Altered functional connectivity after acute sleep deprivation reveals potential locations for noninvasive brain stimulation techniques.
Non-invasive brain stimulation (NIBS) techniques are emerging as efficacious treatments for sleep deprivation (SD). However, the stimulation location of NIBS (e.g. transcranial magnetic stimulation and transcranial direct current stimulation) on intervening acute SD is limited in previous studies. In this study, we aimed to investigate potentially effective targets of NIBS on intervening acute SD. We firstly performed a meta-analysis of 95 functional magnetic resonance imaging studies to find SD-related brain regions as regions of interest (ROI). Subsequently, we used resting-state functional connectivity analysis in 32 young individuals suffering from 24 h SD to identify brain surface regions associated with the ROIs. Finally, we applied 10-20 system coordinates to locate scalp sites for NIBS corresponding to the brain surface regions. We identified the bilateral dorsolateral prefrontal cortex, bilateral inferior frontal gyrus, left supplementary motor area, precentral, right precuneus, bilateral inferior parietal gyrus, right middle temporal gyrus, and superior frontal gyrus as potential targets of NIBS for intervening SD. The 10-20 system coordinates corresponding to these brain surface regions were identified as potential sites for NIBS. In conclusion, we identified several potential targets which could provide alternative stimulation locations for the use of NIBS on young patients suffering from acute SD.


Transcriptomic responses of oil palm (Elaeis guineensis) stem to waterlogging at plantation in relation to precipitation seasonality.
Global warming-induced climate change causes significant agricultural problems by increasing the incidence of drought and flooding events. Waterlogging is an inevitable consequence of these changes but its effects on oil palms have received little attention and are poorly understood. Recent waterlogging studies have focused on oil palm seedlings, with particular emphasis on phenology. However, the transcriptomic waterlogging response of mature oil palms remains elusive in real environments. We therefore investigated transcriptomic changes over time in adult oil palms at plantations over a two-year period with pronounced seasonal variation in precipitation. A significant transcriptional waterlogging response was observed in the oil palm stem core but not in leaf samples when gene expression was correlated with cumulative precipitation over two-day periods. Pathways and processes upregulated or enriched in the stem core response included hypoxia, ethylene signaling, and carbon metabolism. Post-waterlogging recovery in oil palms was found to be associated with responses to heat stress and carotenoid biosynthesis. Nineteen transcription factors (TFs) potentially involved in the waterlogging response of mature oil palms were also identified. These data provide new insights into the transcriptomic responses of planted oil palms to waterlogging and offer valuable guidance on the sensitivity of oil palm plantations to future climate changes.


Significance of eosinophilia after stem cell transplantation as a possible prognostic marker for favorable outcome.
Although eosinophilia after stem cell transplantation (SCT) has been addressed in recent reports, the significance of eosinophilia in disease outcome after SCT has not been well studied. In this study, we investigate the frequency of eosinophilia after SCT to determine its prognostic value. The subjects were 113 patients with malignant or nonmalignant diseases who underwent SCT treatment. In these patients, eosinophilia was detected in 44 cases (38.9%), on average 67.5 days after transplantation, and the mean maximum absolute eosinophil count was 840.5 x 10(6)/l. To study the basis of eosinophilia after SCT, various serum cytokine levels during SCT in patients both with and without eosinophilia were analyzed. Statistical analysis indicated that the overall patient survival rates improved in those with eosinophilia compared to those without eosinophilia (88.7 vs 43.0%, P=0.0034). In particular, in patients with malignant diseases, those with eosinophilia showed a higher event-free survival (81.1 vs 44.6%, P=0.0025) and a lower relapse rate (16.0 vs 43.0%, P=0.0287) than those without eosinophilia. In conclusion, we propose that eosinophilia after SCT could be a useful prognostic marker for determining favorable outcomes in patients with malignant diseases. The reasons for this good prognosis in SCT patients with eosinophilia are discussed.


First-principles study of CaB12H12 as a potential solid-state conductor for Ca.
Calcium dodecahydro-closo-dodecaborate, CaB12H12, was calculated to have a percolating Ca migration path with low activation barrier (650 meV). The formation of Ca vacancies required for diffusion was calculated to be thermodynamically feasible by substitution of Ca with Al, Bi, or a number of trivalent rare-earth cations.


Astrocytes present myelin basic protein to encephalitogenic T-cell lines.
Astrocyte proliferation and perivascular lymphocyte infiltration are conspicuous among the cellular changes in the active brain lesions of multiple sclerosis patients. Recent observations have indicated that most of the perivascular lymphocytes are T cells which may be actively involved in the generation of the brain lesions. Much less is known about the significance of the proliferative astrocytes, although the fact that they produce an interleukin-1 (IL-1)-like factor that enhances the release of interleukin-2 by T lymphocytes, may provide a clue. We show here that rat astrocytes are able to present antigen to T lymphocytes in a specific manner which is restricted by the major histocompatibility complex (MHC) and that they can in particular activate myelin basic protein (BP)-specific, encephalitogenic T-cell lines. Only on such interaction do astrocytes express Ia antigens in easily detectable amounts. Antigen presentation by astrocytes may have a central role in the generation of immune responses in the brain.


Ultraviolet-A irradiation but not ultraviolet-B or infrared-A irradiation leads to a disturbed zinc homeostasis in cells.
Changes of the redox balance in cells alter the availability of intracellular free Zn(2+). Here, cells were exposed to ultraviolet (UV)-A, UV-B, or infrared (IR)-A light irradiation, and the intracellular free zinc pool was monitored. Under sublethal conditions only UV-A irradiation resulted in a transient cytoplasmic and nuclear increase of intracellular free Zn(2+). Likewise, tert-butyl hydroperoxide and singlet oxygen, but not H(2)O(2) or intracellular generation of O(2)(*-) by redox cyclers, mimicked the effects of UV-A irradiation, while disulfide stress by diamide only led to a transient cytoplasmic zinc release. These results show that only certain types of subtoxic cellular stress massively disturb the zinc homeostasis in cells.


Influence of timing on the analgesic effect of intravenous ketorolac after orthopedic surgery.
This study evaluated the pre-emptive analgesic effect of intravenous (i.v.) ketorolac (KET) for total hip replacement (THR). Sixty patients who underwent surgery for THR under general anesthesia were randomly allocated to 3 groups. Two i.v. injections were administered: one before induction and one after surgery. The patients were studied prospectively in a double-blind manner. The control group (CONT; n = 20) received 2 ml of normal saline (NS) for both injections. The pre-operative KET group (PRE; n = 20) received 60 mg of KET and then 2 ml of NS. The postoperative KET group (POST; n = 20) received 2 ml of NS and then 60 mg of KET. General anesthesia was standardized with a intra-operative cumulated dose of fentanyl limited to 4 micrograms/kg. In the recovery room (RR), pain was controlled with an i.v. tritration of morphine; thereafter, on the surgical ward, patients used a patient-controlled analgesia (PCA) pump (Abbott). Pain was evaluated with a visual analogue scale (VAS) at rest and movement in the RR, then every hour for 6 h and every 6 h for 5 days. The side effects monitored were: sedation, respiratory depression, nausea, perioperative bleeding. The patients and surgery were similar for the 3 groups. Upon arrival in the RR, VAS scores taken at rest and at movement were lower for the PRE group than for the CONT and POST groups. Otherwise, VAS scores were similar in all 3 groups. The cumulative dose of morphine in the PRE group was lower than that for the CONT and POST groups from 0 to 6 h.(ABSTRACT TRUNCATED AT 250 WORDS)


Global farm animal production and global warming: impacting and mitigating climate change.
The farm animal sector is the single largest anthropogenic user of land, contributing to many environmental problems, including global warming and climate change. The aim of this study was to synthesize and expand upon existing data on the contribution of farm animal production to climate change. We analyzed the scientific literature on farm animal production and documented greenhouse gas (GHG) emissions, as well as various mitigation strategies. An analysis of meat, egg, and milk production encompasses not only the direct rearing and slaughtering of animals, but also grain and fertilizer production for animal feed, waste storage and disposal, water use, and energy expenditures on farms and in transporting feed and finished animal products, among other key impacts of the production process as a whole. Immediate and far-reaching changes in current animal agriculture practices and consumption patterns are both critical and timely if GHGs from the farm animal sector are to be mitigated.


Atypical Antipsychotics Mediate Dynamics of Intrinsic Brain Activity in Early-Stage Schizophrenia? A Preliminary Study.
Abnormalities of static brain activity have been reported in schizophrenia, but it remains to be clarified the temporal variability of intrinsic brain activities in schizophrenia and how atypical antipsychotics affect it. We employed a resting-state functional magnetic resonance imaging (rs-fMRI) and a sliding-window analysis of dynamic amplitude of low-frequency fluctuation (dALFF) to evaluate the dynamic brain activities in schizophrenia (SZ) patients before and after 8-week antipsychotic treatment. Twenty-six schizophrenia individuals and 26 matched healthy controls (HC) were included in this study. Compared with HC, SZ showed stronger dALFF in the right inferior temporal gyrus (ITG.R) at baseline. After medication, the SZ group exhibited reduced dALFF in the right middle occipital gyrus (MOG.R) and increased dALFF in the left superior frontal gyrus (SFG.L), right middle frontal gyrus (MFG.R), and right inferior parietal lobule (IPL.R). Dynamic ALFF in IPL.R was found to significant negative correlate with the Scale for the Assessment of Negative Symptoms (SANS) scores at baseline. Our results showed dynamic intrinsic brain activities altered in schizophrenia after short term antipsychotic treatment. The findings of this study support and expand the application of dALFF method in the study of the pathological mechanism in psychosis in the future.


Contributions of genetics to the evolution of the diagnostic classification of renal cell neoplasia: a personal perspective.
The classification system for neoplasms of the cells lining the renal tubules (renal cell neoplasms) has expanded greatly over the last five decades. The criteria for recognising an entity and including it in the classification have changed from being purely morphological and clinical to include genetics; presently, some are defined purely on genetics. Expansion of the number of entities included in the classification has many of the newly included entities and those under consideration for inclusion being very rare. The clinical utility of including entities which are extremely rare, based mainly upon genetic information, is unclear.


Role of proteinkinase C and phosphatidylinositol metabolism in lipopeptide-induced leukocyte activation as signal transducing mechanism.
Synthetic lipopeptides are potent B-lymphocyte and macrophage activators. The role of phosphatidylinositol metabolism and proteinkinase C in lipopeptide induced leukocyte activation were investigated. In murine B-lymphocytes and in bone marrow derived macrophages, lipopeptide failed to induce phosphatidylinositol breakdown, whereas in the macrophage cell line P388D1 formation of inositolphosphates was increased. Translocation of proteinkinase C from a cytosolic to a membrane compartment was only observed in the cell line P388D1 indicating that in the other cells tested lipopeptide acts via different signal transduction pathways.


