Network-based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation.
The brain adapts to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. An example of an epigenetic modification is protein methylation, catalyzed by protein arginine methyltransferases (PRMT). One member, Prmt8, is selectively expressed in the central nervous system during a crucial phase of early development, but little else is known regarding its function. We hypothesize Prmt8 plays a role in synaptic maturation during development. To evaluate this, we used a proteome-wide approach to characterize the synaptic proteome of Prmt8 knockout versus wild-type mice. Through comparative network-based analyses, proteins and functional clusters related to neurite development were identified to be differentially regulated between the two genotypes. One interesting protein that was differentially regulated was tenascin-R (TNR). Chromatin immunoprecipitation demonstrated binding of PRMT8 to the tenascin-r (Tnr) promoter. TNR, a component of perineuronal nets, preserves structural integrity of synaptic connections within neuronal networks during the development of visual-somatosensory cortices. On closer inspection, Prmt8 removal increased net formation and decreased inhibitory parvalbumin-positive (PV+) puncta on pyramidal neurons, thereby hindering the maturation of circuits. Consequently, visual acuity of the knockout mice was reduced. Our results demonstrated Prmt8's involvement in synaptic maturation and its prospect as an epigenetic modulator of developmental neuroplasticity by regulating structural elements such as the perineuronal nets.


Effect of timolol on the amplitude and dynamics of accommodation.
There is still debate about whether the ciliary muscle is innervated by the sympathetic nervous system. We investigated the amplitude and the dynamics of accommodation under influence of the non-selective beta-blocker timolol. For this purpose the variations in thickness of the human lens during step-like changes in accommodation were measured with high-resolution A-scan echography. Results showed that the dynamics of accommodation, expressed in the time constants of the response, were affected as well as the amplitude.


Effects of stanniocalcin hormones on rat hepatic glucose homeostasis under fed and fasted conditions.
To test the hypothesis of conservation of stanniocalcin 1 and 2 (STC-1; STC-2) metabolic functions in vertebrates, we performed an in vitro study to determine if these hormones are implicated in regulation of the gluconeogenesis pathway, glycogen synthesis, and 14C-glucose conversion to 14CO2 in livers from fed and fasting rats (Rattus norvegicus). Stc1 and Stc2 gene expressions increased in the liver after fasting. STC-1 participated in the regulation of the hepatic gluconeogenesis pathway in rats when the precursor was 14C-lactate. STC-2 demonstrated variational signaling on rat hepatic gluconeogenesis activity and Pck1 gene expression, decreasing levels in the fed state when the substrate was 14C-alanine and increasing levels during fasting when the substrate was 14C-lactate. At the concentrations used in this study, STC-1 and STC-2 did not affect glycogen concentration and synthesis from 14C-glucose or 14C-glucose conversion to 14CO2 in the livers from fed or fasting rats. These findings highlight the role of stanniocalcins in the hepatic gluconeogenesis pathway in mammals and confirm the conservation of STC-1 and STC-2 metabolic functions in the vertebrates.


Immune Cell Isolation from Murine Intestine for Antibody Array Analysis.
Gut mucosal immune cells play an essential role in health due to their ability to orchestrate host signaling events in response to exogenous antigens. These antigens may originate from microorganisms including viruses, commensal or pathogenic bacteria, or single-celled eukaryotes, as well as from dietary foodstuff-derived proteins or products. A critical technological capacity to understand host responses to antigens is the ability to efficiently isolate and functionally characterize immune cells from intestinal tissues. Additionally, after characterization, it is of paramount importance to understand the exact functions of these immune cells under different disease states or genetic variables. Here, we outline methods for immune cell isolation from murine small and large intestines with the goal of undertaking a functional analysis of isolated cell types using antibody array platforms.


Plumbagin downregulates UHRF1, p-Akt, MMP-2 and suppresses survival, growth and migration of cervical cancer CaSki cells.
Plumbagin is a natural compound known to impede growth of cancerous cells. However, anti-cervical cancer effects of plumbagin and its underlying molecular mechanism still remains elusive. In this study, plumbagin reduced the viability of CaSki cells in a concentration dependent manner and suppressed their colony formation potential. It led to G2/M phase arrest with downregulation of E2F1 and upregulation of p21. Plumbagin reduced mitochondrial membrane potential and concomitantly increased the percentage of apoptotic cells as revealed by annexin V-propidium iodide staining. Real Time PCR and western blotting confirmed that plumbagin induced apoptosis by reducing the expression of pAkt, procaspase 9 and full-length PARP. Furthermore, scratch assay showed that plumbagin suppressed migratory potential of CaSki cells which could be due to the reduced expression and activity of MMP-2 and upregulation of TIMP2. Interestingly, plumbagin also downregulated UHRF1 expression. Transient silencing of UHRF1 like plumbagin, induced G2/M phase arrest, enhanced apoptosis and suppressed metastasis of CaSki cells suggesting the role of UHRF1 in mediating anti-cancer activities of plumbagin. Plumbagin at IC20 (1 μM) interacted synergistically with cisplatin and reduced its IC50 value by 13.23 fold with improved effectivity as revealed by augmented apoptosis in CaSki cells.


Anti-Saccharomyces cerevisiae Antibodies Are Only Modestly More Common in Subjects Later Developing Crohn's Disease.
The pathogenic processes in the preclinical phase of inflammatory bowel disease (IBD) are mainly unknown. To study typical antibodies for IBD in the preclinical phase in a cohort of Northern Sweden. Antibodies typical for IBD (ASCA, pANCA, lactoferrin-ANCA, antibodies to goblet cells, and pancreas antigen) were analyzed in 123 subjects with preclinical ulcerative colitis (UC), 54 subjects with preclinical Crohn's disease (CD) and in 390 sex- and age-matched controls. In addition, in a subset of subjects, inflammatory markers (CRP, albumin, calprotectin and ferritin) were measured in plasma. The mean years between blood samples and IBD diagnosis were for UC 5.1 (SD 3.5) years and CD 5.6 (SD 3.5) years. There was no difference in the proportion of overall positive antibodies between subjects who later developed IBD compared to controls (16.9% vs. 12.3%; p = 0.137). The subjects who later developed CD had a significantly higher proportion of positive ASCA compared to controls (9.3% vs 2.8%; p = 0.034), but for all other antibodies, there were no differences compared to control subjects. Subjects with preclinical IBD and elevated antibodies showed significantly higher plasma calprotectin levels compared to subjects without antibodies (980 μg/L vs 756 μg/L; p = 0.042), but there was no difference in the levels of CRP, albumin and ferritin. We found no significant increase in antibodies typical for IBD years before diagnosis except for ASCA, which was slightly more common in subjects who later developed CD. Very few subjects had detectable antibodies to goblet cells and pancreas antigen.


Labor decreases the lung water content of newborn rabbits.
To test the prevailing concept that drainage of fetal lung liquid begins after birth, we measured extravascular lung water content of 47 fetal rabbits born at term gestation, with or without prior labor. Rabbits born after labor, either vaginally or operatively, had less water in their lungs than those delivered by cesarean section without preceding labor; there was no difference in lung water content between rabbits born vaginally or operatively after labor. These results suggest that reduction in the volume of fetal lung liquid in rabbits normally begins before birth and depends on the experience of labor, not the mode of delivery.


Evidence that the coproporphyrinogen oxidase activity of rat liver is situated in the intermembrane space of mitochondria.
Preferential rupture of the outer membrane of mitochondria from rat liver releases coproporphyrinogen oxidase in parallel with components of the intermembrane space. Coproporphyrinogen III enters the mitochondrion through the freely-permeable outer membrane. Either protoporphyrinogen IX or protoporphyrin IX must then cross the inner membrane before haem synthesis can be completed.


Design and manufacturing of biomimetic scaffolds for bone repair inspired by bone trabeculae.
Porous scaffold (PorS) implants, particularly those that mimic the structural features of natural cancellous bone (NCanB), are increasingly essential for the treatment of large-area bone defects. However, the mechanical properties of NCanB-based bionic bone scaffold (BioS) and its performance as a bone repair material have not been fully explored. This study investigates the effect of bionic structure parameters on the mechanical properties and bone reconstruction performance of BioS. Using laser powder bed fusion (L-PBF) technology, different BioS with various structural parameters were created and evaluated using Micro-CT, compression testing, Finite Element (FE) Simulation, and computational fluid dynamics (CFD), and compared to commonly used clinical PorS. Assess the capacity of the BioS scaffold to support and enhance bone reconstruction following implantation through the evaluation of its mechanical properties, permeability, and fluid shear stress (FSS). BioS-85-90 and BioS-80-50 showed suitable mechanical properties, performed well in FE simulation of implantation, demonstrated outstanding abilities for osteoinductive ingrowth and bone tissue differentiation, and proved to be reliable materials for the reconstruction of bone defects. Therefore, BioS shows significant potential for clinical application as a bone reconstruction material, providing a solid foundation for the integration of tissue engineering and bionic design.


Biliary obstruction after short-time choledochal clamping in rats.
Biliary complications after liver procedures can lead to morbidity and poor survival. The aim of this study was to evaluate the hepatic function after quick clamping of the common bile duct (BD) in Wistar rats. Twelve male Wistar rats with a mean weight of 323.14 g were anesthetized with sodium thiopental intravenous (IV). The common BD Clamping Group (BDCG; n = 6) was submitted to an abdominal incision (2 cm); the BD was isolated, dissected, and underwent clamping for 10 minutes with a microvascular clamp. After this time, the clamp was removed and the incision closed. The Sham Operation Group (SOG; n = 6 rats), under normal conditions, were subjected only to anesthesia and laparotomy and later control tests. On the 28th day liver and choledoch biopsy and biochemical tests were performed on all animals: total bilirubin (TB), alkaline phosphatase (ALK-P), aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), and gamma-glutamyl transferase (GGT). After the tests all the rats were humanely killed while still under anesthesia. In this study 83% of the animals in the BDCG had large dilatation of the common BD with ductular proliferation, formation of septae, as well as multiple foci of parenchymal necrosis including micro-abscess formation. We also observed alterations in biochemical tests (P < .05). Our study demonstrated that BD clamping even for a short time was sufficient to generate important morphological alterations in the liver and BD, as confirmed by enzymatic and histological analysis. Therefore, this technique can be used as a model of biliary obstruction for future studies.


