Novel Applications of Biocatalysis to Stereochemistry Determination of 2'3'-cGAMP Bisphosphorothioate (2'3'-cGSASMP).
The metazoan second messenger 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is a cyclic dinucleotide (CDN) that induces secretion of type I interferons and activates the immune system and has thus attracted significant interest as a vaccine adjuvant or immunotherapeutic. CDN bisphosphorothioates are of particular interest because of their increased hydrolytic stability and improved cell activities. In our work with CDN bisphosphorothioates, we sought a method for systematic determination of the absolute stereochemistry of their phosphorothioate stereocenters. A novel biocatalytic method employing snake venom phosphodiesterase (svPDE) and nP1 has been developed and successfully applied to stereochemistry determination of 2'3'-cGAMP bisphosphorothioates. This method unambiguously assigned the phosphorothioate stereochemistry of four diastereomers of 2'3'-cGAMP bisphosphorothioate by analyzing distinct hydrolysis patterns of the bisphosphorothioate diastereomers upon incubation with svPDE and nP1. Furthermore, the regiospecificity as well as stereospecificity of both svPDE and nP1 toward 2'3'-cGAMP bisphosphorothioate has been elucidated.


Radial nerve injuries and outcomes: Our surgical experience.
The aim of this study was to retrospectively evaluate patients who underwent surgery in our department for radial nerve lesions in terms of surgical outcomes. Thirty-eight patients were admitted to our department with radial nerve lesion. Twenty-seven of the patients had entrapment neuropathy and 11 had radial nerve injury secondary to other traumas. Various factors such as surgical results, time to surgical intervention, injury mechanism, and reconstruction technique were analyzed. In all of 27 patients who were operated for radial nerve entrapment neuropathy, a complete improvement in wrist dorsal flexion was detected at postoperative 3rd month. Seven of the 11 patients who were operated for radial nerve lesion had different degrees of improvement in wrist dorsal flexion at the postoperative 3rd month. Two of the seven patients underwent anastomosis using a sural nerve graft. The recovery rate in our series was 89%. Three of the 4 patients who did not recover after the radial nerve injury were the patients who were operated within the 1st month after the trauma. Better functional results were obtained in the postoperative period in patients who were operated after the 1st month, underwent internal neurolysis and used a short nerve graft for anastomosis in the radial nerve lesions. In patients with entrapment neuropathy, the earliest surgery revealed satisfactory results in the postoperative period.


[Changes in thyroid hormone levels following severe burns treated topically with povidone-iodine].
The serum concentrations of thyroxine (T4), triiodothyronine (T3) and TSH as well as the effective thyroxine ratio (ETR) and the resin-T3-uptake (RT3U) were studied in 23 severely burned patients during the whole time of hospitalisation. Topical treatment was carried out with povidone-iodine. In all patients T4 and T3 concentrations decreased significantly during the first two weeks especially in extensive burns. Lack of increase was a bad prognostic sign. ETR and RT3U underwent no remarkable changes. The TSH levels increased distinctively until the third week, decreased slowly and turned to normal values only in the late period of illness. The influence of iodine uptake due to external application is discussed.


Associations between clinical data and computed tomography features in patients with epidermal growth factor receptor mutations in lung adenocarcinoma.
To analyse the differences in computed tomography (CT) features between patients with lung adenocarcinoma who have epidermal growth factor receptor (EGFR) mutations and those who have wild-type EGFR. Patients with lung adenocarcinoma (n = 156) were enrolled from October 2013 to March 2016, including 56 patients with wild-type EGFR and 100 patients with EGFR mutations. Two independent radiologists evaluated patient characteristics and imaging features. Chi-squared test, Fisher's exact test or ANOVA was applied to discriminate clinical and CT characteristics between the genotypes. A prediction tool for EGFR mutation was devised from principal component analysis. The proportion of females and non-smokers in the exon 19 deletion and exon 21 missense groups was higher than in the wild-type group (P < 0.01). Severe emphysema was higher in the wild-type group than in the exon 19 deletion group (P < 0.01). The maximum diameter in the mediastinal window (MaxDmediastinal) in the wild-type group was longer than in the exon 19 deletion and exon 21 missense groups. The minimum diameter in the mediastinal window (MinDmediastinal) in the wild-type group was also longer than in the exon 21 missense group, with a significant difference (P < 0.05). The tumor shadow disappearance rate (TDR) in the exon 19 deletion group was higher than in the wild-type group. Ground glass opacity (GGO) appeared to be more common in the exon 19 deletion group (P = 0.010). The prediction score for exon 19 deletion mutation was: 0.305 × gender + 0.254 × smoking history + 0.198 × MaxDmediastinal + TDR × 0.254 + 0.280 × GGO + 0.095 × emphysema. The sensitivity and specificity for predicting exon 19 deletion were 59.09 and 76.79%, respectively. The prediction score for the exon 21 missense mutation was: 0.354 × gender + 0.291 × smoking history + 0.410 × MaxDmediastinal + 0.408 × MinDmediastinal. The sensitivity and specificity for predicting exon 21 missense mutation were 72.34 and 78.57%, respectively. As well as gender, smoking history and GGO, adenocarcinomas with EGFR mutation were significantly associated with emphysema, TDR, and the diameter in the mediastinal window. As exon 19 deletion and 21 missense mutations might be predicted by those features, the scoring system might be valuable for clinical diagnosis.


Intestinal epithelial cell injury is rescued by hydrogen sulfide.
Oxidative stress is implicated in the pathogenesis of necrotizing enterocolitis (NEC). Hydrogen sulfide (H2S) has been reported to have a protective function against oxidative stress in the gut. We hypothesize that administration of H2S can help decrease intestinal epithelial cell injury in vitro. Intestinal epithelial cells (IEC-18) were treated with 200μM hydrogen peroxide (H2O2) for 21h. At 21h sodium hydrosulfide (NaHS), an H2S donor, was administered as a rescue treatment at two different concentrations: 0.1mM and 0.2mM. At 24h, cell viability was measured using a colorimetric assay (MTT). Oxidative stress was studied by glutathione peroxidase (GPx) activity and thiobarbituric acid reactive substances (TBARS). IL-6 and TNFα levels were tested to study inflammation. Data were presented as mean±SD and compared using one-way ANOVA with Bonferroni post-test. Compared to control, H2O2-treated IEC-18 had reduced viability (p<0.01), lower GPx activity (p<0.01), higher TBARS levels (p<0.01), and increased IL6 and TNFα (p<0.001). Compared to H2O2-treated IEC-18, treatment with 0.2mM NaHS rescued viability (p<0.01), increased GPx activity (p<0.05), and reduced TBARS (p<0.01), IL6 and TNFα (p<0.001). H2S successfully rescues epithelial cell damage induced by oxidative stress in vitro. This indicates that H2S could be a potential pharmacological intervention in conditions like NEC.


Structure of the biliverdin cofactor in the Pfr state of bathy and prototypical phytochromes.
Phytochromes act as photoswitches between the red- and far-red absorbing parent states of phytochromes (Pr and Pfr). Plant phytochromes display an additional thermal conversion route from the physiologically active Pfr to Pr. The same reaction pattern is found in prototypical biliverdin-binding bacteriophytochromes in contrast to the reverse thermal transformation in bathy bacteriophytochromes. However, the molecular origin of the different thermal stabilities of the Pfr states in prototypical and bathy bacteriophytochromes is not known. We analyzed the structures of the chromophore binding pockets in the Pfr states of various bathy and prototypical biliverdin-binding phytochromes using a combined spectroscopic-theoretical approach. For the Pfr state of the bathy phytochrome from Pseudomonas aeruginosa, the very good agreement between calculated and experimental Raman spectra of the biliverdin cofactor is in line with important conclusions of previous crystallographic analyses, particularly the ZZEssa configuration of the chromophore and its mode of covalent attachment to the protein. The highly homogeneous chromophore conformation seems to be a unique property of the Pfr states of bathy phytochromes. This is in sharp contrast to the Pfr states of prototypical phytochromes that display conformational equilibria between two sub-states exhibiting small structural differences at the terminal methine bridges A-B and C-D. These differences may mainly root in the interactions of the cofactor with the highly conserved Asp-194 that occur via its carboxylate function in bathy phytochromes. The weaker interactions via the carbonyl function in prototypical phytochromes may lead to a higher structural flexibility of the chromophore pocket opening a reaction channel for the thermal (ZZE → ZZZ) Pfr to Pr back-conversion.


Letter discrimination as a function of culture, orthography and dimensionality of letters.
46 4-yr.-old children from the United States and 80 from Bangalore, India made fewer discrimination errors when letters were three- rather than two-dimensional. More errors were made on Kannada (Indian) than on English orthographic tasks, but there were relatively fewer errors made by Indian than American children. Younger subjects and boys made relatively more errors than other groups. The findings suggest visually perceived depth may activate the young child's enactive system dominant during the preoperational period and serve to increase accuracy of letter discrimination.


Experiences with Surgical Reconstruction of Penoscrotal Extramammary Paget's Disease: A review of 21 cases.
Penoscrotal extramammary Paget's disease is a rarely found intraepithelial adenocarcinoma in older male patients. The challenge for surgeons to perform high-quality post-surgery reconstruction is mostly case-dependent. Here, we present a review of post-surgical reconstruction practice in 21 cases using various scrotal skin flaps. During the 10-year study period (from 2008 to 2018), all 21 male patients diagnosed with penoscrotal extramammary Paget's diseases at Sun Yat-sen memorial hospital were enrolled in this study. All patients underwent expanding resections guided by frozen sections and penoscrotal reconstructions using various scrotal skin flaps alone or combined with pubic skin flaps and partial thickness skin graft depending on individual defects. The patient's clinical data, specifically the diagnosis, surgical outcome, and follow-up evaluation were retrospectively analyzed. The size of skin lesions ranged from 4 × 5 cm to 16 × 18 cm approximately. Out of 21 total cases, 13 patients received combined scrotal and pubic flaps, three patients received single scrotal flaps, and five patients received scrotal flaps and partial thickness skin grafts. Limited flap tip necrosis (two cases) and wound dehiscence (one case) were observed, and secondary resections were performed in four cases with positive post-operative pathological results. All patients experienced complete wound healing and had well-maintained penile morphology and function. Various scrotal skin flaps alone or combined with pubic skin flaps designed for individual lesion conditions in patients with penoscrotal extramammary Paget's disease are efficient for scrotal reconstruction. A good match of the local skin texture helps to maintain the morphology and function of the penis and scrotum.