BrainKnowledge: a human brain function mapping knowledge-base system.
Associating fMRI image datasets with the available literature is crucial for the analysis and interpretation of fMRI data. Here, we present a human brain function mapping knowledge-base system (BrainKnowledge) that associates fMRI data analysis and literature search functions. BrainKnowledge not only contains indexed literature, but also provides the ability to compare experimental data with those derived from the literature. BrainKnowledge provides three major functions: (1) to search for brain activation models by selecting a particular brain function; (2) to query functions by brain structure; (3) to compare the fMRI data with data extracted from the literature. All these functions are based on our literature extraction and mining module developed earlier (Hsiao, Chen, Chen. Journal of Biomedical Informatics 42, 912-922, 2009), which automatically downloads and extracts information from a vast amount of fMRI literature and generates co-occurrence models and brain association patterns to illustrate the relevance of brain structures and functions. BrainKnowledge currently provides three co-occurrence models: (1) a structure-to-function co-occurrence model; (2) a function-to-structure co-occurrence model; and (3) a brain structure co-occurrence model. Each model has been generated from over 15,000 extracted Medline abstracts. In this study, we illustrate the capabilities of BrainKnowledge and provide an application example with the studies of affect. BrainKnowledge, which combines fMRI experimental results with Medline abstracts, may be of great assistance to scientists not only by freeing up resources and valuable time, but also by providing a powerful tool that collects and organizes over ten thousand abstracts into readily usable and relevant sources of information for researchers.


Update on the Role of Imaging in Detection of Intimate Partner Violence.
Intimate partner violence (IPV) is a major public health problem with adverse health and mental consequences. Patient- and clinician-related barriers to screening include underreporting, misattribution of IPV to other causes, and patients not seeking help or facing social stigmas and discrimination. Radiology may help overcome these barriers through objective imaging evaluation, noting mismatches between image findings and provided clinical history. Recognizing injury patterns specific to IPV on imaging aids early identification and intervention even when the patient is not forthcoming. This article examines the ways radiologists have adapted to meet an ever-increasing demand for diagnosis and reporting of IPV.


CRISPR/Cas technology for improving nutritional values in the agricultural sector: an update.
The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system was initially identified in bacteria and archaea as a defense mechanism to confer immunity against phages. Later on, it was developed as a gene editing tool for both prokaryotic and eukaryotic cells including plant cells. CRISPR/Cas9 approach has wider applications in reverse genetics as well as in crop improvement. Various characters involved in enhancing economic value and crop sustainability against biotic/abiotic stresses can be targeted through this tool. Currently, CRISPR/Cas9 gene editing mechanism has been applied on around 20 crop species for improvement in several traits including yield enhancement and resistance against biotic and abiotic stresses. In the last five years, maximum genome editing research has been validated in rice, wheat, maize and soybean. Genes targeted in these plants has been involved in causing male sterility, conferring resistance against pathogens or having certain nutritional value. Current review summarizes various applications of CRISPR/Cas system and its future prospects in plant biotechnology targeting crop improvement with higher yield, disease tolerance and enhanced nutritional value.


Heat-Denatured Lysozyme is a Novel Potential Non-alcoholic Disinfectant Against Respiratory Virus.
Respiratory diseases are significant recurrent threats to global public health. Since the 1918 Spanish flu pandemic, seasonal influenza viruses continue to cause epidemics around the world each year. More recently, the COVID-19 global pandemic conducted a public health crisis with more than 6 million deaths and it also severely affected the global economy. Due to the phenomenon that people get infection from objects carrying viruses, it has aroused people's attention to home disinfection. As there is no ideal existing common domestic disinfectant, new and safer antiviral disinfectants are urgently needed. Lysozyme is a natural antibacterial agent widespread in nature and widely used in healthcare and food industry because of is recognized safety. Recently, it has been shown that thermally denatured lysozyme has the ability to kill murine norovirus and hepatitis A virus. In our study, we also demonstrated that heat-denatured lysozyme (HDLz) had an antiviral effect against H1N1 influenza A virus, and we optimized its antiviral activities by testing different heating denaturation conditions, to generalize this property, using pseudotype virus neutralization assay, we found that HDLz can also inhibit the entry of H5N1, H5N6, and H7N1 avian influenza viruses as well as SARS-CoV and SARS-CoV-2 particles in cell with IC50 at the ng/mL range. Finally, using western blot analysis, we provide evidence that HDLz polymerization correlates with antiviral effect, which may be a precious possible quality control test. Altogether, our data support HDLz as a powerful anti-respiratory virus disinfectant as a sole or additive of current disinfectants to reduce concentration of toxic component.


Activation of alphaVbeta3 on vascular cells controls recognition of prothrombin.
Regulation of vascular homeostasis depends upon collaboration between cells of the vessel wall and blood coagulation system. A direct interaction between integrin alphaVbeta3 on endothelial cells and smooth muscle cells and prothrombin, the pivotal proenzyme of the blood coagulation system, is demonstrated and activation of the integrin is required for receptor engagement. Evidence that prothrombin is a ligand for alphaVbeta3 on these cells include: (a) prothrombin binds to purified alphaVbeta3 via a RGD recognition specificity; (b) prothrombin supports alphaVbeta3-mediated adhesion of stimulated endothelial cells and smooth muscle cells; and (c) endothelial cells, either in suspension and in a monolayer, recognize soluble prothrombin via alphaVbeta3. alphaVbeta3-mediated cell adhesion to prothrombin, but not to fibrinogen, required activation of the receptor. Thus, the functionality of the alphaVbeta3 receptor is ligand defined, and prothrombin and fibrinogen represent activation- dependent and activation-independent ligands. Activation of alphaVbeta3 could be induced not only by model agonists, PMA and Mn2+, but also by a physiologically relevant agonist, ADP. Inhibition of protein kinase C and calpain prevented activation of alphaVbeta3 on vascular cells, suggesting that these molecules are involved in the inside-out signaling events that activate the integrin. The capacity of alphaVbeta3 to interact with prothrombin may play a significant role in the maintenance of hemostasis; and, at a general level, ligand selection by alphaVbeta3 may be controlled by the activation state of this integrin.


Detection of alpha-interferon in nasopharyngeal secretions and sera in children infected with respiratory syncytial virus.
We investigated the relationship between respiratory syncytial virus (RSV) antigen and interferon (IFN) in nasopharyngeal secretions (NPS) and sera obtained from 252 patients infected with RSV. A total of 146 (57.9%) of 252 patients had IFN in NPS with a mean titer of 28 units/ml and IFN was detected in 164 (71.6%) of 229 patients in the acute stage sera with a mean titer of 28 units/ml. IFN activities were neutralized with antiserum to IFN-alpha. RSV antigen in NPS decreased on Day 5 and later in parallel with the change of mean titer of IFN in NPS. IFN in NPS was detected in 40 to 60% of the samples with some fluctuation in the acute stage. Within 4 days IFN was detected in more than 70% of the sera whereas on Day 5 and later the IFN positivity rate decreased in sera. RSV antigen in NPS decreased in the older patient groups. No significant change of positive rate of IFN in NPS was observed in different age groups and the mean titer of IFN in NPS and sera did not vary with age, except in those younger than 3 months and older than 3 years of age.


Acute gastroenteritis in children attending day-care centres with special reference to rotavirus infections. I. Aetiology and epidemiologic aspects.
Acute gastroenteritis (GE) among 214 children (aged 6 months-7 years) attending day-care centres (DDCs) in the Copenhagen County was studied during a 12-month period. A total of 197 cases of GE was observed in 109 children (i.e. 51% of the participants). The aetiology was as follows: rotavirus (n = 48) (24%), pathogenic bacteria (n = 11) (6%), Giardia lamblia (n = 3) (2%), while the aetiology of 68% remains unknown. The pathogenic bacteria included Yersinia enterocolitica, thermophilic Campylobacter, Clostridium difficile (+/- toxin) and enteropathogenic E. coli. In 4% of the GE the infections were multiple and Cryptosporidium was seen in one of these cases. The rate of GE declined with age from 1.35 GE per child per year (age group 1.0- less than 2.0 years) to 0.36 (6.0- less than 8.0 years). Serum sampled at the start of the study period showed that the frequency of detectable rotavirus IgG increased with age from 48% in the 6 months- less than 1.0 year group to 96% in the 4.0- less than 7.0 year group. The highest rates of rotavirus GE occurred from January to April (i.e. the rotavirus season). Moreover, rotavirus GE was almost absent after the age of 4. Hence, the rates of rotavirus GE per rotavirus season per child were 0.80 (age group 6 months-less than 1.0 year), 0.32 (1.0-less than 2.0), 0.14 (2.0-less than 3.0), 0.16 (3.0-less than 4.0), 0.06 (4.0-less than 5.0) and 0.04 (5.0-less than 6.0). Only 2 out of the 48 rotavirus GE were reinfections.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of nocturnal hemodialysis on sleep parameters in patients with end-stage renal disease: a systematic review and meta-analysis.
Recently, a small but growing literature has depicted the beneficial effects of nocturnal hemodialysis (NHD) over conventional hemodialysis (CHD) in the fields of sleep disorders such as sleep apnea. The impact of various dialysis models on sleep disorders, however, has not been determined. The objective of our meta-analysis is to examine the potential effects of NHD, compared with CHD, on sleep disorders in HD patients. Several electronic databases including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and CNKI were searched, using the search terms "nocturnal" (or "nightly") and "dialysis" (or "hemodialysis" or "renal dialysis") from the earliest available date of indexing to March 2018. Two authors independently extracted data, evaluated the study quality, and conducted random-effects meta-analyses using STATA 12.0. Of 1789 potentially relevant citations, 9 fulfilled eligibility criteria, consisting of 6 single-arm studies (comparing pre- and post-intervention outcomes), 1 observational study, and 2 randomized controlled trials (a total of 286 participants). Regarding objective sleep assessments, conversion from CHD to NHD resulted in a significant reduction in the AHI (Mean difference was -14.90; 95% CI, -20.12 to -9.68), a significant increase of SaO2 (Mean difference was 1.38%; 95% CI, 0.35% to 2.42%), and a significant decrease of TST (Mean difference was -0.31; 95% CI, -0.47 to -0.15). The trends were even stronger in the HD patients with sleep disorders. However, regarding subjective sleep assessments, improved sleep quality was found in the prospective pre-post intervention studies and cohort studies, while no significant improvements were found in the randomized controlled trials. Although a significant improvement of sleep apnea was observed by switching from CHD to NHD, it may not yield a net benefit in overall subjective sleep quality.