Oscillations in the capacitance of a nanopore containing an electrolyte due to pore width and nonzero size ions.
Jiang, Jin, and Wu (Nano Lett., 11 (2011), pp. 5373-5377) have reported the results of a density functional theory (DFT) study of the capacitance of a nanopore containing an electrolyte consisting of charged hard spheres of equal diameter and charge. They find that the capacitance of the nanopore and electrolyte oscillates. The 'period' of the oscillations is of the order of the ionic diameter. Intuitively, the capacitance should tend to zero when the pore diameter is too small to accommodate the electrolyte ions and, thus, would contains no charge. A superficial glance at their table of contents figure might lead one to think that this does not occur in their calculation. However, they do not report results for exceedingly small pore diameters. In order to gain insight into their results, the Poisson-Boltzmann (PB) theory, which does not account for the diameter, is examined briefly. Unsurprisingly, the PB capacitance decreases monotonically to zero as the pore diameter decreases. The effect of a nonzero ion diameter is included in a semi-empirical manner by appealing to the results of the mean spherical approximation (MSA). The resulting capacitance oscillates and is qualitatively similar to the DFT results; it is zero at small pore diameter.


Experience with "second-look" operations in pediatric solid tumors.
"Second-look" operations were performed in 32 infants and children with initially unresectable or recurrent solid tumors treated with combination chemotherapy and/or irradiation. Tumors were resectable in 26 of 32 cases (81%). These procedures often yielded information affecting staging and treatment. Disease-free survival was achieved in 18 of 32 patients (56%). Mortality was related to progressive disease in seven cases and opportunistic infections due to immunosuppression in three. Four additional patients are alive with evidence of persistent tumor. Second-look procedures were beneficial in patients with Wilms' tumor previously operated upon by a flank approach and in children with bilateral tumors. These procedures were particularly useful in children with stage III localized neuroblastoma and cases of metastatic neuroblastoma that respond to chemotherapy. Second-look operations were also useful in selected cases of rhabdomyosarcoma, teratoma, and Ewing's sarcoma. These observations suggest that combination chemotherapy has increased the use of second-look operations in a variety of less favorable (e.g. initially unresectable or recurrent) pediatric solid tumors.


Cerebral amyloidoma mimicking intracranial tumor: a case report.
Cerebral amyloidoma is an infrequently recognized condition that can be confused with a more malignant etiology. Few cases have been reported. We present a case report and a review of the literature. Our patient was a 64-year-old Caucasian man who was incidentally discovered to have a brain mass. He was found to have a cerebral amyloidoma. After discovery of the true etiology of his brain abnormality, it was determined that our patient had a more benign disease than was initially feared. Cases such as this demonstrate why consideration of this disorder is important.


A mathematical model for membrane transport of amino acid and Na+ in vesicles.
A model with a carrier having sites for both amino acid and Na+ can account for AIB (alpha-aminoisobutyric acid) transport kinetics observed in membrane vesicles from SV3T3 (simian virus 40-tranformed Balb/c33 cells) and 3T3 (the parent cell line). The main feature of this cotransport model is that Na+ binding to carrier decreases the effective Km for AIB transport. Na+ transport kinetics observed in both vesicle systems can be described by passive (possibly facilitated) diffusion. The lag of Na+ transport across the membrane compared to that for AIB, coupled to the Na+-dependent decrease in the Km for AIB, accounts for the overshoot in intravesicular AIB observed for SV3T3 in the presence of an initial Na+ gradient. Extra-vesicular Na+ maintains a decrease in the Km for AIB influx before intra-vesicular Na+ has accumulated to balance it with a comparable decrease in the Km for AIB efflux. 3T3 vesicles display little overshoot, and this finding can be explained mostly by a lower carrier affinity for Na+.


Biosynthesis of silver nanoparticles using Ocimum basilicum cultured under controlled conditions for bactericidal application.
Biological synthesis involves the reduction and stabilization of metal ions using different types of organisms. Plants are an attractive source for silver nanoparticles (Ag NPs) synthesis because of their strong reducing potentials by production of a wide range of secondary metabolites. The present study describes the biosynthesis of Ag NPs using plant extract of Ocimum basilicum extract grown under in vitro condition for the first time. The surface Plasmon resonance found at 450 nm confirmed the formation of Ag NPs. FESEM images revealed relatively spherical- shaped of Ag NPs. The biosynthesized Ag NPs were crystalline in nature with mean diameter about 13.82 nm. FTIR results expounded the functional groups of plant extract responsible for the bio-reduction of silver ions and the interactions between them. The obtained nanoparticles showed good inhibitory activity against both Gram positive and Gram negative bacteria. These results suggest that with changes in plant's culture condition it may be possible to obtain nanoparticles with desired characteristics.


Caffeic acid attenuates rat liver injury after transplantation involving PDIA3-dependent regulation of NADPH oxidase.
The transplanted liver inevitably suffers from ischemia reperfusion (I/R) injury, which represents a key issue in clinical transplantation determining early outcome and long-term graft survival. A solution is needed to deal with this insult. This study was undertaken to explore the effect of Caffeic acid (CA), a naturally occurring antioxidant, on I/R injury of grafted liver and the mechanisms involved. Male Sprague-Dawley rats underwent orthotopic liver transplantation (LT) in the absence or presence of CA administration. In vitro, HL7702 cells were subjected to hypoxia/reoxygenation. LT led to apparent hepatic I/R injury, manifested by deteriorated liver function, microcirculatory disturbance and increased apoptosis, along with increased PDIA3 expression and nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase activity, and membrane translocation of NADPH oxidase subunits. Treatment with CA attenuated the above alterations. siRNA/shRNA-mediated knockdown of PDIA3 in HL7702 cells and rats played the same role as CA not only in inhibiting ROS production and NADPH oxidase activity, but also in alleviating hepatocytes injury. CA protects transplanted livers from injury, which is likely attributed to its protection of oxidative damage by interfering in PDIA3-dependent activation of NADPH oxidase.


Factors influencing patient satisfaction after rotator cuff repair.
A number of variables are used to assess the outcome of rotator cuff repair (RCR), including patient satisfaction. The purpose of this study was to determine the factors that affect patient satisfaction after RCR. The study assessed 112 patients (118 shoulders) with chronic rotator cuff tears preoperatively and at a mean of 54 months (range, 34-85 months) after RCR by using several functional outcome questionnaires and an evaluation of patient satisfaction. Of these, 95% were satisfied with the outcome of the surgery. Satisfaction was significantly correlated with the improvement in functional outcomes and general health status and absolute postoperative functional outcomes. Married, currently working, and nondisabled patients had greater satisfaction. High preoperative and postoperative met expectations were also positively correlated with patient satisfaction. Patient satisfaction is most highly correlated with the pain, function, and general health status of the patient after RCR. We conclude that aspects of treatment that maximize the functional outcome are important in achieving patient satisfaction after RCR.


The use of spleen antigen in the tube agglutination test for diagnosis of anaplasmosis in cattle.
An antigen was prepared from the spleen of an infected bovine calf and was used in the tube agglutination test. Cases having rare and very low parasitaemia as well as the carrier cases were detected by this procedure and no non-specific reaction was observed with other haemoprotozoan infections. The maximum titre obtained with the Anplasma positive sera was 1:20, about 60 per cent showed a titre of 1:10 and 90 per cent showed a titre of 1:5 or more. The test provided satisfactory results in detecting the cases even at the early phase of the infection. The test also proved useful in judging the efficacy of a drug employed to destroy the carrier status.


Amitriptyline and carbamazepine utilize voltage-gated ion channel suppression to impair excitability of sensory dorsal horn neurons in thin tissue slice: An in vitro study.
Amitriptyline, carbamazepine and gabapentin are often used for the treatment of neuropathic pain. However, their analgesic action on central sensory neurons is still not fully understood. Moreover, the expression pattern of their target ion channels is poorly elucidated in the dorsal horn of the spinal cord. Thus, we performed patch-clamp investigations in visualized neurons of lamina I-III of the spinal cord. The expression of the different voltage-gated ion channels, as the targets of these drugs, was detected by RT-PCR and immunohistochemistry. Neurons of the lamina I-III express the TTX-sensitive voltage-gated Na(+) as well as voltage-gated K(+) subunits assembling the fast inactivating (A-type) currents and the delayed rectifier K(+) currents. Our pharmacological studies show that tonically-firing, adapting-firing and single spike neurons responded dose-dependently to amitriptyline and carbamazepine. The ion channel inhibition consecutively reduced the firing rate of tonically-firing and adapting-firing neurons. This study provides evidence for the distribution of voltage-gated Na(+) and K(+) subunits in lamina I-III of the spinal cord and for the action of drugs used for the treatment of neuropathic pain. Our work confirms that modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs.


