Molecular mechanisms and signaling pathways of black cumin (Nigella sativa) and its active constituent, thymoquinone: a review.
Nigella sativa and its main bioactive ingredient, thymoquinone, exhibit various pharmacological activities, including neuroprotective, nephroprotective, cardioprotective, gastroprotective, hepatoprotective, and anti-cancer effects. Many studies have been conducted trying to elucidate the molecular signaling pathways that mediate these diverse pharmacological properties of N. sativa and thymoquinone. Accordingly, the goal of this review is to show the effects of N. sativa and thymoquinone on different cell signaling pathways. The online databases Scopus, PubMed and Web of Science were searched to identify relevant articles using a list of related keywords such as Nigella sativa, black cumin, thymoquinone, black seed, signal transduction, cell signaling, antioxidant, Nrf2, NF-κB, PI3K/AKT, apoptosis, JAK/STAT, AMPK, MAPK, etc. Only articles published in the English language until May 2022 were included in the present review article. Studies indicate that N. sativa and thymoquinone improve antioxidant enzyme activities, effectively scavenges free radicals, and thus protect cells from oxidative stress. They can also regulate responses to oxidative stress and inflammation via Nrf2 and NF-κB pathways. N. sativa and thymoquinone can inhibit cancer cell proliferation through disruption of the PI3K/AKT pathway by upregulating phosphatase and tensin homolog. Thymoquinone can modulate reactive oxygen species levels in tumor cells, arrest the cell cycle in the G2/M phase as well as affect molecular targets including p53, STAT3 and trigger the mitochondrial apoptosis pathway. Thymoquinone, by adjusting AMPK, can regulate cellular metabolism and energy hemostasis. Finally, N. sativa and thymoquinone can elevate brain GABA content, and thus it may ameliorate epilepsy. Taken together, the improvement of antioxidant status and prevention of inflammatory process by modulating the Nrf2 and NF-κB signaling and inhibition of cancer cell proliferation through disruption of the PI3K/AKT pathway appear to be the main mechanisms involved in different pharmacological properties of N. sativa and thymoquinone.


Hypertension in the elderly.
The incidence of definite hypertension increases with advancement of age, and one third of the elderly population is affected. Isolated systolic hypertension is frequent in this population (10 to 12 percent in subjects between 65 and 74 years of age). The role of hypertension as a cardiovascular risk factor has been confirmed in the elderly population by the increase in cerebrovascular accidents, and by the incidence of myocardial infarction with the rise in blood pressure. The relationship between elevated diastolic and systolic blood pressure and mortality rates in the elderly is also well documented (Framingham). Effective treatment of hypertension significantly reduces the risk of associated complications: cardiovascular death, congestive heart failure, and stroke. However, the goal of antihypertensive therapy in the elderly should be not only to reduce morbidity and mortality rates, but also to do so without adverse effects on the functional well-being of patients.


Clinical evaluation of targeted arterial perfusion of verapamil and chemotherapeutic drugs in interventional therapy of advanced lung cancer.
To assess the clinical efficacy of targeted arterial perfusion of verapamil and chemotherapeutic agents in the interventional therapy of lung cancer. Forty patients with advanced lung cancer underwent treatment with targeted arterial perfusion of verapamil and chemotherapeutic agents using Seldinger technique. Interventional therapy was performed once a month, and each subject received interventional treatment for 2 or more cycles. The therapeutic efficacy was evaluated 2 months post-treatment. Out of 40 patients with advanced lung cancer, 5 cases achieved complete remission (CR) and 29 cases achieved partial remission (PR), with a total effectiveness (CR + PR) rate of 85 %. Besides, 32 cases achieved significantly alleviated clinical symptoms, and 29 cases had decreased clinical tumor stage. All subjects had stable karnofsky performance status score and body weight. Among the 40 patients, 13 cases had leucopenia, 10 cases had gastrointestinal reactions, 3 cases presented with elevated alanine aminotransferase/aspartate aminotransferase ratio, and 3 cases had fever. However, all these side effects relieved quickly. No elevation of BUN/Cr ratio and allergic reactions was observed. No significant changes in cardiac function and electrocardiogram were noticed after the treatment. Targeted arterial perfusion of verapamil and chemotherapeutic drugs can improve the clinical symptoms of patients with advanced lung cancer and increase the efficacy of chemotherapeutic agents, thereby providing an opportunity for radiotherapy or surgical treatment for advanced lung cancer.