Influence of external factors on the composition of the soil microflora.
The changes in the soil microflora as a result of introducing various organic substances (gelatin, chitin, cellulose and beech sawdust) into the soil were studied. The work was supplemented by electron-microscopic observations. Substantial shifts in the quantitative composition of the microorganisms take place only in the case of compounds easily accessible to them. Certain substances induce changes in the ratio of the groups comprising the soil micropopulation.


Application of graphene for the analysis of pharmaceuticals and personal care products in wastewater.
A novel and reliable analytical method based on a graphene adsorbent for solid-phase extraction (SPE) derivatized with N-tert-butyldimethylsilyl-N- methyltrifluoroacetamide and analyzed by gas chromatography-mass spectrometry was developed for determination of nine pharmaceuticals and personal care products (PPCPs) in wastewater samples. Different ratios of graphene/silica gel were tested, with 20 % graphene/silica gel giving the best performance as an SPE adsorbent. The mean recoveries of the target analytes obtained by 20 % graphene/silica gel SPE ranged from 58.1 to 87.6 %. The limit of quantification ranged from 30 to 259 ng/L and from 13 to 115 ng/L for the influent and effluent, respectively. By comparing the accuracy and precision of 20 % graphene/silica gel and Oasis HLB SPE cartridges, we demonstrated that the method can be satisfactorily used for the analysis of PPCPs in wastewater samples. We applied the method to wastewater samples from a sewage treatment plant near Riverside, California, to track the concentration change of PPCPs in the treatment processes.


Biosynthesis and metabolic engineering of 1-hydroxyphenazine in Pseudomonas chlororaphis H18.
1-Hydroxyphenazine (1-OH-PHZ) is a phenazine microbial metabolite with broad-spectrum antibacterial activities against a lot of plant pathogens. However, its use is hampered by the low yield all along. Metabolic engineering of microorganisms is an increasingly powerful method for the production of valuable organisms at high levels. Pseudomonas chlororaphis is recognized as a safe and effective plant rhizosphere growth-promoting bacterium, and faster growth rate using glycerol or glucose as a renewable carbon source. Therefore, Pseudomonas chlororaphis is particularly suitable as the chassis cell for the modification and engineering of phenazines. In this study, enzyme PhzS (monooxygenase) was heterologously expressed in a phenazine-1-carboxylic acid (PCA) generating strain Pseudomonas chlororaphis H18, and 1-hydroxyphenazine was isolated, characterized in the genetically modified strain. Next, the yield of 1-hydroxyphenazine was systematically engineered by the strategies including (1) semi-rational design remodeling of crucial protein PhzS, (2) blocking intermediate PCA consumption branch pathway, (3) enhancing the precursor pool, (4) engineering regulatory genes, etc. Finally, the titer of 1-hydroxyphenazine reached 3.6 g/L in 5 L fermenter in 54 h. The 1-OH-PHZ production of Pseudomonas chlororaphis H18 was greatly improved through systematically engineering strategies, which is the highest, reported to date. This work provides a promising platform for 1-hydroxyphenazine engineering and production.


Efficacy and gastrointestinal risk of aspirin used for the treatment of pain and cold.
To analyse major sources of evidence-based information on the efficacy and gastrointestinal tolerability of aspirin, used short-term, in over-the-counter (OTC) doses, to relieve acute pain and cold symptoms, including associated feverishness. Evidence was largely collected from published meta-analyses and systematic reviews that focused on randomised, controlled, double-blind clinical trials, in which aspirin was compared to placebo and, in some cases also, to active comparators such as OTC doses of paracetamol or ibuprofen. Across a large number of comparisons, aspirin was superior to placebo in treating pain, cold or fever. Efficacy was essentially similar to that of comparators used in equivalent doses. There was no serious GI adverse event attributed to ASA in any study, but mild-to-moderate dyspepsia in small percentages of cases was commonly reported. OTC aspirin is safe and effective. Safety concerns should not limit brief use to relieve acute pain, cold or fever.


Changing expression profiles of long non-coding RNAs, mRNAs and circular RNAs in ethylene glycol-induced kidney calculi rats.
To explore long non-coding RNA (lncRNA), mRNA and circular RNA (circRNA) expression profiles and their biological functions in the pathogenesis of kidney stones in ethylene glycol-induced urolithiasis rats. The expression of 1440 lncRNAs, 2455 mRNAs and 145 circRNAs was altered in the kidneys of urolithiasis rats. GO and KEGG biological pathway analysis were performed to predict the functions of differentially expressed lncRNAs, circRNAs and co-expressed potential targeting genes. Co-expression networks of lncRNA-mRNA and circRNA-miRNA were constructed based on correlation analysis between differentially expressed RNAs. mRNAs coexpressed with lncRNAs were involved in many kidney diseases, e.g., Ephb6 was associated with the reabsorption ability of the kidney. Arl5b was associated with the dynamic changes in the podocyte foot process in podocyte injury. miRNAs co-expressed with circRNAs, such as rno-miR-138-5p and rno-miR-672-5p, have been proven to be functional in hypercalciuria urolithiasis. The expression profile provided a systematic perspective on the potential functions of lncRNAs and circRNAs in the pathogenesis of kidney stones. Differentially expressed lncRNAs and circRNAs might serve as treatment targets for kidney stones.


Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.
Ca2+ leak from cardiomyocyte sarcoplasmic reticulum (SR) via hyperactive resting cardiac ryanodine receptor channels (RyR2) is pro-arrhythmic. An exogenous peptide (DPc10) binding promotes leaky RyR2 in cardiomyocytes and reports on that endogenous state. Conversely, calmodulin (CaM) binding inhibits RyR2 leak and low CaM affinity is diagnostic of leaky RyR2. These observations have led to designing a FRET biosensor for drug discovery targeting RyR2. We used FRET to clarify the molecular mechanism driving the DPc10-CaM interdependence when binding RyR2 in SR vesicles. We used donor-FKBP12.6 (D-FKBP) to resolve RyR2 binding of acceptor-CaM (A-CaM). In low nanomolar Ca2+, DPc10 decreased both FRETmax (under saturating [A-CaM]) and the CaM/RyR2 binding affinity. In micromolar Ca2+, DPc10 decreased FRETmax without affecting CaM/RyR2 binding affinity. This correlates with the analysis of fluorescence-lifetime-detected FRET, indicating that DPc10 lowers occupancy of the RyR2 CaM-binding sites in nanomolar (not micromolar) Ca2+ and lengthens D-FKBP/A-CaM distances independent of [Ca2+]. To observe DPc10/RyR2 binding, we used acceptor-DPc10 (A-DPc10). CaM weakens A-DPc10/RyR2 binding, with this effect being larger in micromolar versus nanomolar Ca2+. Moreover, A-DPc10/RyR2 binding is cooperative in a CaM- and FKBP-dependent manner, suggesting that both endogenous modulators promote concerted structural changes between RyR2 protomers for channel regulation. Aided by the analysis of cryo-EM structures, these insights inform further development of the DPc10-CaM paradigm for therapeutic discovery targeting RyR2.


The immediate effect of IASTM vs. Vibration vs. Light Hand Massage on knee angle repositioning accuracy and hamstrings flexibility: A pilot study.
The effectiveness of novel soft-tissue interventions relative to traditional ones requires further exploration. The purpose of this pilot study was to evaluate the immediate effect of Instrument Assisted Soft Tissue Mobilization (IASTM) compared to Vibration Massage or Light Hand Massage on hamstrings' flexibility and knee proprioception. 16 healthy non-injured male participants (mean age 23.7 years, height 1.80 cms and body mass 77.7 kg) were randomly assigned to the following interventions: (a) 5min IASTM, (b) 5min Vibration Massage and (c) 8min Light Hand-Massage, sequentially delivered to all participants with an in-between 1-week time interval. A single application of each intervention was given over the hamstrings of their dominant leg (repeated measures under 3 different experimental conditions). An active knee angle reproduction proprioception test and the back-saver sit and reach flexibility test were performed before and immediately after each intervention. Reliability of outcomes was also assessed. Reliability for flexibility (ICC3,1 = 0.97-0.99/SEM = 0.83-1.52 cm) and proprioception (ICC3,1 = 0.83-0.88/SEM = 1.63-2.02°) was very good. For flexibility, statistically significant immediate improvement (p < 0.001) was noted in all 3 groups (1.61-3.23 cm), with no between-group differences. For proprioception, improvement in the IASTM (2.12°), Vibration Massage (0.32°) and Light Hand-Massage (1.17°) conditions was not statistically significant; no between-group differences were also evident. Our findings indicate that muscle flexibility was positively influenced immediately after a single intervention of IASTM, Vibration Massage or Light Hand Massage. Proprioception changes were not statistically significant either within or between groups. Further evaluation of those interventions in a larger population with hamstrings pathology is required.


Prevalence of ten LRRK2 variants in Parkinson's disease: A comprehensive review.
Variants in the leucine-rich repeat kinase 2 gene (LRRK2) are risk factors for Parkinson's disease (PD), but their prevalence varies geographically, reflecting the locations of founder events and dispersion of founders' descendants. A comprehensive literature review was conducted to identify studies providing prevalence estimates for any of ten variants in LRRK2 (G2019S, R1441C, R1441G, R1441H, I2020T, N1437H, Y1699C, S1761R, G2385R, R1628P) among individuals with PD globally. We calculated crude country-specific variant prevalence estimates and, when possible, adjusted estimates for ethno-racial composition. For clinic-based studies, probands were used over other familial cases, whereas for population-based studies, all PD cases were used. The analysis included 161 articles from 52 countries yielding 581 prevalence estimates across the ten variants. G2019S was the most common variant, exceeding 1.0% in 26 of 51 countries with estimates. The other variants were far less common. G2385R and R1628P were observed almost exclusively in East Asian countries, where they were found in ∼5-10% of cases. All prevalence estimates adjusted for ethno-racial composition were lower than their unadjusted counterparts, although data permitting this adjustment was only available for six countries. Except for G2019S, the LRRK2 variants covered in this review were uncommon in most countries studied. However, there were countries with higher prevalence for some variants, reflecting the uneven geographic distribution of LRRK2 variants. The fact that ethno-racial group‒adjusted estimates were lower than crude estimates suggests that estimates derived largely from clinic-based studies may overstate the true prevalence of some LRRK2 variants in PD.


