The simple bread tag - a menace to society?
Foreign bodies are potentially life-threatening when inhaled by a child, depending on where they lodge. Symptoms can range from acute upper airway obstruction to mild, vague respiratory complaints. Between 80% and 90% of inhaled foreign bodies occlude the bronchi, while the larynx is a less common site. The commonest inhaled paediatric foreign bodies are organic, e.g. seeds or nuts. Plastic foreign bodies are less common and more difficult to diagnose. They are generally radiolucent on lateral neck radiographs and are often clear and thin. We report three cases of an unusual plastic laryngeal foreign body, the bread tag. Plastic bread tags were first reported in the medical literature as an ingested gastrointestinal foreign body in 1975. Since then, over 20 cases of gastrointestinal complications have been described. We report what is to our knowledge the first paediatric case of an inhaled bread tag, and also the first case series, briefly discuss the symptoms and options for removal of laryngeal foreign bodies, and highlight the dangers of the apparently harmless bread tag. Images of the bread tags in situ and after their removal are included.


Assessing The Impact Of State Policies For Prescription Drug Monitoring Programs On High-Risk Opioid Prescriptions.
Policies and practices have proliferated to optimize prescribers' use of their states' prescription drug monitoring programs, which are statewide databases of controlled substances dispensed at retail pharmacies. Our study assessed the effectiveness of three such policies: comprehensive legislative mandates to use the program, laws that allow prescribers to delegate its use to office staff, and state participation in interstate data sharing. Our analysis of information from a large commercial insurance database indicated that comprehensive use mandates implemented during 2011-15 were associated with a 6-9 percent reduction in opioid prescriptions with high risk for misuse and overdose. We also found delegate laws to be associated with reductions of a similar magnitude for selected outcomes. In general, the effects of all three policies strengthened over time, especially beginning in the second year after implementation. Our findings support comprehensive use mandates and delegate laws to optimize prescribers' use of drug monitoring programs, but the results will need updates in the context of evolving state opioid policies-including the increasing integration of drug monitoring data with electronic health records.


Aboriginal and Torres Strait Islander family access to continuity of health care services in the first 1000 days of life: a systematic review of the literature.
Aboriginal women and their infants experience significant disadvantage in health outcomes compared to their non-Aboriginal counterparts. Access to timely, effective and appropriate maternal and child healthcare can contribute to reducing these existing health disparities. However, accessing mainstream healthcare services often results in high levels of fear and anxiety, and low attendance at subsequent appointments among Aboriginal women, due to inefficient communication, poor service coordination and a lack of continuity of care. This integrative literature review sought to explore factors that contribute to continuity of care and consider service features that contribute to positive care experiences and satisfaction with care received by Aboriginal women and their infants. In total, 28 studies were included in the review and were thematically analysed using Braun and Clarke's six steps of thematic analysis. This was followed by a collaborative, computer-assisted qualitative analysis, which resulted in the emergence of five key themes: lack of continuity of care, impact of lack of continuity of care, continuity of care interventions, impact of continuity of care interventions, and strategies to improve continuity of care. Most studies focused on health services in rural or remote Aboriginal communities and there was a lack of documented evidence of continuity of care (or lack thereof) for Aboriginal women living and birthing in regional and metropolitan areas. The majority of studies focused explicitly on continuity of care during the antenatal, birthing and immediate postnatal period, with only two studies considering continuity through to an infant's first 1000 days. The review highlights a lack of studies exploring continuity of care for Aboriginal families from the antenatal period through to an infants' first 1000 days of life. Included studies identified a lack of continuity in the antenatal, peri- and postnatal periods in both regional and metropolitan settings. This, along with identified strategies for enhancing continuity, have implications for communities, and healthcare services to provide appropriate and culturally safe care. It also marks an urgent need to incorporate and extend continuity of care and carer through to the first 1000 days for successful maternal and infant health outcomes for Aboriginal peoples.


Therapeutic failures of antibiotics used to treat macrolide-susceptible Streptococcus pyogenes infections may be due to biofilm formation.
Streptococcus pyogenes infections often fail to respond to antibiotic therapy, leading to persistent throat carriage and recurrent infections. Such failures cannot always be explained by the occurrence of antibiotic resistance determinants, and it has been suggested that S. pyogenes may enter epithelial cells to escape antibiotic treatment. We investigated 289 S. pyogenes strains isolated from different clinical sources to evaluate their ability to form biofilm as an alternative method to escape antibiotic treatment and host defenses. Up to 90% of S. pyogenes isolates, from both invasive and noninvasive infections, were able to form biofilm. Specific emm types, such as emm6, appeared to be more likely to produce biofilm, although variations within strains belonging to the same type might suggest biofilm formation to be a trait of individual strains rather than a general attribute of a serotype. Interestingly, erythromycin-susceptible isolates formed a significantly thicker biofilm than resistant isolates (P < 0.05). Among resistant strains, those carrying the erm class determinants formed a less organized biofilm than the mef(A)-positive strains. Also, prtF1 appeared to be negatively associated with the ability to form biofilm (P < 0.01). Preliminary data on a selection of strains indicated that biofilm-forming isolates entered epithelial cells with significantly lower efficiency than biofilm-negative strains. We suggest that prtF1-negative macrolide-susceptible or mef(A)-carrying isolates, which are poorly equipped to enter cells, may use biofilm to escape antimicrobial treatments and survive within the host. In this view, biofilm formation by S. pyogenes could be responsible for unexplained treatment failures and recurrences due to susceptible microorganisms.


Region of birth and mortality from circulatory diseases among black Americans.
This study examines the relationship between birth-place and mortality from circulatory diseases among American Blacks. All Black deaths from circulatory diseases (International Classification of Diseases, 9th Revision. codes 390 through 459) were extracted from the National Center for Health Statistics mortality detail files for 1979 through 1991. Age-specific and age-adjusted mortality rates with 95% confidence intervals were calculated for males and females for combinations of five regions of residence at birth and four regions of residence at death. Males had higher mortality rates from circulatory diseases than females in every regional combination of birthplace and residence at death. For both genders, the highest rates were for those who were born in the South but died in the Midwest; the lowest rates were for those who were born in the West but died in the South. Excess mortality for both Southern-born males and females begins at ages 25 through 44. There is a region-of-birth component that affects mortality risk from circulatory diseases regardless of gender or residence at time of death. We must examine how early life experiences affect the development of circulatory disorders.


Measuring the prevalence of sleep disturbances in people with dementia living in care homes: a systematic review and meta-analysis.
Sleep disturbances are a feature in people living with dementia, including getting up during the night, difficulty falling asleep, and excessive daytime sleepiness and may precipitate a person with dementia moving into residential care. There are varying estimates of the frequency of sleep disturbances, and it is unknown whether they are a problem for the individual. We conducted the first systematic review and meta-analysis on the prevalence and associated factors of sleep disturbances in the care home population with dementia. We searched Embase, MEDLINE, and PsycINFO (29/04/2019) for studies of the prevalence or associated factors of sleep disturbances in people with dementia living in care homes. We computed meta-analytical estimates of the prevalence of sleep disturbances and used meta-regression to investigate the effects of measurement methods, demographics, and study characteristics. We included 55 studies of 22,780 participants. The pooled prevalence on validated questionnaires of clinically significant sleep disturbances was 20% (95% confidence interval, CI 16% to 24%) and of any symptom of sleep disturbance was 38% (95% CI 33% to 44%). On actigraphy using a cutoff sleep efficiency of <85% prevalence was 70% (95% CI 55% to 85%). Staff distress, resident agitation, and prescription of psychotropic medications were associated with sleep disturbances. Studies with a higher percentage of males had a higher prevalence of sleep disturbance. Clinically significant sleep disturbances are less common than those measured on actigraphy and are associated with residents and staff distress and the increased prescription of psychotropics. Actigraphy appears to offer no benefit over proxy reports in this population.


Does arthroscopic débridement with or without interposition material address carpometacarpal arthritis?
Thumb carpometacarpal (CMC) joint arthritis is a common problem in clinical practice with a variety of treatment options. Arthroscopic procedures can preserve all or part of the trapezium in the setting of treatment of basilar joint arthritis, and such procedures (even without stabilization or ligament reconstruction) have high reported success rates. However, little is documented about the limitations of these procedures in terms of patient selection, the optimal type of interposition, if any, and rehabilitation. A systematic review was performed to determine the influence of (1) interposition material (manufactured, biological, or none); and (2) patient-related factors (including metacarpophalangeal joint hyperextension, ligamentous laxity, and severity of arthritis) on pain, functional scores, and postoperative complications unique to each approach. A systematic review of the English language literature regarding thumb basilar joint arthritis and arthroscopic partial trapeziectomy or débridement was performed. Those procedures including ligament reconstruction or stabilization were excluded. Biological materials and no interposition were both associated with satisfactory improvement and low rates of complications; complication rates with synthetic materials were higher. Eaton Stages I to III were treated successfully with this technique. The effect of scaphotrapeziotrapezoid (STT) changes was variably described across series. In most series, metacarpophalangeal hyperextension did not seem to have an adverse effect on outcomes, although these patients were excluded in some series. Arthroscopic débridement with or without interposition can be used for treatment of Eaton Stages I to III CMC osteoarthritis with satisfactory outcomes. Some series suggest satisfactory outcomes in the setting of STT changes and metacarpophalangeal hyperextension.