Plasma exosomes and contained MiRNAs affect the reproductive phenotype in polycystic ovary syndrome.
Anovulation is the main feature of infertile women with polycystic ovary syndrome (PCOS), and there is very limited understanding of the role of plasma exosomes and miRNAs in it. To identify the effect of PCOS patients' plasma exosomes and exosomal miRNAs, we isolated plasma exosomes of PCOS patients and normal women and injected into 8-week-old ICR female mice via tail vein. The changes in estrus cycle, serum hormone levels, and ovarian morphology were observed. KGN cells were cultured and transfected with mimics and inhibitors of differentially expressed exosomal miRNAs (miR-18a-3p, miR-20b-5p, miR-106a-5p, miR-126-3p, and miR-146a-5p) and then tested for steroid hormone synthesis, proliferation, and apoptosis. The results showed that female ICR mice injected with plasma exosomes from PCOS patients presented ovarian oligo-cyclicity. Hormone synthesis and proliferation of granulosa cells were affected by differentially expressed PCOS plasma-derived exosomal miRNAs, of which miR-126-3p having the most evident effect. MiR-126-3p affected the proliferation of granulosa cells by inhibiting PDGFRβ and its downstream PI3K-AKT pathway. Our results demonstrated plasma exosomes and contained miRNAs in PCOS patients affect the estrus cycle of mice, hormone secretion, and proliferation of granulosa cells. This study provides a novel understanding about the function of plasma exosomes and exosomal miRNAs in PCOS.


Examining the mediating effect of job satisfaction on the relationship between leader-member exchange and safety behavior among Algerian healthcare workers.
This study aims to examine the long-term impact of leader-member exchange (LMX) on employee safety behavior. It proposes a conceptual model that includes the mediating role of job satisfaction (JS) in the relationship between LMX and safety behaviors, regarding safety compliance behavior (SCB) and safety participation behavior (SPB). Data were collected from 325 health-care workers across public hospitals in Algeria at three waves. Data were analyzed with partial least square structural equation modeling. The findings revealed that LMX positively influenced employees' job satisfaction. However, the relationship between LMX and SCB was found to be mediated by job satisfaction. LMX was not directly related to both dimensions of safety behavior, whereas JS was positively associated with safety compliance and safety participation. This is the first paper, to the best of the authors' knowledge, to report on the significant mediating role of JS on the reciprocal process used to exchange resources between leaders and subordinates and safety behaviors among health-care workers, thereby filling an important research gap in existing literature.


Insulin-like growth factors I and II are present in the skeletal tissues of ten vertebrates.
Previous studies have shown that insulin-like growth factor I and insulin-like growth factor II (IGF I and IGF II) constitute an important family of skeletal growth-regulating peptides. We undertook this study to determine if, as in the case of sera in various animals, IGF I and IGF II are conserved in the skeletal tissues of various vertebrates. Skeletal tissues of ten animals representing five of the six vertebrate classes were studied: monkey, dog, sheep, adult mice, neonatal mice, chicken, lizard, frog, trout, and shark. The skeletal tissues were pulverized and demineralized with 10% ethylenediaminetetraacetic acid (pH 7.0) to extract the soluble matrix proteins. The tissue extracts were concentrated, dialized, and subjected to specific human IGF assays. IGF I and IGF II were measured with a radioimmunoassay and a radioreceptor assay, respectively. We found that 1) there are detectable human IGF I- and II-like substances in all extracts, 2) IGF values obtained in the skeletal extracts were not caused by binding protein artifacts, 3) in general there is more IGF II than IGF I, and 4) the skeletal tissue levels of the IGFs are comparable with their respective serum levels. We conclude that, in the skeletal tissues of vertebrates, the IGFs are conserved and may be important regulators of osteogenesis.


PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1).
Platelets have been regarded as static cells that do not move once they adhere to a matrix. The present study explored, whether platelets are able to migrate. In contrast to the current opinion, we found that platelets were mobile, able to migrate over a surface, and transmigrate through a transwell membrane and endothelium toward a source of stromal cell-derived factor 1 (SDF-1). Platelet migration was stimulated by SDF-1, which led to the downstream activation and phosphorylation of Wiskott-Aldrich syndrome protein. SDF-1 signaling and subsequent platelet migration could be inhibited by CXCR4-receptor blocker AMD3100, pertussis toxin, inhibition of phosphoinositol 3-kinase (PI3 kinase) with LY294002 or wortmannin, and disruption of actin polymerization with cytochalasin B. The potential of platelets to migrate in an SDF-1-mediated fashion may redefine the role of platelets in the pathophysiology of vascular inflammation, subsequent atherosclerotic degeneration, and vascular regeneration.


Possible influence of measles virus infection of cynomolgus monkeys on the outcome of the neurovirulence test for oral poliovirus vaccine.
Macaque monkeys are susceptible to measles infection which triggers temporary immuno-depression similar to the well known phenomenon in humans. It is known that feral monkeys become infected with measles virus when they are exposed to humans. Since Macaca mulatta and M. fascicularis are species used to assay the neurovirulence of oral poliovirus vaccine, the immunodepression caused by measles infection of the test monkeys could significantly alter the results of the neurovirulence test. The serum titers of measles-neutralizing antibodies were studied in over 1500 monkeys used for neurovirulence tests. A high proportion of the feral monkeys had measles antibodies (51-100%); in contrast, none of 493 M. fascicularis monkeys which had been bred in a primate colony under strict isolation measures was found positive for measles antibodies. An increase in the prevalence of measles in the population of Ontario and Quebec provinces was accompanied with an increase in the proportion of measles-positive monkey and their serum antibody titers were found higher. It was observed that monkeys used in tests that had been performed during high measles prevalence presented with a poliomyelitis of more pronounced severity clinically and histologically. The analysis of 29 tests conducted on type 1 vaccines over several years showed a positive correlation (correlation coefficient = 0.5141, P less than 0.0022) between severity of poliomyelitis and the presence of measles serum antibodies in test monkeys (some animals seroconverted during the test). A similar observation, when type 3 Sabin vaccines were tested in M. fascicularis, was recently reported from another laboratory in Ontario.


Meiosis: polo, FEAR and the art of dividing reductionally.
Recent studies on the regulation of meiosis have uncovered new roles for old acquaintances: the polo-like kinase Cdc5 has been found to dictate proper kinetochore orientation during meiosis I, while the FEAR pathway is essential for some, but not all, aspects of meiosis I exit.


Effects of acute pentobarbital administration on GABAA receptor-regulated chloride uptake in rat brain synaptoneurosomes.
Effects of acute pentobarbital administration on GABAA receptor-regulated muscimol-stimulated, pentobarbital-stimulated, or flunitrazepam-enhanced, muscimol-stimulated chloride uptake were studied in the brains of Sprague-Dawley rats. Animals received sodium pentobarbital, 60 mg/kg IP, and cerebral cortical and cerebellar synaptoneurosomes were isolated at 10 min, 1 h, and when animals had awakened. The basal uptake of chloride was not changed in either cerebral cortex or cerebellum at different time periods after pentobarbital administration. Ten minutes after sodium pentobarbital administration, muscimol-stimulated chloride uptake was significantly reduced in cerebellum when the muscimol concentration was 2.5, 5, or 20 microM and in cerebral cortex when the concentration of muscimol was 5 or 10 microM (p less than 0.05, Duncan multiple-range test). One hour after pentobarbital administration or after animals had awakened, chloride uptake in brains from pentobarbital-treated animals was less at low concentration of muscimol (2.5 microM). No significant difference was found in either cerebral cortex or cerebellum in pentobarbital-(125-1,000 microM) stimulated or flunitrazepam-(2.5-20 microM) enhanced, muscimol-(3 microM) stimulated chloride uptake at different time periods after pentobarbital administration. Saline treatment had no effects on the basal or muscimol-stimulated chloride uptake in cerebellar synaptoneurosomes when compared with naive animals. The results demonstrate that GABAA receptor-regulated chloride uptake is decreased after acute pentobarbital administration, an effect that is reversible.