Oxytocin and vasopressin 1a receptor gene expression in the cycling or pregnant human uterus.
Our purpose was to compare concentrations of messenger ribonucleic acid specific for the oxytocin receptor and for the vasopressin 1a receptor in myometrial and endometrial tissues of pregnant and nonpregnant women. Tissues from pregnant uteri were obtained from 95 women who were undergoing cesarean delivery between 26 and 42 weeks' gestation. Tissues from nonpregnant uteri were obtained from 7 cycling women who were undergoing hysterectomy. The competitive reverse-transcription polymerase chain reaction method was used to determine messenger ribonucleic acid concentrations. A significant increase in oxytocin receptor messenger ribonucleic acid was found during the first half of pregnancy. Oxytocin receptor messenger ribonucleic acid concentrations were lower in tissues with spontaneous contractions than in quiescent tissues and were decreased in patients with advanced labor. Vasopressin 1a receptor messenger ribonucleic acid concentrations were high in tissues from both cycling and pregnant uteri but remained unchanged throughout gestation. The increase in oxytocin receptor protein concentrations seen in pregnancy is only partially controlled by messenger ribonucleic acid abundance. High concentrations of vasopressin 1a receptor messenger ribonucleic acid confirm the biologically active role of this receptor in both the cycling and the pregnant uterus.


Hepatocellular carcinoma with obstructive jaundice successfully treated with a self-expandable metallic stent.
We report on a 71-year old man with hepatocellular carcinoma (HCC) whose obstructive jaundice was successfully treated with external irradiation and a self-expandable metallic stent (EMS); Wallstent; Schneider (Europe) AG, Bülach, Switzerland. He was admitted to our hospital because of jaundice. HCC was found in S8; the tumor had invaded the bile duct with growth in the common hepatic duct. Endoscopic nasobiliary drainage was performed with difficulty. Radiation therapy to the stenosis enabled us to place a Wallstent endoscopically. He survived without icterus for 1 year.


Estimation of Organ Activity using Four Different Methods of Background Correction in Conjugate View Method.
To make an accurate estimation of the uptake of radioactivity in an organ using the conjugate view method, corrections of physical factors, such as background activity, scatter, and attenuation are needed. The aim of this study was to evaluate the accuracy of four different methods for background correction in activity quantification of the heart in myocardial perfusion scans. The organ activity was calculated using the conjugate view method. A number of 22 healthy volunteers were injected with 17-19 mCi of (99m)Tc-methoxy-isobutyl-isonitrile (MIBI) at rest or during exercise. Images were obtained by a dual-headed gamma camera. Four methods for background correction were applied: (1) Conventional correction (referred to as the Gates' method), (2) Buijs method, (3) BgdA subtraction, (4) BgdB subtraction. To evaluate the accuracy of these methods, the results of the calculations using the above-mentioned methods were compared with the reference results. The calculated uptake in the heart using conventional method, Buijs method, BgdA subtraction, and BgdB subtraction methods was 1.4 ± 0.7% (P < 0.05), 2.6 ± 0.6% (P < 0.05), 1.3 ± 0.5% (P < 0.05), and 0.8 ± 0.3% (P < 0.05) of injected dose (I.D) at rest and 1.8 ± 0.6% (P > 0.05), 3.1 ± 0.8% (P > 0.05), 1.9 ± 0.8% (P < 0.05), and 1.2 ± 0.5% (P < 0.05) of I.D, during exercise. The mean estimated myocardial uptake of (99m)Tc-MIBI was dependent on the correction method used. Comparison among the four different methods of background activity correction applied in this study showed that the Buijs method was the most suitable method for background correction in myocardial perfusion scan.


Effects of density dependence, zooplankton and temperature on blue whiting Micromesistius poutassou growth.
Blue whiting Micromesistius poutassou mean total length at age in the north-east Atlantic Ocean was found to vary by around ±6% during the period 2004-2011 and mean mass at age by ±22% during the years 1981-2013. Linear modelling provided strong evidence that these phenotypic growth variations can be explained by trophic conditions, mainly negative density dependence and also food availability, and a negative long-term temperature effect on asymptotic size.


Down-regulation of S-phase kinase associated protein 2 (Skp2) induces apoptosis in oral cancer cells.
S-phase kinase associated protein 2 (Skp2) is a member of an F-box family of substrate-recognition subunits of SCF ubiquitin-protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G1 progression, including the cyclin-dependent kinase inhibitor p27Kip1, a dosage-dependent tumor suppressor protein. The anti-sense effect was confirmed in two cell lines of oral cancer cells that also exhibited over-expression of the Skp2 protein. In this study, we examined the mechanism responsible for anti-sense-mediated growth inhibition of oral cancer cells in vitro and in vivo. Skp2-anti-sense treatment induced apoptosis characterized by an increase in the early apoptosis, fragmentation of nuclei and activation of caspase-3, -8 and -9. Moreover, the growth of xenograft tumors was markedly suppressed by Skp2-anti-sense treatment. Furthermore, histological specimen revealed apoptotic cell death was increased in Skp2-anti-sense treated tumors. Our results suggest that down-regulation of Skp2 appears to induce apoptosis in oral cancer cells, targeting this molecule could represent a promising new therapeutic approach for this type of cancer.


Association of polymorphisms in TRAIL1 and TRAILR1 genes with susceptibility to lymphomas.
The TRAILR1/TRAIL system is implicated in the induction of the extrinsic apoptotic pathway and constitutes an emerging target in cancer therapeutics. The objective of this study is to assess lymphoma risk associated with certain polymorphisms in TRAILR1 and TRAIL1 genes. DNA was extracted from 381 subjects (190 lymphoma cases and 191 matched controls) and genotyped for polymorphisms rs20576, rs2230229 and rs20575 in TRAILR1 and rs12488654 in TRAIL gene. In contrast to TRAILR1 polymorphisms, the genotype distribution of rs12488654 in TRAIL gene was different between cases and controls, A allele carriers (CA/AA) being much more common in the cases with different lymphoma types (follicular, 45 %; diffuse large B cell, 45.2 % and Hodgkin lymphomas, 40 %) than in controls (15.7 %) (odds ratio (OR), 3.5; CI, 2.1–5.9; p<0.001; OR, 3.5; CI, 1.6–7.9; p=0.001; OR, 2.9; CI, 1.1–7.5; p=0.027, respectively). This effect was consistently independent of the association with the TRAILR1 polymorphisms studied, as demonstrated by linkage disequilibrium and haplotype analyses. This study is the first one to report an association between a TRAIL polymorphism and lymphoma risk and suggests a possible role of TRAIL in B cell lymphomagenesis.


Treating low back pain - Bridging the gap between manual therapy and exercise.
As therapists, we often recommend exercise to reduce patients' low-back pain, as well as increase their active range of motion and muscle strength. However, physical therapists face a challenge when recommending exercise to reduce low-back pain because the pain itself often inhibits the patient's ability to exercise or perform activities of daily living. This situation becomes even more challenging if the prescribed exercise program aggravates the individual's low-back pain. This article discusses a method which provides for the effective treatment of low back pain by allowing patients to exercise pain free earlier in the rehabilitation process. The method comprises a unique approach utilizing the following four components simultaneously from the onset of treatment: isometric muscle contraction (IMC); assisted active oscillatory mobilization; end-of-range passive stretch; and mindfulness.


Imaging of Head and Neck Infections.
The complex anatomy and deep spaces of the head and neck limit physical examination while also offering many points for entry and spread of infection. Radiologic imaging plays a crucial role in managing head and neck infections by defining the location and extent of disease, facilitating abscess drainage, and identifying complications. This review provides essential background and examples for imaging infection throughout the head and neck region.


Bcl-XL and Bcl-2 expression in bilharzial squamous cell carcinoma of the urinary bladder: which protein is prognostic?
Bcl-2 and Bcl-XL are the most important antiapoptotic members of the Bcl-2 family frequently overexpressed in bladder cancer. Overexpression of Bcl-XL bilharzial-related bladder cancer was associated with tumor progression. However, the negative prognostic value of Bcl-2 expression is still questionable. This work studied the expression of Bcl-XL and Bcl-2 immunohistochemically in bilharzial-related squamous cell carcinoma of the urinary bladder and determined their prognostic value in relation to recurrence after radical cystectomy. A total of 72 patients with muscle-invasive bilharzial squamous cell carcinoma of the urinary bladder underwent radical cystectomy at our institution. The specimens were examined immunohistochemically for Bcl-XL and Bcl-2 expression. The patients were followed up for 3 years or until recurrence. The expression of Bcl-XL and Bcl-2 were related to the other prognostic indicators and patient survival. The expressions of both Bcl-2 and Bcl-XL were significantly different according to the grade of malignancy. Bcl-XL expression was significantly related to tumor recurrence, but Bcl-2 expression was not. To our knowledge, the present study is the first report of a negative prognostic value for Bcl-XL in bilharzial squamous cell carcinoma of the urinary bladder. However, this is another negative report on the prognostic value of bcl-2 in bilharzial bladder tumors.


MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration.
Recent increases in human longevity have been accompanied by a rise in the incidence of dementia, highlighting the need to preserve cognitive function in an aging population. A small percentage of individuals with pathological hallmarks of neurodegenerative disease are able to maintain normal cognition. Although the molecular mechanisms that govern this neuroprotection remain unknown, individuals that exhibit cognitive resilience (CgR) represent a unique source of therapeutic insight. For both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR. To understand potential drivers of this phenomenon, we began by profiling the molecular changes that arise from environmental enrichment in mice, which led to the identification of MEF2 transcription factors (TFs). We next turned to repositories of human clinical and brain transcriptomic data, where we found that the MEF2 transcriptional network was overrepresented among genes that are most predictive of end-stage cognition. Through single-nucleus RNA sequencing of cortical tissue from resilient and nonresilient individuals, we further confirmed up-regulation of MEF2C in resilient individuals to a subpopulation of excitatory neurons. Last, to determine the causal impact of MEF2 on cognition in the context of neurodegeneration, we overexpressed Mef2a/c in the PS19 mouse model of tauopathy and found that this was sufficient to improve cognitive flexibility and reduce hyperexcitability. Overall, our findings reveal a previously unappreciated role for MEF2 TFs in promoting CgR, highlighting their potential as biomarkers or therapeutic targets for neurodegeneration and healthy aging.


Assessing the relative efficacy of new drugs: an emerging opportunity.
The increasing availability of individual-level data from clinical trials could allow the relative efficacy of new drugs to be assessed in a robust, cost-effective and timely way.