Preferential association of glycoproteins to the euchromatin regions of cross-fractured nuclei is revealed by fracture-label.
We used fracture-label to establish ultrastructural localization of glycoproteins in cross-fractured nuclei of duodenal columnar and exocrine pancreatic cells. Mannose residues were detected in cell nuclei by labeling freeze-fractured tissues with concanavalin A-horseradish peroxidase X colloidal gold (Con A-HRP X CG) or direct concanavalin A X colloidal gold (Con A X CG); fucose residues were detected with Ulex Europaeus I X colloidal gold (UEA I X CG) markers. Areas of the three main intranuclear compartments (euchromatin, heterochromatin, and nucleolus) exposed by freeze-fracture were determined by automated image analysis. Colloidal gold particles bound to each nuclear subcompartment were counted and the results expressed in number of colloidal gold particles per square micrometer +/- SEM. Duodenal and pancreatic tissues fractured and labeled with Con A-HRP X CG complex or direct Con A X CG conjugates showed that the vast majority of Con A binding sites was confined to euchromatin regions with only sparse labeling of the heterochromatin and nucleolus. UEA I labeling of duodenal columnar cells showed that colloidal gold particles were almost exclusively confined to cross-fractured areas where euchromatin is exposed. Trypsinization of the fractured tissues before labeling with Con A and UEA I abolished 95-100% of the original label. Our results show that, within the nucleoplasm, mannose and fucose are residues of glycoproteins preferentially located within the regions of euchromatin.


Computer aided detection of tuberculosis on chest radiographs: An evaluation of the CAD4TB v6 system.
There is a growing interest in the automated analysis of chest X-Ray (CXR) as a sensitive and inexpensive means of screening susceptible populations for pulmonary tuberculosis. In this work we evaluate the latest version of CAD4TB, a commercial software platform designed for this purpose. Version 6 of CAD4TB was released in 2018 and is here tested on a fully independent dataset of 5565 CXR images with GeneXpert (Xpert) sputum test results available (854 Xpert positive subjects). A subset of 500 subjects (50% Xpert positive) was reviewed and annotated by 5 expert observers independently to obtain a radiological reference standard. The latest version of CAD4TB is found to outperform all previous versions in terms of area under receiver operating curve (ROC) with respect to both Xpert and radiological reference standards. Improvements with respect to Xpert are most apparent at high sensitivity levels with a specificity of 76% obtained at a fixed 90% sensitivity. When compared with the radiological reference standard, CAD4TB v6 also outperformed previous versions by a considerable margin and achieved 98% specificity at the 90% sensitivity setting. No substantial difference was found between the performance of CAD4TB v6 and any of the various expert observers against the Xpert reference standard. A cost and efficiency analysis on this dataset demonstrates that in a standard clinical situation, operating at 90% sensitivity, users of CAD4TB v6 can process 132 subjects per day at an average cost per screen of $5.95 per subject, while users of version 3 process only 85 subjects per day at a cost of $8.38 per subject. At all tested operating points version 6 is shown to be more efficient and cost effective than any other version.


Unraveling a fine-scale high genetic heterogeneity and recent continental connections of an Arabian Peninsula population.
Recent studies have showed the diverse genetic architecture of the highly consanguineous populations inhabiting the Arabian Peninsula. Consanguinity coupled with heterogeneity is complex and makes it difficult to understand the bases of population-specific genetic diseases in the region. Therefore, comprehensive genetic characterization of the populations at the finest scale is warranted. Here, we revisit the genetic structure of the Kuwait population by analyzing genome-wide single nucleotide polymorphisms data from 583 Kuwaiti individuals sorted into three subgroups. We envisage a diverse demographic genetic history among the three subgroups based on drift and allelic sharing with modern and ancient individuals. Furthermore, our comprehensive haplotype-based analyses disclose a high genetic heterogeneity among the Kuwaiti populations. We infer the major sources of ancestry within the newly defined groups; one with an obvious predominance of sub-Saharan/Western Africa mostly comprising Kuwait-B individuals, and other with West Eurasia including Kuwait-P and Kuwait-S individuals. Overall, our results recapitulate the historical population movements and reaffirm the genetic imprints of the legacy of continental trading in the region. Such deciphering of fine-scale population structure and their regional genetic heterogeneity would provide clues to the uncharted areas of disease-gene discovery and related associations in populations inhabiting the Arabian Peninsula.


Moving From Digitalization to Digitization in Cardiovascular Care: Why Is it Important, and What Could it Mean for Patients and Providers?
So far, the digitization of health care is best exemplified by electronic medical records, which have been far from favorably or uniformly accepted. However, properly implemented digitization can enable better patient outcomes, improve convenience, potentially lower healthcare costs, and possibly lead to much greater physician satisfaction. Precision (also known as personalized or individualized) medicine is frequently discussed today, but, in reality, it is what physicians have attempted to do as best they could for millennia. But now we have new tools that can begin to give us a much more high-definition view of our patients; from affordable and rapid genetic testing to wearable sensors that track a wide range of important physiologic parameters continuously. Although seemingly counterintuitive, the digitization of health care can also markedly improve the physician-patient relationship, allowing more time for human interaction when care is bolstered by digital technologies that better individualize diagnostics and treatments.


Carvacrol together with TRPC1 elimination improve functional recovery after traumatic brain injury in mice.
Death of Central Nervous System (CNS) neurons following traumatic brain injury (TBI) is a complex process arising from a combination of factors, many of which are still unknown. It has been found that inhibition of transient receptor potential (TRP) channels constitutes an effective strategy for preventing death of CNS neurons following TBI. TRP channels are classified into seven related subfamilies, most of which are Ca(2+) permeable and involved in many cellular functions, including neuronal cell death. We hypothesized that TRP channels of the TRPC subfamily may be involved in post-TBI pathophysiology and that the compound 5-isopropyl-2-methylphenol (carvacrol), by inhibition of TRP channels, may exert neuroprotective effect after TBI. To test these suppositions, carvacrol was given to mice after TBI and its effect on their functional recovery was followed for several weeks. Our results show that neurological recovery after TBI was significantly enhanced by application of carvacrol. To better define the type of the specific channel involved, the effect of carvacrol on the extent and speed of recovery after TBI was compared among mice lacking TRPC1, TRPC3, or TRPC5, relative to wild type controls. We found that neurological recovery after TBI was significantly enhanced by combining carvacrol with TRPC1 elimination, but not by the absence of TRPC3 or TRPC5, showing a synergistic effect between carvacrol application and TRPC1 elimination. We conclude that TRPC1-sensitive mechanisms are involved in TBI pathology, and that inhibition of this channel by carvacrol enhances recovery and should be considered for further studies in animal models and humans.


Hepatitis C is associated with perturbation of intrahepatic myeloid and plasmacytoid dendritic cell function.
In most cases infection with hepatitis C results in chronic infection as a consequence of viral subversion and failed anti-viral immune responses. The suggestion that dendritic cells are defective in chronic HCV infection led us to investigate the phenotype and function of liver-derived myeloid (mDC) and plasmacytoid (pDC) dendritic cells in patients with chronic HCV infection. Liver DCs were isolated without expansion in cytokines from human liver allowing us to study unmanipulated tissue-resident DCs ex vivo. Compared with mDCs isolated from non-infected inflamed liver mDCs from HCV-infected liver (a) demonstrated higher expression of MHC class II, CD86 and CD123, (b) were more efficient stimulators of allogeneic T-cells and (c) secreted less IL-10. Reduced IL-10 secretion may be a factor in the enhanced functional properties of mDCs from HCV infected liver because antibody depletion of IL-10 enhanced the ability of mDCs from non-infected liver to stimulate T-cells. In contrast, pDCs were present at lower frequencies in HCV-infected liver and expressed higher levels of the regulatory receptor BDCA-2. In HCV-infected liver the combination of enhanced mDC function and a reduced number of pDCs may contribute to viral persistence in the face of persistent inflammation.


Models for the rise of the dinosaurs.
Dinosaurs arose in the early Triassic in the aftermath of the greatest mass extinction ever and became hugely successful in the Mesozoic. Their initial diversification is a classic example of a large-scale macroevolutionary change. Diversifications at such deep-time scales can now be dissected, modelled and tested. New fossils suggest that dinosaurs originated early in the Middle Triassic, during the recovery of life from the devastating Permo-Triassic mass extinction. Improvements in stratigraphic dating and a new suite of morphometric and comparative evolutionary numerical methods now allow a forensic dissection of one of the greatest turnovers in the history of life. Such studies mark a move from the narrative to the analytical in macroevolutionary research, and they allow us to begin to answer the proposal of George Gaylord Simpson, to explore adaptive radiations using numerical methods.