Non-Invasive Prediction of IDH Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning.
Isocitrate dehydrogenase (IDH)-1 mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of IDH mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of IDH, directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of IDH status in standard 1H-magnetic resonance spectroscopy (1H-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) for optimized voxel placement in 1H-MRS. Routine 1H-magnetic resonance (1H-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of IDH status. Since 2-HG spectral signals were too overlapped for reliable discrimination of IDH mutated (IDHmut) and IDH wild-type (IDHwt) glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the 1H-MRS data to predict IDH status. Using this approach, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2-99.9%) and a specificity of 75.0% (95% CI, 42.9-94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo 1H-nuclear magnetic resonance (1H-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of IDH status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of IDH status in a standard clinical setting.


Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration.
To investigate the potential influences that affect visual acuity (VA) outcome in a clinic-based cohort of age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) treatment for choroidal neovascularization. Prospective interventional case series. Patients with subfoveal choroidal neovascularization (CNV) secondary to AMD were prospectively recruited. A detailed questionnaire was given to patients at time of enrollment, to collect information relating to demographics, history of visual symptoms, visual acuity (VA), and treatment scheduling. Delay from symptoms to treatment ("Treatment delay") was measured in terms of weeks and analyzed in tertiles. Information pertaining to treatment outcomes was collected over a 6-month period. One hundred eighty-five eyes of 185 patients were recruited into the study. Longer delay from first symptoms suggestive of CNV to first injection was a significant predictor (P=.015) of poorer treatment outcome, when controlling for age, sex, and baseline VA. Patients with a delay in treatment of 21 weeks or more compared to a delay of 7 weeks or less had an odds ratio of 2.62 (1.20, 5.68) for worsening vision after treatment. Patients experiencing a longer delay between their first symptoms of CNV and their first anti-VEGF treatment have a significantly lower chance of improving vision at 6 months following anti-VEGF therapy. It is critical that this information reach those at potential vision loss from AMD, in order that prompt treatment may be instituted, to maximize the benefits of anti-VEGF treatment.


[Changes of p16 gene, cyclin D1 gene, and pRb protein in human pancreatic adenocarcinoma cell lines].
To investigate the abnormalities of the relative factors of pRb-p16 cell regulatory pathway in pancreatic adenocarcinoma. Five strains of human pancreatic adenocarcinoma cell lines were analysed by PCR and single-strand conformation polymorphism (SSCP) for homozygous deletion and mutation of the p16 gene, respectively. The gene amplification of cyclin D1 was detected by Southern blot analysis and the protein expression of pRb gene was examined by Western blot analysis. Homozygous deletion of exon 1 were found in two cell lines and no mutation was found within exon 1 and exon 2 in five cell lines. Cyclin D1 gene amplification was observed in one cell line and all of the five cell lines showed hyper-phosphorylated pRb protein. These findings have demonstrated that there are abnormalities of pRb-p16 regulatory pathway in pancreatic adenocarcinoma cell lines, revealing the alteration of the p16 and cyclin D1 genes.


Ruptured globe 20 years after radial and transverse keratotomy.
To report a case of corneal rupture due to blunt trauma occurring 20 years after radial keratotomy (RK) and transverse keratotomy. A 57-year-old woman sustained direct blunt trauma to her right eye. Ocular examination revealed a ruptured globe involving two of the eight RK incisions connected together across the visual axis with iris incarceration in the wound. The transverse keratotomy scars remained intact. The patient underwent primary corneal wound repair and iris repositioning. The postoperative period was uneventful. The patient had a visual acuity of counting fingers at 1 m and is awaiting penetrating keratoplasty. Traumatic rupture of RK incisions can still occur after 20 years. Patients having undergone RK many years before should be warned of a possible life-long risk of traumatic rupture. RK scars appear to be more vulnerable to rupture than astigmatic keratotomy scars.


Randomized, prospective comparison of postoperative pain in low- versus high-pressure pneumoperitoneum.
Reduced postoperative pain after laparoscopic cholecystectomy (LC) compared to open cholecystectomy (OC) may be able to be further optimized. To reduce pain, focus should be directed on the effects of individual components of pain. A double-blind, randomized, controlled trial was carried out in a tertiary care hospital. Fifty-three elective patients with symptomatic gallstones were enrolled into the study. Patients were randomized to low- or high-pressure pneumoperitoneum groups. In all patients, gas pressure was set to 15 mmHg during placement of ports. Later on, in the low-pressure group, the rest of the procedure was performed at 10 mmHg pressure. At 6 and 24 h postoperatively, a short-form McGill Questionnaire (MPQ) was obtained from all patients. Patients were then asked to complete a 10-cm visual analogue scale (VAS) for abdominal pain. Pain scores were generally low for both groups. Statistical comparisons of mean cumulative McGill score and VAS abdominal pain scores in both groups did not reach statistical significance at 6 and 24 h after operation. There was no correlation between high- and low-pressure laparoscopy and postoperative pain after LC. Peritoneal stretching may be more responsible for shoulder pain but has less effect on intensity of abdominal pain or incisional pain. On the basis of these negative findings, routine use of low-pressure pneumoperitoneum for alleviation of postoperative pain following LC is not recommended.


Angiotensin II increases L-type Ca2+ current in gramicidin D-perforated adult rabbit ventricular myocytes: comparison with conventional patch-clamp method.
The effects of angiotensin II (Ang II) on L-type Ca2+ current (I(Ca,L)) remains controversial. We studied the effects of Ang II on I(Ca,L) in single adult rabbit ventricular myocytes using a perforated patch-clamp technique with gramicidin D. Ang II increased I(Ca,L) in a concentration-dependent manner (EC(50)=0.75 nM). In contrast, in conventional whole-cell patch-calmp, I(Ca,L)ran down gradually and the I(Ca,L) response to Ang II was variable, suggesting the potential loss of diffusible components crucial for the Ang II-induced signaling process. An AT(1) antagonist, CV11974 (0.1 microM), completely inhibited the increase in I(Ca,L) induced by Ang II (0.1 microM), whereas an AT(2) antagonist, PD123319 (10 microM), did not influence the I(Ca,L) increase. Neither pre- nor after-treatment with a Na+/H+ exchange (NHE) inhibitor HOE642 (1 microM) affected the Ang II-induced increase in I(Ca,L). The protein kinase C (PKC) inhibitor chelerythrine (1 microM) did not affect the Ang II-induced I(Ca,L) increase. The present findings indicate that Ang II increases I(Ca,L) via AT(1) receptors in adult rabbit ventricular myocytes. Neither the activation of NHE nor PKC may contribute to the Ang II-induced activation of I(Ca,L).


How to appraise the literature: basic principles for the busy clinician - part 1: randomised controlled trials.
Critical appraisal is the process of carefully, judiciously and systematically examining research to adjudicate its trustworthiness and its value and relevance in clinical practice. The first part of this two-part series will discuss the principles of critically appraising randomised controlled trials. The second part will discuss the principles of critically appraising systematic reviews and meta-analyses.Evidence-based dentistry (EBD) is the integration of the dentist's clinical expertise, the patient's needs and preferences and the most current, clinically relevant evidence. Critical appraisal of the literature is an invaluable and indispensable skill that dentists should possess to help them deliver EBD.This article seeks to act as a refresher and guide for generalists, specialists and the wider readership, so that they can efficiently and confidently appraise research - specifically, randomised controlled trials - that may be pertinent to their daily clinical practice.


The potential of intervening on childhood adversity to reduce socioeconomic inequities in body mass index and inflammation among Australian and UK children: A causal mediation analysis.
Lower maternal education is associated with higher body mass index (BMI) and higher chronic inflammation in offspring. Childhood adversity potentially mediates these associations. We examined the extent to which addressing childhood adversity could reduce socioeconomic inequities in these outcomes. We analysed data from two early-life longitudinal cohorts: the Longitudinal Study of Australian Children (LSAC; n=1873) and the UK Avon Longitudinal Study of Parents and Children (ALSPAC; n=7085). low/medium (below university degree) versus high maternal education, as a key indicator of family socioeconomic position (0-1 year). BMI and log-transformed glycoprotein acetyls (GlycA) (LSAC: 11-12 years; ALSPAC: 15.5 years). Mediator: multiple adversities (≥2/<2) indicated by family violence, mental illness, substance abuse and harsh parenting (LSAC: 2-11 years; ALSPAC: 1-12 years). A causal mediation analysis was conducted. Low/medium maternal education was associated with up to 1.03 kg/m2 higher BMI (95% CI: 0.95 to 1.10) and up to 1.69% higher GlycA (95% CI: 1.68 to 1.71) compared with high maternal education, adjusting for confounders. Causal mediation analysis estimated that decreasing the levels of multiple adversities in children with low/medium maternal education to be like their high maternal education peers could reduce BMI inequalities by up to 1.8% and up to 3.3% in GlycA. Our findings in both cohorts suggest that slight reductions in socioeconomic inequities in children's BMI and inflammation could be achieved by addressing childhood adversities. Public health and social policy efforts should help those affected by childhood adversity, but also consider underlying socioeconomic conditions that drive health inequities.


ZnO-functionalized mesoporous inner-empty nanotheranostic platform: upconversion imaging guided chemotherapy with pH-triggered drug delivery.
Here we report a novel drug delivery system using mesoporous inner-empty upconversion microspheres carrying drugs with ZnO quantum dots (UCMPS@ZnO) acting as a 'door-keeper' for pH-triggered drug release. Compared to other upconversion drug delivery systems, it is smarter, simpler, more efficient and more biocompatible. In particular, the UCMPS@ZnO microspheres show low cytotoxicity, are simple to produce and have a high drug loading rate (15%). Promisingly, a mice treatment experiment demonstrated that the multifunctional nanoparticles have efficient inhibition of tumor growth after a 14-day treatment. This makes UCMPS@DOX-ZnO microspheres a promising theranostic candidate in cancer treatment and clinical trials.


