Assessment of image quality and scatter and leakage radiation of an integrated MR-LINAC system.
To assess the image quality, scatter, and leakage radiation of an integrated magnetic resonance linear accelerator (MR-LINAC or MRL) system. A large American College of Radiology (ACR) magnetic resonance imaging (MRI) accreditation phantom was used to evaluate the MRI capabilities of the integrated MRL system compared with those of other diagnostic MRI systems. Multiple sets of T1 and T2/PD images were acquired with the linear accelerator positioned at various angles and with the radiation beam on and off. Images also were acquired on three different occasions over a period of about 12 months. Scatter and leakage radiation were measured with a large (150 cm3 ) ion chamber recalibrated for MV energy. For scatter measurements, a 25-cm stack of solid-water materials was placed at the isocenter on the patient couch to simulate a patient. The head leakage was measured at 1 m from the linear accelerator head in directions determined to produce the maximum leakage. All measurements were repeated with the magnetic field turned off to study the effects of the magnetic field. The geometric distortion, slice thickness accuracy, image uniformity, ghosting ratio, and high-contrast detectability were comparable to other 1.5 T diagnostic MRI scanners. No observable changes in image quality and no appreciable differences were found between radiation beam-on and beam-off images. The measured leakage and scattered radiation changed by less than 5% when the magnetic field was on compared to measurements with the field off. The beam stopper leakage was approximately 0.3 R/1000 MU, and because there was no direct beam imparted on the walls, a vault designed for a modern-day LINAC should have enough required radiation shielding to house the MRL. The image quality generated by the MRI system of the integrated MRL was similar to that of a diagnostic MRI scanner. Interference from the MV radiation was minimal, and there was no measurable difference in image quality with the beam on and off. Scatter radiation and leakage radiation of the MRL system were within the expected range of a comparable MV-LINAC.


Hepatic Computed Tomography Volumetry for Noninvasive Detection of Hepatic Steatosis and Steatohepatitis in Living Liver Donors.
Detection of hepatic steatosis in donors is an important step for selection of a suitable liver allograft in living-donor transplant. This study aimed to investigate the role of hepatic computed tomography volumetry as a noninvasive method for detection of hepatic steatosis in living liver donors. In a cross-sectional study, individuals who had undergone liver biopsy as a pretransplant checkup before living-donor liver transplant were included. The segmental liver volumes were measured by computed tomography scan with intravenous contrast enhancement. Our study included 179 individuals. Mean total volume of the liver was 1705.2 ± 256.5 cm³ in those with steatohepatitis and 1419.4 ± 241.2 cm³ in those without steatohepatitis (P < .001). Higher total volume of the liver (odds ratio of 1.005; 95% confidence interval, 1.001-1.010; P = .012) and total liver volume-to-standard liver volume ratio (odds ratio of 1.090; 95% confidence interval, 1.021-1.163; P = .009) were independent predictors of steatohepatitis. A cutoff value of 1531 cm³ for total liver volume was a predictor of presence of steatohepatitis in liver biopsies of donors (sensitivity = 83%; specificity = 71%; area under the curve = 0.809; P < .001). Computed tomography volumetry may be considered as an auxiliary noninvasive method for estimation of hepatic steatosis/steatohepatitis and may be used as a guide to select donor candidates for liver biopsy.


Protocadherin alpha3 acts at sites distinct from classic cadherins in rat testis and sperm.
The testis expresses a variety of cadherin superfamily members including classic cadherins and protocadherins. This report describes the first localization of a protocadherin protein in testis and sperm. After cloning rat cDNAs for protocadherin alpha3 and alpha4, isoform-specific polyclonal antibodies were generated against protocadherin alpha3. Western blotting of rat testis showed that protocadherin alpha3 was solubilized completely by Triton X-100, in contrast to the adhesion junction components N-cadherin, beta-catenin, and p120 catenin. Corroborating this data, protocadherin alpha3 was immunolocalized to the spermatid acrosomal area, intercellular bridge, and flagellum, but not classic cadherin-based adhesion junctions. Acrosome-associated protocadherin alpha3 was first detected at step 8 of spermiogenesis, and this association remained on cauda epididymal sperm. Acrosome immunostaining was reduced, but present, in acrosome-reacted sperm. Spermatid intercellular bridges became positive for protocadherin alpha3 coincident with the appearance of plectin, occurring at spermiogenic steps 8 to 9, and elongate spermatid bridges remained positive throughout spermatogenesis. The developing flagellum was uniformly immunostained for protocadherin alpha3 up to approximately spermiogenic step 17. Subsequently, flagellar immunostaining was confined to the principal piece, and this pattern continued in cauda epididymal sperm. These data show that protocadherin alpha3 performs functions unique from classic cadherins in spermatogenesis and suggest a role for protocadherin alpha3 in organizing germ cell-specific structures including the intercellular bridge, flagellum, and acrosome.


[An experience promoting evidence-based nursing at a medical center in central Taiwan].
In the 21st Century, evidence-based nursing (EBN) may provide a mechanism by which nurses can manage the explosion in published information in the literature, introduce new techniques, effectively control healthcare costs, and increase attention on nursing quality and health outcomes. The objective of this paper is to share the experience implementing evidence-based nursing. We had applied strategies to implement evidence-based nursing care in our hospital since 2002. Over a more than three-year period (January 2002 to October 2005), we held 46 basic course sessions (around 1,840 attendees) and 58 advanced course sessions (around 500 attendees). There are 445 clinical questions with answered reports, Most questions related to foley care, central vein care and peripheral intravenous injection. Our nursing department revised three guidelines on nursing care skills related to suction and foley and nasal-gastric feeding to meet local conditions. Based on our subjective experience, promotion and implementation of EBN is feasible and helpful to update knowledge and decrease variance in clinical nursing care. However, further outcome research is needed in the future in order to obtain more objective evidence.


Effectiveness of Physical Therapy Interventions for Temporomandibular Disorders Associated with Tinnitus: A Systematic Review.
Temporomandibular disorders (TMDs) refers to different clinical conditions affecting the temporomandibular joints, masticatory muscles, and adjacent structures. Although TMDs signs and symptoms (e.g., pain and limited mouth opening) are common, otological symptoms, such as tinnitus, might also be present. This study aims to summarize the evidence of the effectiveness of physical therapy interventions in individuals with TMDs associated with tinnitus. Randomized controlled trials investigating the effectiveness of physical therapy in individuals of both genders aged 18 or older with TMDs associated with tinnitus were included. The electronic search was performed in the following databases: MEDLINE, EMBASE, CINAHL, PEDro and CENTRAL. A total of four studies were included. All studies showed that physical therapy reduced the intensity of tinnitus, and two trials showed a decrease in the pain intensity caused by TMDs, an increase in the pressure pain thresholds in the masticatory muscles and an improvement of mandibular function. Two studies presented a low risk of bias. Despite a low certainty of the evidence, this review showed that physical therapy reduces the intensity or severity of tinnitus associated with TMDs. Results may support future research on the topic and evidence-based practice by recommending the best physical therapy approach for patients, clinicians, researchers, and health system managers.


G-protein-coupled receptors in drug discovery: nanosizing using cell-free technologies and molecular biology approaches.
Signal transduction by G-protein-coupled receptors (GPCRs) underpins a multitude of physiological processes. Ligand recognition by the receptor leads to activation of a generic molecular switch involving heterotrimeric G-proteins and guanine nucleotides. Signal transduction has been studied extensively with both cell-based systems and assays comprising isolated signaling components. Interest and commercial investment in GPCRs in areas such as drug targets, orphan receptors, high throughput screening, biosensors, and so on will focus greater attention on assay development to allow for miniaturization, ultra-high throughput and, eventually, microarray/biochip assay formats. Although cell-based assays are adequate for many GPCRs, it is likely that these formats will limit the development of higher density GPCR assay platforms mandatory for other applications. Stable, robust, cell-free signaling assemblies comprising receptor and appropriate molecular switching components will form the basis of future GPCR assay platforms adaptable for such applications as microarrays. The authors review current cell-free GPCR assay technologies and molecular biological approaches for construction of novel, functional GPCR assays.


Human brain potential signs of selection by location and frequency in an auditory transient attention situation.
Event-related brain potentials (ERPs) were recorded in human subjects receiving tones. Each tone was preceded by a visual cue indicating a to-be-attended feature. In one part of the experiment, subjects had to attend to tones of the indicated frequency, whereas they had to attend to tones delivered at the designated ear in the other part. ERPs to attended tones showed enhanced frontal negativities as compared with ERPs to unattended tones. Additionally, in the location selection condition, a negative difference (Nd) between attended and unattended EPRs occurred between 100 and 200 ms at parietal areas. This parietal Nd seems to be characteristic for transient spatial attention.


her7 and hey1, but not lunatic fringe show dynamic expression during somitogenesis in medaka (Oryzias latipes).
Epithelialized somites form repeatedly from the unsegmented presomitic mesoderm (PSM) in the tailbud of vertebrate embryos. Mutant analysis has shown that the Delta-Notch pathway is essential for the temporal and spatial control of somite formation. Several components of this pathway show cyclic transcription, which is driven by a molecular oscillator. This oscillator is thought to act similarly in different vertebrates. In this study, we used the Japanese Medaka (Oryzias latipes) to examine the expression of three factors of the Delta-Notch cascade that are known to show cyclic expression in the PSM of higher vertebrates. We report that in contrast to the situation in mice, lunatic fringe (lfng) in medaka is expressed in a non-dynamic fashion in the rostral halves of the formed somites and the anteriormost PSM. On the other hand, her7, a member of the hairy/Enhancer-of-split related (Her) gene family, shows cyclic expression in the medaka PSM. Although this is similar in zebrafish, there are important differences in the distribution of transcripts in the PSM indicating different modes of regulation in both fish species. Finally, we show that hey1, another Delta-Notch regulated bHLH gene, is dynamically expressed in the PSM of medaka, similar to hey1 in zebrafish and the hey2 orthologs in mice and chicken. Interestingly, medaka hey1 is also expressed in the dorsal aorta and the heart, two tissues where hey2, but not hey1, is expressed in zebrafish. This shows that several components of the Delta-Notch pathway are differently regulated during somitogenesis in different species.