Design and field methods of the ARISE Network Adolescent Health Study.
The ARISE Network Adolescent Health Study is an exploratory, community-based survey of 8075 adolescents aged 10-19 in 9 communities in 7 countries: Burkina Faso, Eswatini, Ethiopia, Ghana, Nigeria, Tanzania and Uganda. Communities were selected opportunistically and existing population cohorts maintained by health and demographic surveillance systems (HDSSs). The study is intended to serve as a first round of data collection for African adolescent cohorts, with the overarching goal of generating community-based data on health-related behaviours and associated risk factors in adolescents, to identify disease burdens and health intervention opportunities. Household-based sampling frames were used in each community to randomly select eligible adolescents (aged 10-19 years). Data were collected between July 2015 and December 2017. Consenting participants completed face-to-face interviews with trained research assistants using a standardised questionnaire, which covered physical activity, cigarette and tobacco use, substance and drug use, mental health, sexual behaviours and practices, sexually transmitted infections, pregnancy, food security and food diversity, teeth cleaning and hand washing, feelings and friendship, school and home activities, physical attacks and injuries, health care, health status assessment and life satisfaction, as well as media and cell phone use and socio-demographic and economic background characteristics. Results from this multi-community study serve to identify major adolescent health risks and disease burdens, as well as opportunities for interventions and improvements through policy changes.


Effects of altered left ventricular geometry on quantitative technetium 99m sestamibi defect size in humans: perfusion imaging during coronary angioplasty.
Serial myocardial perfusion imaging is used to assess exercise-induced myocardial ischemia and myocardial risk area, salvage, and viability in patients with myocardial infarction. In an experimental animal model it has been shown that abnormal regional wall motion and altered left ventricular geometry can produce apparent perfusion defects independent of changes in blood flow. The effects of regional alteration in ventricular geometry on perfusion images in humans are not defined. The purpose of our investigation was to evaluate quantitatively the effect of altered left ventricular geometry on myocardial perfusion imaging with technetium 99m sestamibi during coronary angioplasty. Nine patients with normal baseline left ventricular function referred for angioplasty of the left anterior descending coronary artery were studied. 99mTc sestamibi was administered intravenously before angioplasty. Baseline planar electrocardiographic-gated imaging was performed. Imaging was repeated in the catheterization laboratory during angioplasty vessel occlusion when altered left ventricular geometry was produced and again later after angioplasty. Summed static, end-systolic, and end-diastolic images were generated from the electrocardiographic-gated acquisitions. Circumferential count profiles of images obtained during percutaneous transluminal coronary angioplasty (PTCA) were compared with those of a normal 99mTc sestamibi database and their own baseline images. Defect integral (the area below the reference profile) and nadir (maximum percent decrease in activity) were derived. Compared with a normal database, new quantitative defects appeared on PTCA-summed images in only two patients. The defects were small to moderate in size. However, compared with their own baseline profile, six patients had quantitative defects during PTCA (mean defect integral 3 +/- 2; mean defect nadir 12% +/- 7%). Defect nadir was larger on end-diastolic images compared with summed images (22% +/- 7% and 12% +/- 7%, respectively; p < 0.05). Altered left ventricular geometry may create apparent, albeit small, planar myocardial perfusion defects in humans. Changes in defect size on serial images may be only partially caused by changes in regional wall motion or geometry.


Depression and the risk of adverse outcomes at 5 years in patients with coronary heart disease.
Cardiovascular diseases are a public health concern worldwide, with high rates of morbidity and mortality. Depression is a frequent comorbidity in coronary heart disease (CHD). It can be caused by the experience of suffering from heart disease, but it can also influence the prognosis of the CHD. The prevalence of depression in patients with cardiovascular disease is twice as high as that in the general population. Assess the influence of depression in the prognosis at 5 years in patients with CHD. 145 patients diagnosed with CHD were recruited between September 2013 and June 2015. Depression was assessed based on the PHQ-9 results at the time of hospitalization and 3 months after discharged. Sociodemographic and clinical variables were collected. A 5-year follow-up was carried out to verify death, reinfarction or any adverse outcome. 20% of the study population had depression at hospital admission compared with 11% at 3 months. Depression at 3 months after discharged was a differentiating factor to present complications (42.6 months, CI 95% 27.3-57.9) compared with patients without depression (55 months, CI 95%, 50.9-59.1) (Log-Rank p = 0.034). In the unadjusted model, the risk of heart complications increased with patients that have comorbidities, such as diabetes (HR 2.78, 95% CI 1.21-6.3) or hypothyroidism (HR 2.5 95% CI 1.09-5.7). Also, patients with post-hospitalization depression at 3 months were 3 times (95% CI 1.023-8.8) more likely to have complications during the follow-up period than nondepressed patients. After risk factor adjustment, the HR for depression was 2.01 (95% CI 0.57-6.9). Patients with depression at 3 months following the coronary event, presented complications sooner than those without depression.


Cerebellar granule cell signaling is indispensable for normal motor performance.
Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs). It is well established that PC disruption produces motor deficits such as ataxia. This could arise from either decreases in ongoing PC-DCN inhibition, increases in the variability of PC firing, or disruption of the flow of MF-evoked signals. Remarkably, it is not known whether GCs are essential for normal motor function. Here we address this issue by selectively eliminating calcium channels that mediate transmission (CaV2.1, CaV2.2, and CaV2.3) in a combinatorial manner. We observe profound motor deficits but only when all CaV2 channels are eliminated. In these mice, the baseline rate and variability of PC firing are unaltered, and locomotion-dependent increases in PC firing are eliminated. We conclude that GCs are indispensable for normal motor performance and that disruption of MF-induced signals impairs motor performance.


Gelation of wheat arabinoxylans in the presence of Cu(+2) and in aqueous mixtures with cereal β-glucans.
The effect of copper ions (0.63-0.16 mM) on the rheological behavior of arabinoxylan (AX) aqueous solutions was investigated. Moreover, the influence of β-glucan addition (BG, 0.5-3% w/v) on the gelation of mixed AX/BG solutions with and without addition of the peroxidase/H2O2 was examined. Generally, gels formed with inclusion of transition metal-ions differed from those obtained by adding peroxidase/H2O2. Copper ions induced viscosity increase of the AX-solutions and form stronger thermoreversible gels with increasing ion-concentration; optimal gelation was at 15 °C. For added β-glucan at levels >1%, the lower the concentration and the higher the molecular weight of β-glucan, the weaker the gelling ability of the mixed AX/BG system treated with peroxidase/H2O2. The polysaccharide-ratio affected both the gelling rate and the network melting temperature, with the β-glucan itself giving the strongest network. Calorimetry provided evidence for existence of β-glucan ordered domains in the mixed gel structures of AX/BG1, indicative of phase separation events.


Focal cortical seizures prevent HRP and HRP-WGA labeling only in neurons bidirectionally connected to the cortex.
Intracortical implants of polyacrylamide gel containing horseradish peroxidase labeled cortical efferents and perikarya in some cortical areas and a number of subcortical formations. When epileptogenic penicillin was added to the gel, no labeling was seen in the efferents and cell bodies of the cortex, thalamus, or claustrum, whereas the magnocellular nuclei of the basal forebrain, raphe nuclei and locus coeruleus did contain the label.


Industrial source identification of polyhalogenated carbazoles and preliminary assessment of their global emissions.
Polyhalogenated carbazoles (PHCZs) are emerging global pollutants found in environmental matrices, e.g., 3000 tonnes of PHCZs have been detected in the sediments of the Great Lakes. Recognition of PHCZ emissions from ongoing industrial activities worldwide is still lacking. Here, we identify and quantify PHCZ emissions from 13 large-scale industries, 12 of which previously have no data. Congener profiles of PHCZs from investigated industrial sources are clarified, which enables apportioning of PHCZ sources. Annual PHCZ emissions from major industries are estimated on the basis of derived emission factors and then mapped globally. Coke production is a prime PHCZ emitter of 9229 g/yr, followed by iron ore sintering with a PHCZ emission of 3237 g/yr. China, Australia, Japan, India, USA, and Russia are found to be significant emitters through these industrial activities. PHCZ pollution is potentially a global human health and environmental issue.


Oxidized phospholipids affect small intestine neuromuscular transmission and serotonergic pathways in juvenile mice.
Oxidized phospholipid derivatives (OxPAPCs) act as bacterial lipopolysaccharide (LPS)-like damage-associated molecular patterns. OxPAPCs dose-dependently exert pro- or anti-inflammatory effects by interacting with several cellular receptors, mainly Toll-like receptors 2 and 4. It is currently unknown whether OxPAPCs may affect enteric nervous system (ENS) functional and structural integrity. Juvenile (3 weeks old) male C57Bl/6 mice were treated intraperitoneally with OxPAPCs, twice daily for 3 days. Changes in small intestinal contractility were evaluated by isometric neuromuscular responses to receptor and non-receptor-mediated stimuli. Alterations in ENS integrity and serotonergic pathways were assessed by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (LMMPs). Tissue levels of serotonin (5-HT), tryptophan, and kynurenine were measured by HPLC coupled to UV/fluorescent detection. OxPAPC treatment induced enteric gliosis, loss of myenteric plexus neurons, and excitatory hypercontractility, and reduced nitrergic neurotransmission with no changes in nNOS+ neurons. Interestingly, these changes were associated with a higher functional response to 5-HT, altered immunoreactivity of 5-HT receptors and serotonin transporter (SERT) together with a marked decrease in 5-HT levels, shifting tryptophan metabolism toward kynurenine production. OxPAPC treatment disrupted structural and functional integrity of the ENS, affecting serotoninergic tone and 5-HT tissue levels toward a higher kynurenine content during adolescence, suggesting that changes in intestinal lipid metabolism toward oxidation can affect serotoninergic pathways, potentially increasing the risk of developing functional gastrointestinal disorders during critical stages of development.