Real-time in vivo computed optical interferometric tomography.
High-resolution real-time tomography of scattering tissues is important for many areas of medicine and biology1-6. However, the compromise between transverse resolution and depth-of-field in addition to low sensitivity deep in tissue continue to impede progress towards cellular-level volumetric tomography. Computed imaging has the potential to solve these long-standing limitations. Interferometric synthetic aperture microscopy (ISAM)7-9 is a computed imaging technique enabling high-resolution volumetric tomography with spatially invariant resolution. However, its potential for clinical diagnostics remains largely untapped since full volume reconstructions required lengthy postprocessing, and the phase-stability requirements have been difficult to satisfy in vivo. Here we demonstrate how 3-D Fourier-domain resampling, in combination with high-speed optical coherence tomography (OCT), can achieve high-resolution in vivo tomography. Enhanced depth sensitivity was achieved over a depth-of-field extended in real time by more than an order of magnitude. This work lays the foundation for high-speed volumetric cellular-level tomography.


Engineering the Extracellular Matrix to Model the Evolving Tumor Microenvironment.
Clinical evidence supports a role for the extracellular matrix (ECM) in cancer risk and prognosis across multiple tumor types, and numerous studies have demonstrated that individual ECM components impact key hallmarks of tumor progression (e.g., proliferation, migration, angiogenesis). However, the ECM is a complex network of fibrillar proteins, glycoproteins, and proteoglycans that undergoes dramatic changes in composition and organization during tumor development. In this review, we will highlight how engineering approaches can be used to examine the impact of changes in tissue architecture, ECM composition (i.e., identity and levels of individual ECM components), and cellular- and tissue-level mechanics on tumor progression. In addition, we will discuss recently developed methods to model the ECM that have not yet been applied to the study of cancer.


The use of preoperative exercise testing to predict cardiac complications after arterial reconstruction.
To assess the value of exercise testing in the prediction of cardiac risk, 100 patients requiring arterial reconstructive surgery had either treadmill testing or arm ergometry before operation. Thirty-four patients then had abdominal aortic aneurysm repair, 48 had reconstructions for aortoiliac occlusive disease, and 18 had infrainguinal revascularization procedures. Cardiac complications included myocardial infarction in 10%, acute congestive failure in 5%, malignant ventricular arrhythmias in 7%, and cardiac death in 7%. Contingency table analysis showed that patients who achieved less than 85% of their predicted maximum heart rate (PMHR) during exercise testing had a complication rate of 24%, whereas patients who achieved more than 85% of PMHR had a 6% complication rate (p = 0.0396). The degree of ST segment depression during exercise testing was not a significant predictor of cardiac complications. However, patients who had a positive stress test (ST depression more than 1 mm) and achieved less than 85% of their PMHR had a complication rate of 33%, whereas patients with a positive stress test who achieved more than 85% of their PMHR had no complications (p = 0.048). Statistical analysis with a logistic regression model showed two factors to be significant. Patients who achieved a high maximum heart rate during exercise testing had a low probability of developing postoperative cardiac complications (p = 0.04), as did patients who achieved high cardiac work load maximal oxygen uptake (p = 0.03). We conclude that preoperative exercise testing is useful to predict cardiac complications after arterial reconstruction. Patients who are able to achieve more than 85% of their PMHR and a high maximal oxygen uptake represent a low-risk group.