Antipodal alpha-N-(methyl through decyl)-N-normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans): in vitro and in vivo properties.
The enantiomeric (-)- and (+)-N-(methyl through decyl) normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans) were synthesized and their in vitro and in vivo activities determined. Increasingly bulky enantiomeric N-alkyl homologs were prepared until their interaction with the sigma 1 receptor decreased and their insolubility became a hindrance to their evaluation in vivo and/or in vitro. The (-)-methyl, -pentyl, -hexyl, and -heptyl homologs were essentially as potent as, or more potent than, morphine in the tail-flick, phenylquinone, and hot-plate assays for antinociceptive activity; the (-)-propyl homolog had narcotic antagonist activity between that of nalorphine and naloxone in the tail-flick vs morphine assay, and it also displayed antagonist properties in the single-dose suppression assay in the rhesus monkey. The antinociceptively potent (-)-heptyl homolog did not substitute for morphine in monkeys but did show morphine-like properties in a primary physical-dependence study in continuously infused rats. All five potent compounds showed high affinity for the mu opioid receptor from both rat and monkey preparations and the kappa opioid receptor (< 0.05 microM), and all except the (-)-methyl homolog interacted reasonably well at the delta receptor (K(i) < 0.1 microM). The (-)-propyl compound was equipotent (K(i) 1.5-2.0 nM) at mu and kappa receptors. The pattern of interaction of the (-)-enantiomeric homologs with mu receptors from rat and monkey preparations was similar, but not identical. The enantioselectivity of the homologs for mu receptors was greater in the rat than in the monkey preparation for all but the N-H and butyl compounds, and the enantioselectivity of the lower homologs (methyl through butyl) for the mu (monkey) receptor was greater than for the kappa or delta receptors. However, bulkier homologs (hexyl through decyl) displayed higher enantioselectivity at kappa or delta receptors than at the mu (monkey) receptor. The (+)-butyl through (+)-octyl homologs were essentially equipotent with, or more potent than, (+)-pentazocine at the sigma receptor. Only the (+)-H and (+)-methyl homologs had high affinity (< 0.05 microM) at PCP binding sites.


Genome-Wide SNP Analysis Reveals Distinct Origins of Trypanosoma evansi and Trypanosoma equiperdum.
Trypanosomes cause a variety of diseases in man and domestic animals in Africa, Latin America, and Asia. In the Trypanozoon subgenus, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause human African trypanosomiasis, whereas Trypanosoma brucei brucei, Trypanosoma evansi, and Trypanosoma equiperdum are responsible for nagana, surra, and dourine in domestic animals, respectively. The genetic relationships between T. evansi and T. equiperdum and other Trypanozoon species remain unclear because the majority of phylogenetic analyses has been based on only a few genes. In this study, we have conducted a phylogenetic analysis based on genome-wide SNP analysis comprising 56 genomes from the Trypanozoon subgenus. Our data reveal that T. equiperdum has emerged at least once in Eastern Africa and T. evansi at two independent occasions in Western Africa. The genomes within the T. equiperdum and T. evansi monophyletic clusters show extremely little variation, probably due to the clonal spread linked to the independence from tsetse flies for their transmission.


Prevention and management of venous thromboembolism in pregnancy.
Normal pregnancy is accompanied by an increase in clotting factors. The resulting hypercoagulable state has likely evolved to protect women from hemorrhage at the time of miscarriage and childbirth. During pregnancy, women are 4 times more likely to suffer from venous thromboembolism (VTE) compared with when they are not pregnant. Relative to pregnancy, the risk postpartum is even higher. The incidence of VTE is approximately 2 per 1,000 births, and VTE accounts for 1 death per 100,000 births, or approximately 10% of all maternal deaths. The most important risk factors during pregnancy are thrombophilia and a history of thrombosis. A history of thrombosis increases the risk for VTE to 2% to 12%. Thrombophilia increases not only the risk for maternal thrombosis but also the risk of poor pregnancy outcome. Despite the increased risk for thrombosis during pregnancy and the postpartum period, most women do not require anticoagulation. Those who do require anticoagulation include women with current VTE, women on lifelong anticoagulation, and many women with thrombophilia or a history of thrombosis. Recommended options for anticoagulation in pregnancy are limited to heparins, which do not cross the placenta. Low-molecular-weight heparin (LMWH) is preferred over unfractionated heparin because LMWH has a longer half-life and is presumed to have fewer side effects. The longer half-life is a disadvantage around the time of delivery, when unfractionated heparin, with its shorter half-life, is easier to manage. For women who develop or are at high risk for heparin-induced thrombocytopenia or severe cutaneous reactions, fondaparinux is probably the agent of choice. Women who do not require lifelong anticoagulation, but require anticoagulation during pregnancy, will still require anticoagulation for the first 6 weeks postpartum.


[Methods of eliminating putrefaction in TCM surgery].
Eliminating putrefaction is a characteristic therapy in TCM surgery. It is more inclusive, reliable and safer nowadays after development for thousands of years. From the 20(th) century, with the development of science and technology, personal injury resulting from heavy metals has drawn more and more attention. Many drugs with heavy metal ingredients such as arsenic, mercury and lead were forbidden in clinical practice. This therapy had played an important role in Chinese medical history and it should not be abandoned as refraining from treatment with a necessary method for fear of a slight risk. With a long history, various methods of eliminating putrefaction have been developed by doctors, especially doctors in Ming and Qing Dynasties. The thoughts and experience of those doctors are still well worth learning and researching.


Neurogenic Lower Urinary Tract Dysfunction in the First Year After Spinal Cord Injury: A Descriptive Study of Urodynamic Findings.
We aimed to provide a real-world description of neurogenic lower urinary tract dysfunction within the first year after spinal cord injury with a focus on unfavorable urodynamic parameters that are associated with urological morbidity. Urodynamic investigations from 97 patients with traumatic or ischemic acute spinal cord injury and managed according to the European Association of Urology Guidelines on Neuro-Urology were analyzed at a single university spinal cord injury center at 1 month, 3 months, 6 months, and 12 months after injury. Unfavorable urodynamic parameters were defined as detrusor overactivity in combination with detrusor sphincter dyssynergia, maximum storage detrusor pressure of 40 cm H2O or higher, bladder compliance less than 20 mL/cm H2O, and vesicoureteral reflux of any grade. One or more unfavorable urodynamic parameter was observed in 87 out of 97 patients (90%) within the first year after spinal cord injury. Eighty-eight percent of the patients showed detrusor overactivity with detrusor sphincter dyssynergia, 39% a maximum storage detrusor pressure of 40 cm H2O or higher, and 7% vesicoureteral reflux. No patient developed a low-compliance bladder. Using a standardized urodynamic follow-up schedule, we found unfavorable urodynamic parameters in a majority of the population within the first year after spinal cord injury. As early treatment based on urodynamic findings might reduce the risk of deterioration of upper and lower urinary tract function, thereby improving long-term outcomes, there is need for further research regarding recommendations for a urodynamic follow-up schedule during the first year after spinal cord injury.


Extraction of bioactive compounds against cardiovascular diseases from Lentinula edodes using a sequential extraction method.
Three extraction methods were sequentially combined to obtain fractions from Lentinula edodes (shiitake mushrooms) containing bioactive compounds against cardiovascular diseases (CVDs). Fruiting bodies were first extracted with plain water, obtained residue was then submitted to supercritical fluid extraction (SFE) and remaining residue submitted to hot water extraction. Sequential design allowed reutilization of the nonextracted material as raw material for the successive extractions increasing extraction yields and separating interesting compounds. Obtained fractions contained different amounts of ß-glucans, chitins, eritadenine, lenthionine, ergosterol, proteins/peptides and phenolic compounds conferring them different bioactivities. Water soluble fractions showed high antioxidant activities (ABTS+• and DPPH• scavenging capacity and reducing power), they were also able to inhibit one of the main enzymes involved in hypertension (angiotensin-I converting enzyme) and the key enzyme of cholesterol metabolism (3-hydroxy-3-methylglutaryl coenzyme A reductase). The latter inhibitory activity was also noticed in SFE extracts although ergosterol and other lipid-like molecules were isolated. Dietary fibers were separated in the third extraction. Therefore, with this sequential extraction procedure bioactive compounds against CVDs can be selectively separated from a single batch of shiitake powder. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:746-755, 2018.


Intellectual property-The Foundation of Innovation: A scientist's guide to intellectual property.
Increasingly, the activities of the practicing scientist inextricably intersect with the business world. Science is central to the development and delivery of many goods or services, and scientific discovery can directly, or indirectly, lead to substantial revenue generation. Scientists, however, have little training in the complex issues of intellectual property (IP), and often little understanding of their rights and obligations. Here, we define IP and disuss what it means to be an inventor or creator of IP. We define and differentiate between the primary forms of IP-trade secrets, copyright, trademarks, and patents-and discuss their implementation and implications for the practicing scientist.