Clinicopathologic Features of Gastroenteropancreatic Neuroendocrine Tumors: A Single-center Experience
Gastroenteropancreatic neuroendocrine tumors, a heterogeneous group of neoplasms, originates from the neuroendocrine system of the gastrointestinal tract and pancreas. There are limited number of studies investigating neuroendocrine tumors in Turkey. To define the clinicopathologic, demographic, and survival features of patients with gastroenteropancreatic neuroendocrine tumors. A retrospective observational cohort study. We reviewed hospital records of patients and data was analyzed retrospectively. We investigated the clinical, pathological, survival features, and prognosis of patients with gastroenteropancreatic neuroendocrine tumors (n=128) admitted to the medical oncology department between year 2003 and 2014. Survival estimation was performed by the Kaplan-Meier method. Univariate and multivariate Cox regression models were utilized to investigate the prognostic factors for survival. Of 128 patients with gastroenteropancreatic neuroendocrine tumors, 61 (47.7%) were female and 67 (52.3%) were male. The most common site of the tumor was stomach (36.7%), while the most common stage of tumor at diagnosis was stage 4 (40.9%). The median follow-up period was 37 months, while the 3- and 5-year overall survival rates were 78% and 69%, respectively. The factors significantly affecting overall survival rate were clinical stage, grade, presence of metastasis at diagnosis, and Ki-67 proliferation index. These factors were associated with the 3- and 5-year overall survival rate. Moreover, grade (hazard ratio: 8.34, 95% confidence interval: 2.16-32.22, p=0.01) and presence of metastasis at diagnosis (hazard ratio: 3.18, 95% confidence interval: 1.30-7.77, p=0.01) independently predicted overall survival in multivariate model following adjustment for age and gender. Higher-grade and presence of metastasis at diagnosis are negative independent prognostic indicators of survival in patients with gastroenteropancreatic neuroendocrine tumors.


Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells.
Ser/Thr protein kinase CK2 regulates multiple processes that play important roles in the sensitivity of cancer to epidermal growth factor receptor targeting therapeutics, including PI3K-Akt-mTOR signaling, Hsp90 activity, and inhibition of apoptosis. We hypothesized that top-down inhibition of EGFR, combined with lateral suppression of multiple oncogenic pathways by targeting CK2, would create a pharmacologic synthetic lethal event and result in an improved cancer therapy compared to EGFR inhibition alone. This hypothesis was tested by combining CX-4945, a first-in-class clinical stage inhibitor of CK2, with the EGFR tyrosine kinase inhibitor, erlotinib, in vitro and in vivo in models of non-small cell lung carcinoma, NCI-H2170, and squamous cell carcinoma, A431. Our results demonstrate that combination of CX-4945 with erlotinib results in enhanced attenuation of the PI3K-Akt-mTOR pathway. We also observed an increase in apoptosis, synergistic killing of cancer cells in vitro, as well as improved antitumor efficacy in vivo. Taken together, these data position CK2 as a valid pharmacologic target for drug combinations and support further evaluation of CX-4945 in combination with EGFR targeting agents.


Organotin mixtures reveal interactions that modulate adipogenic differentiation in 3T3-L1 preadipocytes.
Organotin chemicals (butyltins and phenyltins) are the most widely used organometallic chemicals worldwide and are used in industrial applications, such as biocides and anti-fouling paints. Tributyltin (TBT) and more recently, dibutyltin (DBT) and triphenyltin (TPT) have been reported to stimulate adipogenic differentiation. Although these chemicals co-exist in the environment, their effect in combination remains unknown. We first investigated the adipogenic effect of eight organotin chemicals (monobutyltin (MBT), DBT, TBT, tetrabutyltin (TeBT), monophenyltin (MPT), diphenyltin (DPT), TPT, and tin chloride (SnCl4)) in the 3T3-L1 preadipocyte cell line in single exposures at two doses (10 and 50 ng/ml). Only three out of the eight organotins induced adipogenic differentiation with TBT eliciting the strongest adipogenic differentiation (in a dose-dependent manner) followed by TPT and DBT, as demonstrated by lipid accumulation and gene expression. We then hypothesized that, in combination (TBT, DBT, and TPT), adipogenic effects will be exacerbated compared to single exposures. However, at the higher dose (50 ng/ml), TBT-induced differentiation was reduced by TPT and DBT when in dual or triple combination. We tested whether TPT or DBT would interfere with adipogenic differentiation stimulated by a peroxisome proliferator-activated receptor (PPARγ) agonist (rosiglitazone) or a glucocorticoid receptor agonist (dexamethasone). Both DBT50 and TPT50 reduced rosiglitazone-, but not dexamethasone-stimulated adipogenic differentiation. In conclusion, DBT and TPT interfere with TBT's adipogenic differentiation possibly via PPARγ signaling. These findings highlight the antagonistic effects among organotins and the need to understand the effects and mechanism of action of complex organotin mixtures on adipogenic outcomes.


No Increased Risk of Colorectal Neoplasia in Patients With Inflammatory Bowel Disease and Postinflammatory Polyps.
Patients with inflammatory bowel disease (IBD) who have postinflammatory polyps (PIPs) may have an increased risk of developing colorectal neoplasia. Current guidelines recommend an intensified surveillance strategy in these patients, although the evidence for this recommendation is conflicting. The aim of our study was to assess whether IBD patients with PIPs are at increased risk of colorectal neoplasia. We established a retrospective cohort in a tertiary IBD center with IBD patients undergoing colorectal cancer (CRC) surveillance in the current era. We compared cumulative incidences of colorectal neoplasia since IBD diagnosis between patients with and without PIPs and corrected for confounders. Second, we compared the risk of receiving a colectomy. In our cohort with >22 years of median follow-up, 154 of 519 patients had PIPs. PIPs were associated with extensive disease (odds ratio [OR], 2.76; 95% confidence interval [CI], 1.61-4.42; P < 0.001) and with more severe inflammation at colonoscopy (OR, 3.54; 95% CI, 2.28-5.50; P < 0.001). After correction for confounders, the presence of PIPs was not associated with development of colorectal neoplasia (hazard ratio [HR], 1.28; 95% CI, 0.85-1.93; P = 0.24) or with development of advanced neoplasia (HR, 1.38; 95% CI, 0.52-3.68; P = 0.52). There was a higher risk of colectomy in patients with PIPs (HR, 3.41; 95% CI, 1.55-7.54; P = 0.002). In this cohort, PIPs were associated with disease extent, inflammation, and higher rates of colectomy. However, the presence of PIPs was not associated with the development of neoplasia. These findings suggest that patients with PIPs may not need an intensified surveillance strategy.


The role of estrogen in the feedback regulation of follicle-stimulating hormone secretion in the female rat.
Letrozole (CGS 20267) is a non-steroidal aromatase inhibitor which, at its maximally effective dose of 1 mg/kg p.o., elicits endocrine effects equivalent to those seen after ovariectomy. Adult, female cyclic rats were administered letrozole (1 mg/kg p.o.) once daily for 14 days. A control group of animals was ovariectomized on day 1 of treatment and a third group of animals served as untreated controls. During the experiment, vaginal smears were taken daily and at the end of 14 days all animals were sacrificed, trunk blood was taken for serum estradiol, LH and FSH measurements and the uterus and ovaries were removed and weighed. The ovaries were then fixed and prepared for histological examination. Serum hormone measurements showed that after treatment with letrozole, serum estradiol levels were reduced by 76% of untreated controls and serum LH was elevated to 378% of control values. These compared favorably with those seen after ovariectomy, serum estradiol was reduced by 78% and serum LH was elevated to 485% of untreated controls. However, FSH was unchanged after letrozole treatment (125% of control), whereas after ovariectomy FSH rose to 398% of control. Uterine weight was suppressed in the letrozole-treated animals as well as the ovariectomized animals by 60 and 70%, respectively. The histology of the ovaries of animals treated with letrozole were consistent with the serum hormone findings. Except for the effects on serum FSH, these results confirm previous findings that treatment with letrozole elicits endocrine effects similar to those seen after ovariectomy. Furthermore, these results demonstrate that FSH secretion is not under the control of estradiol whereas LH secretion is under feedback control of ovarian estrogen.


The role of adjuvant chemotherapy in nasopharyngeal carcinoma with bulky neck lymph nodes in the era of IMRT.
Nasopharyngeal carcinoma (NPC) patients with N2-3 diseases are prone to develop distant metastasis even treated with standard concurrent chemoradiotherapy (CCRT). Our study is aim to determine the optimal treatment strategy of these patients. Patients with histologically proven NPC were retrospectively analyzed according to the AJCC 2002 stage classification system. A total of 547 patients who had N2-3 diseases were enrolled. They were all treated with Intensity-modulated radiation therapy (IMRT) combined with systemic treatments, including radiotherapy alone (RT alone), neoadjuvant chemotherapy followed by radiotherapy (NACT+RT), CCRT, NACT+CCRT, NACT followed by radiotherapy and adjuvant chemotherapy (NACT+RT+AC), CCRT+AC and NACT+CCRT+AC. A subgroup analysis was also conducted. With a median follow-up time of 53.8 months, adjuvant chemotherapy significantly decreased the risk of distant metastasis (HR 0.413, 95% CI 0.194-0.881, p = 0.022) as well as significantly increased the OS (HR 0.398, 95% CI 0.187-0.848, p = 0.017) in patients with N3 disease. The addition of adjuvant chemotherapy seemed to provide benefits to patients with N3 stage NPC and the current study may indicate the need for further randomized investigation.


Mandibular fracture in a neonate: report of a case.
Neonatal mandibular fractures are rare and are mostly due to traumatic delivery. Attempted infanticide has also been reported as a cause. A case of a fractured mandible in a neonate assaulted by its mother suffering from postpartum psychosis is presented.


Carrier and prenatal diagnosis of Lesch-Nyhan disease due to a defect in HPRT gene expression regulation.
Lesch-Nyhan disease (LND) is caused by lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. Mutations in HPRT1 gene show variability in type and location within the gene, and in certain patients the HPRT coding sequence is normal and the molecular defect cannot be found. These patients presented a decreased HPRT1 expression of unknown cause. This is the first report of a carrier and prenatal diagnosis of LND due to a defect in HPRT gene expression regulation.


Discordant pathologic diagnoses of myelodysplastic neoplasms and their implications for registries and therapies.
Myelodysplastic neoplasms (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Accurate pathologic diagnoses present challenges because of interobserver variability in interpreting morphology and quantifying dysplasia. We compared local clinical site diagnoses with central, adjudicated review from 918 participants enrolled in the ongoing National Heart, Lung, and Blood Institute National MDS Natural History Study, a prospective observational cohort study of participants with suspected MDS or MDS/myeloproliferative neoplasms (MPNs). Locally, 264 (29%) were diagnosed as having MDS, 15 (2%) MDS/MPN overlap, 62 (7%) idiopathic cytopenia of undetermined significance (ICUS), 0 (0%) acute myeloid leukemia (AML) with <30% blasts, and 577 (63%) as other. Approximately one-third of cases were reclassified after central review, with 266 (29%) diagnosed as MDS, 45 (5%) MDS/MPN overlap, 49 (5%) ICUS, 15 (2%) AML with <30%, and 543 (59%) as other. Site miscoding errors accounted for more than half (53%) of the local misdiagnoses, leaving a true misdiagnosis rate of 15% overall, 21% for MDS. Therapies were reported in 37% of patients, including 43% of patients with MDS, 49% of patients with MDS/MPN, and 86% of patients with AML with <30% blasts. Treatment rates were lower (25%) in cases with true discordance in diagnosis compared with those for whom local and central diagnoses agreed (40%), and receipt of inappropriate therapy occurred in 7% of misdiagnosed cases. Discordant diagnoses were frequent, which has implications for the accuracy of study-related and national registries and can lead to inappropriate therapy. This trial was registered at www.clinicaltrials.gov as #NCT05074550.