Intravenous endothelin-1 and ventilatory sensitivity to hypoxia in humans.
The effects of intravenous endothelin-1 (ET-1) on the ventilatory response to hypoxia were studied in healthy humans. Nine volunteers were each exposed twice to 4 hr eucapnic hypoxia. They received a continuous infusion of ET-1 during the ET-1 protocol and an infusion of saline during the control protocol. Plasma ET-1 levels and an index of ventilation were measured regularly. Hypoxia caused a rise in plasma ET-1 in the control protocol. Hypoxia also caused the index of ventilation to increase in both protocols, and this increase was greater in the ET-1 protocol than in the control protocol. These results are consistent with the hypothesis that ET-1 plays a role in controlling the ventilatory response to hypoxia in man.


Transition metal speciation in the cell: insights from the chemistry of metal ion receptors.
The essential transition metal ions are avidly accumulated by cells, yet they have two faces: They are put to use as required cofactors, but they also can catalyze cytotoxic reactions. Several families of proteins are emerging that control the activity of intracellular metal ions and help confine them to vital roles. These include integral transmembrane transporters, metalloregulatory sensors, and diffusible cytoplasmic metallochaperone proteins that protect and guide metal ions to targets. It is becoming clear that many of these proteins use atypical coordination chemistry to accomplish their unique goals. The different coordination numbers, types of coordinating residues, and solvent accessibilities of these sites are providing insight into the inorganic chemistry of the cytoplasm.


Creatine Transporter Deficiency in Two Brothers with Autism Spectrum Disorder.
Creatine transporter deficiency (CTD) is a treatable, X-linked, inborn error of metabolism. Two brothers with autism spectrum disorder were diagnosed with CTD at the ages of 17 and 12 years. Both were found to have a previously reported hemizygous p.408delF (c.1216_1218delTTC) deletion mutation. Both patients were given creatine monohydrate, L-arginine, L-glycine and S-adenosylmethionine, which partially improved the behavioral problems. Serum creatinine levels, creatine peak at brain MR spectroscopy or creatine/creatinine ratio in urine should be evaluated to identify CTD in children with autistic behavior and language disorders.


DNA microarray analyses of genes expressed differentially in 3T3-L1 adipocytes co-cultured with murine macrophage cell line RAW264.7 in the presence of the toll-like receptor 4 ligand bacterial endotoxin.
Recent studies have suggested that macrophages were integrated into adipose tissues to interact with adipocytes, thereby exacerbating inflammatory responses. Furthermore, both adipocytes and macrophages appear to express toll-like receptor-4 (TLR-4), and free fatty acids may stimulate cells through TLR-4. Herein, we analyzed genes differentially expressed in adipocytes when co-cultured with macrophages in the presence of a ligand for TLR-4, bacterial lipopolysaccharide (LPS). RAW264.7, a murine macrophage cell line and differentiated 3T3-L1 adipocytes were co-cultured using a transwell system. Genes differentially expressed in adipocytes were analyzed by the DNA microarray method following 4, 8, 12 and 24 h stimulation with 1 ng ml(-1) of Escherichia coli LPS. Randomly selected genes with high expressions were confirmed by quantitative methods at both the gene and the protein level. Co-culture of macrophages and adipocytes with a low LPS concentration (1 ng ml(-1)) markedly upregulated gene expressions associated with inflammation and/or angiogenesis, such as those of interleukin-6 (IL-6), MCP-1, RANTES and CXCL1/KC, in adipocytes. Furthermore, several genes associated with insulin resistance were differentially expressed. Upregulations of genes encoding MCP-1, RANTES and CXC/KC were confirmed by quantitative methods. These results suggest that ligands for TLR-4 stimulate both adipocytes and macrophages to upregulate the expressions of many genes associated with inflammation and/or angiogenesis.


eB4CAST Approach Improves Science Communication With Stakeholders in a College-Based Health Program.
Communicating scientific results with community partners is often lacking in intervention programs, thus eB4CAST was developed to facilitate impact sharing. This article investigated using the eB4CAST dissemination tool to communicate impact from a campus-based obesity prevention program. Data from Get Fruved RCT university sites collected at baseline were used to generate eB4CAST reports. Experts (n = 13) and RCT sites (n = 15) were asked to provide feedback on eB4CAST reports based on appeal, understanding, and clarity. On all Likert items, participants rated above 7 on each (out of 10). Positive responses from open-ended questions included eB4CAST reports being clear, visually appealing, and aid in program understanding. Overall, eB4CAST was successful in relaying data and information for the Get Fruved program, thus a means for science communication that could be used in interventions. Utilizing infographics to report data and information is a feasible way to disseminate and communicate in a cost-effective, timely manner.


Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells.
Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.


Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency.
The removal of extracellular amino acids or leucine alone inhibits the ability of the mammalian target of rapamycin (mTOR) to signal to the raptor-dependent substrates, p70 S6 kinase and 4E-BP. This inhibition can be overcome by overexpression of the Rheb GTPase. Rheb binds directly to the amino-terminal lobe of the mTOR catalytic domain, and activates mTOR kinase in a GTP-dependent manner. Herein we show that the binding of Rheb to endogenous and recombinant mTOR is reversibly inhibited by withdrawal of all extracellular amino acids or just leucine. The effect of amino acid withdrawal is not attributable to changes in Rheb-GTP charging; amino acid withdrawal does not alter the GTP charging of recombinant Rheb. Moreover, the binding of mTOR to Rheb mutants that are unable to bind guanyl nucleotide in vivo is also inhibited by amino withdrawal. The inhibitory effect of amino acid withdrawal is exerted through an action on mTOR, at a site largely distinct from that responsible for the binding of Rheb; deletion of the larger, carboxyl-terminal lobe of the mTOR catalytic domain eliminates the inhibitory effect of amino acid withdrawal on Rheb binding, without altering Rheb binding per se. The lesser ability of the mTOR catalytic domain to bind Rheb after amino acid withdrawal does not persist after extraction and purification of the mTOR polypeptide. Amino acid withdrawal may generate an inhibitor of the Rheb-mTOR interaction that interferes with the signaling function of TOR complex 1.


Delayed presentation of post-traumatic diaphragm rupture repaired by laparoscopy.
Diaphragmatic rupture is a serious but frequently missed condition that is potentially curable. While surgical management has classically been performed through open thoracotomy, a laparoscopic approach has been suggested as a preferable alternative. A man in his mid-50s presented with non-specific abdominal symptoms, 8 months after falling down some stairs. Diaphragmatic rupture was suspected after old rib fractures were noticed on an admitting chest radiograph. Further signs and symptoms presented following deterioration due to the unstable pathology. Prompt surgical treatment using laparoscopy was attempted with success and resulted in rapid and lasting improvement in symptoms.


Bowel Sounds Identification and Migrating Motor Complex Detection with Low-Cost Piezoelectric Acoustic Sensing Device.
Interpretation of bowel sounds (BS) provides a convenient and non-invasive technique to aid in the diagnosis of gastrointestinal (GI) conditions. However, the approach's potential is limited by variation between BS and their irregular occurrence. A short, manual auscultation is sufficient to aid in diagnosis of only a few conditions. A longer recording has the potential to unlock additional understanding of GI physiology and clinical utility. In this paper, a low-cost and straightforward piezoelectric acoustic sensing device was designed and used for long BS recordings. The migrating motor complex (MMC) cycle was detected using this device and the sound index as the biomarker for MMC phases. This cycle of recurring motility is typically measured using expensive and invasive equipment. We also used our recordings to develop an improved categorization system for BS. Five different types of BS were extracted: the single burst, multiple bursts, continuous random sound, harmonic sound, and their combination. Their acoustic characteristics and distribution are described. The quantities of different BS during two-hour recordings varied considerably from person to person, while the proportions of different types were consistent. The sensing devices provide a useful tool for MMC detection and study of GI physiology and function.