Homonymous hemianopia caused by occipital lobe infarction in heparin-induced thrombocytopenia and thrombosis syndrome.
A 73-year-old woman developed mental confusion and finger pain after treatment with enoxaparin following arthroplasty. A platelet count was 163,000/microL. Because digital embolism was suspected, she was emergently treated with heparin and recombinant tissue plasminogen activator (rTPA). During rTPA infusion, she reported sudden hemifield loss, so the infusion was aborted. Brain CT disclosed a non-hemorrhagic occipital infarct. Platelets had fallen to 63,000 over eight days, and antibodies against a complex of heparin and platelet factor 4 were detected. These findings led to the diagnosis of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), an immune-mediated disorder in which venous and arterial thromboses occur. Right lower extremity deep venous thromboses were later diagnosed, and an MRI disclosed multiple cerebral infarcts of recent onset but different ages. Previous reports have documented brain arterial strokes in HITTS, mostly in the distribution of the middle cerebral artery, but clinical documentation is sparse, and there have been no imaging reports. This is the first report to document the clinical and imaging features of a HITTS stroke and the first to describe a stroke presumptively caused by a low molecular weight heparin. It emphasizes that HITTS may cause stroke even when the platelet count is normal. Diagnosis of HITTS should prompt immediate cessation of heparin treatment and substitution of a direct thrombin inhibitor or fondaparinux.


5Alpha-androstane-3beta,7alpha,17beta-triol and 5alpha-androstane-3beta,7beta,17beta-triol as substrates for the human 11beta-hydroxysteroid dehydrogenase type 1.
Several studies have shown that the native 7alpha-hydroxy-dehydroepiandrosterone (7alpha-hydroxy-DHEA) is a substrate for the human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which converts the 7alpha- into the 7beta-epimer through an oxido-reduction process. Research on the 11beta-HSD1 has investigated its function and structure through using native glucocorticoid substrates and known inhibitors. Other steroid substrates are also of interest. Among testosterone metabolites, 5alpha-androstane-3beta,17beta-diol (Adiol) is a substrate for the cytochrome P450 7B1 which produces 5alpha-androstane-3beta,7alpha,17beta-triol (7alpha-Adiol). This steroid may be a substrate for the 11beta-HSD1. We used recombinant yeast-expressed 11beta-HSD1 with NADP(H)-regenerating systems for examining the products obtained after incubation with 7alpha-Adiol, 7beta-Adiol or 7-oxo-Adiol. Oxidative conditions for the 11beta-HSD1 provided no trace of 7-oxo-Adiol but the inter-conversion of 7alpha- and 7beta-hydroxy-Adiol with V(max)/K(M) (pmol min(-1) microg(-1)/microM) values of 2 and 0.5, respectively. This state was maintained under reductive conditions. The use of a 7-oxo-Adiol substrate under reductive conditions led to the production of both 7alpha- and 7beta-hydroxy-Adiol with V(max)/K(M) values of 3.43 and 0.22, respectively. These findings support the hypothesis that the oxido-reductase and epimerase activities of 11beta-HSD1 depend on the positioning of the steroid substrates within the active site and may provide insight into its fine structure and mechanism of action.


Multimodal Image Integration for Epilepsy Presurgical Evaluation: A Clinical Workflow.
Multimodal image integration (MMII) is a promising tool to help delineate the epileptogenic zone (EZ) in patients with medically intractable focal epilepsies undergoing presurgical evaluation. We report here the detailed methodology of MMII and an overview of the utility of MMII at the Cleveland Clinic Epilepsy Center from 2014 to 2018, exemplified by illustrative cases. The image integration was performed using the Curry platform (Compumedics Neuroscan™, Charlotte, NC, USA), including all available diagnostic modalities such as Magnetic resonance imaging (MRI), Positron Emission Tomography (PET), single-photon emission computed tomography (SPECT) and Magnetoencephalography (MEG), with additional capability of trajectory planning for intracranial EEG (ICEEG), particularly stereo-EEG (SEEG), as well as surgical resection planning. In the 5-year time span, 467 patients underwent MMII; of them, 98 patients (21%) had a history of prior neurosurgery and recurring seizures. Of the 467 patients, 425 patients underwent ICEEG implantation with further CT co-registration to identify the electrode locations. A total of 351 patients eventually underwent surgery after MMII, including 197 patients (56%) with non-lesional MRI and 223 patients (64%) with extra-temporal lobe epilepsy. Among 269 patients with 1-year post-operative follow up, 134 patients (50%) had remained completely seizure-free. The most common histopathological finding is focal cortical dysplasia. Our study illustrates the usefulness of MMII to enhance SEEG electrode trajectory planning, assist non-invasive/invasive data interpretation, plan resection strategy, and re-evaluate surgical failures. Information presented by MMII is essential to the understanding of the anatomo-functional-electro-clinical correlations in individual cases, which leads to the ultimate success of presurgical evaluation of patients with medically intractable focal epilepsies.


Bilateral parotid swelling in a child--a case report.
Numerous causes for bilateral parotid swellings have been identified. It must be assumed that systemic factors play a key role, thereby the attainment of a definitive diagnosis requires a familiarity with full range of possible etiologies for these swellings. Differential diagnostic skills must be implemented to achieve a precise diagnosis. A case of bilateral parotid swelling in a child is presented and differential diagnosis is discussed.


[SOLAR URTICARIA].
Solar urticaria is a rare photodermatosis. It belongs to the group of physical urticarias. In this particular urticarial, erythema and whealing accompanied by pruritus occur seconds to minutes after exposure to light. The disease might have a severe impact on the patient's quality of life. A correct diagnosis is important in order to allow proper treatment, which is often challenging. A characteristic patient is described with a review of the epidemiology, clinical manifestations, etiology, diagnosis, treatment course and prognosis of this rare disease.


The effect of a disposable probe cover on pulse oximetry.
The re-use of pulse oximeter probes presents the possibility of between-patient contamination. Use of a disposable polyethylene cover may reduce this risk. In a controlled, prospective study we examined the effect of such a cover on the accuracy of pulse oximetry. Each of ten volunteer subjects was monitored simultaneously by two identical Nellcor pulse oximeters, one with a plastic cover and the other, without a cover, used as a control. The pulse oximetry (SpO2) reading for each probe was recorded while subjects breathed 21% O2 and again while they breathed 10% O2. The probe cover was then swapped onto the other probe and the recordings were repeated. Ninety-five per cent limits of agreement in SpO2 (mean difference in SpO2 (1.95 x standard deviation of difference) between covered and non-covered probes were -0.6% to 0.6% while breathing 21% oxygen and -2.0% to 2.9% while breathing 10% oxygen. We conclude that a protective plastic sheath may induce a small error in pulse oximetry reading that is most marked during hypoxaemia. This error is unlikely to be of clinical significance.


Microbial transformation of testosterone by Rhizopus stolonifer and Fusarium lini.
The microbial transformation of testosterone by the fungi Rhizopus stolonifer and Fusarium lini has been investigated for the first time. The bioconversion reactions observed from R. stolonifer included oxidation of a 17beta-hydroxyl group, a hydroxylation at equatorial 11alpha position, reduction of the double bond at C-4 with oxidation of the methylene at C-6 to the corresponding keto group, and lactonisation of ring D; the latter is the first report of this reaction by a Rhizopus species. Fusarium lini promoted 1-dehydrogenation of the steroid, which has been rarely observed in fungi cultures. The other routes of biotransformations included oxidation of the 17beta-hydroxyl group and the hydroxylation at 11alpha position. These reactions are not common for Fusarium species.


Use of colonoscopy in the management of patients with Crohn's disease: appropriateness and diagnostic yield.
Colonoscopy is a necessary tool in the management of Crohn's disease, but the benefit achieved by the procedure is a matter of debate. In the present study we evaluate the clinical impact of performing colonoscopy in Crohn's disease patients. Consecutive patients with Crohn's disease undergoing colonoscopy were considered. The following issues were considered: appropriateness of indications; relevant findings able to change the management of the patients; the endoscopist's management decisions based on patient's clinical picture, i.e. increased, maintained or decreased treatment, compared with those selected after performing endoscopy. 204 patients (116 male/88 female, mean age 41 years) were included. Colonoscopy was judged indicated in 52.9% cases, according to current guidelines. In 54% of patients, endoscopy revealed a significant lesion, and this rate was significantly lower for non-indicated procedures (25.9%, p<0.0001). The endoscopic findings were in disagreement with symptoms in about 25% of cases, but the impact of the endoscopic findings on the endoscopist's decision was likely to be very small without any differences between appropriate and inappropriate procedures. Endoscopy is a potent tool in the management of Crohn's disease, if correctly used, but in the majority of cases a correct therapeutic decision may be established simply on the basis of clinical picture and non-invasive markers, whilst relevant endoscopic findings have a relatively low impact on the medical treatment.


[The transition of the standards and the test-methods of cocain hydrochloride between JP I (1886) and JP XII (1991)].
In 1886, Japanese pharmacopoeia (JP.I) has been published as the 21st pharmacopoeia in the world, and now we have the twelfth revised Pharmacopoeia (JP.XII) published in 1991. During the period of about one century between JP.I and JP.XII, pharmaceutical science has shown remarkable progress in Japan as well as the U.S.A. and Europe. In this report, we have studied the transition of the standards and the test-methods of cocain hydrochloride between JP.I and JP.XII. The test-methods of cocain hydrochloride were gradually progressed. Since the World War II, JP.VI (1951) has been revised in wide range by adjusting into the U.S.A. XIV (1950) and then, many old tests have been eliminated and new tests have been regulated. For instance, optical-rotation test in JP.VI and assay in JP.VIII (1976) were good examples of how JP has been revised. Recently, many local-anaesthetic medicines have become very popular. So, the clinical market of cocain hydrochloride will not be so wide in the future in the Japanese medical field.