The "ad hoc" estimation of outflow does not predict patency of infrainguinal reconstructions.
This prospective study was performed to evaluate the clinical implication of the adhoc estimation (also called SVS score) of outflow on patency of infrainguinal in situ femoropopliteal or -distal bypasses. The bypasses were followed with Duplex scanning at 1, 3, 6, and 12 months after surgery. Fifty-three bypasses were recruited for the study, 20 of which were performed in 17 diabetics. In 47% the adhoc scoring was < or = 4.5 and in 53% it was between 5 and 10 (1 corresponds to an excellent outflow and 10 to a blind segment). Within the first 30 days eight occlusions occurred, all of which were surgically corrected. The adhoc score for these bypasses was 4.2 vs. 4.9 (NS) for those who did not occlude. During follow-up, revisions were performed in 21 cases (40%) with 30 interventions. At the end of 1 year, 68% of the bypasses were patent (80% among diabetics and 64% among non-diabetics, NS). Patency at 1 year was not influenced by the adhoc classification. The estimation of outflow from angiography seems to be of no value in predicting graft patency in infrainguinal grafting.


Prediction of hospital discharge in immediate survivors of ventricular fibrillation or asystole.
Survival from ventricular fibrillation and asystole is influenced by variables measured during resuscitation that affect both immediate survival and discharge from hospital. These variables have been used to develop a formula to calculate an individuals chances of immediate survival and hospital discharge. It has allowed this heterogenous group to be subdivided into groups which can be compared both within and between institutions for the purposes of audit and evaluation of resuscitation protocols. This study evaluates the addition of clinical parameters to the prognostic index. One hundred twelve immediate survivors of ventricular fibrillation or asystole were examined immediately after resuscitation and clinical parameters measured and recorded. At the same time parameters previously described were recorded. The increase in the numbers of survivors improved the reliability (area under the receiver operator curve (ROC) improved from 0.79 to 0.83) of the index for predicting hospital discharge. Addition of the clinical variables of conscious state, respiratory state, blood pressure and pulse rate improved the prognostic index further to an ROC area of 0.86. This ensures that the predictive power of the new index is now highly reliable for predicting hospital discharge after successful resuscitation from ventricular fibrillation and asystole.


Ethyl 2,4-dicarboethoxy pantothenate, a derivative of pantothenic acid, prevents cellular damage initiated by environmental pollutants through Nrf2 activation.
Recently, environmental pollutants have become a concern not only for respiratory organs but also for skin-related human health, because skin is localized at the border between the human body and the external environment and is easily influenced by environmental pollutants. Here, we investigated the effects of a novel pantothenic acid (PA) derivative, ethyl 2,4-dicarboethoxy pantothenate (EDCEP), on a diesel particulate extract (DPE) as a representative environmental pollutant that generates reactive oxygen species (ROS) through the activation of aryl hydrocarbon receptor (AHR) signaling. We characterized the effects of PA and EDCEP on normal human epidermal keratinocytes (NHEKs) exposed to DPE or H2O2 as a general oxidative stress stimulator. Cell viability and intracellular ROS levels were evaluated using the 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide (MTT) assay and the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assay, respectively. Further, we investigated the substantial effects and the underlying mechanism of EDCEP, which elicited a reduction of intracellular ROS. PA and EDCEP restored the decreases of cell viability induced by DPE and also repressed the up-regulation of CYP1A1 mRNA expression induced by DPE. Interestingly, the effects of PA and EDCEP on intracellular ROS levels showed different responses. EDCEP reduced intracellular ROS levels stimulated by DPE or by exposure to H2O2. EDCEP suppressed the secretion of tumor necrosis factor (TNF-α) and reduced the level carbonylated proteins in reconstructed human epidermal equivalents topically treated with DPE. EDCEP up-regulated the mRNA expression levels of nuclear factor E2-related factor 2 (Nrf2), γ-glutamyl cysteine synthase (γ-GCS), heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) and in addition, increased intracellular glutathione (GSH) levels. EDCEP reduces cellular damage initiated by environmental pollutants by stimulating the intracellular defense system against ROS through the activation of Nrf2, and by interfering with AHR signaling pathway activation.


Neuroblastoma: the case for screening infants in North America.
Neuroblastoma is a disease in which easily measured tumor markers are excreted. It is curable when diagnosed in an early stage and at an early age, and it has a high incidence relative to other serious childhood diseases. Recent advances in screening infants for neuroblastoma by detection of urinary homovanillic acid and vanillylmandelic acid, the most useful markers of neuroblastoma, are described. Based on results from Japan's mass-screening program and on the authors' observations, it is estimated that mass screening for neuroblastoma could save 260 lives annually in the United States.


Increased amount and contour length distribution of small polydisperse circular DNA (spcDNA) in Fanconi anemia.
Small polydisperse circular DNA (spcDNA) in Fanconi anemia (FA) was analyzed from cultured fibroblast-like cells by electron microscopy. Application of the mica-press adsorption technique for the semi-quantitative determination of spcDNA amounts to three FA and three normal control skin-derived fibroblast strains revealed 85-fold increased levels of spcDNA in the FA cells. An even higher excess over controls was suggested when the FA fibroblasts were propagated for up to 11 serial in vitro passages, consistent with the short replicative life-span of primary FA cells and their rapid transition into a poorly dividing state, in which spcDNA reportedly further increases. In addition, contour length distributions of gradient-purified spcDNA preparations from five FA fibroblast strains were compared with those from five normal control strains. Mean spcDNA contour lengths were significantly greater in the FA than in the control cells. The reported findings of increased spcDNA amounts and sizes in FA coincide with a similar association of chromosome instability and abnormal spcDNA formation previously observed in cultured cells derived from angiofibromas in tuberous sclerosis. Circumstantial evidence from the present study in the paradigmatic chromosome breakage syndrome FA further supports the suggestion that a common mechanism underlies chromosome instability and the surplus generation of spcDNA. Notably, this apparent mechanism is functional in homonuclear primary cell strains with a distinct inherited basis of their chromosome instability, and is not restricted to heteroploid and neoplastoid cell lines.


Identification and analysis of a retinoblastoma binding motif in the replication protein of a plant DNA virus: requirement for efficient viral DNA replication.
Geminiviruses are plant DNA viruses with small genomes whose replication, except for the viral replication protein (Rep), depends on host proteins and, in this respect, are analogous to animal DNA tumor viruses, e.g. SV40. The mechanism by which these animal viruses create a cellular environment permissive for viral DNA replication involves the binding of a virally encoded oncoprotein, through its LXCXE motif, to the retinoblastoma protein (Rb). We have identified such a LXCXE motif in the Rep protein of wheat dwarf geminivirus (WDV) and we show its functional importance during viral DNA replication. Using a yeast two-hybrid system we have demonstrated that WDV Rep forms stable complexes with p130Rbr2, a member of the Rb family of proteins, and single amino acid changes within the LXCXE motif abolish the ability of WDV Rep to bind to p130Rbr2. The LXCXE motif is conserved in other members of the same geminivirus subgroup. The presence of an intact Rb binding motif is required for efficient WDV DNA replication in cultured wheat cells, strongly suggesting that one of the functions of WDV Rep may be the linking between viral and cellular DNA replication cycles. Our results point to the existence of a Rb-like protein(s) in plant cells playing regulatory roles during the cell cycle.


Molecular and immunological characterization of the C-terminal region of a new Echinococcus granulosus Heat Shock Protein 70.
By screening an expression library of Echinococcus granulosus with IgE from sera of patients with cystic echinococcosis (CE) and allergic reactions, we isolated the C-terminal region of a new heat shock protein (HSP)70 of E. granulosus. The protein, named Eg2HSP70, has close homology with the C-terminal region of Dermatophagoides farinae and human HSP70. We investigated the humoral and cell-mediated immune responses to this antigen in patients with CE grouped according to the presence of allergic reactions. Immunoblotting detected total IgG, IgG4 and IgE specific to Eg2HSP70 (83% of sera contained IgG, 31% IgG4 and 57% IgE). No significant difference was found in immunoglobulin percentages according to the presence of allergic reactions. Immunoblotting inhibition showed that no IgG or IgE specific to Eg2HSP70 cross-reacted with D. farinae or human HSP70. Eg2HSP70-stimulated PBMC from 26 patients produced significantly greater amounts of TNF-alpha, IFN-gamma, and IL-10 than unstimulated cultures in all patients, irrespective of the presence of allergic reactions (P < 0.05). They also produced significantly greater amounts of IL-4 than unstimulated cultures exclusively in patients with allergic reactions (P < 0.05). These findings show that Eg2HSP70 is a new antigenic molecule inducing both B and T cell responses.


Mediating effects of lipids on the association between smoking and coronary artery disease risk among Chinese.
The mechanism between smoking and coronary artery disease (CAD) remains unclear. It is likely that lipid (including triglycerides (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C)) have been functioning as one of the mediators between smoking and the CAD occurrence. The study aimed to investigate the mediating effect of lipid on the relationship between smoking and CAD risk. The case-control study included 2048 subjects. General linear regression analysis was used to corroborate the association between smoking and lipid levels. Univariate and multivariate logistic regression analysis were performed to reveal the relationship between smoking, lipid and the risk of CAD. Mediation analysis was used to investigate whether the association between smoking and CAD risk was mediated by lipid. Smoking was found to be associated with the risk of CAD (odds ratio (OR) = 1.34, 95% confidence interval (CI): 1.05-1.71, P = 0.019). Regression analysis showed that TG, TC and HDL-C were associated with CAD (OR = 2.69, 95%CI: 2.12-3.40, P < 0.001; OR = 0.34, 95%CI: 0.29-0.43, P < 0.001; OR = 0.37, 95%CI: 0.30-0.47, P < 0.001). Moreover, the ratio of TG to HDL-C (TG/HDL-C) was also related to CAD (OR = 4.45, 95%CI: 3.52-5.64, P < 0.001). Mediation analysis showed that among the effects of smoking on CAD, 17.52% was mediated by lipid, in which HDL-C accounted for 11.16% and TG accounted for 6.36%. Further analysis showed that the effect was also partially mediated by TG/HDL-C, which was accounted for 28%. Lipid plays a partial mediation on the association between smoking and CAD risk. The study provides a clue on the mediation effect of lipids on the relationship between smoking and CAD risks, which is a novel insight to the progression of CAD.