Cytoplasmic activation of starfish oocytes by sperm and divalent ionophore A-23187.
The relationship between onset of the early cytoplasmic stages of oocyte activation (vitelline membrane separation and elevation) and nuclear meiotic maturation was investigated in starfish oocytes after their exposure to divalent ionophore (A-23187) or sperm. Meiotically mature oocytes, isolated in calcium-free seawater, underwent activation in response to sperm or ionophore as previously reported. Large, immature starfish oocytes, arrested in prophase I of meiosis (germinal vesicle stage), underwent vitelline membrane elevation when treated with divalent ionophore A-23187 or starfish sperm. Histological studies demonstrated that cortical granule breakdown in the oocyte cortex was associated with vitelline membrane elevation after these treatments. Activation of oocytes by sperm occurred only in response to starfish sperm. Sea urchin, sand dollar, surf clam, or marine worm sperm did not induce vitelline membrane elevation of either immature or mature starfish oocytes. Sperm- or ionophore-activated immature oocytes underwent nuclear maturation after addition of the meiosis-inducing hormone, l-methyladenine; however, parthenogenetic development did not occur and embryonic development was markedly inhibited. In contrast to previous studies, the present results indicate that cytoplasmic activation can be initiated before and without hormone induction of the nuclear maturation process. Differentiation of the oocyte cell surface or cortex reactivity therefore appears to occur during oogenesis rather than as a consequence of maturation. The data further support the view that divalent ions mediate certain of the early activation responses initiated by sperm at the time of fertilization and that synchronization of fertilization to the meiotic process in the oocyte is important for the occurrence of normal development.


Antihypertensive effect of carvedilol: a preliminary dose-response study.
The blood pressure (BP) lowering effect of low doses of antihypertensive agents is not usually explored because of the difficulty in detecting small changes in BP. Since ambulatory blood pressure monitoring in a cross-over trial design can reliably detect differences of 5 mmHg with less than 20 subjects, we have used this technique to assess the dose-response curve of a new beta-blocker, carvedilol. Twenty subjects were enrolled after diagnostic ambulatory BP monitoring had shown a day-time average diastolic BP of over 90 mmHg. Three doses of carvedilol (6.25, 12.5 and 25 mg daily) and placebo were then given double-blind in random order for periods of 4 weeks each. No period effects were detected. The antihypertensive effect was statistically significant at doses of 12.5 mg and 25 mg daily. There was, however, no evidence that 25 mg/day produced the peak effect. The lowest dose (6.25 mg/day) produced a small fall in both systolic and diastolic BP but neither of these were significant. We conclude that doses of 12.5 and 25 mg carvedilol once a day are adequate for the treatment of hypertension.


Intravenous thrombolysis in ischemic stroke patients with intracranial neoplasms: two cases and a literature review.
Based on exclusion criteria in the landmark NINDS-rtPA trial, current expert consensus guidelines preclude the use of intravenous recombinant tissue plasminogen activator (IV rtPA) in acute ischemic stroke (AIS) patients with intracranial neoplasm. There are only 3 published cases of administration of IV rtPA to AIS patients with intracranial neoplasms in the literature. Two of these published cases involved malignant brain parenchymal lesions discovered only after rtPA was inadvertently given, and one of these cases was associated with hemorrhage within the tumor. In this paper, we report two cases of administration of IV rtPA in AIS patients with intracranial neoplasms observed on neuroimaging prior to IV rtPA administration. In both cases, the tumor was outside of the brain parenchyma. The first case was an acoustic schwannoma and the second a falcine meningioma. Neither case was associated with intratumoral hemorrhage as of at least one week following IV rtPA treatment. More published cases are definitely warranted, but our experience with these two cases suggests that administration of IV rtPA to AIS patients in the presence of extraparenchymal brain tumors may not necessarily precipitate intra-tumoral bleeding and thereby worsen clinical outcomes.


Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection.
Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the α3β1, αVβ3, and xCT receptors, but not αVβ5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin-mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-α3β1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (α3β1 and αVβ3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis-associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection.


A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors.
Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes. In this study, we employed a colon cancer model to assess potential mechanisms driving resistance to cetuximab. Resistant cells displayed increased ability to grow in suspension as colonspheres and this phenotype was associated with poorly organized structures. Factors secreted from resistant cells were causally involved in sustaining resistance, indeed administration to parental cells of conditioned medium collected from resistant cells was sufficient to reduce cetuximab efficacy. Among secreted factors, we report herein that a signature of inflammatory cytokines, including IL1A, IL1B and IL8, which are produced following EGFR pathway activation, was associated with the acquisition of an unresponsive phenotype to cetuximab in vitro. This signature correlated with lack of response to EGFR targeting also in patient-derived tumour xenografts. Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting.


Retrieval of the zero-dispersion wavelength map of an optical fiber from measurement of its continuous-wave four-wave mixing efficiency.
We present a novel algorithm for reconstruction of the longitudinal distribution of zero-dispersion wavelength in an optical fiber from low power, end-to-end measurements of four-wave mixing efficiency. It is based on a modified version of the error-reduction approach used in classic phase-retrieval problems. Experimental results demonstrate the validity of this algorithm.


TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle.
TWIST proteins are important for development of embryonic skeletal muscle and play a role in the metabolism of tumor and white adipose tissue. The impact of TWIST on metabolism in skeletal muscle is incompletely studied. Our aim was to assess the impact of TWIST1 and TWIST2 overexpression on glucose and lipid metabolism. In intact mouse muscle, overexpression of Twist reduced total glycogen content without altering glucose uptake. Expression of TWIST1 or TWIST2 reduced Pdk4 mRNA, while increasing mRNA levels of Il6, Tnfα, and Il1β. Phosphorylation of AKT was increased and protein abundance of acetyl CoA carboxylase (ACC) was decreased in skeletal muscle overexpressing TWIST1 or TWIST2. Glycogen synthesis and fatty acid oxidation remained stable in C2C12 cells overexpressing TWIST1 or TWIST2. Finally, skeletal muscle mRNA levels remain unaltered in ob/ob mice, type 2 diabetic patients, or in healthy subjects before and after 3 months of exercise training. Collectively, our results indicate that TWIST1 and TWIST2 are expressed in skeletal muscle. Overexpression of these proteins impacts proteins in metabolic pathways and mRNA level of cytokines. However, skeletal muscle levels of TWIST transcripts are unaltered in metabolic diseases.


Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia.
Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia.


Defensive spray of the bombardier beetle: a biological pulse jet.
The defensive spray of the bombardier beetle Stenaptinus insignis is ejected in quick pulses (at about 500 pulses per second) rather than as a continuous stream. The pulsation may be a consequence of intermittency in the explosive chemical process that generates the spray. The ejection system of the beetle shows basic similarity to the pulse jet propulsion mechanism of the German V-1 "buzz" bomb of World War II.


Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells.
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.


Population differentiation and genetic variation in host choice among pea aphids from eight host plant genera.
Habitat choice plays a critical role in the processes of host range evolution, specialization, and ecological speciation. Pea aphid, Acyrthosiphon pisum, populations from alfalfa and red clover in eastern North America are known to be genetically differentiated and show genetic preferences for the appropriate host plant. This species feeds on many more hosts, and here we report a study of the genetic variation in host plant preference within and between pea aphid populations collected from eight genera of host plants in southeastern England. Most host-associated populations show a strong, genetically based preference for the host plant from which they were collected. Only in one case (populations from Vicia and Trifolium) was there little difference in the plant preference spectrum between populations. All populations showed a significant secondary preference for the plant on which all the aphid lines were reared: broad bean, Vicia faba, previously suggested to be a "universal host" for pea aphids. Of the total genetic variance in host preference within our sample, 61% could be attributed to preference for the collection host plant and a further 9% to systematic differences in secondary preferences with the residual representing within-population genetic variation between clones. We discuss how a combination of host plant preference and mating on the host plant may promote local adaptation and possibly ecological speciation, and whether a widely accepted host could oppose speciation by mediating gene flow between different populations.


Role of endogenous sleep-wake and analgesic systems in anesthesia.
Classical anesthetics of the gamma-aminobutyric acid type A receptor (GABA(A))-enhancing class (e.g., pentobarbital, chloral hydrate, muscimol, and ethanol) produce analgesia and unconsciousness (sedation). Dissociative anesthetics that antagonize the N-methyl-D-aspartate (NMDA) receptor (e.g., ketamine, MK-801, dextromethorphan, and phencyclidine) produce analgesia but do not induce complete loss of consciousness. To understand the mechanisms underlying loss of consciousness and analgesia induced by general anesthetics, we examined the patterns of expression of c-Fos protein in the brain and correlated these with physiological effects of systemically administering GABAergic agents and ketamine at dosages used clinically for anesthesia in rats. We found that GABAergic agents produced predominantly delta activity in the electroencephalogram (EEG) and sedation. In contrast, anesthetic doses of ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects, ketamine induced Fos expression in cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep-promoting ventrolateral preoptic nucleus (VLPO). In contrast, GABAergic agents suppressed Fos in the same arousal-promoting systems but increased the number of Fos-immunoreactive neurons in the VLPO compared with waking control animals. All anesthetics tested induced Fos in the spinally projecting noradrenergic A5-7 groups. 6-hydroxydopamine lesions of the A5-7 groups or ibotenic acid lesions of the ventrolateral periaqueductal gray matter (vlPAG) attenuated antinociceptive responses to noxious thermal stimulation (tail-flick test) by both types of anesthetics. We hypothesize that neural substrates of sleep-wake behavior are engaged by low-dose sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the analgesic effects of both NMDA receptor antagonists and GABA(A) receptor-enhancing anesthetics.