[The surveillance system of decubital lesions of the University Polyclinic in Udine: results of an incidence study].
A retrospective study of the incidence of pressure sores was one of the principal component of the ad hoc program of surveillance, prevention and treatment of pressure sores started in 1996 at University Hospital of Udine. Data were collected from the nursing records of patients defined at risk according to the Waterlow scale and admitted during 1998-99. Aims of the study were to quantify the number of patients who developed a pressure sore while in hospital and their risk level; stage of the lesions; to qualify the main risk factors and the management strategies adopted (i.e. mattresses, medications). Overall, 151 subjects (20.7% of those recruited) developed a pressure sore the greatest majority (96%) were classified as transient and reactive redness or superficial sore, while 14 patients (4%) developed a severe sore. For 50.4% of the lesions a regression to a lower risk level or healing were documented.


Implementation of planar proton minibeam radiation therapy using a pencil beam scanning system: A proof of concept study.
Proton minibeam radiation therapy (pMBRT) is an innovative approach that combines the advantages of minibeam radiation therapy with the more precise ballistics of protons to further reduce the side effects of radiation. One of the main challenges of this approach is the generation of very narrow proton pencil beams with an adequate dose-rate to treat patients within a reasonable treatment time (several minutes) in existing clinical facilities. The aim of this study was to demonstrate the feasibility of implementing pMBRT by combining the pencil beam scanning (PBS) technique with the use of multislit collimators. This proof of concept study of pMBRT with a clinical system is intended to guide upcoming biological experiments. Monte Carlo simulations (TOPAS v3.1.p2) were used to design a suitable multislit collimator to implement planar pMBRT for conventional pencil beam scanning settings. Dose distributions (depth-dose curves, lateral profiles, Peak-to-Valley Dose Ratio (PVDR) and dose-rates) for different proton beam energies were assessed by means of Monte Carlo simulations and experimental measurements in a water tank using commercial ionization chambers and a new p-type silicon diode, the IBA RAZOR. An analytical intensity-modulated dose calculation algorithm designed to optimize the weight of individual Bragg peaks composing the field was also developed and validated. Proton minibeams were then obtained using a brass multislit collimator with five slits measuring 2 cm × 400 μm in width with a center-to-center distance of 4 mm. The measured and calculated dose distributions (depth-dose curves and lateral profiles) showed a good agreement. Spread-out Bragg peaks (SOBP) and homogeneous dose distributions around the target were obtained by means of intensity modulation of Bragg peaks, while maintaining spatial fractionation at shallow depths. Mean dose-rates of 0.12 and 0.09 Gy/s were obtained for one iso-energy layer and a SOBP conditions in the presence of multislit collimator. This study demonstrates the feasibility of implementing pMBRT on a PBS system. It also confirms the reliability of RAZOR detector for pMBRT dosimetry. This newly developed experimental methodology will support the design of future preclinical research with pMBRT.


Temperature and nutrients as drivers of microbially mediated arsenic oxidation and removal from acid mine drainage.
Microbial oxidation of iron (Fe) and arsenic (As) followed by their co-precipitation leads to the natural attenuation of these elements in As-rich acid mine drainage (AMD). The parameters driving the activity and diversity of bacterial communities responsible for this mitigation remain poorly understood. We conducted batch experiments to investigate the effect of temperature (20 vs 35 °C) and nutrient supply on the rate of Fe and As oxidation and precipitation, the bacterial diversity (high-throughput sequencing of 16S rRNA gene), and the As oxidation potential (quantification of aioA gene) in AMD from the Carnoulès mine (France). In batch incubated at 20 °C, the dominance of iron-oxidizing bacteria related to Gallionella spp. was associated with almost complete iron oxidation (98%). However, negligible As oxidation led to the formation of As(III)-rich precipitates. Incubation at 35 °C and nutrient supply both stimulated As oxidation (71-75%), linked to a higher abundance of aioA gene and the dominance of As-oxidizing bacteria related to Thiomonas spp. As a consequence, As(V)-rich precipitates (70-98% of total As) were produced. Our results highlight strong links between indigenous bacterial community composition and iron and arsenic removal efficiency within AMD and provide new insights for the future development of a biological treatment of As-rich AMD.


Surgical Management of Multijoint Septic Arthritis due to Rat-Bite Fever in a Pediatric Patient: A Case Study.
In the United States, rat-bite fever is a rare systemic illness principally caused by Streptobacillus moniliformis, an organism found in the nasopharyngeal flora of rodents. Infection through direct exposure to rat excreta such as saliva, urine, or feces can lead to fever, rash, and an asymmetric migratory polyarthritis. As rodents are becoming more popular as pets, more pediatric cases are being documented. We report a pediatric case of delayed onset septic arthritis in the left wrist and right knee due to S. moniliformis from a rat bite. Previously reported pediatric case studies of suppurative arthritis due to S. moniliformis have only involved the hip. This case study demonstrates the importance of a thorough exposure history and consideration of zoonotic infections as a cause of septic arthritis in a pediatric patient that requires antibiotics and surgical intervention.


[Travel distance and the utilisation of out-of-hours services].
It has been documented from a number of out-of-hours primary health care services that the utilisation of the services declines with increasing travel distances. In this study we have investigated the correlation between travel distances and the use of out-of-hours medical services for all Norwegian municipalities that provide such services at a single permanent casualty clinic round the clock. In addition, we have sought to reveal any differences in consultation rates between municipalities that maintain single-municipality or inter-municipal out-of-hours services, as well as between municipalities in which the casualty clinics are co-located with a hospital or located separately. Information on the types of out-of-hours services existing in 2011 was retrieved from the Norwegian Emergency Primary Health Care Registry, and 315 municipalities with single permanent casualty clinic premises were included. Rates for various types of utilisation of these clinics were calculated on the basis of statistics generated from reimbursement claims. The number of medical consultations and house calls per inhabitant fell by 48 % and 55 % respectively when average travel distance increased from 0 to 50 kilometres. The use of telephone/letter contact was not significantly associated with distances. Single-municipality casualty clinics located outside hospitals had the highest consultation rate for out-of-hours medical services when adjusted for distance. This supports previous findings to the fact that distance is a crucial factor for the utilisation of out-of-hours medical services. Establishing inter-municipal casualty clinics and co-locating them with hospitals may contribute to a lower rate of use of out-of-hours medical services.


Lansoprazole versus omeprazole: influence on meal-stimulated gastric acid secretion.
To investigate, by means of meal-stimulated acid secretion, the extent to which differences in plasma half-life, bioavailability and the recommended therapeutic dose can influence the antisecretory potency of lansoprazole and omeprazole. In this double-blind, placebo-controlled, crossover study, 10 healthy male volunteers received 15 mg or 30 mg lansoprazole, 20 mg or 40 mg omeprazole or placebo for 5 days, in a randomized order. Meal-stimulated acid secretion was determined by means of a homogenized test meal and intragastric titration. On day 1, meal-stimulated acid secretion was decreased by 35% and 45% after administration of 15 mg or 30 mg lansoprazole, and by 16% and 42% after 20 mg or 40 mg omeprazole. After 3 and 5 days of dosing the decreases were 53% and 48% with 15 mg lansoprazole, 82% and 82% with 30 mg lansoprazole, 43% and 39% with 20 mg omeprazole, and 76% and 83% with 40 mg omeprazole. At all measuring points during the 5-day dosing periods, lansoprazole 15 mg and 30 mg proved superior to 20 mg omeprazole in inhibiting meal-stimulated gastric acid secretion, but the differences were only statistically significant for the lansoprazole 30 mg dose, 30 mg lansoprazole and 40 mg omeprazole proved equipotent. On day 1 only 30 mg lansoprazole was significantly better than placebo. This study demonstrated the following order of antisecretory potency: 30 mg lansoprazole = 40 mg omeprazole > 15 mg lansoprazole approximately 20 mg omeprazole.


Effects of VEGF inhibitors on human retinal pigment epithelium under high glucose and hypoxia.
Retinal pigment epithelium (RPE) is known to secrete factors important for retinal homeostasis. How this secretome changes in diabetic eyes treated with anti-vascular endothelial growth factor (VEGF) inhibitors is unclear. Diabetic conditions were simulated in vitro using ARPE-19 cell-line culture, with high glucose (25 mM) culture media, and hypoxia was chemically induced using cobalt chloride. Stress was assessed using cell viability assays as well as Western blots and enzyme-linked immunosorbent assay (ELISA) for production of HIF-1a and VEGF-A. Production of neurotrophic factors was quantified once conditions were established using ELISA under stress with and without the addition of VEGF inhibitors. Changes were analysed with one-way ANOVA. Hypoxia downregulated pigment epithelium-derived factor (PEDF) expression. The addition of bevacizumab, ranibizumab and aflibercept in normoxic conditions all led to a significant downregulation of PEDF. Glucose concentration had no effect on secretion of PEDF. Brain-derived neurotrophic factor (BDNF) secretion was downregulated in high glucose and was upregulated in hypoxia. Placental growth factor (PlGF) secretion by ARPE-19 was undetectable by ELISA. We found that hypoxia, high glucose or VEGF inhibitors affected secretion of neurotrophic factors. This variation under different conditions may influence neuron and photoreceptor survival in the diabetic state and VEGF inhibitor treated eyes.


Review on the Processing and Properties of Polymer Nanocomposites and Nanocoatings and Their Applications in the Packaging, Automotive and Solar Energy Fields.
For the last decades, nanocomposites materials have been widely studied in the scientific literature as they provide substantial properties enhancements, even at low nanoparticles content. Their performance depends on a number of parameters but the nanoparticles dispersion and distribution state remains the key challenge in order to obtain the full nanocomposites' potential in terms of, e.g., flame retardance, mechanical, barrier and thermal properties, etc., that would allow extending their use in the industry. While the amount of existing research and indeed review papers regarding the formulation of nanocomposites is already significant, after listing the most common applications, this review focuses more in-depth on the properties and materials of relevance in three target sectors: packaging, solar energy and automotive. In terms of advances in the processing of nanocomposites, this review discusses various enhancement technologies such as the use of ultrasounds for in-process nanoparticles dispersion. In the case of nanocoatings, it describes the different conventionally used processes as well as nanoparticles deposition by electro-hydrodynamic processing. All in all, this review gives the basics both in terms of composition and of processing aspects to reach optimal properties for using nanocomposites in the selected applications. As an outlook, up-to-date nanosafety issues are discussed.