Enhanced tumorigenicity of insulinoma by X-irradiation of the gastric regions in Sprague-Dawley male rats.
There has been no suitable animal model for human insulinoma because incidence of pancreatic tumours induced by whole-body irradiation or chemicals has been very low. The purpose of this study was to establish an experimental model with a high incidence of insulinoma. The induction of islet cell tumour by X-irradiation was investigated. Forty Sprague-Dawley male rats were used in this study. Twenty-eight rats were irradiated with two 10-Gy doses to the gastric region at a 3-day interval, and 12 rats not subjected to X-irradiation served as a control group. The rats were killed 16 months after the first irradiation. Expression of insulin mRNA and protein was examined by northern blot analysis and immunohistochemistry, respectively. Rat serum insulin and glucose levels were measured using enzyme-linked immunosorbent assay. Tumour incidence was 89.3% (25/28) in X-ray group and 8.3% (1/12) in the control group (P < 0.05). Pancreatic tumours, which appeared in all 25 rats with tumours, showed the highest incidence of all neoplasms detected. Tumour cells showed strong immunoreactivity for insulin in 20 of 25 pancreatic tumours (80%). Expression of insulin mRNA was confirmed by northern blot analysis. Furthermore, rats with pancreatic tumours had lower serum glucose levels and higher insulin levels than the control rats. X-irradiated SD rats may be considered a suitable model for insulinoma because of their high tumorigenicity.


Biogenesis and Function of Transfer RNA-Related Fragments (tRFs).
Noncoding small RNAs arise from the various un-annotated and annotated regions of the genome. When they arise from annotated genes, the noncoding small RNAs are functionally different from the parent genes. This is a brief review of one class of noncoding small RNAs, tRNA-related fragments (tRFs), which are generated from tRNA. tRFs have been suggested to have roles in cell proliferation, priming of viral reverse transcriptases, regulation of gene expression, RNA processing, modulation of the DNA damage response, tumor suppression, and neurodegeneration.


An increase in relative contribution of compensatory postural adjustments during voluntary movement while standing in adolescents and young adults with bilateral spastic cerebral palsy.
Previous studies have revealed several deficits in anticipatory postural adjustments (APAs) during voluntary movements while standing in individuals with bilateral spastic cerebral palsy (BSCP). However, it remains unclear whether compensatory postural adjustments (CPAs) during movement increase to compensate for APA deficits. We investigated the anticipatory and compensatory activities of postural muscles during voluntary movement while standing in adolescents and young adults with BSCP. The study included seven participants with BSCP with level II on the Gross Motor Function Classification System (GMFCS), seven with BSCP with level III on the GMFCS, and fourteen healthy controls. The participants stood on a force platform and lifted a load under two weight conditions (light and heavy). The electromyographic activities of postural muscles were analyzed at time intervals typical for APAs and CPAs. The percentage of muscle activity in the CPA time epoch against the total muscle activity during the APA and CPA time epochs was higher in the two BSCP groups than in the control group. In the control group, a load-related modulation was observed only in the APA time epoch, whereas in the BSCP-II group, the load-related increase was observed in both the APA and CPA time epochs. No load-related modulations were observed in the BSCP-III group. These findings suggest that adolescents and young adults with BSCP exhibit an increase in the relative contribution of CPAs during voluntary movement and that there exist severity-related differences in the modulation of APAs and CPAs.


Localization of importin alpha (Rch1) at the plasma membrane and subcellular redistribution during lymphocyte activation.
Rch1 belongs to the importin alpha subfamily and works as an adapter between karyophilic proteins and the nuclear import machinery. Its level of expression varies among species and tissues, and depends on the state of cellular metabolism. In the present study we examined the level of expression of nuclear envelope and nuclear transport proteins (Rch1, importin beta, lamins A/C, lamin B, gp210, p62 and transportin) after human lymphocyte activation with phytohemagglutinin. We observed that the level of Rch1 increases dramatically, especially in larger lymphocytes, in response to activation. Moreover, using immunoelectron microscopy, this nuclear transport factor was found to be localized at the plasma membrane and also in tracks from the cytoplasm through the nuclear envelope into the nucleus. Similar localization was also observed in the human melanoma cell line A375. In addition, metabolic activation led to a redistribution of Rch1 from the cytoplasm to both the plasma membrane and the nuclear interior. These results suggest that, during lymphocyte activation, Rch1 may be involved in a signal transduction pathway that involves the shuttling of karyophilic proteins from the plasma membrane to the nucleus.


Synthesis and hybridizing properties of P-stereodefined chimeric [PS]-{DNA:RNA} and [PS]-{DNA:(2'-OMe)-RNA} oligomers.
Oxathiaphospholane derivatives of 2'-OMe-ribonucleosides and 2'-O-TBDMS-ribonucleosides (MN-OTP and TN-OTP, respectively; nucleobase protected) were synthesized and separated into pure P-diastereomers. X-ray analysis showed the R P absolute configuration of the phosphorus atom in the fast-eluting diastereomer of TA-OTP. The fast- and slow-eluting P-diastereomers of MN-OTP and TN-OTP were used in the solid-phase synthesis of phosphorothioate dinucleotides (MNPST and NPST, respectively), which were subsequently hydrolyzed with R P-selective phosphodiesterase svPDE and S P-selective nuclease P1 to determine the absolute configuration of the phosphorus atoms. P-Stereodefined phosphorothioate ([PS]) 10-mer chimeric oligomers [PS]-{DNA:(2'-OMe)-RNA} and isosequential [PS]-{DNA:RNA} containing two MNPS or NPS units were synthesized. Melting experiments performed for their complexes with Watson-Crick paired DNA matrix showed that MNPS or NPS units decrease the thermal stability of the duplexes (ΔT m = -0.5 ÷ -5.5 °C per modification) regardless of the absolute configuration of the P-atoms. When the (2'-OMe)-RNA matrix was used an increase in T m was noted in all cases (ΔT m = +1 ÷ +7 °C per modification). The changes in thermal stability of the duplexes formed by [PS]-chimeras with DNA and (2'-OMe)-RNA matrices do not correlate with the absolute configuration of the phosphorus atoms.


Hot water as a tubal occluding agent.
Experimental studies in living rabbits and autopsy human oviducts are presented which demonstrate a reasonable possibility that one could introduce hot water into the proximal portion of the human oviduct with a hysteroscope or balloon catheter, to destroy the epithelium of the first portion of that structure, leading to its occlusion, while still maintaining safety for the woman because the water would cool to tolerable temperatures before it entered the peritoneal cavity. Before trying the procedure in human beings, research on non-human primates is clearly needed.


Early enteral nutrition in patients with severe traumatic brain injury: a propensity score-matched analysis using a nationwide inpatient database in Japan.
Whether enteral nutrition (EN) should be administered early in severe traumatic brain injury (TBI) patients has not been fully addressed. The present study aimed to evaluate whether early EN can reduce mortality or nosocomial pneumonia among severe TBI patients. Using the Japanese Diagnosis Procedure Combination inpatient database from April 2014 to March 2017 linked with the Survey for Medical Institutions, we identified patients admitted for intracranial injury with Japan Coma Scale scores ≥30 (corresponding to Glasgow Coma Scale scores ≤8) at admission. We designated patients who started EN within 2 d of admission as the early EN group, and those who started EN at 3-5 d after admission as the delayed EN group. The primary outcome was in-hospital mortality. The secondary outcome was nosocomial pneumonia. Propensity score-matched analyses were performed to compare the outcomes between the 2 groups. We identified 3080 eligible patients during the 36-mo study period, comprising 1100 (36%) in the early EN group and 1980 (64%) in the delayed EN group. After propensity score matching, there was no significant difference in in-hospital mortality (difference: -0.3%; 95% CI: -3.7%, 3.1%) between the 2 groups. The proportion of nosocomial pneumonia was significantly lower in the early EN group than in the delayed EN group (difference: -3.2%; 95% CI: -5.9%, -0.4%). Early EN may not reduce mortality, but may reduce nosocomial pneumonia in patients with severe TBI.


The dimensional stability of elastomeric impression materials following disinfection.
Public awareness of infectious diseases has focused attention on the prevention of nosocomial disease. Difficulties in sterilizing impressions have led to chemical disinfection as an alternative. Recent literature indicated a lack of consensus between researchers about distortion caused by disinfection. A polysulfide, polyether, and vinyl polysiloxane were disinfected by immersion in iodophor, sodium hypochlorite, and glutaraldehyde. Distortion was evaluated by use of a stainless steel die (ADA specification No. 19). Linear dimension variations after disinfection were clinically insignificant.


Prevalence and gross pathology of liver fluke in macropods cohabiting livestock farms in north eastern NSW, Australia, and diagnosis using cELISA.
Liver fluke (Fasciola hepatica) is a parasite of herbivores including wildlife. Macropods, such as Eastern grey kangaroo (Macropus giganteus) and Common wallaroo (Osphranter robustus), are frequently observed sharing grazing sites with domestic livestock. The impact of Macropods, as reservoirs of infection, on livestock production and risks to cross-species transmission are largely unknown. In Phase 1 of this study, liver and faecal samples were collected from 245 Macropods (181 Eastern grey kangaroos, 64 Common wallaroos) cohabiting livestock farms (n = 7) in the Northern Tablelands regions of New South Wales. Total fluke (TFC) and fluke eggs (FEC) were counted in the liver and faeces, respectively, to assess prevalence. Faecal antigens were also measured using the commercial Bio-X Diagnostic Monoscreen AgELISA Fasciola hepatica kit (cELISA) to assess suitability as a diagnostic tool. In Phase 2, Macropod faecal samples were collected from 60 livestock farms to conduct FEC and assess prevalence by region. Liver fluke was prevalent in 22% of Eastern grey kangaroo and 20% of Common wallaroos with prevalence as high as 45% in the Eastern grey kangaroo. Fluke burdens ranged from 1 to 122 flukes (mean = 9 flukes) with a FEC range of 0-195 eggs per gram (epg) of faeces (mean = 18 epg). Evidence of dead and live flukes trapped within fibrotic capsules confirms the ability of Macropods to resolve infections. cELISA proved highly specific (100%) and sensitive (98%) in liver fluke detection however fibrotic capsules observed in the liver may reduce the correlation of coproantigens with fluke burden. Phase 2 revealed that 27% of livestock farms had Macropods infected with liver fluke. Overall, this study confirmed Eastern grey kangaroo and Common wallaroo are susceptible hosts and potential reservoirs for liver fluke and, monitoring infections in Macropods would assist in livestock disease management.


Cross-hybridization between the cytadhesin genes of Mycoplasma pneumoniae and Mycoplasma genitalium and genomic DNA of Mycoplasma gallisepticum.
Immunological cross-reactivity was observed between the cytadhesin proteins of Mycoplasma pneumoniae and Mycoplasma genitalium and a 155 kDa protein of Mycoplasma gallisepticum. Furthermore, the cytadhesin genes of M. pneumoniae and M. genitalium were used to demonstrate homology with M. gallisepticum genomic DNA under low stringency conditions suggesting that a family of adhesin-related genes exists among these pathogenic mycoplasmas.