Into Tibet: An Early Pliocene Dispersal of Fossil Zokor (Rodentia: Spalacidae) from Mongolian Plateau to the Hinterland of Tibetan Plateau.
This paper reports the fossil zokors (Myospalacinae) collected from the lower Pliocene (~4.4 Ma) of Zanda Basin, southwestern Tibet, which is the first record in the hinterland of Tibetan Plateau within the Himalayan Range. Materials include 29 isolated molars belonging to Prosiphneus eriksoni (Schlosser, 1924) by having characters including large size, highly fused roots, upper molars of orthomegodont type, m1 anterior cap small and centrally located, and first pair of m1 reentrants on opposing sides, high crowns, and high value of dentine tract parameters. Based on the cladistics analysis, all seven species of Prosiphneus and P. eriksoni of Zanda form a monophyletic clade. P. eriksoni from Zanda, on the other hand, is nearly the terminal taxon of this clade. The appearance of P. eriksoni in Zanda represents a significant dispersal in the early Pliocene from its center of origin in north China and Mongolian Plateau, possibly via the Hol Xil-Qiangtang hinterland in northern Tibet. The fast evolving zokors are highly adapted to open terrains at a time when regional climates had become increasingly drier in the desert zones north of Tibetan Plateau during the late Miocene to Pliocene. The occurrence of this zokor in Tibet thus suggests a rather open steppe environment. Based on fossils of large mammals, we have formulated an "out of Tibet" hypothesis that suggests earlier and more primitive large mammals from the Pliocene of Tibet giving rise to the Ice Age megafauna. However, fossil records for large mammals are still too poor to evaluate whether they have evolved from lineages endemic to the Tibetan Plateau or were immigrants from outside. The superior record of small mammals is in a better position to address this question. With relatively dense age intervals and numerous localities in much of northern Asia, fossil zokors provide the first example of an "into Tibet" scenario--earlier and more primitive taxa originated from outside of the Tibetan Plateau and the later the lineage became extinct in southwestern Tibet.


Epidemiology of canine heartworm (Dirofilaria immitis) infection in domestic dogs in Ontario, Canada: Geographic distribution, risk factors and effects of climate.
Dirofilaria immitis is the causal agent of heartworm, a mosquito-borne parasite that primarily infects domestic and wild canids. The infection is endemic in parts of Canada, and Ontario has been identified as the province where the majority of heartworm infections occur. Test results for blood samples submitted by veterinary clinics for the years 2007-2016 were used to conduct a spatial risk analysis of heartworm among domestic dogs in Ontario. The geographic extent of the apparent heartworm prevalence was examined through smoothed choropleth maps for all 49 census division regions. Furthermore, the regions were assessed for local clusters in apparent prevalence using the flexible spatial scan statistic. Three clusters were found and located in western, southern and eastern Ontario, respectively. A spatial Poisson regression model for heartworm prevalence among pet dog populations in southern Ontario census divisions was fit to determine the association between human population size, heartworm development units (HDUs), climate moisture index (CMI), precipitation and directions, east or north, with heartworm infection. The model identified the spatial distribution of HDUs and CMI as positively associated with heartworm infection and therefore important predictors of the infection. In contrast, human population size, increasing northern latitude and drier areas were negatively associated with heartworm infection. The east direction and precipitation were not significant.


Inhibitory effect of chlorophyll on the genotoxicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
Genotoxicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) on Drosophila was suppressed by chlorophyll. Using the wing hair spot test, we found that the formation of mutant hairs in adult flies as a result of feeding them with Trp-P-2 in their larval stage was efficiently inhibited by coadministration of chlorophyll. The decrease in the spot frequencies was dependent on the dose of chlorophyll, and at the highest dose used, where the ratio in weight of Trp-P-2 to chlorophyll was 1:80, a complete prevention of the small single-spot formation was observed. A similar inhibitory effect was detected for chlorophyllin, the chromophore of chlorophyll. In the studies to investigate the mechanism of inhibition, we observed that the mutagenicity of 3-hydroxy-amino-1-methyl-5H-pyrido[4,3-b]indole [Trp-P-2(NHOH)], the metabolically activated form of Trp-P-2, in Salmonella typhimurium TA98 was suppressed effectively with chlorophyll and chlorophyllin. We also found that chlorophyll and chlorophyllin can produce complexes with Trp-P-2 and Trp-P-2(NHOH). A straightforward mechanism of these inhibitions is that Trp-P-2 [and Trp-P-2(NHOH)] becomes no longer available to organisms on forming the chlorophyll complex.


Factors related to the formation of buccal mucosa ridging in university students.
Buccal mucosa ridging (BMR) is known as a clinical sign of clenching, which is one of the major manifestations of bruxism. However, there are few reports about the formation of BMR and no data regarding the association between BMR and factors such as malocclusion. The purpose of the current study was to investigate the relationship between BMR and factors such as the number of teeth present, gender, body mass index (BMI), occlusion and clenching habit in university students. A total of 2101 students (1164 males, 937 females), aged 18-29 years old, were included in the study. BMR and the number of teeth present were recorded and malocclusion was defined using a modified version of the Index of Orthodontic Treatment Need. Additional information regarding gender, clenching habit and BMI was collected via a questionnaire. Forty-six per cent of the subjects had BMR and the prevalence of BMR in females was significantly higher than that of males (chi square test, p < 0.001). According to logistic regression analysis, the probability of BMR was significantly associated with female gender (OR = 1.501, 95% CI = 1.259-1.790, p < 0.001), crowding (OR = 2.102, 95% CI = 1.706-2.590, p < 0.001) and overjet (OR = 0.585, 95% CI = 0.418-0.818, p = 0.002). On the other hand, BMR was not associated with awareness of clenching habit and BMI. Gender, crowding and overjet were related to the formation of BMR in university students. When evaluating BMR as a clinical sign of clenching, one might have to take factors such as gender and crowding into consideration.


Is tapentadol different from classical opioids? A review of the evidence.
Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids.


Persistence of nondysplastic Barrett's esophagus identifies patients at lower risk for esophageal adenocarcinoma: results from a large multicenter cohort.
Recent population-based studies have shown a low risk of esophageal adenocarcinoma (EAC) in patients with nondysplastic Barrett's esophagus (NDBE). We evaluated whether persistence of NDBE over multiple consecutive surveillance endoscopic examinations could be used in risk stratification of patients with Barrett's esophagus (BE). We performed a multicenter outcomes study of a large cohort of patients with BE. Based on the number of consecutive surveillance endoscopies showing NDBE, we identified 5 groups of patients. Patients in group 1 were found to have NDBE at their first esophagogastroduodenoscopy (EGD). Patients in group 2 were found to have NDBE on their first 2 consecutive EGDs. Similarly, patients in groups 3, 4, and 5 were found to have NDBE on 3, 4, and 5 consecutive surveillance EGDs. A logistic regression model was built to determine whether persistence of NDBE independently protected against development of cancer. Of a total of 3515 patients with BE, 1401 patients met the inclusion criteria (93.3% white; 87.5% men; median age, 60 ±17 years). The median follow-up period was 5 ± 3.9 years (7846 patient-years). The annual risk of EAC in groups 1 to 5 was 0.32%, 0.27%, 0.16%, 0.2%, and 0.11%, respectively (P for trend = .03). After adjusting for age, sex, and length of BE, persistence of NDBE, based on multiple surveillance endoscopies, was associated with a gradually lower likelihood of progression to EAC. Persistence of NDBE over several endoscopic examinations identifies patients who are at low risk for development of EAC. These findings support lengthening surveillance intervals or discontinuing surveillance of patients with persistent NDBE.


Targeting telomerase with radiolabeled inhibitors.
The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy. However the lag period between initiation of telomerase inhibition and growth arrest makes direct inhibition alone an insufficient method of treatment. However, telomerase inhibition has been shown to enhance cancer cell radiosensitivity. To investigate the strategy of simultaneously inhibiting telomerase while delivering targeted radionuclide therapy to cancer cells, 123I-radiolabeled inhibitors of telomerase were synthesized and their effects on cancer cell survival studied. An 123I-labeled analogue of the telomerase inhibitor MST-312 inhibited telomerase with an IC50 of 1.58 μM (MST-312 IC50: 0.23 μM). Clonogenic assays showed a dose dependant effect of 123I-MST-312 on cell survival in a telomerase positive cell line, MDA-MB-435.


Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Clinical Cancer Patients.
Voltage-gated calcium channels (VGCCs) are well documented to play roles in cell proliferation, migration, and apoptosis; however, whether VGCCs regulate the onset and progression of cancer is still under investigation. The VGCC family consists of five members, which are L-type, N-type, T-type, R-type and P/Q type. To date, no holistic approach has been used to screen VGCC family genes in different types of cancer. We analyzed the transcript expression of VGCCs in clinical cancer tissue samples by accessing ONCOMINE (www.oncomine.org), a web-based microarray database, to perform a systematic analysis. Every member of the VGCCs was examined across 21 different types of cancer by comparing mRNA expression in cancer to that in normal tissue. A previous study showed that altered expression of mRNA in cancer tissue may play an oncogenic role and promote tumor development; therefore, in the present findings, we focus only on the overexpression of VGCCs in different types of cancer. This bioinformatics analysis revealed that different subtypes of VGCCs (CACNA1C, CACNA1D, CACNA1B, CACNA1G, and CACNA1I) are implicated in the development and progression of diverse types of cancer and show dramatic up-regulation in breast cancer. CACNA1F only showed high expression in testis cancer, whereas CACNA1A, CACNA1C, and CACNA1D were highly expressed in most types of cancer. The current analysis revealed that specific VGCCs likely play essential roles in specific types of cancer. Collectively, we identified several VGCC targets and classified them according to different cancer subtypes for prospective studies on the underlying carcinogenic mechanisms. The present findings suggest that VGCCs are possible targets for prospective investigation in cancer treatment.


Cytohistological correlation in diagnosis of lung tumors by using fiberoptic bronchoscopy: study of 200 cases.
Examination of specimens obtained through flexible fiberoptic bronchoscope is an important and often the initial diagnostic technique performed in patients with suspected malignant lung lesion. To evaluate the correlation of cytological findings of bronchial washings, bronchial brushing and imprint smear of bronchial biopsy in the diagnosis of lung tumors, with histopathology of bronchial biopsy taking the latter as the confirmatory diagnostic test. A total of 200 patients with lung mass were included in the study. Bronchial brushings were obtained from all 200 cases. In the first 100 cases, pre-biopsy bronchial washing (washing collected before the brushing and biopsy procedure) while post-biopsy washing (washing at the end of the procedure) was procured in all 200 cases. Imprint smears of bronchial biopsy were prepared in 150 cases. Sensitivity and specificity of brushing was 76.58% and 77.78% respectively and that of imprint smear was 81.35% and 78.12% respectively. Pre-biopsy and post-biopsy washing showed high specificity of 88.89%, but low sensitivity of 30.14 and 36.77% respectively. No significant difference was found in sensitivity between brushing and imprint smear (Chi-square; P = 0.4187); and between pre-biopsy and post-biopsy washing (Chi-square; P = 0.7982). However, there was a significant difference between sensitivity of brushing and washing (Chi-square; P = 0.0001). The sensitivity of combination of three cytological diagnostic techniques was 87.29%. Bronchial brushing and washing cytology in combination with imprint cytology aids in the diagnosis of lung tumors. Therefore, all these techniques may be used concurrently along with bronchial biopsy to diagnose lung tumors.


The transsortative structure of networks.
Network topologies can be highly non-trivial, due to the complex underlying behaviours that form them. While past research has shown that some processes on networks may be characterized by local statistics describing nodes and their neighbours, such as degree assortativity, these quantities fail to capture important sources of variation in network structure. We define a property called transsortativity that describes correlations among a node's neighbours. Transsortativity can be systematically varied, independently of the network's degree distribution and assortativity. Moreover, it can significantly impact the spread of contagions as well as the perceptions of neighbours, known as the majority illusion. Our work improves our ability to create and analyse more realistic models of complex networks.


Hyperforin, a new lead compound against the progression of cancer and leukemia?
Extracts of the plant St John's wort, Hyperforin perforatum L., have been used for centuries in traditional medicine, notably for the treatment of depression. One of their main lipophilic components, a natural prenylated phloroglucinol termed hyperforin (HF), has been identified as the major molecule responsible for the antidepressant effects of this plant. Within the last few years, a number of studies have demonstrated that HF displays, in addition, several other biological properties of potential pharmacological interest. They include an antibacterial capacity and inhibitory effects on inflammatory mediators. It is worth noting that HF also promotes apoptosis of various cancer cells from solid tumors and hematological malignancies, including B-cell chronic lymphocytic leukemia. In addition, HF inhibits the capacity of migration and invasion of different tumor cells, as well as exhibiting antiangiogenic effects. Altogether, these properties qualify HF as a lead structure for the development of new therapeutic molecules in the treatment of various diseases, including some malignant tumors.


Effects of temperature on the reproductive physiology of female elasmobranchs: The case of the narrownose smooth-hound shark (Mustelus schmitti).
The knowledge of how temperature influences elasmobranchs reproductive physiology allows a better understanding of their reproductive patterns. This study describes the relationship between temperature fluctuations and the plasmatic changes of the sex steroids related to reproduction: testosterone (T), estradiol (E2) and progesterone (P4), throughout the female reproductive cycle of the shark Mustelus schmitti. A total of 123 adult females were bi-monthly sampled in Buenos Aires, Argentina, coastal waters. Bottom temperatures were recorded at each sampling point and blood samples were taken from each female for plasma sex steroids measurement. Sex steroid plasma levels were analyzed in relation with maximum follicular diameter (MFD), uterosomatic index (USI, as indicator of pregnancy) and temperature using Generalized Additive Models. Plasmatic E2 and T increased during follicular growth until MFD reached 1.34 and 1.46 cm, respectively. Peak of T occurred at the follicular stage associated with parturition (MFD, 1.4-1.6 cm), just prior to final maturation and ovulation (MFD, 1.6-2.0 cm). Progesterone significantly increased at this last ovarian phase, while T and E2 decreased. The increase of USI with pregnancy was associated to a decrease in T and mainly E2 levels, while P4 remained unaffected. Prior to ovulation, T plasma levels decreased with temperature below to 13 °C and then increased progressively with a pronounced elevation above 17 °C, while E2 presented an opposite pattern. Progesterone plasma levels changed with temperature showing a similar pattern to that observed for T. Using M. schmitti shark as model species, this study shows a clear picture of how seawater temperature variations can affect the reproductive physiology in elasmobranch females. A hypothetical mechanism (based on T elevation driven by temperature increase and its connection by feedback with a P4 rise and parturition/ovulation induction) is proposed as evidence to support that the increase in temperature can trigger reproductive events in elasmobranchs. In addition to its ecological scope, this work contributes to reinforce the relatively scarce general knowledge of elasmobranchs reproductive physiology.


Effect of humic acid on Cd(II), Cu(II), and Pb(II) uptake by freshwater algae: kinetic and cell wall speciation considerations.
Thepresent study examines the effect of humic acid on the uptake kinetics of Cd(II), Cu(II), and Pb(II) by the freshwater alga Chlorella kesslerii. The results demonstrated that the relative proportion of Pb in the cell wall layer is greater than that of the internalized Pb, while internalized Cd and Cu were comparable or greater than the adsorbed metal concentration. In the presence of 10 mg L(-1) humic acid (HA), Cd and Cu uptake kinetics were consistent with that predicted by measured free metal concentrations. For Pb, the uptake flux and amount of lead bound to internalization and adsorption sites were an order of magnitude higher than those found at the same free lead ion concentrations in the presence of citric acid. Chemodynamic modeling suggested that the enhancement of the Pb uptake flux in the presence of HA originates from an increasing amount of Pb bound to the internalization sites through a ternary complex formation between lead-humic acid complex and internalization sites. Cell wall speciation calculations indicated that the lead-humic acid complex is the predominant species in the cell wall layer, while for Cu(II) and Cd(II) metal bound to the internalization (Cu) and adsorption (Cd) sites significantly dominated over the M-HA complex. The findings of the work show the relevance of the cell wall layer concentration and speciation and its key role in defining the local equilibrium conditions between metal and internalizations sites. The results of the present kinetic study have important consequences for improvement of the mechanistic understanding of the role of dissolved organic matter in metal uptake in phytoplankton and biogeochemical cycling of metals in the surface waters.


Femtosecond time-resolved X-ray absorption spectroscopy of liquid using a hard X-ray free electron laser in a dual-beam dispersive detection method.
We present femtosecond time-resolved X-ray absorption spectroscopy of aqueous solution using a hard x-ray free electron laser (SACLA) and a synchronized Ti:sapphire laser. The instrumental response time is 200 fs, and the repetition rate of measurement is 10 Hz. A cylindrical liquid beam 100 μm in diameter of aqueous ammonium iron(III) oxalate solution is photoexcited at 400 nm, and the transient X-ray absorption spectra are measured in the K-edge region of iron, 7.10 - 7.26 keV, using a dual X-ray beam dispersive detection method. Each of the dual beams has the pulse energy of 1.4 μJ, and pump-induced absorbance change on the order of 10(-3) is successfully detected. The photoexcited iron complex exhibits a red shifted iron K-edge with the appearance time constant of 260 fs. The X-ray absorption difference spectra, with and without the pump pulses, are independent of time delay after 1.5 ps up to 100 ps, indicating that the photoexcited species is long-lived.


