have not been adequately emphasized. Herein, we review the main recent findings and insights on physical activity during pregnancy, and provide a practical set of recommendations.


Cumulative Effect of Cardiovascular Risk Factors on Regulation of AMPK/SIRT1-PGC-1α-SIRT3 Pathway in the Human Erectile Tissue.
Cardiovascular disease risk factors (CVDRF), especially diabetes mellitus (DM), disrupt oxidative stress response. This condition underlies endothelial dysfunction, early manifested in men as erectile dysfunction. The current study is aimed at elucidating the impact of CVDRF in the oxidation responsive AMPK/SIRT1-PGC-1α-SIRT3 pathway and related miRNAs in the human corpus cavernosum. Human penile tissue fragments from individuals submitted to programmed urological surgeries (n = 27), aged 43-63 years, were clustered depending on the presence of CVDRF; the control group included samples from patients without CVDRF, and groups A and B included samples from patients with DM and additional CVDRF, totalizing ≤2 CVDRF (group A) and ≥3 CVDRF (group B). Dual-immunolabelling of SIRT3, SOD2, or GPX1 with α-actin in tissue sections was carried out. The assessment of expression levels of NOX1, phospho-AMPKα, total AMPKα, SIRT1, PGC-1α, SIRT3, SOD2, and GPX1 was performed by western blotting and of miR-200a, miR-34a, miR-421, and miR-206 by real-time PCR. Phospho-AMPKα and SIRT3 expression was found significantly increased in group B relative to other groups, suggesting a marked influence of CVDRF, additional to DM, in the regulation of these enzymes. NOX1 was also increased in group B relative to controls. Only an increasing tendency was observed in the phospho-AMPKα/total AMPKα ratio, SIRT1, and PGC-1α expression in groups A and B when compared with controls. Concerning antioxidant enzymes, GPX1 expression was found incremented in group A, but SOD2 expression was decreased in groups A and B, comparative with controls. Group B presented significantly diminished levels of miR-421 and miR-200a, but only a decreasing trend on miR-34 and miR-206 expression was observed. Taken together, our findings demonstrated that besides DM, additional CVDRF presented a cumulative effect in the cellular response to oxidative unbalance, contributing to AMPK/SIRT1-PGC-1α-SIRT3 pathway activation. SOD2, a major mitochondrial antioxidant defence, did not follow the same variation.


Preparing unbiased T-cell receptor and antibody cDNA libraries for the deep next generation sequencing profiling.
High-throughput sequencing has the power to reveal the nature of adaptive immunity as represented by the full complexity of T-cell receptor (TCR) and antibody (IG) repertoires, but is at present severely compromised by the quantitative bias, bottlenecks, and accumulated errors that inevitably occur in the course of library preparation and sequencing. Here we report an optimized protocol for the unbiased preparation of TCR and IG cDNA libraries for high-throughput sequencing, starting from thousands or millions of live cells in an investigated sample. Critical points to control are revealed, along with tips that allow researchers to minimize quantitative bias, accumulated errors, and cross-sample contamination at each stage, and to enhance the subsequent bioinformatic analysis. The protocol is simple, reliable, and can be performed in 1-2 days.


[Comparison of Novel Oral Anticoagulants and Warfarin in Elderly Patients With Nonvalvular Atrial Fibrillation].
We compared efficacy and safety of warfarin with those of direct thrombin inhibitor dabigatran, factor Xa inhibitors rivaroxaban and apixaban used for stroke prevention in 280 patients aged 65-80 years with non-valvular atrial fibrillation. Treatment for two years with dabigatran (110 mg twice daily), apixaban (5 mg twice daily) or rivaroxaban (20 mg/day) prevented strokes no less successfully than warfarin, but more rarely caused severe intracranial hemorrhages. When selecting antithrombotic therapy in geriatric patients with non-valvular AF new oral anticoagulants may be regarded as an acceptable alternative to warfarin.