HSP90 cleavage associates with oxidized proteins accumulation after oxidative stress.
Oxidative stress, OS, has been associated to a variety of phenomena as cancer progression, neurodegeneration and ageing itself. At a molecular level, OS leads to protein carbonylation, a non-enzymatic irreversible event and common feature of aged cells. Carbonylated proteins are dysfunctional and can accumulate, in the form of protein aggregates that alter cellular functionality. To cope with carbonylated proteins, cells employ the proteasome, the main non-lysosomal structure for carbonylated proteins turnover. However, if the degrading rate is inferior to carbonylated proteins formation rate, protein aggregates form. In a previous study, in oxidative stress challenged Jurkat cells we could verify that cytoplasmatic actin becomes heavily carbonylated and forms oxidized actin aggregates, which lead to proliferation impairment and proteasome activity diminishment, similar to senescence like states. Because under these oxidative conditions there is a proteostasis disturbance, such as oxidized proteins (especially actin) accumulation and proteasome activity impairment, Hsp90 involvement was studied. Hsp90, a molecular chaperone, assists oxidized proteins degradation and also protects the 20S proteasome from oxidative inactivation. We reasoned that the mechanism by which protein aggregates can form, mainly happens due to Hsp90 lesser functionality, which we attribute to cleavage. In our study, we were able to verify that cleaved Hsp90 is present in protein aggregates and that it occurs before actin insolubilization, verified after fractioning soluble and insoluble cellular extracts. We are convinced, supported by our data, that cleaved Hsp90 is an important intervenient for oxidized protein accumulation and proteasome inactivation. However, further studies should follow to confirm our hypothesis.


Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Gastric lavage in iron overdose.
A short cut review was carried out to establish whether gastric lavage is of use after an overdose of ionic compounds. Altogether 74 papers were found using the reported search but none answered the question posed.


Diagnostic and prognostic factors in patients with prostate cancer: a systematic review.
As part of the PIONEER Consortium objectives, we have explored which diagnostic and prognostic factors (DPFs) are available in relation to our previously defined clinician and patient-reported outcomes for prostate cancer (PCa). We performed a systematic review to identify validated and non-validated studies. MEDLINE, Embase and the Cochrane Library were searched on 21 January 2020. Only quantitative studies were included. Single studies with fewer than 50 participants, published before 2014 and looking at outcomes which are not prioritised in the PIONEER core outcome set were excluded. After initial screening, we extracted data following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of prognostic factor studies (CHARMS-PF) criteria and discussed the identified factors with a multidisciplinary expert group. The quality of the included papers was scored for applicability and risk of bias using validated tools such as PROBAST, Quality in Prognostic Studies and Quality Assessment of Diagnostic Accuracy Studies 2. The search identified 6604 studies, from which 489 DPFs were included. Sixty-four of those were internally or externally validated. However, only three studies on diagnostic and seven studies on prognostic factors had a low risk of bias and a low risk concerning applicability. Most of the DPFs identified require additional evaluation and validation in properly designed studies before they can be recommended for use in clinical practice. The PIONEER online search tool for DPFs for PCa will enable researchers to understand the quality of the current research and help them design future studies. There are no ethical implications.


Dance of live adult filarial worms is a reliable sign of scrotal filarial infection.
To determine the value of the filarial dance sign as a diagnostic sign of scrotal filarial infection and to recognize unsuspected scrotal filariasis by this sign. Eight symptomatic patients in whom the filarial dance sign was shown on high-resolution ultrasonography were studied, investigated, and followed after treatment with diethylcarbamazine citrate. Two patients underwent fine-needle aspiration. Multiple foci (nests) of motile (live) filarial worms were observed in most patients. Fine-needle aspiration of the dilated lymphatic vessels in 2 patients confirmed the presence of microfilariae. Five of 8 patients had a favorable response to treatment with diethylcarbamazine citrate. High-resolution ultrasonography is a useful technique for diagnosing scrotal filariasis in symptomatic patients and is very useful in the follow-up period for assessing the response of worms to treatment.


Impact of nanoscale zero valent iron on bacteria is growth phase dependent.
The toxic effect of nanoscale zero valent iron (nZVI) particles on bacteria from different growth phases was studied. Four bacterial strains namely Escherichia coli strains JM109 and BW25113, and Pseudomonas putida strains KT2440 and F1 were experimented. The growth curves of these strains were determined. Bacterial cells were harvested based on the predetermined time points, and exposed to nZVI. Cell viability was determined by the plate count method. Bacterial cells in lag and stationary phases showed higher resistance to nZVI for all four bacterial strains, whereas cells in exponential and decline phases were less resistant to nZVI and were rapidly inactivated when exposed to nZVI. Bacterial inactivation increased with the concentration of nZVI. Furthermore, less than 14% bacterial inactivation was observed when bacterial cells were exposed to the filtrate of nZVI suspension suggesting that the physical interaction between nZVI and cell is necessary for bacterial inactivation.


Accuracy of sizers for aortic valve prostheses.
Accurate sizing of the aortic anulus is a prerequisite of prosthetic valve implantation, because it is usually desirable to insert the largest possible prosthesis. Although it is generally assumed that commercial valve sizers are accurately labeled, our measurements reveal that the sizers for the St. Jude Medical, Björk-Shiley, and Ionescu-Shiley prostheses are larger than their nominal sizes. These findings are relevant to the selection of prosthetic valves.


Determination of fluorescent diamidines in plasma of experimental animals by high-performance liquid chromatography.
The fluorescent diamidines (E)-2,2'-vinylenedi-1-benzo [b] furane-5-carboxamidine dihydrochloride (I) and 2-[2-(6-amidinoindole-2-yl)-(E)-vinyl]-1-benzofurane-5-ca rbo xamidine dihydrochloride (II) were determined in the plasma of experimental animals by high-performance liquid chromatography with a mobile phase of methanol-water (60:40, v/v) containing 0.005 M octanesulphonic acid and 0.003 M dimethyloctylamine. Samples were prepared by precipitation of plasma proteins with methanol-perchloric acid. Quantitation was performed by measuring the peak heights after monitoring the native fluorescence. The assay was linear over the range 5-750 ng/ml for I and 5-500 ng/ml for II, with limits of determination of 2.5 ng/ml for I and 1.5 ng/ml for II. Coefficients of variation were below 10% at all concentrations studied.


Magnetic Separation of Cell-Secreted Vesicles with Tailored Magnetic Particles and Downstream Applications.
The analysis of the receptors on the surface of the cell-secreted vesicles provides valuable information of the cell signature and may also offer diagnosis and/or prognosis of a wide range of diseases, including cancer.Due to their low concentration, conventional procedures for extracellular vesicle (EV) detection usually require relatively large sample volumes, involving preliminary purification or preconcentration steps from complex specimens. Here, we describe the separation and preconcentration in magnetic particles of extracellular vesicles obtained from cell culture supernatants from MCF7, MDA-MB-231, and SKBR3 breast cancer cell lines, human fetal osteoblastic cell line (hFOB), and human neuroblastoma SH-SY5Y cell line, as well as exosomes from human serum. The first approach involves the covalent immobilization for the exosomes directly on micro (4.5 μm)-sized magnetic particles. The second approach is based on tailored magnetic particles modified with antibodies for further immunomagnetic separation of the exosomes. In these instances, micro (4.5 μm)-sized magnetic particles are modified with different commercial antibodies against selected receptors, including the general tetraspanins CD9, CD63, and CD81 and the specific receptors (CD24, CD44, CD54, CD326, CD340, and CD171). The magnetic separation can be easily coupled with downstream characterization and quantification methods, including molecular biology techniques such as immunoassays, confocal microscopy, or flow cytometry.


Interstitial pulsed-dose-rate brachytherapy for head and neck cancer--Single-institution long-term results of 385 patients.
To assess the long-term results of protocol-based pulsed-dose-rate (PDR) interstitial brachytherapy (iBT) in 385 patients with head and neck cancer who underwent PDR-iBT preferably after minimal, nonmutilating surgery. From 1997 to 2009, a total of 385 patients received protocol-based PDR-iBT for head and neck cancer. Brachytherapy was preceded by surgery in most of our patients (326/385, 84.7%). Altogether, 246 of 385 patients (63.9%) received iBT alone and 135 of 385 patients (36.1%) in combination with external beam radiation therapy. The analysis was done after a median followup of 63 months. The 5-, 10-, and 15-year local relapse-free survival rates according to Kaplan-Meier test for all analyzed patients were 85.8%, 83.1%, and 80.2%, respectively. The 5-, 10-, and 15-year overall survival and disease-free survival rates were 68.9%, 52.2%, and 44.1%, and 81.3%, 79.3%, and 76.3%, respectively. For N0-/N1- vs. N2-patients, we observed significantly different 5-year local recurrence-free survival rates with values of 92.3% and 73.7%, respectively (p=0.007). No other patient or treatment-related parameters had a significant influence on treatment results. Serious late side effects, such as soft tissue or bone necrosis, were observed in 39 of 385 patients (10.2%) and 18 of 385 patients (4.9%), respectively. The PDR-iBT with 0.4-0.7Gy each hour, 24h per day for patients with head and neck cancer is a proven, effective, and safe treatment method with excellent long-term data.


[Evaluation of the hepatitis B prevention program in newborn infants. II. Amsterdam, 1989-1991].
To evaluate the efficiency of the hepatitis B surface antigen (HBsAg) screening programme in pregnant women and the hepatitis B prevention programme in neonates of HBsAg-positive mothers from October 1989 to December 1991. Retrospective. Amsterdam Public Health Service, the Netherlands. Analysis of the data routinely collected from pregnant women and neonates of these women and calculation of the protective efficiency of this immunisation programme. In 1990, 79% and in 1991, 91% of all pregnant women were screened for HBsAg. The overall prevalence was 1.2% in 1990 as in 1991. Of the HBsAg-positive women 96% originated from countries where hepatitis B virus (HBV) is known to be endemic. At the age of ten months all infants had received passive and active immunisation. The anti-HBs titre was 10-50 IU/l in 8 (7%) infants, > 50 IU/l in 94 (88%), 3 were HBsAg-negative with no information on the anti-HBs titre and in 2 HBsAg was present. The protective efficiency of the immunisation schedule was 94% in children born of e-antigen-positive and 93% in children born of e-antigen-negative mothers. Active surveillance and intense follow-up are essential in achieving high coverage rates in screening of pregnant women and in immunising neonates of HBsAg-positive mothers.


Prevention of sexually transmitted infections in women.
Because the acquisition of sexually transmitted infections (STIs) is based on individual sexual behaviors, the most successful STI prevention initiatives have been behavioral interventions seeking to change individual risk behaviors. This article explores systematic and community-based prevention initiatives and the steps in development and validation of behavioral interventions to reduce STIs. Key interventions and the trials in which they were proven effective are discussed in detail. It is hoped that a greater understanding of the development and validation of behavioral interventions for STI prevention will encourage physicians to accept these interventions as additional tools to prevent disease and suffering.