Chemical composition, antioxidant and antigenotoxic activities of different fractions of Gentiana asclepiadea L. roots extract.
The aim of this study was to evaluate the antioxidant and antigenotoxic activities of chloroform, ethyl acetate and n-butanol fractions obtained from Gentiana asclepiadea L. roots methanolic extract. The main secondary metabolites sweroside, swertiamarin and gentiopicrine were quantified in G. asclepiadea root extracts using HPLC-DAD analysis. Amount of total phenols, flavonoids, flavonols and gallotannins was also determined. The antigenotoxic potential of extracts from roots of G. asclepiadea was assessed using the standard in vivo procedure for the detection of sex linked recessive lethal mutations in Drosophila melanogaster males treated with ethyl methanesulfonate (EMS). The results showed that the most abundant secoiridoid in G. asclepiadea roots was gentiopicrine and its content in the n-butanol fraction (442.89 mg/g) was the highest. Among all extracts, ethyl acetate fraction showed the highest antioxidant activity, as well as total phenolics (146.64 GAE/g), flavonoids (44.62 RUE/g), flavonols (22.71 RUE/g) and gallotannins (0.99 mg GAE/g) content. All the fractions showed antioxidant activity using in vitro model systems and the results have been correlated with total phenolics, flavonoids, flavonols and gallotannins content. In addition to antioxidant activity, G. asclepiadea root extract fractions possess an antigenotoxic effect against DNA damage induced by alkylation with EMS. The antioxidant activity exhibited by G. asclepiadea depended on the phenolic compounds content of the tested extracts, while there was no significant difference in the antigenotoxic potential between fractions.


The effect of regular aquatic exercise on blood pressure: A meta-analysis of randomized controlled trials.
Background No meta-analysis has examined the effect of regular aquatic exercise on blood pressure. The purpose of this study was to perform a meta-analysis to evaluate the effects of regular aquatic exercise on blood pressure. Design A meta-analysis of randomized controlled trials. Methods Databases were searched for literature published up to April 2017. The randomized controlled trials analysed involved healthy adults, an intervention group that only performed aquatic exercise and a control group that did not exercise, no other intervention, and trials indicated mean systolic blood pressure or diastolic blood pressure. The net change in blood pressure was calculated from each trial, and the changes in blood pressure were pooled by a random effects model, and the risk of heterogeneity was evaluated. Subgroup analysis of subjects with hypertension, subjects who performed endurance exercise (or not), and subjects who only swam (or not) was performed, and the net changes in blood pressure were pooled. Results The meta-analysis examined 14 trials involving 452 subjects. Pooled net changes in blood pressure improved significantly (systolic blood pressure -8.4 mmHg; diastolic blood pressure -3.3 mmHg) and the changes in systolic blood pressure contained significant heterogeneity. When subjects were limited to those with hypertension, those who performed endurance exercise and subjects who did not swim, pooled net changes in systolic and diastolic blood pressure decreased significantly, but the heterogeneity of systolic blood pressure did not improve. Conclusion Like exercise on land, aquatic exercise should have a beneficial effect by lowering blood pressure. In addition, aquatic exercise should lower the blood pressure of subjects with hypertension, and other forms of aquatic exercise besides swimming should also lower blood pressure.


COVID-19 due to the B.1.617.2 (Delta) variant compared to B.1.1.7 (Alpha) variant of SARS-CoV-2: a prospective observational cohort study.
The Delta (B.1.617.2) variant was the predominant UK circulating SARS-CoV-2 strain between May and December 2021. How Delta infection compares with previous variants is unknown. This prospective observational cohort study assessed symptomatic adults participating in the app-based COVID Symptom Study who tested positive for SARS-CoV-2 from May 26 to July 1, 2021 (Delta overwhelmingly the predominant circulating UK variant), compared (1:1, age- and sex-matched) with individuals presenting from December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the predominant variant). We assessed illness (symptoms, duration, presentation to hospital) during Alpha- and Delta-predominant timeframes; and transmission, reinfection, and vaccine effectiveness during the Delta-predominant period. 3581 individuals (aged 18 to 100 years) from each timeframe were assessed. The seven most frequent symptoms were common to both variants. Within the first 28 days of illness, some symptoms were more common with Delta versus Alpha infection (including fever, sore throat, and headache) and some vice versa (dyspnoea). Symptom burden in the first week was higher with Delta versus Alpha infection; however, the odds of any given symptom lasting ≥ 7 days was either lower or unchanged. Illness duration ≥ 28 days was lower with Delta versus Alpha infection, though unchanged in unvaccinated individuals. Hospitalisation for COVID-19 was unchanged. The Delta variant appeared more (1.49) transmissible than Alpha. Re-infections were low in all UK regions. Vaccination markedly reduced the risk of Delta infection (by 69-84%). We conclude that COVID-19 from Delta or Alpha infections is similar. The Delta variant is more transmissible than Alpha; however, current vaccines showed good efficacy against disease. This research framework can be useful for future comparisons with new emerging variants.


Evolutionary origin of GnIH and NPFF in chordates: insights from novel amphioxus RFamide peptides.
Gonadotropin-inhibitory hormone (GnIH) is a newly identified hypothalamic neuropeptide that inhibits pituitary hormone secretion in vertebrates. GnIH has an LPXRFamide (X = L or Q) motif at the C-terminal in representative species of gnathostomes. On the other hand, neuropeptide FF (NPFF), a neuropeptide characterized as a pain-modulatory neuropeptide, in vertebrates has a PQRFamide motif similar to the C-terminal of GnIH, suggesting that GnIH and NPFF have diverged from a common ancestor. Because GnIH and NPFF belong to the RFamide peptide family in vertebrates, protochordate RFamide peptides may provide important insights into the evolutionary origin of GnIH and NPFF. In this study, we identified a novel gene encoding RFamide peptides and two genes of their putative receptors in the amphioxus Branchiostoma japonicum. Molecular phylogenetic analysis and synteny analysis indicated that these genes are closely related to the genes of GnIH and NPFF and their receptors of vertebrates. We further identified mature RFamide peptides and their receptors in protochordates. The identified amphioxus RFamide peptides inhibited forskolin induced cAMP signaling in the COS-7 cells with one of the identified amphioxus RFamide peptide receptors expressed. These results indicate that the identified protochordate RFamide peptide gene is a common ancestral form of GnIH and NPFF genes, suggesting that the origin of GnIH and NPFF may date back to the time of the emergence of early chordates. GnIH gene and NPFF gene may have diverged by whole-genome duplication in the course of vertebrate evolution.


Availability of essential health services in post-conflict Liberia.
To assess the availability of essential health services in northern Liberia in 2008, five years after the end of the civil war. We carried out a population-based household survey in rural Nimba county and a health facility survey in clinics and hospitals nearest to study villages. We evaluated access to facilities that provide index essential services: artemisinin combination therapy for malaria, integrated management of childhood illness, human immunodeficiency virus (HIV) counselling and testing, basic emergency obstetric care and treatment of mental illness. Data were obtained from 1405 individuals (98% response rate) selected with a three-stage population-representative sampling method, and from 43 of Nimba county's 49 health facilities selected because of proximity to the study villages. Respondents travelled an average of 136 minutes to reach a health facility. All respondents could access malaria treatment at the nearest facility and 55.9% could access HIV testing. Only 26.8%, 14.5%, and 12.1% could access emergency obstetric care, integrated management of child illness and mental health services, respectively. Although there has been progress in providing basic services, rural Liberians still have limited access to life-saving health care. The reasons for the disparities in the services available to the population are technical and political. More frequently available services (HIV testing, malaria treatment) were less complex to implement and represented diseases favoured by bilateral and multilateral health sector donors. Systematic investments in the health system are required to ensure that health services respond to current and future health priorities.


Single-session endoscopic resection and focal radiofrequency ablation for short-segment Barrett's esophagus with early neoplasia.
The management of early neoplasia in Barrett's esophagus (BE) requires endoscopic resection of visible lesions, followed by radiofrequency ablation (RFA) of the remaining BE. We evaluated the safety and efficacy of combining endoscopic resection and focal RFA in a single endoscopic session in patients with early BE neoplasia. This was a retrospective analysis of patients with early BE neoplasia and a visible lesion undergoing combined endoscopic resection and focal RFA in a single session. Consecutive ablation procedures were performed every 8 to 12 weeks until complete endoscopic and histologic eradication of dysplasia and intestinal metaplasia were reached. Forty patients were enrolled, with a median C1M2 BE segment, a visible lesion with a median diameter of 15 mm, and invasive carcinoma in 68% of cases. Endoscopic resection was performed by using the multiband mucosectomy technique in 80% of cases, and the Barrx(90) catheter (Barrx Medical, Sunnyvale, Calif) was used for focal ablation. When an intention-to-treat analysis was used, both complete remission of all neoplasia and intestinal metaplasia were 95% after a median follow-up of 19 months. Stenoses occurred in 33% of cases and were successfully managed with a median number of 2 dilations. In 43% of patients, 1 single-session treatment resulted in complete histologic remission of intestinal metaplasia. Combining endoscopic resection and focal RFA in a single session appears to be effective. Less-aggressive RFA regimens could limit the adverse event rates.