The use of restriction fragment length polymorphism (RFLP) analysis for epidemiological studies of tuberculosis in developing countries.
DNA fingerprinting, of which restriction fragment length polymorphism (RFLP) typing is the most common method used, has permitted novel investigations of the epidemiology and pathogenesis of tuberculosis. The use of IS6110, an insertion sequence which is present in Mycobacterium tuberculosis, is generally considered to be the standard RFLP method, but other molecular typing techniques may be used as adjuncts in selected circumstances. A number of epidemiologic studies using RFLP typing have been done in both industrialized and developing countries. The major findings include the confirmation or identification of chains of transmission (of both drug-sensitive and drug-resistant strains of tuberculosis), distribution of strain clusters within populations, differentiation of relapse from exogenous reinfection, better understanding of the pathogenesis of tuberculosis, identification of laboratory cross-contamination, and insight into the molecular evolution of the species. For developing countries, where the burden of tuberculosis is greatest, three major areas of investigation for the use of RFLP analysis in epidemiologic studies of tuberculosis have been identified: 1) community transmission, 2) nosocomial transmission, and 3) human immunodeficiency virus (HIV)-related tuberculosis. Elements of protocols are suggested which can be used by investigators to perform well-designed epidemiologic studies which will be relevant to developing countries and which are likely to have an impact on control programmes in these settings.


The appearance of isometamidium resistant Trypanosoma congolense in West Africa.
The frequent reappearance of patent parasitemia, mainly Trypanosoma congolense, in cattle maintained under isometamidium prophylaxis in the Upper Volta indicated that drug-resistant forms might be appearing. To investigate this possibility, trypanosome stocks were isolated in mice, their isometamidium sensitivity estimated and compared to that of stocks isolated before drug use was widespread. Most T. congolense stocks isolated in 1982-1983 were 4-8 times less sensitive to isometamidium than those isolated in 1979-1980.


The Role of Aplnr Signaling in the Developmental Regulation of Mesenchymal Stem Cell Differentiation from Human Pluripotent Stem Cells.
Stem cells are invaluable resources for personalized medicine. Mesenchymal stem cells (MSCs) have received great attention as therapeutic tools due to being a safe, ethical, and accessible option with immunomodulatory and controlled differentiation properties. Apelin receptor (Aplnr) signaling is reported to be involved in biological events, including gastrulation, mesoderm migration, proliferation of MSCs. However, the knowledge about the exact role and mechanism of Aplnr signaling during mesoderm and MSCs differentiation is still primitive. The current study aims to unveil the role of Aplnr signaling during mesoderm and MSC differentiation from pluripotent stem cells (PSCs) through peptide/small molecule activation, overexpression, knock down or CRISPR/Cas9 mediated knock out of the pathway components. Morphological changes, gene and protein expression analysis, including antibody array, LC/MS, mRNA/miRNA sequencing, reveal that Aplnr signaling promotes mesoderm commitment possibly via EGFR and TGF-beta signaling pathways and enhances migration of cells during mesoderm differentiation. Moreover, Aplnr signaling positively regulates MSCs differentiation from hPSCs and increases MSC characteristics and differentiation capacity by regulating pathways, such as EGFR, TGFβ, Wnt, PDGF, and FGF. Osteogenic, chondrogenic, adipogenic, and myogenic differentiations are significantly enhanced with Aplnr signaling activity. This study generates an important foundation to generate high potential MSCs from PSCs to be used in personalized cell therapy.


INTRACELLULAR ANTIOXIDANT ACTIVITY OF A STREPTOMYCES SP. 8812 SECONDARY METABOLITE, 6,7-DIHYDROXY-3,4-DIHYDROISOQINO- LINE-3-CARBOXYLIC ACID, AND ITS SYNTHETIC DERIVATIVES.
The aim of this study was to determine the antioxidant properties of 6,7-dihydroxy-3,4-dihydroiso- quinoline-3-carboxylic acid (1) and its derivatives in living cells against reactive forms of oxygen and nitrogen, i.e., hydrogen peroxide and nitric oxide. Four of tested compounds scavenged the reactive form of nitrogen more efficiently or similarly to Trolox (EC50 = 55.80 µM). Two compounds exhibited antioxidant activity against reactive oxygen species better than Trolox (EC50 = 51.88 µM). The most active derivative of 1 was the compound containing an iodine atom at position 8 (6,7-dihydroxy-8-iodo-3,4-dihydroisoquinoline-3-carboxylic acid). Our studies showed that some of the derivatives had the ability to cross the cell membrane and scavenge free radicals inside living cells. Thus, they are able to protect DNA and other cellular structures from the dam- aging effects of reactive oxygen and nitrogen species. In addition, some molecular descriptors of the tested compounds were determined with the use of ICM Pro (Molsoft L.L.C.).


Mathematical modeling of living cell metabolism using the method of steady-state stoichiometric flux balance.
This approach uses a set of algebraic linear equations for reaction rates (the method of steady-state stoichiometric flux balance) to model the purposeful metabolism of the living self-reproducing biochemical system (i.e. cell), which persists in steady-state growth. Linear programming (SIMPLEX method) is used to derive the solution for the model equations set (determining reaction rates which provide flux balance at given conditions). Here, we demonstrate the approach through the mathematical modeling of steady-state metabolism in Saccharomyces cerevisiae mitochondria.


Exposure assessment to road traffic noise levels and health effects in an arid urban area.
Road traffic noise exposures have been recognized as serious environmental health concerns, especially in most developing countries with arid climate conditions, rapid increase in vehicle population, and limited traffic management systems. The excessive noise exposure level is associated with increase in the incidence of cardiovascular diseases and anxiety, including annoyance. This study aimed at determining traffic noise levels in residential areas, including the assessment of its annoyance and health effects based on the people's perception and reportage. To do so, field measurement and traffic noise modeling were carried out in six road points to estimate the current noise levels along various roads close to human inhabitants in Muscat Governorate, Sultanate of Oman. The detailed measured noise levels in urban residential areas across the selected roads showed that noise levels have exceeded the local and international threshold limits at all locations during the entire day. The high sound levels (48.0-56.3 dBA) were observed using the US Federal Highway Administration's Traffic Noise Model (TNM, version 2.5) results, which were in agreement with the observed (56.3-60.4 dBA) data. To assess health implication to residents through interviews (n = 208), annoyance at home was found to be little (32%), moderate (28%), and high (9%) in comparison with workplace settings of 42%, 43%, and 15%, respectively. Nineteen percent of the interviewees had difficulties in sleeping, while 19.8% experienced stress due to road traffic noise exposures. Moreover, a strong association (p < 0.05) was established between the use and objection of noise barriers. The study revealed high noise levels and the prevalence of annoyance and health effects among the exposed population. Therefore, immediate action is required to tackle the current noise levels.


Power of 1 Malaysian Ringgit: A Low-Cost Prescription Cost-Sharing Model in Malaysia.
To calculate the total revenue under a hypothetical 1 Malaysian Ringgit (MYR) prescription cost sharing model in government healthcare facilities in Pahang, Malaysia. A cross-sectional study was conducted at outpatient pharmacy in all government healthcare facilities in Pahang from year 2013 to 2017. Each dispensed medication was calculated as 1 MYR and contributed to the total revenue. A total of 11 hospitals and 81 health clinics were recruited into the study. A hospital could generate 0.311 million MYR per year, and a district health department could generate 0.623 million MYR per year, giving a total of 10.268 million MYR revenue every year in Pahang, Malaysia. Under the prescription medicines cost sharing scheme, it was shown that an average of 9.4% of the total pharmaceutical spending could be recovered. The recovery percentage was approximately fourfold higher in health clinics (16.5%-21.7%) when compared with that in hospitals (4.3%-5.2%). An estimated 10 million MYR or 10% from the total Ministry of Health pharmaceutical spending could be collected under the proposed 1 MYR prescription cost sharing model.


Purification, crystallization and X-ray analysis of swine vesicular disease virus.
Swine vesicular disease virus (SVDV) is the etiological agent of swine vesicular disease, a highly contagious disease in pigs, and is related to coxsackie B virus. Crystalline arrays of SVDV can be observed in the cytoplasm of cells 4.5 h after inoculation to porcine kidney cells (IBRS-2 cells). Crystals of the JX/78 strain of SVDV were obtained from virus in two wells of crystallization conditions and present preliminary X-ray data to 3.6 A resolution.


Plant performance was greater in the soils of more distantly related plants for an herbaceous understory species.
Growing evidence suggests that plant-soil interactions have important implications for plant community composition. However, the role of phylogenetic relatedness in governing interactions between plants and soil biota is unclear, and more case studies are needed to help build a general picture of whether and how phylogeny might influence plant-soil interactions. We performed a glasshouse experiment to test whether degree of phylogenetic relatedness between Aquilegia canadensis and six co-occurring heterospecifics affects A. canadensis biomass through soil legacy effects. We also compared performance of A. canadensis in soils conditioned by invasive Alliaria petiolata versus native heterospecifics, hypothesizing that conditioning by A. petiolata would suppress the performance of the focal native plant. A. canadensis performed significantly better in distant relatives' soils than in close relatives' soils, and this effect disappeared with soil sterilization, consistent with close relatives sharing similar pathogens. Contrary to our expectations, soils conditioned by the invasive species A. petiolata versus by native species had similar effects on A. canadensis. The greater performance of A. canadensis in soils of more versus less distant relatives is consistent with a hypothesis of phylogenetically constrained pathogen escape, a phenomenon expected to promote coexistence of phylogenetically distant species. However, pairwise plant-soil feedback experiments are needed to create a stronger coexistence prediction.