Delirium after lung transplantation: Association with recipient characteristics, hospital resource utilization, and mortality.
Delirium is associated with increased morbidity and mortality. The factors associated with post-lung transplant delirium and its impact on outcomes are under characterized. The medical records of 163 consecutive adult lung transplant recipients were reviewed for delirium within 5 days (early-onset) and 30 hospital days (ever-onset) post-transplantation. A multivariable logistic regression model assessed factors associated with delirium. Multivariable negative binomial regression and Cox proportional hazards models assessed the association of delirium with ventilator duration, intensive care unit (ICU) length of stay (LOS), hospital LOS, and one-year mortality. Thirty-six percent of patients developed early-onset, and 44% developed ever-onset delirium. Obesity (OR 6.35, 95% CI 1.61-24.98) and bolused benzodiazepines within the first postoperative day (OR 2.28, 95% CI 1.07-4.89) were associated with early-onset delirium. Early-onset delirium was associated with longer adjusted mechanical ventilation duration (P=.001), ICU LOS (P<.001), and hospital LOS (P=.005). Ever-onset delirium was associated with longer ICU (P<.001) and hospital LOS (P<.001). After adjusting for clinical variables, delirium was not significantly associated with one-year mortality (early-onset HR 1.65, 95% CI 0.67-4.03; ever-onset HR 1.70, 95% CI 0.63-4.55). Delirium is common after lung transplant surgery and associated with increased hospital resources.


The contributions of individual factors to thromboembolic stroke.
To determine the importance of individual factors to thromboembolic stroke (TES) risk, the authors performed a hospital-based case-control study. Ninety cases (56 men and 34 women, ages 15 to 65) discharged from the hospital between January 1981 and December 1984 with a diagnosis of TES supported by computed tomography were matched to 174 control patients (106 men and 68 women). Data on potential risk factors were obtained from the medical record and telephone interview. Using multivariate analysis, three variables were significantly associated with TES risk: hypertension (odds ratio [OR] = 3.4; 95% confidence interval [CI] 1.9-6.0), diabetes (OR = 4.0; 95% CI 2.0-8.3), and smoking (OR = 2.0; 95% CI 1.2-3.6). The data were also analyzed using a direct risk assessment method. This analysis describes the risk in patients with any one factor compared with patients without any of the factors. The direct estimates of risk increased by 71% for hypertension (OR = 5.8), 28% for diabetes (OR = 5.1), and 90% for smoking (OR = 3.8). The authors conclude that hypertension, diabetes, and smoking are the major risk factors for TES in patients 65 years old or younger.


Different dissolution conditions affect stability and dissolution profiles of bioequivalent levodopa-containing oral dosage forms.
Parkinson's disease is frequently treated with combinations of levodopa/carbidopa and, at the occurrence of motor fluctuations, levodopa/carbidopa/entacapone. For these (and other) medications, using generic versions can reduce costs. To show that generic drugs are equivalent to the originator drug, regulations usually refer to the bioavailability of active ingredients, which is influenced by the selected dosage form and the chosen excipients. However, while registration trials administer drugs under standardized conditions, these conditions often do not reflect the conditions of patients' daily intake. Thus, this study aimed to characterize levodopa combinations from different manufacturers in biorelevant media. Dissolution profiles of bioequivalent levodopa/carbidopa combinations and levodopa/carbidopa/entacapone combinations were tested in different media, such as tap water, gastric fluid without pepsin and whole milk. Results showed distinct discrepancies in the drugs' dissolution profiles between manufactures. Using whole milk as a dissolution medium led to the most differing dissolution profiles. Furthermore, carbidopa was unstable in tap water and milk, and it rapidly degraded. This effect was less pronounced if entacapone was present. In contrast to reports in the literature, stability testing did not show that vitamin C helps to protect against carbidopa degradation. Entacapone hardly dissolved in an acidic environment. This study found that dissolution of bioequivalent levodopa formulations varied with changing media. Further, the stability of carbidopa was found to be critical. As an implication, an acidic environment must be ensured when these drugs are applied, and generic exchange of levodopa combinations should be considered only with great caution.


Changing demographics of the Canadian cow-calf industry for the period 2011 to 2016.
From 2011 to 2016, both the number of cow-calf producers and farm operations in Canada decreased by 12.4%. Furthermore, the current demographics portend a similar or greater loss in the number of producers and farms by the next census (2021). This level of consolidation has implications with respect to veterinary education and how practitioners will service the cow-calf sector.


Update on pneumococcal vaccination in adults: Simpler is better.
Recommendations for pneumococcal vaccination in adults have been updated in the hopes not only of preventing more cases of invasive pneumococcal disease but also of making the recommendations simpler and easier to follow.


Cingulate sulcus morphology and paracingulate sulcus variations: Anatomical and radiological studies.
The sulci and gyri found across the cerebrum differ in morphology between individuals. The cingulate sulcus is an important landmark for deciding the surgical approach for neighboring pathological lesions. Identifying the anatomical variations of anterior cingulate cortex morphology would help to determine the safe-entry route through neighboring lesions. In this study, magnetic resonance imaging data acquired from 149 healthy volunteers were investigated retrospectively for anatomical variations of the paracingulate sulcus. Also, human cadaveric brain hemispheres were investigated for cingulate and paracingulate sulcus anatomy. All participants had cingulate sulci in both hemispheres (n = 149, 100%). Three types of paracingulate sulcus patterns were identified: "prominent," "present," and "absent." Hemispheric comparisons indicated that the paracingulate sulcus is commonly "prominent" in the left hemisphere (n = 48, 32.21%) and more commonly "absent" in the right hemisphere (n = 73, 48.99%). Ten (6.71%) people had a prominent paracingulate sulcus in both the right and left hemispheres. Seven (4.70%) of them were male, and 3 (2.01%) of them were female. Paracingulate sulci were present in both hemispheres in 19 people (12.75%), of which 9 (6.04%) were male and 10 (6.71%) were female. There were 35 (23.49%) participants without paracingulate sulci in both hemispheres. Eleven (7.38%) were male and 24 (16.11%) were female. There were 73 (48.99%) participants without right paracingulate sulcus and 57 (38.26%) participants without left paracingulate sulcus (p = 0.019). In the examinations of the cadaver hemispheres, the paracingulate sulcus was present and prominent in 25%, and the intralimbic sulcus was present in 15%. It has been observed that the paracingulate sulcus is more prominent in the normal male brain compared to females. In females, there were more participants without paracingulate sulcus. This study shows that there are both hemispheric and sex differences in the anatomy of the paracingulate sulcus. Understanding the cingulate sulcus anatomy and considering the variations in the anterior cingulate cortex morphology during surgery will help surgeons to orient this elegant and complex area.


Long noncoding RNA MALAT1 polymorphism predicts MACCEs in patients with myocardial infarction.
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) participates in the occurrence and development of cardiovascular and cerebrovascular diseases such as stroke and coronary heart disease by regulating inflammatory reactions, programmed cell death, and other pathological processes. Previous studies revealed that the MALAT1 gene polymorphism was associated with cardiac and cerebrovascular diseases. However, the prognostic role of the MALAT1 polymorphism in major adverse cardiac and cerebrovascular events (MACCEs) remains unknown. Therefore, this study intends to explore the association between the MALAT1 rs3200401 polymorphism and MACCEs. We enrolled 617 myocardial infarction (MI) patients and 1125 control participants who attended the First Affiliated Hospital of Xinjiang Medical University from January 2010 to 2018. SNPscan™ typing assays were used to detect the MALAT1 rs3200401 genotype. During the follow-up, MACCEs were recorded. Kaplan-Meier curves and univariate and multivariate Cox survival analyses were used to explore the correlation between MALAT1 gene polymorphisms and the occurrence of MACCEs. Among the total participants and MI patients, the frequencies of the T allele (total Participants 19.5% vs. 15.3%, P = 0.047, MI patients 20.7% vs. 14.1%, P = 0.014) and CT + TT genotypes (total Participants 37.4% vs. 28.1%, P = 0.013, MI patients 39.5% vs. 25.8%, P = 0.003) were significantly higher in subjects with MACCEs than in subjects without MACCEs. However, in control participants, the frequencies of the T allele (16.6% vs. 16.0%, P = 0.860) and CT + TT genotypes (31.4% vs. 29.3%, P = 0.760) were not higher in subjects with MACCEs than in subjects without MACCEs. In addition, among the total participants and MI patients, the Kaplan-Meier curve analysis indicated that the subjects with rs3200401 CT + TT genotypes had a higher incidence of MACCEs than CC genotype carriers (P = 0.015, P = 0.001). Nevertheless, similar results were not observed in the control participants (P = 0.790). Multivariate Cox regression indicated that compared with patients with the CC genotype, patients with CT + TT genotypes had a 1.554-fold increase in MACCE risk (hazard ratio: 1.554, 95% confidence interval: 1.060-2.277, P = 0.024). The MALAT1 rs3200401 CT + TT genotypes could be a risk factor for MACCEs in MI patients, suggesting that the MALAT1 gene may become a biomarker for poor prognosis in MI patients.


Objective speech intelligibility measurement for cochlear implant users in complex listening environments.
Objective intelligibility measurement allows for reliable, low-cost, and repeatable assessment of innovative speech processing technologies, thus dispensing costly and time-consuming subjective tests. To date, existing objective measures have focused on normal hearing model, and limited use has been found for restorative hearing instruments such as cochlear implants (CIs). In this paper, we have evaluated the performance of five existing objective measures, as well as proposed two refinements to one particular measure to better emulate CI hearing, under complex listening conditions involving noise-only, reverberation-only, and noise-plus-reverberation. Performance is assessed against subjectively rated data. Experimental results show that the proposed CI-inspired objective measures outperformed all existing measures; gains by as much as 22% could be achieved in rank correlation.


Rapid Synthesis of Carbon Dots by Hydrothermal Treatment of Lignin.
A rapid approach has been developed for the fluorescent carbon dots (CDs) by the hydrothermal treatment of lignin in the presence of H₂O₂. The as-synthesized CDs were found to emit blue photoluminescence with excellent photostability. Moreover, the CDs displayed biocompatibility, low cytotoxicity, and high water solubility properties. Finally, the as-resulted CDs were demonstrated to be excellent probes for bioimaging and biosensing applications.