Identifying studies for systematic reviews. An example from medical imaging.
To determine if published figures on the proportion of articles included in systematic reviews and identified in electronic databases are applicable to an example from medical imaging. A systematic review was performed. Additionally, sensitivity and precision of a MEDLINE search were compared with values from three published searches, each customized for a specific field. All articles included in the systematic review were in electronic databases. The MEDLINE search had low precision compared with searches in other fields. In a specific area of medical imaging, electronic databases, including MEDLINE, are reliable sources of articles.


[Significance of the hemodynamics for the extent of the rejection. Comparison of immunological reactions in artery transplantation in high pressure and vein transplantation in low pressure systems in matching inbred rat strain combinations].
Systemic sensitization is induced by arterial transplants in the high pressure system and by venous transplants in the low pressure system. In aorta transplantation the severity of the rejection corresponds directly to the immunogenetic differences between donor and recipient; the efferent limb is triggered into action. For application of allogeneic veno-venous transplants this is not the case: despite systemic sensitization, even strongly allogeneic venous transplants are maintained over long periods. A threshold value is not reached unless there is presensitization with strong antigens, after which morphologically comprehensible rejection reactions, i.e. round cell infiltration, are demonstrated even in veno-venous transplants.


[Determination of chlorogenic acid and baicalin in Yinhuang film-coated tablets by HPLC isocratic elution].
To establish an HPLC method for determination of chlorogenic acid and baicalin in Yinhuang film-coated tablets. HPLC isocratic elution was adopted, with the C18 column (4.6 mm x 250 mm, 5 microm) as the chromatographic column, methanol-water-phosphoric acid (45: 55: 0.2) as the mobile phase. The flow rate was set at 1.0 mL x min(-1), and column temperature was set at 30 degrees C. The detection wavelength was 328 nm, and the sample size was 20 microL. At concentrations ranging between 2.200-44.00, 24.20-242.0 mg x L(-1), peak area of chlorogenic acid and baicalin showed good linear relationship, the average recoveries were 99.63% (RSD 1.8%, n = 9) and 99.72% (RSD 1.9%, n = 9), respectively. The method is simple that it can accurately measure the content of chlorogenic acid and baicalin in Yinhuang film-coated tablets.


Ride Safe: a child passenger safety program for American Indian/Alaska Native children.
In American Indian/Alaska Native (AI/AN) communities, child safety seat (CSS) use rates are much lower than in non-native communities. To reduce this disparity, Indian Health Service (IHS) staff developed, pilot-tested, and implemented Ride Safe, which provided education, training, and child safety seats for children aged 3-5 participating in Tribal Head Start Centers. Focus groups, key informant interviews, and technical review guided program development and implementation. Progress reports and child safety seat use observations, conducted at the beginning and end of three program years (Fall 2003 to Spring 2006), assessed program reach and impact. To examine CSS use, we used three multiple logistic regressions, including a conservative intent to treat analysis. Ride Safe reached approximately 3,500 children and their families at 14 sites in six states, providing over 1,700 parents/family members with educational activities, 2,916 child safety seats, and child passenger safety (CPS) technician certification training for 78 Tribal staff. Children were 2.5 times (OR = 2.55, p < .01) as likely to be observed in child safety seats comparing Rounds 1 and 2 data, with the most conservative model showing that the odds of being observed restrained were 74% higher (OR = 1.74, p = or<.01) after implementation of the program. The Ride Safe Program effectively increased child safety seat use in AI/AN communities, however, observed use rates ranging from 30% to 71% remain well below the 2006 all US rate of 93%. Results from CSS educational and distribution/installation programs such as Ride Safe should be considered in light of the need to increase distribution programs and enhance enforcement activities in AI/AN communities, thereby reducing the disparity in AI/AN motor vehicle injuries and death.


Nonequilibrium fluctuations of mechanically stretched single red blood cells detected by optical tweezers.
We study the thermal and out-of-equilibrium mechanical dynamics of single, living human red blood cells (RBCs) by combining two-probe passive and active microrheology techniques. Both experiments were performed quasisimultaneously on the same cell using two identical polystyrene probes, biochemically attached to the cell membrane. We obtained compelling evidence of nonequilibrium fluctuations in the RBCs under physiological condition and without the influence of any external chemicals. The spectral distributions of metabolically driven forces and viscoelastic response were evaluated in the relaxed and stretched states, intended to simulate the varying natural environment of the cells during blood circulation. We found that the internally generated forces are more pronounced in the stretched state, suggesting a stress-dependent RBC activity.


Implication of graphene oxide in Cd-contaminated soil: A case study of bacterial communities.
The application of graphene oxide (GO) has attracted increasing concerns in the past decade regarding its environmental impacts, except for the impact of GO on a metal-contaminated soil system, due to its special properties. In the present work, the effects of GO on the migration and transformation of heavy metals and soil bacterial communities in Cd-contaminant soil were systematically evaluated. Soil samples were exposed to different doses of GO (0, 1, and 2 g kg-1) over 60 days. The Community Bureau of Reference (BCR) sequential extraction procedure was used to reflect the interaction between GO and Cd. Several microbial parameters, including enzyme activities and bacterial community structure, were measured to determine the impacts of GO on polluted soil microbial communities. It was shown that Cd was immobilized by GO throughout the entire exposure period. Interestingly, the structure of the bacterial community changed. The relative abundance of the major bacterial phyla (e.g., Acidobacteria and Actinobacteria) increased, which was possibly attributed to the reduced toxicity of Cd in the presence of GO. However, GO exerted an adverse influence on the relative abundance of some phyla (e.g., WD272 and TM6). The diversity of bacterial communities was slightly restricted. The functional bacteria related to carbon and the nitrogen cycling were also affected, which, consequently, may influence the nutrient cycling in soil.


Prenatal diagnosis and mRNA profiles of fetal tetralogy of Fallot.
Tetralogy of fallot (TOF) in the fetus is a typical congential heart disease that occurs during the early embryonic period, being characterized by the abnormal development of conus arteriosus. The early diagnosis and prevention of fetal TOF is very important and there is a great need for exploring the pathogenesis of it in clinic. In this study, there were three cases being detected with TOF by fetal echocardiogram and confirmed by autopsy. We characterize the difference of expression of lncRNAs and mRNAs through sequencing analysis of 3 pairs of myocardial tissues of fetal TOF and those of age-matched controls. Compared with normal group, there were 94 differentially expressed lncRNAs and 83 mRNA transcripts in TOF (P < 0.05). Correlation analysis between lncRNA and mRNA further showed that differentially expressed lncRNA can be linked to mRNAs, suggesting the potential regulator role of lncRNA in mRNA expression. Our data serve as a fundamental resource for understanding the disease etiology of TOF.


Lactobacillus-fermented yogurt exerts hypoglycemic, hypocholesterolemic, and anti-inflammatory activities in STZ-induced diabetic Wistar rats.
Hyperglycemia is a symptom of type 2 diabetes mellitus, a chronic metabolic disease characterized by elevated blood glucose concentrations. Antidiabetic drugs are common treatments for this metabolic disorder; however, they may have unpleasant side effects. This study hypothesized that probiotic fermented products could preserve nutritional value, maintain metabolic homeostasis, and attenuate the inflammatory response associated with diabetes while reducing side effects. Lactobacillus plantarum KU985438 and Lactobacillus rhamnosus KU985439 showed the lowest alfa-amylase enzyme (α-amylase) activity among 8 lactobacilli tested. These 2 strains were used to develop functional fermented milk products, and their antidiabetic efficacy was tested in induced diabetic Wistar rats. The treatment of diabetic rats with L. plantarum KU985438 or L. rhamnosus KU985439 fermented yogurt resulted in a considerable reduction in blood glucose concentrations (136.79% and 145.17%, respectively) and α-amylase concentrations (56.84% and 56.84%, respectively) compared with conventional treatments. Diabetes relief began after 4 days of yogurt consumption compared with drug-based treatment. Significant improvements in both liver and kidney enzyme concentrations were also observed, in addition to a significant increase in high-density lipoprotein cholesterol concentrations and improved lipid profiles. Inhibition in nuclear factor κB and an increase in Bcl-2 concentrations were also detected. Histopathological examination of both hepatic and pancreatic cells revealed the positive effects of the studied treatment compared with standard treatment. Therefore, the selected Lactobacilli, which has hypoglycemic potential, could be used to produce functional nutraceutical antidiabetic supplements.


Misonidazole and benznidazole inhibit hydroxylation of CCNU by mouse liver microsomal cytochrome P-450 in vitro.
On the basis of promising experimental studies, the nitroimidazoles misonidazole (MISO) and benznidazole (BENZO) are under clinical investigation as chemosensitizers in combination with the chloroethylnitrosourea CCNU. We have shown previously that MISO and BENZO can alter the pharmacokinetics of CCNU leading to an improved therapeutic index in mice. Here we demonstrate using optical difference spectroscopy that MISO and BENZO are able to bind to cytochrome P-450 of mouse liver microsomes in vitro. Binding was type II in nature, indicating co-ordination of the free imidazole nitrogen with the heme moiety of cytochrome P-450. This results in an inhibition of CCNU hydroxylation by the hemoprotein. The kinetics of inhibition were of a mixed competitive-non-competitive type. At a CCNU concentration of 0.05 mM the concentrations causing 50% inhibition (I50) were 5.8 and 0.37 mM for MISO and BENZO respectively. At doses producing a similar improvement in therapeutic index in mice (2.5 mmoles/kg MISO and 0.3 mmoles/kg BENZO) the plasma and tissue concentrations achieved would inhibit CCNU hydroxylation by 30%. For BENZO, but not MISO, similar inhibition would also occur at concentrations which can be achieved safely in man.