Comparison of fit and trueness of zirconia crowns fabricated by different combinations of open CAD-CAM systems.
This study aims to clinically compare the fitness and trueness of zirconia crowns fabricated by different combinations of open CAD-CAM systems. Total of 40 patients were enrolled in this study, and 9 different zirconia crowns were prepared per patient. Each crown was made through the cross-application of 3 different design software (EZIS VR, 3Shape Dental System, Exocad) with 3 different processing devices (Aegis HM, Trione Z, Motion 2). The marginal gap, absolute marginal discrepancy, internal gap(axial, line angle, occlusal) by a silicone replica technique were measured to compare the fit of the crown. The scanned inner and outer surfaces of the crowns were compared to CAD data using 3D metrology software to evaluate trueness. There were significant differences in the marginal gap, absolute marginal discrepancy, axial and line angle internal gap among the groups (P < .05) in the comparison of fit. There was no statistically significant difference among the groups in terms of occlusal internal gap. The trueness ranged from 36.19 to 43.78 µm but there was no statistically significant difference within the groups (P > .05). All 9 groups showed clinically acceptable level of marginal gaps ranging from 74.26 to 112.20 µm in terms of fit comparison. In the comparison of trueness, no significant difference within each group was spotted. Within the limitation of this study, open CAD-CAM systems used in this study can be assembled properly to fabricate zirconia crown.


High-order exceptional point based optical sensor.
Exceptional points (EPs) could potentially enhance the sensitivity of an optical sensing system by orders of magnitude. Higher-order EP systems, having more complex physics, can further boost this parameter. In this paper, we investigate the response order of high-order non-Hermitian systems and provide a guideline for designing a sensor with high response order. Based on this design rule, we propose and demonstrate an optical sensor with a fourth-order response, and analyze its associated properties. The four resonant wavelengths of our optical sensor simultaneously collapse at a high-order exceptional point in the parameter space, providing a fourth root relation between the amount of wavelength splitting and the amplitude of the perturbation. A large sensitivity enhancement factor over 100, is observed when the wavelength splitting is compared with traditional single resonator-based sensors under small perturbation conditions.


Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling.
Thymidine kinase 1 (TK1) is a key enzyme involved in the synthesis of DNA precursors and thus, cell proliferation-dependent. Antibodies against TK1 have provided attractive tools for cancer diagnosis. Expression of TK1 in 158 non-small cell lung cancer (NSCLC) patients with 59 adenocarcinoma (AC) and 99 squamous cell carcinoma (SCC) was determined by anti-TK1 monoclonal antibody (mAb) 1E3 (AC, n=50; SCC, n=70). Parallel tumor sections were stained for Ki-67 (MIB-1), and TK1 expression was also investigated with anti-TK1 chicken IgY Ab (AC, n=9; SCC, n=29; normal lung tissues, n=10). In one AC and one SCC patient, gene profiling was done by cDNA array. Using the mAb 1E3, a significantly higher TK1 labeling index (LI) of AC patients was found (68%) compared to the LI of Ki-67 (36%). This difference was due to a significantly higher TK1 LI of tumor stage II and grade 2. Although no difference in the LI of TK1 and Ki-67 of SCC patients was found (54 vs. 53%), significantly higher TK1 LI of SCC patients of tumor grade 1 was found. Using the anti-TK1 IgY Ab, a higher TK1 LI of AC patients (78%) and SCC patients (66%) was found compared to staining with mAb 1E3 (68 vs. 54%), but it was not significantly different. Samples stained only for TK1 represented mostly tumor stages I and II and grades 1 and 2 of both AC and SCC. AC patients whose samples stained only for Ki-67 were found to be in stage I and grade 1. cDNA profiling showed that the expression of BRCA1, cyclin B1 and cdc2p34 was higher in AC compared to SCC, while the expression of IGFBP-3 and EGFR was higher in SCC. TK1 is apparently a more reliable marker in AC patients than Ki-67. However, a combination of the two markers may help identify patients of different stages and grades more efficiently, and cyclin/kinase complexes and growth factors/receptors may be useful markers in distinguishing AC from SCC.


A respiratory syncytial virus (RSV) anti-G protein F(ab')2 monoclonal antibody suppresses mucous production and breathing effort in RSV rA2-line19F-infected BALB/c mice.
Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Increased airway resistance and increased airway mucin production are two manifestations of RSV infection in children. RSV rA2-line19F infection induces pulmonary mucous production and increased breathing effort in BALB/c mice and provides a way to assess these manifestations of RSV disease in an animal model. In the present study, we investigated the effect of prophylactic treatment with the F(ab')2 form of the anti-G protein monoclonal antibody (MAb) 131-2G on disease in RSV rA2-line19F-challenged mice. F(ab')2 131-2G does not affect virus replication. It and the intact form that does decrease virus replication prevented increased breathing effort and airway mucin production, as well as weight loss, pulmonary inflammatory-cell infiltration, and the pulmonary substance P and pulmonary Th2 cytokine levels that occur in mice challenged with this virus. These data suggest that the RSV G protein contributes to prominent manifestations of RSV disease and that MAb 131-2G can prevent these manifestations of RSV disease without inhibiting virus infection.


Induction of peripheral blood lymphocyte transformation by autologous synovial fluid lymphocytes and synovial fluid.
Synovial fluid lymphocytes and synovial fluid from most patients with rheumatoid arthritis induced blastogenesis of autologous peripheral blood lymphocytes. In vitro transfer of the mitogenic activity of the synovial fluid to peripheral blood lymphocytes was not accomplished, but diminished response of the peripheral blood lymphocytes to phytohemagglutinin stimulation after incubation in synovial fluid was demonstrated. These findings suggest that a similar blastogenic response in vivo may induce the lymphoid hyperplasia regularly observed in rheumatoid arthritis.


Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and tumor promotion by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) in mouse skin.
N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) inhibited epidermal ornithine decarboxylase (ODC) induction caused either by 12-O-tetradecanoylphorbol-13-acetate (TPA) or teleocidin in CD-1 mice. Inhibitory effect of W-7 on TPA-caused ODC induction was also observed in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated skin and even after repetitive TPA treatment. TPA-induced skin tumor promotion was also suppressed by W-7. Meanwhile, W-7 showed only slight inhibitory effects on calcium-activated, phospholipid-dependent protein kinase (protein kinase C) activity of mouse epidermis stimulated either by Ca2+ or TPA in the presence of phosphatidylserine. Thus, it is unlikely that the anti-ODC-inducing and anti-tumor-promoting actions of W-7 are due to its inhibitory effect on protein kinase C. It may be possible that a calmodulin-mediating process is involved in the mechanism of epidermal ODC induction and tumor promotion caused by tumor promoters such as TPA and teleocidin.


Dexamethasone inhibits pancreatic tumor growth in preclinical models: Involvement of activating glucocorticoid receptor.
Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Prioritization and Refinement of Clinical Data Elements within EHR Systems.
Standardization of clinical data element (CDE) definitions is foundational to track, interpret, and analyze patient states, populations, and costs across providers, settings and time - critical activities to achieve the Triple Aim: improving the experience of care, improving the health of populations, and reducing per capita healthcare costs. We defined and implemented two analytical methods to prioritize and refine CDE definitions within electronic health records (EHRs), taking into account resource restrictions to carry out the analysis and configuration changes: 1) analysis of downstream data needs to identify high priority clinical topics, and 2) gap analysis of EHR CDEs when compared to reference models for the same clinical topics. We present use cases for six clinical topics. Pain Assessment and Skin Alteration Assessment were topics with the highest regulatory and non-regulatory downstream data needs and with significant gaps across documention artifacts in our system, confirming that these topics should be refined first.


Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex.
We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.


Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.
Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.


Tumor-infiltrating CCR2+ inflammatory monocytes counteract specific immunotherapy.
Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA2). In our present work, we revealed the therapeutic effect of DIVA2 in an MC38 tumor model and specifically focused on the mechanisms induced in the TME after immunization. DIVA2 resulted in transient tumor control followed by an immune evasion phase within three weeks after the initial tumor inoculation. High-dimensional flow cytometry analysis and single-cell mRNA-sequencing of tumor-infiltrating leukocytes revealed cytotoxic CD8+ T cells as key players in the immune control phase. In the immune evasion phase, inflammatory CCR2+ PDL-1+ monocytes with immunosuppressive properties were recruited into the tumor leading to suppression of DIVA2-induced tumor-reactive T cells. Depletion of CCR2+ cells with specific antibodies resulted in prolonged survival revealing CCR2+ monocytes as important for tumor immune escape in the TME. In summary, the present work provides a platform for generating a strong antigen-specific primary and memory T cell immune response using the optimized transcutaneous immunization method DIVA2. This enables protection against tumors by therapeutic immune control of solid tumors and highlights the immunosuppressive influence of tumor infiltrating CCR2+ monocytes that need to be inactivated in addition for successful cancer immunotherapy.


Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures.
Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.


Toward understanding insulin fibrillation.
Formation of insulin fibrils is a physical process by which partially unfolded insulin molecules interact with each other to form linear aggregates. Shielding of hydrophobic domains is the main driving force for this process, but formation of intermolecular beta-sheet may further stabilize the fibrillar structure. Conformational displacement of the B-chain C-terminal with exposure of nonpolar, aliphatic core residues, including A2, A3, B11, and B15, plays a crucial role in the fibrillation process. Recent crystal analyses and molecular modeling studies have suggested that when insulin fibrillates this exposed domain interacts with a hydrophobic surface domain formed by the aliphatic residues A13, B6, B14, B17, and B18, normally buried when three insulin dimers form a hexamer. In rabbit immunization experiments, insulin fibrils did not elicit an increased immune response with respect to formation of IgG insulin antibodies when compared with native insulin. In contrast, the IgE response increased with increasing content of insulin in fibrillar form. Strategies and practical approaches to prevent insulin from forming fibrils are reviewed. Stabilization of the insulin hexameric structure and blockage of hydrophobic interfaces by addition of surfactants are the most effective means of counteracting insulin fibrillation.