Symmetry of extremely floppy molecules: Molecular states beyond rotation-vibration separation.
Traditionally, molecules are theoretically described as near-static structures rotating in space. Vibrational motion causing small structural deformations induces a perturbative treatment of the rotation-vibration interaction, which fails in highly fluxional molecules, where all vibrational motions have amplitudes comparable in size to the linear dimensions of the molecule. An example is protonated methane (CH5(+)) [P. Kumar and D. Marx, Phys. Chem. Chem. Phys. 8, 573 (2006); Z. Jin et al., J. Phys. Chem. A 110, 1569 (2006); and A. S. Petit et al., J. Phys. Chem. A 118, 7206 (2014)]. For these molecules, customary theory fails to simulate reliably even the low-energy spectrum [T. Oka, Science 347, 1313-1314 (2015) and O. Asvany et al., Science 347, 1346-1349 (2015)]. Within the traditional view of rotation and vibration being near-separable, rotational and vibrational wavefunctions can be symmetry classified separately in the molecular symmetry (MS) group [P. Bunker and P. Jensen, Molecular Symmetry and Spectroscopy, NRC Monograph Publishing Program (NRC Research Press, 2006)]. In this article, we discuss a fundamental group theoretical approach to the problem of determining the symmetries of molecular rotation-vibration states. We will show that all MS groups discussed so far are isomorphic to subgroups of the special orthogonal group in three dimensions SO(3). This leads to a group theoretical foundation of the technique of equivalent rotations [H. Longuet-Higgins, Mol. Phys. 6, 445 (1963)]. The group G240 (the MS group of protonated methane) represents, to the best of our knowledge, the first example of a MS group which is not isomorphic to a subgroup of SO(3) (nor of O(3) or of SU(2)). Because of this, a separate symmetry classification of vibrational and rotational wavefunctions becomes impossible in this MS group, consistent with the fact that a decoupling of vibrational and rotational motion is impossible. We discuss here the consequences of this. In conclusion, we show that the prototypical, extremely floppy molecule CH5(+) represents a new class of molecules, where customary group theoretical methods for determining selection rules and spectral assignments fail so that new methods have to be developed.


Associations Between Hypernasality, Intelligibility, and Language and Reading Skills in 10-Year-Old Children With a Palatal Cleft.
This study investigated the associations between hypernasality and intelligibility, and language and reading skills in 10-year old children with a cleft palate ± lip. Cross-sectional data collected during routine assessments of speech and language in a centralized treatment setting. Children aged 10, born with cleft palate ± lip from 4 birth cohorts (N = 123). Hypernasality and intelligibility: Swedish Articulation and Nasality Test-N; language: Language 6-16 (Sentence recall, Serial recall, Vocabulary); reading: word chain test and reading comprehension test. A total of 71.3% of the children had no occurrence of hypernasality and 82.8% had intelligibility scores within the normal range. For all children with hypernasality and intelligibility within the normal range, reading and language scores were also within normal ranges. Children with presence of hypernasality had significantly lower language skills, with mean scores within the lower normal range. Children with reduced intelligibility had lower scores on reading comprehension. The findings highlight a possible association between hypernasality and language skills, and intelligibility and reading skills. Cleft teams should consider routine assessments of language and reading skills in children with speech impairment, in order to identify potential needs for intervention as early as possible.


Mechanisms of anti-proliferative effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on human liver cancer cells.
Selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to inhibit the proliferation of a variety of cancer cells including hepatocellular carcinoma (HCC). We sought to explore the mechanisms by which JTE-522, a selective COX-2 inhibitor, suppressed the growth of human HCC cells. HCC cells (HepG2, HLF, huH1, Huh7, and PLC/PRF/5 cells) did not express COX-2 at either the mRNA or protein level. Prostaglandin E2 (PGE2) levels in medium were not significantly modulated by the JTE-522 treatment. However, MTT assays disclosed that escalating doses (100 nM to 100 microM) of JTE-522 significantly inhibited the growth of all HCC cells in a dose- and time-dependent manner. JTE-522 induced cell cycle arrest at the G1 phase, which was in part mediated by downregulation of cyclin E. Hallmarks of apoptosis, including the sub-G1 fraction by flow cytometric analysis and nuclear fragmentation by nuclear staining, were not significantly induced after the JTE-522 treatment. In addition, JTE-522 enhanced the expression of peroxisome proliferator-activated receptor (PPAR)-gamma protein in HepG2 and PLC/PRF/5 cells. Our data demonstrate that JTE-522 inhibited the growth of HCC cells in a COX-2-independent manner, and that the growth inhibition was in part mediated by the cell cycle arrest and the upregulation of PPAR-gamma protein.