Occurrence, potential sources and risks of organophosphate esters in the high-elevation region, Tibet, China.
Organophosphate esters (OPEs) are widely used flame retardants that are frequently released into the environment, causing potential harm to humans and ecosystems. Tibet is located on the Tibetan Plateau, known as the "roof of the world", but the occurrence of OPEs in Tibet remains unclear. This is the first report of the occurrence, potential sources and risks of 12 OPEs in water, soil, sediment and snow from Xainza, a typical town at high-elevation in Tibet (average elevation = 4700 m). Ten OPEs were observed, with ∑OPE concentrations of 46.45-1744.73 ng/L in surface water, 29.74-73.85 ng/g in soil, and 13.30-32.23 ng/g in sediment. Moreover, the mean ∑OPE concentration in snow was 413.90 ng/L. Tris (2-chloroethyl) phosphate (TCEP) and tris (2-chloroisopropyl) phosphate (TCPP) were the main OPEs in surface water and snow, while 2-ethylhexyl diphenyl phosphate (EHDPP) was dominant in soil and sediment. Local human activities and long-distance atmospheric transport may be the main sources of OPEs in Xainza. The assessment of ecological risk indicated that EHDPP in soil poses potential risk. The occurrence of OPEs in Xainza showed that more attention should be paid to persistent organic pollutants in high-elevation regions.


Anti-tumor-promoting activity of lignans from the aerial part of Saussurea medusa.
In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Compositae plants were screened. Consequently, the lignans, arctiin (ARC) and arctigenin (ARC-G), were obtained from the aerial part of Saussurea medusaas active constituents. These compounds exhibited the remarkable anti-tumor-promoting effect on two-stage carcinogenesis test of mouse skin tumors induced by 7, 12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoyl phorbol-13-acetate as a promoter by both topical application and oral administration. Furthermore, ARC-G exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse pulmonary tumors induced by 4-nitroquinoline-N-oxide as an initiator and glycerol as a promoter.


Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.
To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses.


Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS)-Based Biowaivers: A workshop Summary Report.
The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.


Palladium-catalyzed post-Ugi arylative dearomatization/Michael addition cascade towards plicamine analogues.
A palladium-catalyzed intramolecular cyclization of Ugi-adducts via a cascade dearomatization/aza-Michael addition process has been developed. Diverse plicamine analogues are constructed in a rapid, highly efficient and step-economical manner, through the combination of an Ugi-4CR and a palladium-catalyzed dearomatization. The synthetic utility of this approach is illustrated by further functional group transformations.


The Influence of Murine Genetic Background in Adeno-Associated Virus Transduction of the Mouse Brain.
Adeno-associated virus (AAV) vectors have become an important tool for delivering therapeutic genes for a wide range of neurological diseases. AAV serotypes possess differential cellular tropism in the central nervous system. Although several AAV serotypes or mutants have been reported to transduce the brain efficiently, conflicting data occur across studies with the use of various rodent strains from different genetic backgrounds. Herein, we performed a systematic comparison of the brain transduction properties among five AAV serotypes (AAV2, 5, 7, 8, and 9) in two common rodent strains (C57BL/6J and FVB/N), following local intrastriatal injection of AAV vectors encoding enhanced green fluorescent protein (EGFP) driven by the CBh promoter. Important differences were found regarding overall cellular tropism and transduction efficiency, including contralateral transduction among the AAV serotypes and between the mouse strains. We have further found loss of NeuN-immunoreactivity and microglial activation from AAV transduction in the different mouse strains. The important strain-specific differences from our study suggest that the genetic background of the mouse may affect AAV serotype transduction properties in the brain. These data can provide valuable information about how to choose an effective AAV vector for clinical application and interpret the data obtained from preclinical studies and clinical trials.


Morphometric analysis of mucous granule depletion and replenishment in rat colon.
Computer-assisted morphometric analysis was used to quantify mucous granule discharge and the subsequent replenishment of secretory granules in the rat colon following cholinergic challenge. Within 5 min of stimulation (250 micrograms/kg carbachol, subcutaneous), the volume of intracellular mucous granules decreased to 61.5% of the control. The apical plasma membranes of goblet cells in the midcrypt region became deeply cavitated, indicating that they had accelerated mucous granule secretion by a process of compound exocytosis. Goblet cells at the base of the crypt rarely showed cavitated apical membranes but clearly became depleted of intracellular mucous granules. At 60 min after stimulation, cavitated profiles were very rare (< or = 0.4%) but intracellular stores of mucous granules were still significantly depressed (54.7% of control). By 4 hr after stimulation, mucous granule stores recovered to 94.9% of control levels. Morphometric quantification was found to be a reliable and sensitive measure of recent goblet cell secretory activity.


Social determinants of vulnerabilities in type 2 diabetes: a call to action.
Type 2 diabetes (T2D) is a chronic disease which leads to high morbidity, mortality and healthcare costs. Although relevant gains have been made towards evidence-based diabetes care, patients with T2D still experience diabetes complications and excess mortality risk, owing to multiple contributors, including non-clinical factors. The aim of this paper is to provide an overview of the main social determinants of vulnerabilities, which are known to have a relevant impact on T2D outcomes. As chronic diseases are under the influence of social inequalities, medicine and sociology are intertwined in the attempt to understand, explain and address them. There is robust evidence about a clear relationship between social determinants of health (SDOH), such as socio-economic status (occupation, education, income), and the likelihood of developing T2D and its complications. Furthermore, the uncontrolled widespread of T2D in urban areas, mainly among suburban communities, suggests that cities might act as amplifiers of SDOH, enhancing inequalities in health care and, therefore, life expectancy. In light of the strong association between socio-cultural aspects and T2D outcomes, a global action is needed to raise awareness about disparities in diabetes prevention and treatment to reduce the burden of the disease.


Signature of antiphase boundaries in iron oxide nanoparticles.
Iron oxide nanoparticles find a wide variety of applications, including targeted drug delivery and hyperthermia in advanced cancer treatment methods. An important property of these particles is their maximum net magnetization, which has been repeatedly reported to be drastically lower than the bulk reference value. Previous studies have shown that planar lattice defects known as antiphase boundaries (APBs) have an important influence on the particle magnetization. The influence of APBs on the atomic spin structure of nanoparticles with the γ-Fe2O3 composition is examined via Monte Carlo simulations, explicitly considering dipole-dipole interactions between the magnetic moments that have previously only been approximated. For a single APB passing through the particle centre, a reduction in the magnetization of 3.9% (for 9 nm particles) to 7.9% (for 5 nm particles) is found in saturation fields of 1.5 T compared with a particle without this defect. Additionally, on the basis of Debye scattering equation simulations, the influence of APBs on X-ray powder diffraction patterns is shown. The Fourier transform of the APB peak profile is developed to be used in a whole powder pattern modelling approach to determine the presence of APBs and quantify them by fits to powder diffraction patterns. This is demonstrated on experimental data, where it could be shown that the number of APBs is related to the observed reduction in magnetization.


Vesicle pools and synapsins: new insights into old enigmas.
Synapsins are a multigene family of neuron-specific phosphoproteins and comprise the most abundant synaptic vesicle proteins. They have been proposed to tether synaptic vesicles to each other to maintain a reserve pool in the vicinity of the active zone. Such a role is supported by the observation that disruption of synapsin function leads to a depletion of the reserve pool of vesicles and an increase in synaptic depression. However, other functions for synapsins have been proposed as well, and there currently exists no coherent picture of how these abundant proteins modulate synaptic transmission. Here, we discuss novel insights into how synapsins may regulate neurotransmitter release.


Respiratory depression in goats by stable xenon: implications for CT studies.
The pharmacology of stable xenon is of practical importance to users of the xenon CT-regional cerebral blood flow method. In a study in goats we have demonstrated that xenon has a characteristic respiratory depressant effect, unlike effects of comparable anesthetic concentrations of nitrous oxide and halothane.


Earthquake damage as a catalyst to abandonment of a Middle Bronze Age settlement: Tel Kabri, Israel.
For years there has been much speculation surrounding the abandonment of the Middle Bronze Age IIB palace of Tel Kabri, ca. 1700 BCE. There are no weapons, hoards of money and jewelry, or visible evidence for fire, which rules out hostile attack or conquest. There are also no indications of drought or environmental degradation that might have forced the inhabitants to vacate the site, nor mass graveyards to indicate a pandemic. The current study uses micro-geoarchaeological methods to show that the demise of the palace was rapid, with walls and ceilings collapsing at once prior to abandonment. Macroscopic data (stratigraphic and structural) from five excavation seasons were reexamined, showing that at least nine Potential Earthquake Archaeological Effects (PEAEs) are found and associated with the last occupation phase of the site's palace. All lines of evidence point to the possibility that an earthquake damaged the palace, possibly to a point where it was no longer economically viable to repair. This conclusion is compounded by the discovery of a 1-3 m wide trench that cuts through the palace for 30 m, which may be the result of ground shaking or liquefaction caused by an earthquake. This study shows the importance of combining macro- and micro-archaeological methods for the identification of ancient earthquakes, together with the need to evaluate alternative scenarios of climatic, environmental, and economic collapse, as well as human-induced destruction before a seismic event scenario can be proposed.


Differences in the cleavage of DNA by bleomycin under light (300-350 nm) and dark conditions.
Incubation of supercoiled plasmid DNA (both pBR 322 and pPLC-28) with increasing concentrations of bleomycin in the presence and absence of light (300-350 nm) showed extensive conversion of supercoiled to linear DNA which occurred at much lower levels of bleomycin (BLM) in the light than in the dark. Preliminary results indicate that superoxide dismutase (SOD) may offer DNA more protection against bleomycin in the dark than in the light conditions.