The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages.
The Toll-like receptors (TLRs) play a pivotal role in innate immunity for the detection of highly conserved, pathogen-expressed molecules. Previously, we demonstrated that lipopolysaccharide (LPS, TLR4 ligand)-increased macrophage motility required the participation of Src and FAK, which was inducible nitric oxide synthase (iNOS)-dependent. To investigate whether this iNOS/Src/FAK pathway is a general mechanism for macrophages to mobilize in response to engagement of TLRs other than TLR4, peptidoglycan (PGN, TLR2 ligand), polyinosinic-polycytidylic acid (polyI:C, TLR3 ligand) and CpG-oligodeoxynucleotides (CpG, TLR9 ligand) were used to treat macrophages in this study. Like LPS stimulation, simultaneous increase of cell motility and Src (but not Fgr, Hck, and Lyn) was detected in RAW264.7, peritoneal macrophages, and bone marrow-derived macrophages exposed to PGN, polyI:C and CpG. Attenuation of Src suppressed PGN-, polyI:C-, and CpG-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by the reintroduction of siRNA-resistant Src. Besides, knockdown of FAK reduced the mobility of macrophages stimulated with anyone of these TLR ligands. Remarkably, PGN-, polyI:C-, and CpG-induced Src expression, FAK Pi-Tyr861, and cell mobility were inhibited in macrophages devoid of iNOS, indicating the importance of iNOS. These findings corroborate that iNOS/Src/FAK axis occupies a central role in macrophage locomotion in response to engagement of TLRs.


A medical nutriment has supportive value in the treatment of colorectal cancer.
MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients' choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, P<0.01; new metastases: 7.6 vs 23.1%, P<0.01; deaths: 12.1 vs 31.7%, P<0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P=0.0184) and overall survivals (P=0.0278) probabilities. Survival predictors in Cox's proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival.


CNT-TiO2 coating bonded onto stainless steel wire as a novel solid-phase microextraction fiber.
A novel solid-phase microextraction (SPME) fiber based on carbon nanotubes-titanium oxide (CNT-TiO2) composite coating bonded onto stainless steel wire was prepared via electroless plating and sol-gel techniques. The SPME coating was characterized by scanning electron microscopy and Raman microscopy. Coupled to gas chromatography (GC), the fiber was investigated with seven polycyclic aromatic hydrocarbons (PAHs) in direct-immersion mode. The SPME-GC analytical method was evaluated under optimized extraction conditions. Compared with other reports, higher sensitivity (LODs, 0.002-0.004 μg L(-1)) and better linear range (0.01-100 and 0.01-200 μg L(-1)) were obtained by the proposed method. The fiber exhibited high thermal stability to 300 °C and excellent durability in HCl and NaOH solutions. The as-established SPME-GC method was used to analyze the real water samples and satisfactory results were obtained.


A General and Efficient Strategy for Gene Delivery Based on Tea Polyphenols Intercalation and Self-Polymerization.
Gene therapy that employs therapeutic nucleic acids to modulate gene expression has shown great promise for diseases therapy, and its clinical application relies on the development of effective gene vector. Herein a novel gene delivery strategy by just using natural polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) as raw material is reported. EGCG first intercalates into nucleic acids to yield a complex, which then oxidizes and self-polymerizes to form tea polyphenols nanoparticles (TPNs) for effective nucleic acids encapsulation. This is a general method to load any types of nucleic acids with single or double strands and short or long sequences. Such TPNs-based vector achieves comparable gene loading capacity to commonly used cationic materials, but showing lower cytotoxicity. TPNs can effectively penetrate inside cells, escape from endo/lysosomes, and release nucleic acids in response to intracellular glutathione to exert biological functions. To demonstrate the in vivo application, an anti-caspase-3 small interfering ribonucleic acid is loaded into TPNs to treat concanavalin A-induced acute hepatitis, and excellent therapeutic efficacy is obtained in combination with the intrinsic activities of TPNs vector. This work provides a simple, versatile, and cost-effective gene delivery strategy. Given the biocompatibility and intrinsic biofunctions, this TPNs-based gene vector holds great potential to treat various diseases.


Electroacupuncture Could Regulate the NF-κB Signaling Pathway to Ameliorate the Inflammatory Injury in Focal Cerebral Ischemia/Reperfusion Model Rats.
The activated nuclear factor-KappaB signaling pathway plays a critical role in inducing inflammatory injury. It has been reported that electroacupuncture could be an effective anti-inflammatory treatment. We aimed to explore the complex mechanism by which EA inhibits the activation of the NF- κ B signal pathway and ameliorate inflammatory injury in the short term; the effects of NEMO Binding Domain peptide for this purpose were compared. Focal cerebral I/R was induced by middle cerebral artery occlusion for 2 hrs. Total 380 male Sprague-Dawley rats are in the study. The neurobehavioral scores, infarction volumes, and the levels of IL-1 β and IL-13 were detected. NF- κ B p65, I κ B α , IKK α , and IKK β were analyzed and the ability of NF- κ B binding DNA was investigated. The EA treatment and the NBD peptide treatment both reduced infarct size, improved neurological scores, and regulated the levels of IL-1 β and IL-13. The treatment reduced the expression of IKK α and IKK β and altered the expression of NF- κ B p65 and I κ B α in the cytoplasm and nucleus; the activity of NF- κ B was effectively reduced. We conclude that EA treatment might interfere with the process of NF- κ B nuclear translocation. And it also could suppress the activity of NF- κ B signaling pathway to ameliorate the inflammatory injury after focal cerebral ischemia/reperfusion.


Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator.
Pax6 is a highly conserved transcription factor among vertebrates and is important in various developmental processes in the central nervous system (CNS), including patterning of the neural tube, migration of neurons, and formation of neural circuits. In this review, we focus on the role of Pax6 in embryonic and postnatal neurogenesis, namely, production of new neurons from neural stem/progenitor cells, because Pax6 is intensely expressed in these cells from the initial stage of CNS development and in neurogenic niches (the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricle) throughout life. Pax6 is a multifunctional player regulating proliferation and differentiation through the control of expression of different downstream molecules in a highly context-dependent manner.


MicroRNA miR-263b-5p Regulates Developmental Growth and Cell Association by Suppressing Laminin A in Drosophila.
Basement membranes (BMs) play important roles under various physiological conditions in animals, including ecdysozoans. During development, BMs undergo alterations through diverse intrinsic and extrinsic regulatory mechanisms; however, the full complement of pathways controlling these changes remain unclear. Here, we found that fat body-overexpression of Drosophila miR-263b, which is highly expressed during the larval-to-pupal transition, resulted in a decrease in the overall size of the larval fat body, and ultimately, in a severe growth defect accompanied by a reduction in cell proliferation and cell size. Interestingly, we further observed that a large proportion of the larval fat body cells were prematurely disassociated from each other. Moreover, we present evidence that miR-263b-5p suppresses the main component of BMs, Laminin A (LanA). Through experiments using RNA interference (RNAi) of LanA, we found that its depletion phenocopied the effects in miR-263b-overexpressing flies. Overall, our findings suggest a potential role for miR-263b in developmental growth and cell association by suppressing LanA expression in the Drosophila fat body.


Paclitaxel inhibits cell proliferation and collagen lattice contraction via TGF-β signaling pathway in human tenon's fibroblasts in vitro.
As an anti-microtubule agent, paclitaxel has been widely applied clinically. However, the effects of paclitaxel on human tenon's fibroblast (HTF) proliferation and migration in vitro was still unclear. In the present study, we explored the influences of paclitaxel on HTF cell proliferation, cell viability, cell cycle phase distribution under various concentrations of paclitaxel (i.e., 0, 10(-8), 10(-7), 10(-6)mol/l) via real-time cell electronic system and flow cytometry, further determined the expression of TGF-β1 and connective tissue growth factor (CTGF) after treatment with different concentrations of paclitaxel. Moreover, extra cellular matrix production and collagen lattice contraction assay were also explored. The results indicate that paclitaxel could apparently inhibit the cell viability, induces the elevation of S and G2/M phases of HTFs, and downregulates the expression of both TGF-β1 and CTGF. Meanwhile, the levels of fibronectin extra domain A (EDA), collagen and collagen lattice contraction were apparently reduced after treatment with paclitaxel. Overall, paclitaxel could apparently inhibit the proliferation of HTFs and leads to cell cycle arrest at both S and G2/M phases, attenuates the generation of collagen and collagen lattice contraction, decreases the expressions of TGF-β1, CTGF and fibronectin EDA. The inhibitory mechanism of paclitaxel on HTFs is involved in TGF-β1 signaling pathway.


An investigation of PreMCI: subtypes and longitudinal outcomes.
To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI). We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination. The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression. Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits.


5-Bromo-2'-deoxyuridine incorporation into DNA in hepatic VX2 tumor-bearing rabbits.
The halogenated pyrimidine 5-bromo-2'-deoxyuridine (BrdUrd) possesses both radiosensitizing and antimetabolite effects through its incorporation as a thymidine analog in replicating DNA. To evaluate the regional advantage for treatment of hepatic malignancy by hepatic arterial infusion, BrdUrd was infused into either the hepatic artery (HA) or a central vein (iv) in 26 rabbits with intrahepatic VX2 tumor. After a 24-hr constant rate infusion of 10, 20, or 40 mg/kg/24 hr, the percentage BrdUrd incorporation into the DNA of bone marrow, duodenal mucosa, liver, and hepatic VX2 tumor was measured by gas chromatography/mass spectrometry methods. VX2 tumor BrdUrd incorporation was greater by HA than by iv routes (P less than 0.001). At doses of 10 and 20 mg/kg/day, HA to iv BrdUrd incorporation ratios for VX2 tumor significantly exceeded those for bone marrow and duodenum (P less than 0.05). At appropriate dose rates, hepatic arterial administration of BrdUrd provides a regional advantage for DNA BrdUrd incorporation in the rabbit intrahepatic VX2 tumor.


Effectiveness of a 10-week tier-1 response to intervention program in improving fine motor and visual-motor skills in general education kindergarten students.
This study examined the efficacy of a 10-wk Tier 1 Response to Intervention (RtI) program developed in collaboration with classroom teachers to improve the fine motor and visual-motor skills of general education kindergarten students. We recruited 113 students in six elementary schools. Two general education kindergarten classrooms at each school participated in the study. Classrooms were randomly assigned to the intervention and control groups. Fine motor skills, pencil grip, and visual-motor integration were measured at the beginning of the school year and after the 10-wk intervention. The intervention group demonstrated a statistically significant increase in fine motor and visual-motor skills, whereas the control group demonstrated a slight decline in both areas. Neither group demonstrated a change in pencil grip. This study provides preliminary evidence that a Tier 1 RtI program can improve fine motor and visual-motor skills in kindergarten students.