"History, Theory and Ethics of Medicine": The Last Ten Years. A Survey of Course Content, Methods and Structural Preconditions at Twenty-nine German Medical Faculties.
Objective: "History, Theory, Ethics of Medicine" (German: "Geschichte, Theorie, Ethik der Medizin", abbreviation: GTE) forms part of the obligatory curriculum for medical students in Germany since the winter semester 2003/2004. This paper presents the results of a national survey on the contents, methods and framework of GTE teaching. Methods: Semi-structured questionnaire dispatched in July 2014 to 38 institutions responsible for GTE teaching. Descriptive analysis of quantitative data and content analysis of free-text answers. Results: It was possible to collect data from 29 institutes responsible for GTE teaching (response: 76%). There is at least one professorial chair for GTE in 19 faculties; two professorial chairs or professorships remained vacant at the time of the survey. The number of students taught per academic year ranges from <100 to >350. Teaching in GTE comprises an average of 2.18 hours per week per semester (min: 1, max: 6). Teaching in GTE is proportionally distributed according to an arithmetic average as follows: history: 35.4%, theory 14.7% and ethics 49.9%. Written learning objectives were formulated for GTE in 24 faculties. The preferred themes of teaching in history, theory or ethics which according to respondents should be taught comprise a broad spectrum and vary. Teaching in ethics (79 from a max. of 81 possible points) is, when compared to history (61/81) and theory (53/81), attributed the most significance for the training of medical doctors. Conclusion: 10 years after the introduction of GTE the number of students and the personnel resources available at the institutions vary considerably. In light of the differences regarding the content elicited in this study the pros and cons of heterogeneity in GTE should be discussed.


Morning chronotype is a protective factor against chemotherapy-induced hot flashes in premenopausal women with breast cancer.
Adjuvant chemotherapy in patients with breast cancer often causes hot flashes, impairing quality of life. However, the chronobiological or psychiatric factors associated with the development of chemotherapy-induced hot flashes (CIHFs) remain undetermined. The purpose of this study was to investigate whether chronotype was associated with the incidence of CIHFs. A total of 119 premenopausal women with non-metastatic breast cancer awaiting adjuvant chemotherapy after surgery without hot flashes were included. The presence of CIHF was defined as having moderate to severe hot flashes, as measured by the subscale of hot flashes in the Menopause Rating Scale, at 4 weeks after the completion of chemotherapy. Chronotype (Morning/Intermediate/Evening) was assessed with the Composite Scale of Morningness before adjuvant chemotherapy. To examine the association between chronotype and CIHF, we built logistic regression models, adjusting for age, body mass index, sleep quality, and radiation therapy. CIHF occurred in 50.4% of participants. Morning type was inversely associated with CIHF (reference: Intermediate type, odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16-0.94; p = 0.040) in the univariate model, and the association remained significant (OR, 0.37; CI, 0.13-0.96; p = 0.045) after adjusting for age, body mass index, sleep quality, and radiation therapy. Morning chronotype is a protective factor against the development of CIHF in patients with breast cancer. Chronotypes should be assessed and considered in the prediction and management of CIHF.


Molecular characterization of the recombination region of six murine major histocompatibility complex (MHC) I-region recombinants.
Using Southern DNA hybridization techniques, restriction enzyme site polymorphisms have been used to correlate the molecular maps of the murine major histocompatibility complex (MHC) I region with the genetic map derived from analyses of recombinant mouse strains. The data indicated that the DNA that maps between the I-A and I-E subregions is limited to 3.4 kilobases (kb) and includes the 3' end of the E beta gene. According to classical genetic mapping by recombinational analysis of serological markers, this region should encode the I-B and I-J subregions. These observations are surprising in two respects. First, 3.4 kb is a small amount of DNA to encode even one complete murine gene. Second, this region, which putatively encodes the I-J gene, appears to reside at least partially within the E beta gene. To analyze these apparent paradoxes, further, we cloned the 3.4-kb region in question from six I-region combinant strains [B10.A(3R), B10.a(5R), B10.A(4R), B10.GD, B10.HTT, and B10.S(9R)] and four strains used in the derivation of the recombinants (B10.D2, B10.A, C57BL/10, and ASW) into a lambda phage vector. By direct restriction enzyme mapping of polymorphic sites, we have confirmed the previously identified boundaries of the I-A and I-E subregions and have narrowed the estimate of the distance between these subregions to approximately 2.0 kb of DNA. This 2.0-kb region encompasses part of the intron between the first- (beta 1) and second-domain (beta 2) exons and the second-domain exon (beta 2) of the E beta gene.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of naturally occurring human immune complexes on monocyte movement in vitro.
The influence of naturally occurring immune complexes (IC) on monocyte motility has been investigated. Both chemokinesis and chemotaxis have been measured, using modified Boyden chambers, in response to sera containing IC and to the same sera depleted of IC with 2% polyethylene glycol. Chemokinetic activity was markedly increased in the presence of IC-containing sera, and this increased activity was largely abolished, following IC depletion. The chemotactic activity of the IC-containing sera was largely independent of the IC content, since IC depletion only resulted in a modest decrease in stimulated movement. The chemotactic response to a standard chemoattractant (zymosan-treated sera) was significantly increased with the cells in the presence of IC-containing sera, and this effect was abolished following IC depletion. There was no relationship between the total IC concentration and changes in monocyte movement. These results indicate that circulating IC may markedly alter monocyte locomotion in such a way that more cells may be attracted more rapidly to an inflammatory focus.


Detachable fiber optic tips for use in thulium fiber laser lithotripsy.
The thulium fiber laser (TFL) has recently been proposed as an alternative to the Holmium:YAG (Ho:YAG) laser for lithotripsy. The TFL's Gaussian spatial beam profile provides higher power transmission through smaller optical fibers with reduced proximal fiber tip damage, and improved saline irrigation and flexibility through the ureteroscope. However, distal fiber tip damage may still occur during stone fragmentation, resulting in disposal of the entire fiber after the procedure. A novel design for a short, detachable, distal fiber tip that can fit into an ureteroscope's working channel is proposed. A prototype, twist-lock, spring-loaded mechanism was constructed using micromachining methods, mating a 150-μm-core trunk fiber to 300-μm-core fiber tip. Optical transmission measuring 80% was observed using a 30-mJ pulse energy and 500-μs pulse duration. Ex vivo human calcium oxalate monohydrate urinary stones were vaporized at an average rate of 187 μg/s using 20-Hz modulated, 50% duty cycle 5 pulse packets. The highest stone ablation rates corresponded to the highest fiber tip degradation, thus providing motivation for use of detachable and disposable distal fiber tips during lithotripsy. The 1-mm outer-diameter prototype also functioned comparable to previously tested tapered fiber tips.


The Roles of Dietary, Nutritional and Lifestyle Interventions in Adipose Tissue Adaptation and Obesity.
The obesity and the associated non-communicable diseases (NCDs) are globally increasing in their prevalence. While the modern-day lifestyle required less ventilation of metabolic energy through muscular activities, this lifestyle transition also provided the unlimited accession to foods around the clock, which prolong the daily eating period of foods that contained high calorie and high glycemic load. These situations promote the high continuous flux of carbon substrate availability in mitochondria and induce the indecisive bioenergetic switches. The disrupted bioenergetic milieu increases the uncoupling respiration due to the excess flow of the substrate-derived reducing equivalents and reduces ubiquinones into the respiratory chain. The diversion of the uncoupling proton gradient through adipocyte thermogenesis will then alleviate the damaging effects of free radicals to mitochondria and other organelles. The adaptive induction of white adipose tissues (WAT) to beige adipose tissues (beAT) has shown beneficial effects on glucose oxidation, ROS protection and mitochondrial function preservation through the uncoupling protein 1 (UCP1)-independent thermogenesis of beAT. However, the maladaptive stage can eventually initiate with the persistent unhealthy lifestyles. Under this metabolic gridlock, the low oxygen and pro-inflammatory environments promote the adipose breakdown with sequential metabolic dysregulation, including insulin resistance, systemic inflammation and clinical NCDs progression. It is unlikely that a single intervention can reverse all these complex interactions. A comprehensive protocol that includes dietary, nutritional and all modifiable lifestyle interventions, can be the preferable choice to decelerate, stop, or reverse the NCDs pathophysiologic processes.


Real-time finite element modeling for surgery simulation: an application to virtual suturing.
Real-time finite element (FE) analysis can be used to represent complex deformable geometries in virtual environments. The need for accurate surgical simulation has spurred the development of many of the new real-time FE methodologies that enable haptic support and real-time deformation. These techniques are computationally intensive and it has proved to be a challenge to achieve the high modeling resolutions required to accurately represent complex anatomies. The authors present a new real-time methodology based on linear FE analysis that is appropriate for a wide range of surgical simulation applications. A methodology is proposed that is characterized by high model resolution, low preprocessing time, unrestricted multipoint surface contact, and adjustable boundary conditions. These features make the method ideal for modeling suturing, which is an element common to almost every surgical procedure. This paper describes constraints in the context of a Suturing Simulator currently being developed by the authors.


Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha.
The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic progenitor cells, are resistant to the growth inhibitory effects of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). CML is also relatively resistant to chemotherapy and the disease is difficult to cure using conventional therapeutic routes. CML is associated with increased abl oncogene protein tyrosine kinase (PTK) activity. Here, we have tested the hypothesis that these aberrant responses to MIP-1alpha and the relative resistance to chemotherapy are directly related to this increased abl PTK activity in primitive haemopoietic cells. To do this we have expressed a temperature sensitive abl PTK in a growth factor dependent, multipotent stem cell line (FDCP-Mix) in which growth is normally suppressed by MIP-1alpha. In FDCP-Mix cells expressing the ts v-abl PTK and grown at the restrictive temperature for PTK activity the cells were relatively sensitive to cytotoxic agents such as cytosine arabinoside and 5-fluorouracil but MIP-1alpha could induce growth inhibition and confer some degree of protection from these agents. At the permissive temperature for abl PTK, the cells were relatively resistant to cytotoxic drugs and MIP-1alpha treatment neither induced growth inhibition nor protected the cells from cytotoxic drug induced cell death. This lack of response to MIP-1alpha was not due to receptor down modulation as neither the affinity nor the number of 125I-MIP-1alpha binding sites was altered by activating Abl PTK. However, MIP-1alpha mediated increases in cytosolic Ca2+ levels were abrogated by switching cells to the permissive temperature for Abl PTK activity. These data suggest that the relative resistance of CML progenitor cells to therapeutic drugs and the lack of response to MIP-1alpha occurs as a direct consequence of abl PTK activity and involves desensitisation of signal transduction events stimulated by MIP-1alpha receptors. Thus one contributory mechanism to transformation of primitive haemopoietic cells is abrogation of response to a growth inhibitor.


Hippocampal subfield morphology in monozygotic twins discordant for affective disorders.
Unipolar and bipolar disorders aggregate in families and have been associated with a reduced gray-matter volume in hippocampal and prefrontal cortex. Here we used structural MRI to clarify whether abnormalities in hippocampal subfield and prefrontal cortical morphology are associated with familial vulnerability (i.e., changes present both in patients and unaffected relatives compared to healthy individuals), resilience (i.e., changes differentiating unaffected relatives and patients), or sequalae of illness in a sample of monozygotic twins. We investigated regional differences in gray-matter volume extracted using FreeSurfer 6.0 between remitted affected twins (AT) with either unipolar or bipolar disorder (n = 67), unaffected discordant co-twins (UT, n = 39), and low-risk twins (LT, n = 31) with no personal or first-degree family history of affective disorders. The UT showed greater bilateral hippocampal volumes compared to AT. Between group differences in left hippocampal volume were driven by greater cornu ammonis 1-3 and 4, subiculum and subfield of dentate gyrus. For the right hippocampus, differences were driven by greater hippocampal tail and subiculum. There was a trend for UT having a larger left hippocampus than LT, but no significant differences in hippocampal volumes between AT and LT. Outside the hippocampus, AT showed a smaller volume of left dorsomedial prefrontal cortex compared to LT. Our results suggest that larger volume of specific hippocampal subfields may be associated with resilience in healthy relatives of patients with an affective illness. Moreover, a smaller volume of left dorsomedial prefrontal cortex may reflect a sequalae of illness.


Hepatitis B Virus Capsid Assembly Modulators, but Not Nucleoside Analogs, Inhibit the Production of Extracellular Pregenomic RNA and Spliced RNA Variants.
The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes. Representative compounds from the sulfonamide carboxamide and heteroaryldihydropyrimidine series of CAMs were evaluated and compared to nucleos(t)ide analogs as inhibitors of the viral polymerase. The results showed that CAMs blocked extracellular HBV RNA with efficiencies similar to those with which they blocked pregenomic RNA (pgRNA) encapsidation, HBV DNA replication, and Dane particle production. Nucleos(t)ide analogs inhibited viral replication and virion production but not encapsidation or production of extracellular HBV RNA. Profiling of HBV RNA from both culture supernatants and patient serum showed that extracellular viral RNA consisted of pgRNA and spliced pgRNA variants with an internal deletion(s) but still retained the sequences at both the 5' and 3' ends. Similar variants were detected in the supernatants of infected cells with and without nucleos(t)ide analog treatment. Overall, our data demonstrate that HBV CAMs represent direct antiviral agents with a profile differentiated from that of nucleos(t)ide analogs, including the inhibition of extracellular pgRNA and spliced pgRNA.


Poly(p-phenylenediamine)-Coated Metal-Organic Frameworks for High-Performance Sodium-Ion Batteries: The Balance of Capacity and Stability.
Metal-organic frameworks (MOFs) with well-defined porous structures and highly active frameworks are considered as promising electrode materials for sodium-ion batteries (SIBs). However, the structure pulverization upon sodiation/desodiation impacts on their practical application in SIBs. To address this issue, poly(p-phenylenediamine) (PPA) was uniformly coated onto the surface of MIL-88A, a typical Fe-based MOF through in situ polymerization initiated by the metal ions (Fe3+) of MIL-88A. Used as an anode material for SIBs, the PPA-coated MIL-88A, denoted as PPA@MIL-88A, showed significantly improved electrochemical performance. A reversible capacity as high as 230 mAh g-1 was achieved at 0.2 A g-1 even after 500 cycles. MIL-88A constructed with electrochemically active Fe3+ and fumaric acid ligands guarantees the high specific capacity, while the PPA polymer coating effectively inhibits the pulverization of MIL-88A. This work provides an efficient strategy for improving the structure and cycling stability of MOFs-based electrode materials.


(-)-Epicatechin Modulates Mitochondrial Redox in Vascular Cell Models of Oxidative Stress.
Diabetes mellitus affects 451 million people worldwide, and people with diabetes are 3-5 times more likely to develop cardiovascular disease. In vascular tissue, mitochondrial function is important for vasoreactivity. Diabetes-mediated generation of excess reactive oxygen species (ROS) may contribute to vascular dysfunction via damage to mitochondria and regulation of endothelial nitric oxide synthase (eNOS). We have identified (-)-epicatechin (EPICAT), a plant compound and known vasodilator, as a potential therapy. We hypothesized that mitochondrial ROS in cells treated with antimycin A (AA, a compound targeting mitochondrial complex III) or high glucose (HG, global perturbation) could be normalized by EPICAT, and correlate with improved mitochondrial dynamics and cellular signaling. Human umbilical vein endothelial cells (HUVEC) were treated with HG, AA, and/or 0.1 or 1.0 μM of EPICAT. Mitochondrial and cellular superoxide, mitochondrial respiration, and cellular signaling upstream of mitochondrial function were assessed. EPICAT at 1.0 μM significantly attenuated mitochondrial superoxide in HG-treated cells. At 0.1 μM, EPICAT nonsignificantly increased mitochondrial respiration, agreeing with previous reports. EPICAT significantly increased complex I expression in AA-treated cells, and 1.0 μM EPICAT significantly decreased mitochondrial complex V expression in HG-treated cells. No significant effects were seen on either AMPK or eNOS expression. Our study suggests that EPICAT is useful in mitigating moderate ROS concentrations from a global perturbation and may modulate mitochondrial complex activity. Our data illustrate that EPICAT acts in the cell in a dose-dependent manner, demonstrating hormesis.


Real-time monitoring of beta-d-glucuronidase activity in sediment laden streams: A comparison of prototypes.
Detection of enzymatic activities has been proposed as a rapid surrogate for the culture-based microbiological pollution monitoring of water resources. This paper presents the results of tests on four fully automated prototype instruments for the on-site monitoring of beta-d-glucuronidase (GLUC) activity. The tests were performed on sediment-laden stream water in the Hydrological Open Air Laboratory (HOAL) during the period of March 2014 to March 2015. The dominant source of faecal pollution in the stream was swine manure applied to the fields within the catchment. The experiments indicated that instrument pairs with the same construction design yielded highly consistent results (R(2) = 0.96 and R(2) = 0.94), whereas the results between different designs were less consistent (R(2) = 0.71). Correlations between the GLUC activity measured on-site and culture-based Escherichia coli analyses over the entire study period yielded R(2) = 0.52 and R(2) = 0.47 for the two designs, respectively. The correlations tended to be higher at the event scale. The GLUC activity was less correlated with suspended sediment concentrations than with E. coli, which is interpreted in terms of indicator applicability and the time since manure application. The study shows that this rapid assay can yield consistent results over a long period of on-site operation in technically challenging habitats. Although the use of GLUC activity as a proxy for culture-based assays could not be proven for the observed habitat, the study results suggest that this biochemical indicator has high potential for implementation in early warning systems.


Diagnostic Imaging and Newer Modalities for Thoracic Diseases: PET/Computed Tomographic Imaging and Endobronchial Ultrasound for Staging and Its Implication for Lung Cancer.
Modalities to detect and characterize lung cancer are generally divided into those that are invasive [endobronchial ultrasound (EBUS), esophageal ultrasound (EUS), and electromagnetic navigational bronchoscopy (ENMB)] versus noninvasive [chest radiography (CXR), computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI)]. This chapter describes these modalities, the literature supporting their use, and delineates what tests to use to best evaluate the patient with lung cancer.


2,6-Dibromo-3,5-dimethylpyridine and 2,6-diiodo-3,5-dimethylpyridine.
The title compounds 2,6-dibromo-3,5-dimethylpyridine, C7H7Br2N, (I), and 2,6-diiodo-3,5-dimethylpyridine, C7H7I2N, (II), constitute the first structurally characterized examples of 2,6-dihalo-3,5-dimethylpyridines. Compound (I) crystallizes as a racemic twin with two symmetry-independent molecules in the asymmetric unit, while (II) is non-planar with the pyridine ring slightly deformed into a saddle shape, and exhibits crystallographically imposed twofold symmetry. Both (I) and (II) exhibit aromatic face-to-face pi-stacking in the solid state, although there are no other long-range interactions. In (I), alternate molecules are oriented at 90 degrees, resulting in X-shaped columns, while in (II), molecules pack in a parallel fashion, leading to a zigzag array.