Comparing smoking behaviors and exposures from flavored and unflavored cigarettes.
Cigarettes with flavors such as mocha and citrus have been introduced in growing numbers. Besides their potential marketing appeal to nonsmokers, there is concern that flavors might mask smoke harshness, making inhalation easier. This pilot study evaluates differences in puff topography and cigarette ratings among 20 college student smokers smoking Camel Light (10mg Tar, 0.9 mg nicotine, 35% filter ventilation) and Camel Exotic Blend cigarettes (11 mg Tar, 0.9 mg nicotine, 23% filter ventilation). Carbon monoxide boost was measured by assessing alveolar carbon monoxide (CO) levels before and after smoking each cigarette. Participants also rated each cigarette on characteristics such as strength, irritation, and taste. We found that participants took smaller puffs on the Exotic Blend versus Camel Light (42 mL vs. 48 mL, p<0.001), but there was no reliable difference in total smoke volume (613.9 mL vs. 630.7 mL, p=0.79) or CO boost (6.2 ppm vs. 6.2 ppm, p=0.90). Exotic Blend cigarettes were rated as more different from the participant's usual brand, but otherwise the taste ratings did not differ. Overall, these preliminary data suggest that adding flavors to cigarettes may not significantly impact how they are smoked by current smokers.


Ruptured cerebral aneurysm patients treated by clipping or coiling: comparison of long-term neuropsychological and personality outcomes.
A prospective study was conducted to compare the neuropsychological outcome of surgical versus endovascular treatment in patients with cerebral aneurysms. From April 2001 to 2005, 211 patients with ruptured cerebral aneurysms were treated at the senior author's institution. Of these 211 patients, 75 that were able and willing to undergo neuropsychological assessment 1 year after treatment of their aneurysm were enrolled in the study. Thirty-five patients were treated surgically and 40 by endovascular therapy. Standardized neuropsychological and personality tests were employed to assess cognitive and personality functions. One neurosurgical team using the same treatment protocols treated all patients. The two groups of patients did not differ significantly with respect to age, gender, concurrent diseases, Hunt and Hess grade, Fisher grade, frequency of complications, vasospasms and hydrocephalus development. No differences in performance on neuropsychological and cognitive tests (AVLT, TMT and WAIS-III) and personality variables and mood scales (TCI, BDI and SMS) were found one year postoperatively. If a full IQ as defined by WAIS-III and 1SD below the mean is considered as the main measure of cognitive deficits, 5.4% of the sample suffered from cognitive deficits. There were no differences between clipped and coiled patients (t=0.03; p=0.97). The differences in the neuropsychological assessment of patients treated by either coiling or clipping were small and non-significant. Given the small number of patients in the study, however, we suggest the need for further research with a larger sample size and the use of a randomized design before drawing any firm conclusions.


Enhanced cytotoxicity of pentachlorophenol by perfluorooctane sulfonate or perfluorooctanoic acid in HepG2 cells.
Chlorinated phenols and perfluoroalkyl acids (PFAAs) are two kinds of pollutants which are widely present in the environment. Considering liver is the primary toxic target organ for these two groups of chemicals, it is interesting to evaluate the possible joint effects of them on liver. In this work, the combined toxicity of pentachlorophenol (PCP) and perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) were investigated using HepG2 cells. The results indicated that PFOS and PFOA could strengthen PCP's hepatotoxicity. Further studies showed that rather than intensify the oxidative stress or promote the biotransformation of PCP, PFOS (or PFOA) might lead to strengthening of the oxidative phosphorylation uncoupling of PCP. By measuring the intracellular PCP concentration and the cell membrane properties, it was suggested that PFOS and PFOA could disrupt the plasma membrane and increase the membrane permeability. Thus, more cellular accessibility of PCP was induced when they were co-exposed to PCP and PFOS (or PFOA), leading to increased cytotoxicity. Further research is warranted to better understand the combined toxicity of PFAAs and other environmental pollutants.


A correction to the TW2 RUS-based tables for predicting adult height.
An error in the table for predicting the adult height of girls from RUS bone age, height and age, is identified and corrected.


High-throughput evaluation of the critical micelle concentration of detergents.
Determination of the critical micelle concentration (CMC) value of detergents routinely used in biological applications is necessary to follow possible changes due to different buffer compositions (e.g., temperature, pH) such as those in solutions that are used for protein activity assays or crystallization. Here we report a method to determine the CMC values of detergents through a fast and robust assay that relies on the fluorescence of Hoechst 33342 using a 96-well plate reader. Furthermore, this assay provides the possibility and sensitivity to measure the CMC of detergent mixtures. The examples described here emphasize the potential and applicability of this assay and demonstrate that analysis of the physicochemical parameters of detergents can now be investigated in virtually every laboratory.


Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.
Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCgamma-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.


Liberation from home mechanical ventilation and decannulation in children.
The prevalence of children requiring outpatient invasive long-term mechanical ventilation is increasing. For some children, liberation from home mechanical ventilation (HMV) and decannulation is the desired outcome. This study describes our experience liberating tracheostomy and HMV (T-HMV) dependent children from respiratory technologies. We reviewed charts of T-HMV dependent children who were cared for at our institution and decannulated between July 1999 and December 2011. Patient characteristics, diagnoses, and important steps leading to decannulation were recorded. Forty-six children achieved HMV independence and decannulation. The most common indications for T-HMV were lower airway and parenchymal lung disease. The median ages at tracheotomy, initiation of HMV, initiation of tracheostomy collar (TC) trials, HMV independence, and decannulation were 3.5, 6.0, 12.0, 25.5, and 40.5 months, respectively. Twenty-five children (54%) skipped either using a speaking valve, tracheostomy capping, or both without increased likelihood of recannulation. (P = 0.03). Common procedures prior to decannulation were airway surgery, bronchoscopy, and polysomnography (n = 30, 46, and 46 children, respectively). A median of 9.5 clinic visits and 5 hospitalizations occurred from initial hospital discharge to just prior to decannulation. HMV was primarily weaned as an outpatient. Liberation from respiratory technology is a complex, multi-step process that can be accomplished in medically complex children with varying underlying disease processes at relatively young ages. Five major steps (tracheotomy, initiation of HMV, initiation of TC trials, HMV independence, and decannulation) performed in conjunction with clinic visits, procedures, and home nursing support were integral in the successful decannulation process. Pediatr Pulmonol. 2016;51:838-849. © 2016 Wiley Periodicals, Inc.


The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells.
mda-7/IL-24 (HGMW-approved symbol IL24) is a tumor suppressor gene whose expression is lost during tumor progression. Gene transfer using adenoviral mda-7/IL-24 (Ad-mda7) exhibits minimal toxicity on normal cells while inducing potent apoptosis in a variety of cancer cell lines. Ad-mda7-transduced cells express high levels of MDA-7 protein intracellularly and also secrete a soluble form of MDA-7 protein. In this study, we sought to determine whether the intracellular or secreted MDA-7 protein was responsible for anti-tumor activity in H1299 lung tumor cells. Ad-mda7 transduction of lung tumor cells increased expression of stress-related proteins, including BiP, GADD34, PP2A, caspases 7 and 12, and XBP-1, consistent with activation of the UPR pathway, a key sensor of endoplasmic reticulum (ER)-mediated stress. Blocking secretion of MDA-7 did not inhibit apoptosis, demonstrating that intracellular MDA-7 was responsible for cytotoxicity. Consistent with this result, when applied directly to lung cancer cells, soluble MDA-7 protein exhibited minimal cytotoxic effect. We then generated mda-7 expression constructs using vectors that target the expressed protein to various subcellular compartments, including cytoplasm, nucleus, and ER. Only full-length and ER-targeted MDA-7 elicited cell death in tumor cells. Thus in lung cancer cells, Ad-mda7 activates the UPR stress pathway and induces apoptosis via intracellular MDA-7 expression in the secretory pathway.


Splenic marginal zone lymphocytes and related cells in the lymph node: a morphologic and immunohistochemical study.
The marginal zone of the spleen contains a well-defined population of lymphocytes with an unknown function. The question is whether this cell population is unique to the spleen or is it also present in the lymph node. These cells have medium-sized nuclei and a moderate amount of cytoplasm. Immunohistochemistry and enzyme histochemistry revealed a marker pattern by which these cells could be distinguished from the lymphocytes of the mantle zone of the spleen: IgD-, CD23-, KiB3-, and alkaline phosphatase+. In the lymph node, the outer side of the follicular mantle contains a subpopulation of B lymphocytes with a similar morphology and the same marker pattern. This subpopulation differs from the marginal zone cells in the spleen in that it does not form a distinct zone. These cells are especially prominent in lymph nodes with fatty atrophy. Their relationship to other subpopulations of B lymphocytes and to malignant lymphomas is evaluated but remains questionable.


Effects of bipolar disorder on maternal and fetal health during pregnancy: a systematic review.
Bipolar disorder (BD) is a mental disorder characterized by mood shifts from severe depression to mania. Pregnant women with BD may experience manic or depressive episodes, so they are usually concerned about the effects of BD on their pregnancy. The aim of this systematic review is to determine the effects of BD on maternal health and fetal health, weight, and development. It also addresses how BD affects the probability of incidence of pregnancy complications in women with bipolar compared with healthy controls. Seven electronic databases (Ovid MEDLINE, Embase, MIDRIS, APA PsychINFO, Scopus, Web of Science, and ScienceOpen) were searched, and 1728 eligible studies were identified. After deduplication, screening, and manual search processes, we included only 15 studies. Descriptive analysis, and calculation of the probability of incidence for each pregnancy outcome were used to analyze the results. The findings of the included studies suggest that BD during pregnancy may affect both fetal growth and maternal health by increasing the risk of giving birth to an infant with some birth defects such as microcephaly, CNS problems, small for gestational age, and other congenital anomalies, in addition to causing some obstetric complications such as gestational hypertension, preterm labor, need for assisted delivery, hospital readmission, and others. Bipolar disorder during pregnancy negatively affects mothers and their fetuses and increases the probability of incidence of obstetrics complications.