Constructing nickel cobaltate @nickel-manganese layered double hydroxide hybrid composite on carbon cloth for high-performance flexible supercapacitors.
Flexible supercapacitors have received considerable interest owing to their potential application in wearable electronics. Designing subtle hybridization of active materials and constructing smart electrode architectures are effective strategies for developing high-performance flexible supercapacitors. Herein, a hierarchically hybrid electrode is engineered by integrating nanoneedle-like structural NiCo2O4 and NiMn layered double hydroxide (NiMn-LDH) composite on highly conductive carbon cloth (CC). This architecture can endow abundant active sites, rapid electron collection pathways and efficient ion transport channels. The resultant hybrid electrode delivers high areal capacitance of 4010.4 mF cm-2, excellent cyclic stability and good rate performance. Furthermore, by pairing with an activated carbon (AC)/CC anode, a flexible solid-state asymmetric supercapacitor (ASC) is assembled, which exhibits the high areal energy/power density of 0.78 mWh cm-2/40.4 mW cm-2 and superior capacitive stability at bending deformation. Meanwhile, the assembled ASC possesses outstanding cycling stability with 97.7% capacitance retention after 10,000 cycles. This work presents the effects of rational design of hybrid electrode with high electrochemical properties and flexibility, holding great potential for flexible energy storages.


The close environments of accreting massive black holes are shaped by radiative feedback.
The majority of the accreting supermassive black holes in the Universe are obscured by large columns of gas and dust. The location and evolution of this obscuring material have been the subject of intense research in the past decades, and are still debated. A decrease in the covering factor of the circumnuclear material with increasing accretion rates has been found by studies across the electromagnetic spectrum. The origin of this trend may be driven by the increase in the inner radius of the obscuring material with incident luminosity, which arises from the sublimation of dust; by the gravitational potential of the black hole; by radiative feedback; or by the interplay between outflows and inflows. However, the lack of a large, unbiased and complete sample of accreting black holes, with reliable information on gas column density, luminosity and mass, has left the main physical mechanism that regulates obscuration unclear. Here we report a systematic multi-wavelength survey of hard-X-ray-selected black holes that reveals that radiative feedback on dusty gas is the main physical mechanism that regulates the distribution of the circumnuclear material. Our results imply that the bulk of the obscuring dust and gas is located within a few to tens of parsecs of the accreting supermassive black hole (within the sphere of influence of the black hole), and that it can be swept away even at low radiative output rates. The main physical driver of the differences between obscured and unobscured accreting black holes is therefore their mass-normalized accretion rate.


A retrospective comparison between digital to conventional drainage systems for secondary spontaneous pneumothorax related to diffuse interstitial lung disease.
Secondary spontaneous pneumothorax (SSP) occurs as one of the complications associated with interstitial pneumonia (IP). Chest drainage is performed when there is a large volume of air in the pleural space. Notably, SSP with IP (SSP-IP) is frequently not curable by chest drainage only. A digital drainage system (DDS) provides an objective evaluation of air leakage and maintains a pre-determined negative pressure, compared to an analog drainage system (ADS). Few studies have reported the effectiveness of DDS in the treatment of SSP-IP. This study aimed to assess the usefulness of DDS for SSP-IP. This retrospective study included patients with SSP-IP who had undergone chest drainage. We reviewed the included patients' medical records, laboratory data, computed tomography findings, and pulmonary function data. DDS was used in 24 patients and ADS in 49 patients. The mean duration of chest drainage was 11.4 ± 1.9 days in the DDS group and 14.2 ± 1.3 days in the ADS group, which was not significantly different (p = 0.218). Surgery, pleurodesis, and/or factor XIII administration were performed in 40 patients. Additionally, five (20.8%) patients in the DDS group and nine (18.4%) in the ADS group had a recurrence of pneumothorax within 4 weeks (p = 1.000). One patient (14%) in the DDS group and six (12.2%) in the ADS group (p = 0.414) were cured of pneumothorax but later died. DDS did not demonstrate a significant difference in the shortening of chest drainage duration. Further study is needed to validate the results of this study.


Ghost Surgery: A Frank Look at the Issue and How to Address It.
Ghost surgery occurs when a physician assistant, a surgical assistant, an RN first assistant, a resident, or another surgeon assists on or performs an operative or other invasive procedure without the patient's knowledge, regardless of whether the surgeon who obtained the consent was scrubbed in or not. This practice denies patients important information, eliminates their ability to provide informed consent, and represents an ethical issue that nurses must deal with when working with peers and patients. The American Nurses Association developed the Code of Ethics for Nurses to help guide nursing practice, and the provisions within the code embody the ethical issues that should guide nurses' practice in advocating for patients.


Plasmid - Chromosome interplay in natural and non-natural hosts: global transcription study of three Bacillus cereus group strains carrying pCER270 plasmid.
The Bacillus cereus group comprises genetically related Gram-positive spore-forming bacteria that colonize a wide range of ecological niches and hosts. Despite their high degree of genome conservation, extrachromosomal genetic material diverges between these species. The discriminating properties of the B. cereus group strains are mainly due to plasmid-borne toxins, reflecting the importance of horizontal gene transfers in bacterial evolution and species definition. To investigate how a newly acquired megaplasmid can impact the transcriptome of its host, we transferred the pCER270 from the emetic B. cereus strains to phylogenetically distant B. cereus group strains. RNA-sequencing experiments allowed us to determine the transcriptional influence of the plasmid on host gene expression and the impact of the host genomic background on the pCER270 gene expression. Our results show a transcriptional cross-regulation between the megaplasmid and the host genome. pCER270 impacted carbohydrate metabolism and sporulation genes expression, with a higher effect in the natural host of the plasmid, suggesting a role of the plasmid in the adaptation of the carrying strain to its environment. In addition, the host genomes also modulated the expression of pCER270 genes. Altogether, these results provide an example of the involvement of megaplasmids in the emergence of new pathogenic strains.


Detection of human cytomegalovirus and Epstein-Barr Virus in symptomatic and asymptomatic apical periodontitis lesions by real-time PCR.
Recent studies have investigated the occurrence of human cytomegalovirus and Epstein-Barr Virus in samples from apical periodontitis lesions and a role in the pathogenesis of this disease has been suggested. Because genotype distribution and seroprevalence of EBV and HCMV differ among populations, it is important to determine the presence of these viruses in endodontic periapical lesions of different populations. The aims of this study were to determine the presence of HCMV and EBV DNAs in samples from Turkish patients with symptomatic and asymptomatic apical periodontitis lesions using real-time polymerase chain reaction method and to evaluate their presence in both symptomatic and asymptomatic apical periodontitis lesions. Periapical samples were collected from 12 asymptomatic and 16 symptomatic periapical lesions in conjunction with apicectomy. HCMV and EBV DNAs were identified in the samples by real-time PCR. The chi-squared test with Yates's correction or the Fisher's exact test was used to analyse the significance of differences. HCMV DNA was detected in 10 of the 16 (62.5%) symptomatic and in five of the 12 (41.7 %) asymptomatic periapical study lesions. The EBV DNA was identified in seven of the 16 (43.7 %) symptomatic and three of the 12 (25 %) asymptomatic periapical lesions. The difference in occurrence of HCMV and EBV DNA between symptomatic and asymptomatic periapical lesions was not statistically significant. (All comparisons have p > 0.05). Our findings suggest that HCMV and EBV is a frequent inhabitant of both symptomatic and asymptomatic apical periodontitis lesions of endodontic origin in Turkish population.


Ethacrynic acid effects on the isolated inner ear: evaluation of the ototoxic potential in an organ culture system.
The ototoxic potential of ethacrynic acid, defined as causing morphologic damage to hair cells or adjacent supporting structures, was analyzed in an organ culture model exposing inner ear structures to concentrations attainable during clinical conditions (0.1 to 10 micrograms/ml). In low doses more) ethacrynic acid caused generalized toxic effects on the tissue morphology of many types of inner ear tissues and an arrest of tissue differentiation. Although by definition ethacrynic acid is an ototoxic agent, there is, at least in the in vitro system, a very narrow dose range between the selective hair cell damaging concentration and that causing generalized toxic effects.


Euler-Lagrange CFD modelling of unconfined gas mixing in anaerobic digestion.
A novel Euler-Lagrangian (EL) computational fluid dynamics (CFD) finite volume-based model to simulate the gas mixing of sludge for anaerobic digestion is developed and described. Fluid motion is driven by momentum transfer from bubbles to liquid. Model validation is undertaken by assessing the flow field in a labscale model with particle image velocimetry (PIV). Conclusions are drawn about the upscaling and applicability of the model to full-scale problems, and recommendations are given for optimum application.


Stereochemical definition and chirospecific synthesis of the peptide deformylase inhibitor Sch 382583.
The recently reported natural product Sch 382583 (1), an inhibitor of peptide deformylase, has been synthesized in 16 steps from commercially available starting materials. The three chiral centers were set by a combination of chiral auxiliary and chiral pool approaches. The succinate 5 and piperazic acid 9 moieties were obtained by Evans oxazolidinone imide enolate alkylation and hydrazination/cyclization, respectively, and the aminohexanone side chain 13 was prepared via Grignard substitution of the Weinreb amide derived from l-valine. Spectroscopic data for the resulting synthetic material, compared with the data reported for the natural product, established that the previously unassigned valine ketone stereocenter (C-4) has the S-configuration.


Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation.
Interleukin-1 receptor associated kinases (IRAKs) are key players in innate immune signaling that mediate the host response to pathogens. In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. IRAK3 is thought to be a negative regulator of innate immune signaling and mutations in IRAK3 are associated with asthma and cancer. Here, we report the crystal structure of the human IRAK3 pseudokinase domain in a closed, pseudoactive conformation. IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. Multiple conserved cysteine residues imply a potential redox control of IRAK3 conformation and dimerization. By analyzing asthma-associated mutations, we identify an evolutionarily conserved surface on IRAK3 that could form an interaction interface with IRAK4, suggesting a model for the negative regulation of IRAK4 by IRAK3.


Functional impact of oxygen-saturated zeolite nanoparticles on macrophages in the context of glioblastoma: an in vitro and in vivo study.
In the context of glioblastoma (GBM), hypoxia and inflammation are two main players of the tumor microenvironment. Hypoxia stimulates various features involves in tumor growth and also maintains a specific environment that favors protumor macrophages. Therefore, targeting hypoxia could potentially restore an anti-tumor M1 phenotype in macrophages. Besides, iron demonstrated its capacity to stimulate the polarization of macrophages towards an M1-like phenotype. In this paper we took advantages of microporous nanoparticles to co-deliver both oxygen and iron to bone marrow derived macrophages (BMDM) enabling the investigation of changes in polarization status and proteomic profiles. The nanoparticles were used in two in vivo models of glioblastoma, specifically, in both immunodeficient and immunocompetent settings. Our in vitro findings revealed that iron doped nanoparticles, saturated with oxygen were deemed safe for macrophages but did not demonstrate the capacity to change the M1 or M2 phenotypes. However, these nanoparticles induced some changes in proteomics pathways. The present study reports on in vivo experimentation that revealed the effects of nanoparticles on the hypoxic fraction, tumor volume, and macrophage phenotype in a GBM model. The findings indicated that the presence of nanoparticles led to a reduction in the hypoxic fraction in one of the GBM models, while no significant changes were observed in the tumor volume or macrophage phenotype. The present data showed that nanoparticles possess the capability of delivering both oxygen and iron to macrophages; though, they do not possess the ability to effectively repolarize M2 macrophages. Such strategies could be used in conjunction with other potent molecules to avoid M1 macrophages to inevitably differentiate to M2 macrophages.