Results of initial low-dose computed tomographic screening for lung cancer.
Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that have staff experienced in chest CT. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).


Effects of dopamine infusion on cerebral blood flow, brain cell membrane function and energy metabolism in experimental Escherichia coli meningitis in the newborn piglet.
In the present study, we tested whether maintenance of adequate cerebral perfusion pressure (CPP) by pharmacologically preventing systemic hypotension with dopamine infusion would prevent cerebral ischemia and attenuate energy depletion and neuronal injury even though intracranial pressure remains elevated in a newborn piglet meningitis model. Cerebral blood flow, measured at the end of the experiment using fluorescent microspheres, was significantly increased by dopamine infusion. The decreased cerebral cortical cell membrane Na+, K+ -ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain damage, were significantly attenuated by dopamine infusion. Dopamine also significantly attenuated the meningitis-induced reduction in both brain ATP and phosphocreatine levels and the increase in brain lactate level. In summary, maintenance of adequate CPP with dopamine prevented cerebral ischemia, reduced cerebral energy depletion, and attenuated brain injury in neonatal bacterial meningitis.


Relative power and sample size analysis on gene expression profiling data.
With the increasing number of expression profiling technologies, researchers today are confronted with choosing the technology that has sufficient power with minimal sample size, in order to reduce cost and time. These depend on data variability, partly determined by sample type, preparation and processing. Objective measures that help experimental design, given own pilot data, are thus fundamental. Relative power and sample size analysis were performed on two distinct data sets. The first set consisted of Affymetrix array data derived from a nutrigenomics experiment in which weak, intermediate and strong PPARalpha agonists were administered to wild-type and PPARalpha-null mice. Our analysis confirms the hierarchy of PPARalpha-activating compounds previously reported and the general idea that larger effect sizes positively contribute to the average power of the experiment. A simulation experiment was performed that mimicked the effect sizes seen in the first data set. The relative power was predicted but the estimates were slightly conservative. The second, more challenging, data set describes a microarray platform comparison study using hippocampal deltaC-doublecortin-like kinase transgenic mice that were compared to wild-type mice, which was combined with results from Solexa/Illumina deep sequencing runs. As expected, the choice of technology greatly influences the performance of the experiment. Solexa/Illumina deep sequencing has the highest overall power followed by the microarray platforms Agilent and Affymetrix. Interestingly, Solexa/Illumina deep sequencing displays comparable power across all intensity ranges, in contrast with microarray platforms that have decreased power in the low intensity range due to background noise. This means that deep sequencing technology is especially more powerful in detecting differences in the low intensity range, compared to microarray platforms. Power and sample size analysis based on pilot data give valuable information on the performance of the experiment and can thereby guide further decisions on experimental design. Solexa/Illumina deep sequencing is the technology of choice if interest lies in genes expressed in the low-intensity range. Researchers can get guidance on experimental design using our approach on their own pilot data implemented as a BioConductor package, SSPA http://bioconductor.org/packages/release/bioc/html/SSPA.html.


Sequential versus simultaneous graphesthesia tasks in 6- and 10-year-old children.
Reported in the statistics of the Southern California Graphesthesia Test are significant sex differences for certain young age groups, with females scoring higher than males. In contrast, another study has reported that adult males scored higher than females on the same test. The purpose of this study was to examine the interaction between sex and age and to investigate a possible explanation for this interaction. Sixty-four normal children between the ages of 6.0 and 7.0 years, and 10.0 and 11.0 years were administered two graphesthesia tasks. One task was an adaptation of the Graphesthesia Test of the Southern California Sensory Integration Test (SCSIT). In this task, shapes were drawn sequentially on the palmar surface of the child's hand. A second task was devised whereby each of the same shapes was presented in a simultaneous manner, that is, the entire outline of each shape was pressed onto the palmar surface of the child's hand. Results indicated that for both tasks, younger boys performed relatively less ably than girls, but older boys equalled or surpassed the girls. At a level approaching significance, females scored relatively higher than males on the sequential task, and males scored relatively higher than females on the simultaneous task. However, this tendency toward an interaction between sex and the type of task does not fully explain the interaction between sex and age on graphesthesia tasks.


A Dual Targeting Dendrimer-Mediated siRNA Delivery System for Effective Gene Silencing in Cancer Therapy.
Small interfering RNA (siRNA) is emerging as a novel therapeutic for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing an RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to deliver siRNA effectively, while the aim of the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing, and more potent anticancer activity compared to nontargeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further developed to provide RNAi-based personalized medicine against cancer. Our study also gives new perspectives on the use of nanotechnology based on self-assembling dendrimers in various biomedical applications.


Influence of resilient support of abutment teeth on fracture resistance of all-ceramic fixed partial dentures: an in vitro study.
The influence of resilient support of abutment teeth on the fracture resistance of all-ceramic three-unit fixed partial dentures (FPDs) was tested in this study. Three groups (n = 8) of glass-infiltrated, alumina-based, all-ceramic FPDs that were adhesively bonded to human molar teeth were investigated. In control group A, teeth that were rigidly inserted in polymethyl methacrylate (PMMA) resin were used for thermocycling and mechanical loading (TCML), as well as for fracture testing. In group B, TCML was conducted on teeth that had their roots covered with a polyether layer. After TCML, the polyether layer was removed entirely, and the teeth were rigidly fixed in PMMA for fracture testing. In group C, teeth roots remained covered with a polyether layer during TCML as well as during fracture testing. Using a resilient attachment, tooth mobility was determined in axial, buccal, and oral directions. Mean tooth mobility was 76 ± 4 Μm in the axial direction, 278 ± 41 Μm in the buccal direction, and 128 ± 17 Μm in the oral direction. Group C showed the lowest mean fracture strength (polyether during both TCML and fracture testing) of 523 N. For group B (polyether during TCML but not during fracture testing), a fracture strength of 676 N was found, and for control group A (rigidly embedded teeth), it was 919 N. These results confirmed the influence of resilient attachments on the aging process and fracture strength testing of FPDs. Fracture resistance was significantly reduced when this particular interface was used in both TCML and fracture testing.


A new lattice Monte Carlo simulation for dielectric saturation in ion-containing liquids.
We develop a new, rapid method for the lattice Monte Carlo simulation of ion-containing liquids that accounts for the effects of the reorganization of solvent dipoles under external electrostatic fields. Our results are in reasonable agreement with the analytical solutions to the dielectric continuum theory of Booth for single ions, ion pairs, and ionic cross-links. We also illustrate the substantial disparity between the dielectric functions for like and unlike charges on the nanometer scale. Our simulation rationalizes the experimental data for the dependence of the bulk dielectric value of water on ion concentrations in terms of saturated dipoles near ions.


Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.
The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.


APO A2 -265T/C Polymorphism Is Associated with Increased Inflammatory Responses in Patients with Type 2 Diabetes Mellitus.
Apolipoprotein A2 (APO A2) is the second most abundant structural apolipoprotein in high density lipoprotein. Several studies have examined the possible effect of APO A2 on atherosclerosis incidence. Due to the role of inflammation in atherosclerosis, we aimed to determine the relationship between APO A2 -265T/C polymorphism and inflammation as a risk factor in type 2 diabetes mellitus (T2DM) patients. In total, 180 T2DM patients, with known APO A2 -265T/C polymorphism, were recruited for this comparative study and were grouped equally based on their genotypes. Dietary intakes, anthropometric parameters, lipid profile, and inflammatory markers (i.e., pentraxin 3 [PTX3], high-sensitivity C-reactive protein [hs-CRP], and interleukin 18) were measured. The data were analyzed using an independent t-test, a chi-square test, and the analysis of covariance. After adjusting for confounding factors, in the entire study population and in the patients with or without obesity, the patients with the CC genotype showed higher hs-CRP (P=0.001, P=0.008, and P=0.01, respectively) and lower PTX3 (P=0.01, P=0.03, and P=0.04, respectively) in comparison with the T allele carriers. In the patients with the CC genotype, no significant differences were observed in the inflammatory markers between the obese or non-obese patients. However, regarding the T allele carriers, the plasma hs-CRP level was significantly higher in the obese patients compared to the non-obese patients (P=0.01). In the T2DM patients, the CC genotype could be considered as a risk factor and the T allele as a protective agent against inflammation, which the latter effect might be impaired by obesity. Our results confirmed the anti-atherogenic effect of APO A2, though more studies are required to establish this effect.