EMG cranial muscle levels in headache sufferers before and during headache.
It has long been assumed that the origin of pain in 'muscle-contraction headache' lies in the peri-cranial muscles, especially in the frontales. Pain, it is assumed, is experienced when the muscles are in spasm. It is further assumed that learned reductions in muscle tone between headache episodes will reduce the probability of future pain episodes. In this experiment, details are given of EMG measures made on the frontal, occipital, and neck muscles of separate groups of migraine and tension headache subjects. The measures were made before the onset of head pain and later when the same subjects reported pain. As part of the experiment, subjects were exposed to an experimental stressor during the pain-free period, and these results were compared with those of a group of non-headache subjects. Results showed that the headache groups did not differ on any of the pre-headache measures. Neck muscle levels varied markedly when compared with control subjects who had comparatively low levels reactive to an experimental stressor. When the data taken during the headache phase were analysed according to diagnosis, the occipital muscle output was found to be significantly lower in the migraine group and higher in the tension group.


Cost-effectiveness of lowering blood pressure with a fixed combination of perindopril and indapamide in type 2 diabetes mellitus: an ADVANCE trial-based analysis.
To determine the cost-effectiveness of routine administration, irrespective of blood pressure (BP), of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus. Prospective cost-effectiveness analysis within the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, an international, multicentre, randomised controlled trial of 11,140 participants with type 2 diabetes randomly allocated to receive perindopril plus indapamide (4 mg-1.25 mg/day) or placebo. Health-related quality-of-life measured by the EuroQol-5D, resource utilisation, and cost-effectiveness (cost per death averted at 4.3 years' average follow-up, and estimated cost per life-year gained, by extrapolation). The mean health-related quality-of-life score of survivors was 0.80 (on a 0-1 scale [death to full health]), with no difference between treatment groups. Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5%. For the Australian participants, perindopril-indapamide cost A$1368 per patient during the trial period, but reduced total hospitalisation costs by A$410 and other medication costs (mainly other BP-lowering drugs) by A$332. The absolute reduction in all-cause mortality for the active treatment group was 1.1%, giving a cost per life saved of A$49,200. Lifetime extrapolation gave an estimated cost per life-year saved of A$10,040 (discounted at 5% per year). The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective. United States National Library of Medicine NCT00145925.


Percutaneous absorption of indomethacin from pluronic F127 gels in rats.
Thermally reversible gels of the poly(oxyethylene)-poly (oxypropylene)-(polyoxyethylene) triblock copolymer, Pluronic F127, were evaluated as vehicles for the percutaneous administration of drugs using indomethacin as a model drug. In-vivo percutaneous absorption studies using a rat model suggest that a 20% w/w aqueous gel of Pluronic F127 may be of practical use as a base for topical administration of the drug. The addition of isopropyl myristate or (+)-limonene to the gel formulation significantly improved percutaneous absorption, particularly when the gel was applied using an occlusive dressing technique.


Induction of heterotopic bone marrow formation in osteopetrotic rats by allogeneic decalcified bone matrix.
Contrary to theoretical expectations in osteopetrotic mutants heterotopic bone marrow formation was closely associated with osteogenesis, what is not observed in the orthotopic skeletal bones in these animals.


Pharmacokinetic modeling of cisplatin disposition in children and adolescents with cancer.
A flow-limited physiologic pharmacokinetic model using volume terms, flow rates, distribution ratios, metabolic rate constants, and clearance terms restricted to physiologic or measured values was used to simulate the disposition of cisplatin in children and adolescents. Physiologic model simulations of parent cisplatin and total platinum serum concentrations were not statistically different from concentrations of these platinum species measured in 14 patients. A simplified first-order multicompartment operational model was also developed, and produced comparable simulations of parent cisplatin disposition but less accurate simulations of total platinum serum concentrations. These data provide further clarification of cisplatin disposition in humans and provide the basis for previously observed changes in the renal clearance of total platinum.


Percutaneous closure of a coronary fistula between the right coronary artery to the left atrium.
We describe a case of a congenital coronary artery fistula of the right coronary artery draining into the left atrium in an eight-year-old boy. The initial diagnosis was made after the detection of a continuous cardiac murmur at the age of six years. Transthoracic echocardiography showed the right coronaric ostium dilatation, the site of drainage in the left atrium and left ventricle volume overload. Catheterization confirmed the diagnosis. The patient underwent percutaneous closure by PDA occluder device. Immediate post-closure angiograms showed complete occlusion of the fistula. The patient showed transient ischemic changes on ECG associated to an increase of plasmatic levels of the cardiac enzyme. ECG and cardiac enzyme were normal one week after the procedure.


Molecular cloning and sequence analysis of prion protein gene in Xiji donkey in China.
Prion diseases are a group of human and animal neurodegenerative disorders caused by the deposition of an abnormal isoform prion protein (PrP(Sc)) encoded by a single copy prion protein gene (PRNP). Prion disease has been reported in many herbivores but not in Equus and the species barrier might be playing a role in resistance of these species to the disease. Therefore, analysis of genotype of prion protein (PrP) in these species may help understand the transmission of the disease. Xiji donkey is a rare species of Equus not widely reared in Ningxia, China, for service, food and medicine, but its PRNP has not been studied. Based on the reported PrP sequence in GenBank we designed primers and amplified, cloned and sequenced the PRNP of Xiji donkey. The sequence analysis showed that the Xiji donkey PRNP was consisted of an open reading frame of 768 nucleotides encoding 256 amino acids. Amino acid residues unique to donkey as compared with some Equus animals, mink, cow, sheep, human, dog, sika deer, rabbit and hamster were identified. The results showed that the amino acid sequence of Xiji donkey PrP starts with the consensus sequence MVKSH, with almost identical amino acid sequence to the PrP of other Equus species in this study. Amino acid sequence analysis showed high identity within species and close relation to the PRNP of sika deer, sheep, dog, camel, cow, mink, rabbit and hamster with 83.1-99.7% identity. The results provided the PRNP data for an additional Equus species, which should be useful to the study of the prion disease pathogenesis, resistance and cross species transmission.


Simultaneous assessment of segmental and global left ventricular function by two-dimensional echocardiography in acute myocardial infarction.
Both segmental and global left ventricular performance were assessed simultaneously in 29 patients with acute myocardial infarction using two-dimensional echocardiography. Comparisons were made between left ventricular wall motion versus peak CK-MB, site of infarction, and occurrence of heart failure. Two-dimensional echocardiography identified areas of dyssynergy which corresponded to electrocardiographic areas of infarction in 89% of all cases. Patients with heart failure had more dyssynergic segments, and these segments manifested more severe dyssynergy than patients without heart failure. Patients with severe global dysfunction manifested higher peak CK-MB values, and those with anterior infarction had more global dyssynergy than did those patients with inferior infarction. These observations suggest that two-dimensional echocardiography is a useful technique for localization and assessment of segmental and global dyssynergy in acute myocardial infarction. Information so derived correlates with the clinical status of patients with acute myocardial infarction, and may offer important insights into both prognosis and treatment.


Efficiency comparison between tracking and optimally fixed flat solar collectors.
We investigate the optimal orientation for a fixed flat plate solar collector using the clear sky model. The ground reflection component of irradiation that hits the collector's surface is ignored due to its relatively small magnitude when compared to the direct beam and sky diffusive components. Analytical calculations demonstrate that regardless of the collector's latitude, the most effective azimuthal angle, [Formula: see text], is 0, which generally corresponds to a North-South direction. However, the optimal tilt angle, [Formula: see text], is dependent on both the Day of Year (DoY) and the collector's local latitude. For latitudes typical of mid-altitude climate zones, we can calculate the optimal tilt angle and the maximum energy that the collector can harvest during each DoY. We compare the maximum daily received energy-which is the sum of the direct beam and sky diffusive energies-associated with this optimal orientation to their corresponding values when the flat plate tracks the Sun. The relative increase in total energy due to Sun tracking depends critically on the DoY, with a minimum value of about [Formula: see text] in early winter and a maximum value of [Formula: see text] over a large interval.


Minimization of immunosuppression: transplant immunology.
Induction of tolerance, which obviates the need for maintenance immunosuppression following organ transplantation remains elusive. In cardiac transplantation, ongoing immunosuppressive therapy is essential to ensure long-term graft survival. Although drug regimens have substantially improved in recent years, their adverse effects continue to cause significant morbidity and affect quality of life. Newer immunosuppressive therapies have been effective at reducing allograft rejection rates in the short term but long term outcomes have changed little in the last two decades. Minimization of immunosuppression requires appreciation of the potential consequence. High risk patients in particular need to be identified and excluded from low intensity immunosuppressive regimens. A variety options exist for lowering of immunosuppression and steroid weaning has now become common practice with about 40% of all cardiac transplant recipients remaining steroid free in the long term. Minimization of calcineurin inhibitor exposure may be achieved with concurrent use of the more potent anti-proliferative agents mycophenolate mofetil and sirolimus. Patients require close monitoring for rejection during weaning. In addition to the conventional clinical parameters which include therapeutic drug monitoring, endomyocardial biopsy and echocardiography, newer techniques for monitoring hold future promise. These include detection of circulating alloantibodies and quantitative measurement of the net state of immunosuppression (Cylex). However, the efficacy of these modalities requires further investigation.