"Single suture" for exposure of the heart in left ventricular assist device placement.
Using the "single suture" technique described for exposure of the heart during off-pump coronary surgery, all surfaces of the heart may be exposed with little hemodynamic compromise. Using this technique, the apex of the heart is easily elevated for left ventricular assist device (LVAD) insertion in patients with either ischemic or dilated cardiomyopathy. This technique may provide the groundwork for routine placement of LVADs without the use of cardiopulmonary bypass.


Detrimental role for CD4+ T lymphocytes in murine diffuse peritonitis due to inhibition of local bacterial elimination.
Abdominal sepsis due to intestinal leakage of endogenous gut bacteria is a life-threatening condition. In healthy individuals, T lymphocytes have essential functions in balancing the immune response to the commensal gut flora. To determine how T lymphocytes shape the process of diffuse faecal peritonitis. In colon ascendens stent peritonitis (CASP), a clinically relevant mouse model of diffuse peritonitis, the kinetics of systemic T cell activation were investigated by assessment of activation markers. CD4(+) T cells were then depleted with monoclonal antibodies, and survival, bacterial dissemination and cytokine concentrations were measured. T cell receptor signalling was blocked with tacrolimus. In diffuse peritonitis, CD4(+) T cells, both Foxp3(-) and Foxp3(+), became systemically involved within hours and upregulated CTLA-4 and other activation markers. Depletion of the CD4(+) T cells enhanced local bacterial clearance from the peritoneal cavity, reduced bacterial dissemination and improved survival. This was accompanied by increased immigration of granulocytes and macrophages into the peritoneum, indicating that CD4(+) T cells inhibit the local innate immune response. Blockade of T cell receptor (TCR) signalling by tacrolimus did not influence the survival in this peritonitis model, showing that the inhibitory effects of the CD4(+) T lymphocytes were independent of TCR-mediated antigen recognition. In diffuse peritonitis caused by commensal gut bacteria the CD4(+) T lymphocytes exert a net negative effect on the local anti-bacterial defence, and thereby contribute to bacterial dissemination and poor outcome.


Ice plant root plasma membrane aquaporins are regulated by clathrin-coated vesicles in response to salt stress.
The regulation of root Plasma membrane (PM) Intrinsic Protein (PIP)-type aquaporins (AQPs) is potentially important for salinity tolerance. However, the molecular and cellular details underlying this process in halophytes remain unclear. Using free-flow electrophoresis and label-free proteomics, we report that the increased abundance of PIPs at the PM of the halophyte ice plant (Mesembryanthemum crystallinum L.) roots under salinity conditions is regulated by clathrin-coated vesicles (CCV). To understand this regulation, we analyzed several components of the M. crystallinum CCV complexes: clathrin light chain (McCLC) and subunits μ1 and μ2 of the adaptor protein (AP) complex (McAP1μ and McAP2μ). Co-localization analyses revealed the association between McPIP1;4 and McAP2μ and between McPIP2;1 and McAP1μ, observations corroborated by mbSUS assays, suggesting that AQP abundance at the PM is under the control of CCV. The ability of McPIP1;4 and McPIP2;1 to form homo- and hetero-oligomers was tested and confirmed, as well as their activity as water channels. Also, we found increased phosphorylation of McPIP2;1 only at the PM in response to salt stress. Our results indicate root PIPs from halophytes might be regulated through CCV trafficking and phosphorylation, impacting their localization, transport activity, and abundance under salinity conditions.


Effects of Asian dust storm events on daily stroke admissions in Taipei, Taiwan.
In spring, windblown dust storms originating in the deserts of Mongolia and China make their way to Taipei city. These occurrences are known as Asian dust storm (ADS) events. The objective of this study was to assess the possible associations of ADS on the hospital stroke admissions of residents in Taipei, Taiwan, during the period from 1996 to 2001. We identified 54 dust storm episodes, which were classified as index days. Daily stroke admissions on the index days were compared with admissions on the comparison days. We selected two comparison days for each index day, 7 days before the index days and 7 days after the index days. The study results indicated a statistically significant association between ADS events and daily primary intracerebral hemorrhagic stroke admissions 3 days after the event (relative risk of 1.15; 95% CI, 1.01-10.10). We also found a positive but nonsignificant association between ADS events and ischemic stroke admissions 3 days following the dust storms. This was due mainly to PM(10). We conclude that more attention be given to ADS events and health in the future.


Antitumor activity of host T and non-T cells recovered from tumor nodules after interferon therapy.
We examined the modification of host T cells of tumor nodules by interferon (IFN) therapy in mouse models. The host cells were recovered from regressing tumor nodules of mice at Day 13 after intradermal tumor inoculation at Day 0 and administration of 5 x 10(5) U/mouse/day IFN at Day 6 to Day 10. These host cells neutralized in vivo Meth A growth in a dose-dependent fashion. In vitro treatment of these cells with anti-Thy 1.2 monoclonal antibody and rabbit sera as a source of complement abrogated their tumor-neutralizing activity, but only partially, indicating that both T cells and non-T cells were involved in tumor neutralization. The finding that host cells from regressing tumor nodules of either Meth A or Meth 1, an antigenically distinct fibrosarcoma, neutralized both Meth A and Meth 1 tumors without much selectivity was consistent with possible non-T cell involvement. Most of these characteristics of host cells of regressing nodules of IFN-administered mice were also noted with host cells of progressing nodules of placebo-administered mice and there was no significant difference in neutralizing activity qualitatively or quantitatively between the two sources of host cells. There was no significant difference in host T and B cell numbers and compositions of regressing and progressing nodules either. These essentially negative findings raise the possibility, among others, that the primary target host cells to be modified by IFN were not T cells, although the therapeutic effect of IFN was dependent on the host T cells.


Cholesterol efflux regulator ABCA1 exerts protective role against high shear stress-induced injury of HBMECs via regulating PI3K/Akt/eNOS signaling.
In brain, microvascular endothelial cells are exposed to various forces, including shear stress (SS). However, little is known about the effects of high shear stress (HSS) on human brain microvascular endothelial cells (HBMECs) and the underlying mechanism. The cholesterol efflux regulator ATP-binding cassette subfamily A member 1 (ABCA1) has been demonstrated to exert protective effect on HBMECs. However, whether ABCA1 is involved in the mechanism underneath the effect of HSS on HBMECs remains obscure. In the present study, a series of experiments were performed to better understand the effect of HSS on cellular processes of HBMECs and the possible involvement of ABCA1 and PI3K/Akt/eNOS in the underlying mechanisms. HBMECs were subjected to physiological SS (PSS) or high SS (HSS). Cell migration was evaluated using Transwell assay. Apoptotic HBMECs were detected by flow cytometry or caspase3/7 activity. IL-1β, IL-6, MCP-1 and TNF-α levels were measured by ELISA. RT-qPCR and western blotting were used for mRNA and protein expression detection, respectively. ROS and NO levels were detected using specific detection kits. Compared to PSS, HBMECs exhibited decreased cell viability and migration and increased cell apoptosis, increased levels of inflammatory cytokines, and improved ROS and NO productions after HSS treatment. Moreover, HSS downregulated ABCA1 but upregulated the cholesterol efflux-related proteins MMP9, AQP4, and CYP46 and activated PI3K/Akt/eNOS pathway. Overexpression of ABCA1 in HBMECS inhibited PI3K/Akt/eNOS pathway and counteracted the deleterious effects of HSS. Contrary effects were observed by ABCA1 silencing. Inhibiting PI3K/Akt/eNOS pathway mimicked ABCA1 effects, suggesting that ABCA1 protects HBMECs from HSS via PI3K/Akt/eNOS signaling. These results advanced our understanding on the mechanisms of HSS on HBMECs and potentiated ABCA1/PI3K/Akt/eNOS pathway as therapeutic target for cerebrovascular diseases.


Polymerase chain reaction analysis of the cystic fibrosis delta F508 mutation in human blastomeres following oocyte injection of a single sperm from a carrier.
The efficiency of the polymerase chain reaction (PCR) in detecting the cystic fibrosis (CF) delta F508 mutation (which is the most common mutation of CF) was assessed in single human blastomeres. Twenty-one human immature oocytes (germinal-vesicle-stage oocytes) that had been donated for research were matured in vitro and a single spermatozoon from a carrier of the CF delta F508 mutation was injected into the ooplasm. Fourteen embryos were obtained after intracytoplasmic sperm injection (ICSI). PCR analysis was carried out on 70 single blastomeres isolated from these 14 embryos. The results showed that the efficiency of DNA amplification by PCR in single nucleate blastomeres was 94 per cent (59/63). There were no false-positive results since none of the blank samples or the blastomeres without a nucleus showed an amplified signal. We found that nine embryos were homozygous for the unaffected genotype and that four embryos were heterozygous since they contained both the unaffected and the delta F508 genotype. In a four-cell embryo, we observed the homozygous unaffected genotype in one blastomere and a heterozygous delta F508/unaffected genotype in the other three blastomeres.


Micro-Finite Element analysis will overestimate the compressive stiffness of fractured cancellous bone.
Recently, micro-Finite Element (micro-FE) analysis based on High Resolution peripheral Quantitative CT (HRpQCT) images was introduced to quantify the state of fracture healing (de Jong et al., 2014). That study suggested that the direct post-fracture stiffness may be overestimated by micro-FE. The aim of this study was to investigate this further by measuring the loss in stiffness of cancellous bone samples under compressive loading and to compare this with predictions based on micro-FE analyses and bone microstructural and fracture morphology. Sixty porcine trabecular cores were micro-CT scanned and tested in compression before and after inducing a fracture in 4 different manners. The loss in stiffness as measured in the experiment was compared to that calculated from micro-FE analysis. Additionally, bone morphology parameters and fracture thickness were calculated. The experimentally measured loss in stiffness ranged from 37% to 80%. The losses calculated from the micro-FE analyses were lower and ranged from 36% to 61%, while in one case an increase in stiffness was calculated. For 2 of the 4 experiments, the results of the experiment and micro-FE analyses were significantly different. Only for very smooth fractures good agreement was obtained between FE and experimental results. The loss in stiffness did not correlate with any investigated bone morphology parameter or the thickness of the fracture region. It was concluded that micro-FE analysis can severely overestimate the stiffness of fractured bone depending on the type of fracture, but in the case of smooth fractures good estimates are possible.