Comparison of Pacing Performance and Clinical Outcomes Between Left Bundle Branch and His Bundle Pacing.
Left bundle branch (LBBP) and His-bundle pacing (HBP) provide physiological ventricular activation. This study investigated differences in feasibility, device performance, and clinical outcomes between LBBP and HBP. Consecutive patients with LBBP and HBP from 2018 to 2021 in 2 centers were prospectively studied. The primary endpoint was optimal device performance during follow-up, defined as the presence of pacing thresholds <2.5 V, R-wave amplitude ≥5 V, and absence of conduction system pacing (CSP)-related complications. The secondary endpoint was the composite of heart failure hospitalizations or all-cause mortality. Among 338 patients, 282 underwent successful CSP (119 HBP, 163 LBBP). Success rates, CSP-related complications, and need for reoperations did not differ between LBBP and HBP (P > 0.05). Pacing thresholds were lower, whereas R-wave amplitudes and lead impedance were higher in LBBP (P < 0.05). The primary endpoint was more frequent in LBBP than HBP (79% vs 34%; P < 0.001), with LBBP independently associated with 9-fold increased odds of optimal device performance (adjusted OR: 9.31; 95% CI: 5.14-16.86). LBBP was less likely to have increased pacing thresholds by >1 V (1% vs 19% HBP, P < 0.001). The secondary outcome was less frequent in LBBP than HBP (9% vs 24%, P = 0.001), with LBBP trending towards higher event-free survival (HR: 0.62; 95% CI: 0.31-1.23). The secondary outcome was independent of pacing burden or pacing indication. Despite similar feasibility and safety profiles, LBBP confers additional benefits in pacing performance and reliability, shows trends towards improved survival compared to HBP, and should be the preferred first-line CSP modality of choice.


The influence of contralateral carotid stenosis and occlusion on cerebral oxygen saturation during carotid artery surgery.
To study the effect of contralateral carotid stenosis on oxygen saturation (CsO2) of both cerebral hemispheres monitored by reflective near-infrared spectroscopy (NIRS) during carotid surgery. NIRS was compared to ipsilateral transcranial Doppler ultrasonography (TCD) of the middle cerebral artery and jugular bulb venous oxygen saturation (JvSO2) in 54 patients undergoing carotid endarterectomy. Median operated side and contralateral CsO2 were 68(54-88)% and 69(55-85)% before carotid clamping falling to 63(44-80)% and 69(55-84)% respectively on clamping the carotid (p < 0.0001 and p = NS). JvSO2 fell from 78(38-98)% to 72(30-97)% on carotid clamping with a percentage fall in peak TCD of -28(0 to -100)% (p < 0.0001). Patients with a contralateral carotid artery occlusion experienced falls in ipsi and contralateral CsO2 of -8(-4 to -10)% and -3(2 to -7)% compared to -4(0 to -14)% and 0(-5 to 4)% in those with a lesser stenosis (p < 0.05). On declamping, median ipsilateral and contralateral CsO2 rose from 65(46-82)% and 67(52-87)% to 68(53-84)% respectively (p < 0.0001 and p = NS). JvSO2 increased from 75(33-95)% to 79(42-95)% (p < 0.0001) with an increase in median peak TCD of 35(-34 to 506)%. The greatest changes in CsO2 occurred in the operated side cerebral hemispheres in those with a contralateral carotid artery occlusion. However, a contralateral carotid artery occlusion does not reliably predict the need for a shunt and cerebral monitoring remains essential; although is only required on the operated side.


The influence of mouse genotype on the changes in brain cyclic nucleotide levels induced by acute alcohol administration.
Two mouse strains (C57BL/6By and BALB/cByJ) were found to differ widely in their sleep-time response to ethanol (3 g/kg), but showed no difference in their hypothermic response to the same ethanol dose. Comparison of brain cyclic nucleotide levels in the two strains revealed a strain difference in the brain cyclic AMP response to ethanol but no strain difference in the magnitude of the brain cyclic GMP change. Alcohol produced a significant drop in cerebellar cyclic GMP in both strains, and a decrease in cerebellar cyclic AMP in C57BL/6By mice. The cyclic AMP/cyclic GMP ratio increased following alcohol in the cerebellum of BALB/cByJ mice but not C57BL/6By mice. The results are discussed in terms of possible relationships between alcohol-induced changes in neurochemistry and behavior.


An improved model for tissue expansion and flap research in the rabbit.
A pocket for tissue expander implantation in the rabbit is described at the level between the skin and the panniculus carnosus. The vascular anatomy of the undermined skin was studied with microangiography which showed a functional (sub)dermal plexus. Expanders were placed in seven rabbits and inflated daily over a period of 10 days. Blood flow in expanded skin, as measured with laser Doppler flowmetry, dropped with increasing inflation pressure. During the course of expansion, the intraluminal pressure returned to a baseline level within 24 hours after each inflation. It is concluded that an expander placed in the described layer in the rabbit causes considerable skin stretch and interferes with cutaneous blood supply and is therefore an improved model for tissue expansion in the human.


Up-regulation of endogenous PML induced by a combination of interferon-beta and temozolomide enhances p73/YAP-mediated apoptosis in glioblastoma.
Interferon-beta (IFN-β) is reported to augment anti-tumor effects by temozolomide in glioblastoma via down-regulation of MGMT. Promyelocytic leukemia (PML), a gene induced by IFN-β, is a tumor suppressor. Here, we report for the first time that in combination therapy, an IFN-β-induced increase in endogenous PML contributes to anti-tumor effects in p53 wild- and mutant glioma cells in a xenograft mice model. The increased PML promoted the accumulation of p73, a structural and functional homolog of p53, to fuse the coactivator Yes-associated-protein in the PML nuclear bodies. The adjuvant therapy targeted at PML may be a promising therapeutic strategy for glioblastoma.


A study of the lengthening and contractility of the surgical margins in digestive tract cancer.
The lengthening and the contractility of the digestive tract were studied. The stretched length of specimens was measured under pull weights of 500 g and 1000 g; the contracted length was measured in natural status and in 10% formalin fixation in vitro. The lengthening or contractility rate was calculated as the length difference divided by the natural length in vivo. The esophagus lengthened 16.5% at 500 g and 30.5% at 1,000 g, stomach 15% and 22.6%, small intestine 66.4% and 120%, large intestine 36% and 56%. In natural status in vitro, the esophagus contracted 44.5%, stomach 13.6%, small intestine 11.4%, and large intestine 15.6%; they continued to contract 12 to 24 hours after formalin fixation. The lengthening and contractility of the digestive tract should be considered in evaluating the resection margin at surgery. The length of different conditions can be converted by the formula: Y = alphaX.


Dissociable controlled retrieval and generalized selection mechanisms in ventrolateral prefrontal cortex.
How does ventrolateral prefrontal cortex (VLPFC) control mnemonic processing? Alternative models propose that VLPFC guides top-down (controlled) retrieval of knowledge from long-term stores or selects goal-relevant products of retrieval from among competitors. A paucity of evidence supports a retrieval/selection distinction, raising the possibility that these models reduce to a common mechanism. Here, four manipulations varied semantic control demands during fMRI: judgment specificity, cue-target-associative strength, competitor dominance, and number of competitors. Factor analysis revealed evidence for a metafactor that accounted for common behavioral variance across manipulations and for functional variance in left mid-VLPFC. These data support a generalized control process that selects relevant knowledge from among competitors. By contrast, left anterior VLPFC and middle temporal cortex were sensitive to cue-target-associative strength, but not competition, consistent with a control process that retrieves knowledge stored in lateral temporal cortex. Distinct PFC mechanisms mediate top-down retrieval and postretrieval selection.


Utilization of montmorillonite nanocomposite incorporated with natural biopolymers and benzyl functionalized dicationic imidazolium based ionic liquid coated fiber for solid-phase microextraction of organochlorine pesticides prior to GC/MS and GC/ECD.
A novel montmorillonite clay (MMT) bionanocomposite modified with chitosan (CH), carboxymethyl cellulose (CMC), and benzylimidazolium based dicationic ionic liquid with tetraethylene glycol linker (DIL) was fabricated on stainless steel wire by in situ process. The MMT-CH-CMC-DIL coated solid-phase microextraction (SPME) fiber was examined for the determination of organochlorine pesticides (OCPs) in real samples by HS-SPME-GC method using mass spectrometry (MS) and electron capture detector (ECD). Under optimized conditions, the proposed method exhibited low limits of detection (0.5 ng L-1 with MS and 0.1 ng L-1 with ECD detection), good linearities (R2 = 0.9972-0.9993 with MS and 0.9987-0.9998 with ECD detection), favorable single-fiber repeatability, and fiber-to-fiber reproducibility (less than 8.2% and 9.9% for both types of detection) and high reusability around 125 cycles. Recovery studies were carried out for OCPs in tap water, green tea, and milk samples to verify the applicability of the developed SPME-GC method.


Ecophysiology of two solar tracking desert winter annuals : IV. Effects of leaf orientation on calculated daily carbon gain and water use efficiency.
This paper represents an empirical study on the effect of different leaf orientations on the daily carbon gain and transpirational water loss of desert winter annuals. Laboratory physiological data on Malvastrum rotundifolium (Gray) and Lupinus arizonicus (Wats) were combined with energy budget concepts and field measurements of water relations and leaf movements to predict carbon gain patterns for horizontally oriented, diaheliotropic and paraheliotropic leaf movement types. The results showed contrasting patterns of carbon gain and water loss. L. arizonicus, which is capable of both dia- and paraheliotropic leaf movements, had the lowest rates of daily carbon gain and water loss. But these low rates resulted in the highest water use efficiencies under early season conditions and high water availability. M. rotundifolium, a diaheliotropic species, was predicted as having the highest rates of carbon gain and water loss on a daily basis over a wide range of environmental conditions and water availability. Despite possessing the highest rates for transpiration, its water use efficiency was higher in relation to other leaf movement types, under a variety of conditions. This result was extremely sensitive to soil water availability. The results were discussed in relation to the ecological ramifications of leaf movements in arid land annuals.