Uptake across the cell envelope and insertion into the inner membrane of ion channel-forming colicins in E coli.
Pore-forming colicins exert their lethal effect on E coli through formation of a voltage-dependent channel in the inner (cytoplasmic-membrane) thus destroying the energy potential of sensitive cells. Their mode of action appears to involve 3 steps: i) binding to a specific receptor located in the outer membrane; ii) translocation across this membrane; iii) insertion into the inner membrane. Colicin A has been used as a prototype of pore-forming colicins. In this review, the 3 functional domains of colicin A respectively involved in receptor binding, translocation and pore formation, are defined. The components of sensitive cells implicated in colicin uptake and their interactions with the various colicin A domains are described. The 3-dimensional structure of the pore-forming domain of colicin A has been determined recently. This structure suggests a model of insertion into the cytoplasmic membrane which is supported by model membrane studies. The role of the membrane potential in channel functioning is also discussed.


Escape the Sim! An Escape Room Innovation to Orient Learners to the Simulation Environment.
Orientation to the environment and equipment promotes psychological safety in simulation. Providing orientation activities also increases learner perceptions of simulation effectiveness, confidence, and learning overall. Escape rooms, used by educators from primary levels through graduate programs, promote skills in teamwork, creative problem-solving, and critical thinking ability. Creating an escape room-themed simulation experience with the objective of orienting learners to the simulation environment and equipment is an interactive way to prepare learners for simulation, while encouraging teamwork and group dynamics.


Induction mechanisms for L-LTP at thalamic input synapses to the lateral amygdala: requirement of mGluR5 activation.
L-LTP (late-phase long-term potentiation) at thalamo-amygdala synapses is thought to be critical for auditory fear conditioning, but it has not been clear what kinds of surface receptors and channels are involved in the induction phase of the L-LTP. Here we report that the NMDA receptor antagonist D-AP5 (50 microM), the L-type calcium channel antagonist nifedipine (30 microM) and the metabotropic glutamate receptor 5 antagonist MPEP (10 microM) prevented L-LTP induction when each antagonist was separately applied at saturating concentrations before and during repeated tetanus. By contrast, the mGluR1 antagonist CPCCOEt (80 microM) failed to show any effects on L-LTP induction. Neither D-AP5 nor MPEP produced any significant effects on potentiated synaptic responses when applied after L-LTP had been established. Thus, our data suggest that NMDA receptors, L-type calcium channels and mGluR5 are involved in L-LTP induction in the thalamo-amygdala pathway.


Biomarkers as targets for CAR-T/NK cell therapy in AML.
The most common kind of acute leukemia in adults is acute myeloid leukemia (AML), which is often treated with induction chemotherapy regimens followed by consolidation or allogeneic hematopoietic stem cell transplantation (HSCT). However, some patients continue to develop relapsed or refractory AML (R/R-AML). Small molecular targeted drugs require long-time administration. Not all the patients hold molecular targets. Novel medicines are therefore needed to enhance treatment outcomes. T cells and natural killer (NK) cells engineered with chimeric antigen receptors (CARs) that target antigens associated with AML have recently been produced and are currently being tested in both pre-clinical and clinical settings. This review provides an overview of CAR-T/NK treatments for AML.


The spectrum of abdominal injuries associated with chance fractures in pediatric patients.
With the increased use of seat belts in motor vehicles, the frequency of morbidity and mortality associated with motor vehicle accidents may have decreased but there is an associated rise in injuries. The purpose of this study was to evaluate the risk of intra-abdominal injury in children who sustained Chance-type fractures in a motor vehicle accident. A retrospective review was conducted of pediatric patients admitted for injuries sustained in motor vehicle accidents between 1984 and 2001. Patients that sustained lumbar Chance fractures and an abdominal injury were reviewed. A total of 25 patients with lumbar Chance fractures were seen at our institution; twelve had associated abdominal injuries. The mean age at the time of injury was 10.9 years and the most recent follow-up was a mean of 4.8 years after injury. All patients were involved in high-speed motor vehicle collisions. Eleven patients were restrained using a 2-point restraint and only one was restrained using a 3-point restraint. The abdominal injury patients had a significantly higher Chance fracture index than those patients who also suffered Chance fractures but no associated abdominal injuries. Success in the management of intra-abdominal injuries is dependent on the awareness that such an injury exists.


The levels of renin-angiotensin related components are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy.
We previously showed that patients with temporal lobe epilepsy (TLE) present an increased expression of angiotensin II (AngII) AT1 and AT2 receptors in the hippocampus, supporting the idea of an upregulation of renin-angiotensin system (RAS) in this disease. This study aimed to verify the relationship between the RAS and TLE during epileptogenesis. Levels of the peptides angiotensin I (AngI), angiotensin II (AngII) and angiotensin 1-7 (Ang 1-7), were detected by HPLC assay. Angiotensin AT1 and AT2 receptors, Mas mRNA receptors and angiotensin converting enzyme (ACE), tonin and neutral endopeptidase (NEP) mRNA were also quantified at the hippocampus of Wistar rats by real time PCR, during acute (n=10), silent (n=10) and chronic (n=10) phases of pilocarpine-induced epilepsy. We observed an increased peptide level of Ang1-7 into acute and silent phases, decreasing importantly (p≤0.05) in the chronic phase, suggesting that AngI may be converted into Ang 1-7 by NEP, which is present in high levels in these periods. Our results also showed increased peptide level of AngII in the chronic phase of this model. In contraposition, the ACE expression is reduced in all periods. These data suggest that angiotensinogen or AngI may be cleaved to AngII by tonin, which showed increased expression in all phases. We found changes in AT1, AT2 and Mas mRNA receptors levels suggesting that Ang1-7 could act at Mas receptor during the silent period. Herein, we demonstrated for the first time, changes in angiotensin-related peptides, their receptors as well as the releasing enzymes in the hippocampus of rats during pilocarpine-induced epilepsy.


Unraveling the Endodontic Archaeome: A Systematic Review with Meta-Analysis.
The controversial issue of whether the Archaea domain plays a role in endodontic infections is the focus of this systematic review with meta-analysis. The aim is to emphasize the significance of minority microbial domains in oral dysbiosis by evaluating the prevalence of archaea in root canals and its association with clinical parameters such as symptomatology and type of endodontic infection. The search strategy involved researching 6 databases and the gray literature. Publications were accepted in any year or language that identified archaea in samples from endodontic canals. A 2-step selection process narrowed the final choice to 16 articles. The methodological quality of the studies was evaluated using tools from the Joanna Briggs Institute, and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The results showed that archaea were present in 20% (95% [confidence interval] CI = 8%-32%) of individuals with endodontic samples analyzed. The samples were about twice as likely to be archaeal-positive if collected from individuals with primary vs. persistent/secondary infection (odds ratio = 2.33; 95% CI = 1.31-4.14; I2 = 0%), or individuals with self-reported vs. symptom-free infections (odds ratio = 2.67; 95% CI = 1.47-4.85; I2 = 0%). Methanogenic archaea were reported in 66% of the included studies. Representative members of phyla Thaumarchaeota and Crenarchaeota were also identified. Archaea are present in about one-fifth of the infected root canals. Recognized biases in experimental approaches for researching archaea must be addressed to understand the prevalence and roles of archaea in endodontic infections, and to determine whether the decontamination process should include the elimination or neutralization of archaea from root canals (International Prospective Register of Systematic Reviews protocol = CRD42021264308).


Utilization of patient-reported outcomes as a step towards collaborative medicine.
Patient-reported outcomes (PROs) have been successfully developed for a variety of chronic respiratory diseases, such as asthma and cystic fibrosis (CF). They have recently been used to evaluate the efficacy of new medications and assess current patient functioning. Although regulatory bodies have favored PROs that measures symptoms, other domains of functioning, such as treatment burden, should be considered. This review examines current guidelines for the development and application of PROs in clinical trials, describes methods for selecting appropriate measures for paediatric populations, and presents a model incorporating PROs into clinical practice. Guidance on interpretation of these measures and graphic presentation of results are illustrated. PROs can serve as the link between the health care provider and patient to foster collaborative and personalized medicine. This model promotes greater patient responsibility, facilitates communication with providers, encourages shared decision-making, and enhances adherence.


Stromal and acinar components of the transition zone in normal and hyperplastic human prostate.
To analyse the histological components of the transition zone in both normal human prostate and benign prostatic hyperplasia (BPH), and to determine the volumetric density (Vv) of the different elements (connective tissue, smooth muscle cells, acini and total stroma). Samples of BPH tissue from the transition zone were obtained from 16 patients with clinical symptoms of bladder outlet obstruction who underwent open prostatectomy. The control samples comprised 16 transition zone samples from prostates obtained during necropsy of adults aged < 30 years (killed in accidents). The Vv of these components was determined by stereological methods. The mean (sd) Vv in the controls and BPH samples were, respectively: connective tissue 40.47 (5.16) and 46.71 (9.91)%; smooth muscle cells 24.86 (2.74) and 31.56 (5.49)%; acini 28.73 (6.25) and 17.78 (10.87)%; all differences were statistically significant. These results confirm the hypothesis that in BPH there is an increase in the stromal component, both smooth muscle fibres and connective tissue.


Protein folding observed by time-resolved synchrotron x-ray scattering. A feasibility study.
A solution to the "protein folding" problem, the successful prediction of tertiary and quaternary protein structure from amino acid or gene sequence, would be a major advance in biology and biotechnology. Knowledge of any intermediate structure between fully unwound and folded would aid folding calculations. The use of high intensity synchrotron x-rays from the SUNY X21 beamline at National Synchrotron Light Source has been investigated as a probe of structural changes during protein folding and unfolding in solution. A temperature jump apparatus was used to study thermally-induced folding and unfolding. Scattering of solutions of myoglobin in the angular range 20 = 1-50 mrad. was measured during temperature jumps between 26 and 76 degrees C. There are clear signs of time/temperature-dependent structural changes, in the small angle region, consistent with those from other equilibrium techniques. Analysis indicates that this experimental technique can be extended to the higher angle region where theoretical calculations indicate more detailed structural information, for example when alpha-helix formation, is present.


Ceriponols A-K, tremulane sesquitepenes from Ceriporia lacerate HS-ZJUT-C13A, a fungal endophyte of Huperzia serrata.
Tremulane sesquiterpenes ceriponols A-K, together with three known ones tremulenediol A, 11,12-dihydroxy-1-tremulen-5-one and conocenol B, were isolated from the cultures of Ceriporia lacerate, a fungal endophyte residing in the stems of the medicinal plant Huperzia serrata. Among these isolates, ceriponol B possessed an unprecedent 12-nortremulane skeleton. The structures of all isolates were elucidated by spectroscopic methods, including MS and NMR (1D and 2D) spectroscopic techniques. The cytotoxic activities of ceriponols A-K were evaluated against three human tumor cell lines (HeLa, HepG2, and SGC 7901). Ceriponols F and K exhibited moderate cytotoxicity against all the tested human cancer cell lines with IC50 values ranging from 32.3 ± 0.4 to 173.2 ± 1.5 μM, while ceriponol G showed slightly better cytotoxicity against a HeLa cell line.


Spectral studies on aluminum ion binding to the ligands with phenolic group(s): implications for the differences between N- and C-terminal binding sites of human serum apotransferrin.
Both the binding and releasing of ferric ions in C-, and N-terminal binding sites of human serum transferrin are different. To understand the difference here the interactions of aluminum with the ligands containing phenolic group(s), including 8-hydroxyquinoline, salicylic acid, N,N'-di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid, N,N'-ethylenebis[2-(o-hydroxyphenolic)glycine], and human serum apotransferrin, respectively, are investigated by using UV difference and fluorescence spectra methods in 0.1 M N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid at pH 7.4. Aluminum binding produces a UV difference peak near 235 nm that is characteristic of phenolic groups binding to aluminum. The peak at 235 nm has been used to determine conditional binding constants of log K(Al-HBED)=8.88+/-0.74 and log K(Al-EHPG)=9.38+/-0.03. However, the effects of aluminum binding on the fluorescence intensity of N,N'-ethylenebis[2-(o-hydroxyphenolic)glycine], salicylic acid and N,N'-di(2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid, 8-hydroxyquinoline are disparate, the former showing a decrease and the latter an increase. At pH 7.4, there is N cdots, three dots, centered H-O type intramolecular hydrogen bond in 8-hydroxyquinoline, N,N'-di(2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid and O cdots, three dots, centered H-O type intramolecular hydrogen bond in salicylic acid, N,N'-ethylenebis[2-(o-hydroxyphenolic)glycine]. The effects of salts on the fluorescence intensity of the ligands containing phenolic group(s) show that fluorescence emission increases with the breaking of an N cdots, three dots, centered H-O type intramolecular hydrogen bond and fluorescence emission decreases with the breaking of an O cdots, three dots, centered H-O type intramolecular hydrogen bond. Fluorescence titrations of apotransferrin and both forms of monoferric transferrin with aluminum indicated that there is O cdots, three dots, centered H-O type intramolecular hydrogen bonds for the phenolic groups of Tyr426 and Tyr517 in the C-terminal binding site. While N cdots, three dots, centered H-O type intramolecular hydrogen bonds are found for the phenolic groups of Tyr95 and Tyr188 in the N-terminal binding site.


Multidisciplinary care in amyotrophic lateral sclerosis: a 4-year longitudinal observational study.
Over a four-year period, ALS patients complied with the modalities of the multidisciplinary management follow-up without any drop-outs. The multidisciplinary management structure also contributes to increasing the experience and knowledge of the clinicians involved in managing patients suffering from this rare disease.


Enhanced viral immunoinflammatory lesions in mice lacking IL-23 responses.
Herpes simplex virus (HSV) infection of the cornea culminates in an immunopathological lesion (stromal keratitis--SK) that impairs vision. This report shows that HSV infection results in IL-23 up-regulation, but if this response fails to occur, as was noted in p19-/- mice, the severity of lesions, their incidence and the level of viral induced angiogenesis were significantly increased compared to wild-type (WT) animals (p<0.05). The higher disease severity in p19-/- mice appeared to be the consequence of an increased IL-12 response that in turn led to the induction of higher numbers of IFN-gamma producing CD4(+)T cells, the principal orchestrators of SK. Our results indicate that the severity of HSV induced immunopathological lesions may be mainly the consequence of IL-12 driven Th1 T cell reactions rather than the action of IL-17 producing cells controlled by IL-23.


Decreased pancreatic CCK receptor binding and CCK-stimulated amylase release in Zucker obese rats.
In Zucker obese rats the response to the effects of CCK on food intake and pancreatic exocrine function are decreased. However, it is unknown whether the decreased responsiveness is due to decreased receptor number and/or sensitivity or abnormal circulating concentrations of CCK. In these experiments percent total binding of 125I-CCK-33 to pancreatic acini from obese rats was one-half that in lean rats when data was expressed on a per microgram DNA basis (19.6 +/- 5.1 vs. 47.4 +/- 11.4, p less than 0.01). In a second experiment while the maximally effective dose of CCK for stimulating amylase secretion from dispersed pancreatic acini was similar in obese and lean rats (10(-10) M), less amylase was secreted in obese rats across the dose range tested (p less than 0.001). In contrast, carbachol had similar potency and efficacy in stimulating amylase release from obese and lean pancreatic acini. The increase of pancreas size by use of a trypsin inhibitor was greater in lean than obese rats (p less than 0.03). In addition, stimulation of amylase release by CCK from obese trypsin inhibitor-treated compared with control obese rats was greater than that from lean trypsin inhibitor-treated compared with control lean rats (p less than 0.002). However, overall, stimulation of amylase secretion by CCK was only 36% of control (p less than 0.001) and by carbachol was only 20% of control (p less than 0.001). Thus, increased size by increased cell number was associated with decreased response per cell.(ABSTRACT TRUNCATED AT 250 WORDS)


Insertion gain repeatability versus loudspeaker location: you want me to put my loudspeaker where?
The traditional 0 degree (straight-ahead) location of the loudspeaker during insertion gain measurements is a poor choice, based on theoretical considerations, from the standpoint of measurement repeatability. In a series of experiments, we were able to demonstrate that a location 45 degrees to the side, or 45 degrees up and 45 degrees to the side, provided a much more repeatable measurement of basically the same insertion gain response.


Sensitizing of pyrene fluorescence by β-cyclodextrin-modified TiO2 nanoparticles.
TiO(2) nanoparticles were synthesized by hydrolysis of tetraisopropyl orthotitanate in an aqueous solution of cyclodextrin. The β-cyclodextrin-modified spherical TiO(2) nanoparticles were water-dispersible and had an average particle diameter of 4.4 ± 1 nm. Pyrene fluorescence was enhanced by increasing the concentration of β-cyclodextrin-modified TiO(2) nanoparticle and the sensitization effect was triply stronger than the case of the β-cyclodextrin only. The increase in a concentration of host (β-cyclodextrin) changes its microenvironment for guest (pyrene), that is, the interaction of pyrene with apolar cavity of β-cyclodextrin increases, resulting in enhancement of fluorescence. The sensitization behavior of pyrene fluorescence in the presence of TiO(2) nanoparticles occurs from the increase in the extinction coefficient of pyrene, demonstrating the charge transfer between pyrene and metal oxide nanoparticle.


News on initiation and elongation of transcription by RNA polymerase II.
Transcription by RNA polymerase II is a complex process that requires additional factors to initiate transcription at the promoters. New developments in the past year have furthered our understanding of the functions of the transcription factors and provided more insights into the mechanisms involved in the regulation of initiation and elongation of transcription. One of the most significant advances of the past year was the discovery of the involvement of the general transcription factor TFIIH in DNA excision repair. Surprisingly, studies aimed at identifying the kinase activity within TFIIH responsible for phosphorylating the carboxy-terminal domain of RNA polymerase II revealed it to be the MO15/Cdk7 kinase and its partner, cyclin H. These exciting observations suggest a paradigm for linking transcription, DNA excision repair and cell cycle progression through one pivotal factor.


Association of parent influenza vaccination and early childhood vaccinations using linked electronic health record data.
Parent and child vaccination behavior is related for human papillomavirus (HPV) and flu vaccine. Thus, it is likely that parental vaccination status is also associated with their children's adherence to guideline-concordant childhood vaccination schedules. We hypothesized that parent influenza (flu) vaccination would be associated with their child's vaccination status at age two. We used electronic health record data to identify children and linked parents seen in a community health center (CHC) within the OCHIN network (292 CHCs in 16 states). We randomly selected a child aged <2 years with ≥1 ambulatory visit between 2009-2018. Employing a retrospective, cohort study design, we used general estimating equations logistic regression to estimate the odds of a child being up-to-date on vaccinations based on their linked parents' flu vaccination status. We adjusted for relevant parent and child covariates and stratified by mother only, father only, and two-parent samples. The study included 40,007 family-units: mother only = 35,444, father only = 2,784, and two parents = 1,779. A higher percentage of children were fully vaccinated if their parent or parents received a flu vaccine. Children in the two-parent sample whose parents both received a flu vaccine had more than twice the odds of being fully vaccinated, and two and a half times the odds of being fully vaccinated except flu vaccine compared to children with two parents who did not receive a flu vaccine (covariate-adjusted odds ratio [aOR] = 2.39, 95% CI = 1.67, 3.43 and aOR = 2.54, 95% CI = 1.54, 4.19, respectively). Parent flu vaccination is associated with routine child vaccination. Future research is needed to understand if this relationship persists over time and in different settings.