Fluorinated 3,6,9-trisubstituted acridine derivatives as DNA interacting agents and topoisomerase inhibitors with A549 antiproliferative activity.
A series of new 3,6,9-trisubstituted acridine derivatives with fluorine substituents on phenyl ring were synthesized and their interaction with calf thymus DNA was investigated. Analysis using UV-Vis absorbance spectra provided valuable information about the formation of the acridine-DNA complex. In addition, compounds 8b and 8d were found to display an increased binding affinity (K = 2.32 and 2.28 × 106 M-1, respectively). Topo I/II inhibition mode assays were also performed, and the results verify that the novel compounds display topoisomerase I and II inhibitory activity; compounds 8a, 8b and 8c completely inhibited topoisomerase I activity at a concentration of 60 × 10-6 M, but only compound 8d showed partial ability to inhibit topoisomerase II at concentrations of 30 and 50 × 10-6 M. The ability of the derivatives to impair cell proliferation was tested through an analysis of cell cycle distribution, quantification of cell number, viability studies, metabolic activity measurement and clonogenic assay. The content and localization of the derivatives in cells were analyzed using flow cytometry and fluorescence microscopy. The compounds 8b and 8d altered the physiochemical properties and improved antiproliferative activity in A549 human lung carcinoma cells (compound 8d displayed the highest level of activity, 4.25 × 10-6 M, after 48 h).


Lysis of placental syncytiotrophoblast by allogenic leukocytes in vitro: effects of neuraminidase and chorionic gonadotropin.
51chromium-labeled syncytiotrophoblasts purified from human placentae were lysed by allogenic leukocytes in vitro. The extent of syncytiotrophoblast lysis was dependent upon the dose of the leukocytes, occurred after a lag period of 42 h, and was inhibited by excess of unlabeled syncytiotrophoblasts. Autologous leukocytes failed to lyse syncytiotrophoblasts. Neuraminidase pretreatment of the syncytiotrophoblasts significantly enhanced their lysis by leukocytes. HCG failed to influence the extent of lysis of untreated syncytiotrophoblasts but significantly reduced the lysis of neuraminidase-treated targets. The significance of these observations in relation to the "immunologic privilege" of the trophoblast in vivo is discussed. (Am J Reprod Immunol. 1982; 204-207.)


Cartilage labelling for mechanical testing in T-peel configuration.
The purpose of this study was to find a suitable method of labelling cartilage samples for the measurement of distraction distances in biomechanical testing. Samples of bovine cartilage were labelled using five different methods: hydroquinone and silver nitrate (AgNO3), potassium permanganate (KMnO4) with sodium thiosulphate (Na2S2O3), India ink, heat, and laser energy. After the labelling, we analysed the cartilage samples with regard to cytotoxity by histochemical staining with ethidiumbromide homodimer (EthD-1) and calcein AM. Furthermore, we tested cartilages labelled with India ink and heat in a T-peel test configuration to analyse possible changes in the mechanical behaviour between marked and unlabelled samples. Only the labelling methods with Indian ink or a heated needle showed acceptable results in the cytotoxity test with regard to labelling persistence, accuracy, and the influence on consistency and viability of the chondrocytes. In the biomechanical T-peel configuration, heat-labelled samples collapsed significantly earlier than unlabelled samples. Labelling bovine cartilage samples with Indian ink in biomechanical testing is a reliable, accurate, inexpensive, and easy-to-perform method. This labelling method influenced neither the biomechanical behaviour nor the viability of the tissue compared to untreated bovine cartilage.


Contralateral retroperitoneal hematoma secondary to percutaneous ultrasonic lithotripsy.
We believe this is the first reported case of symptomatic contralateral retroperitoneal hematoma secondary to percutaneous ultrasonic lithotripsy.


Molecular architecture of the sheathed polar flagellum in Vibrio alginolyticus.
Vibrio species are Gram-negative rod-shaped bacteria that are ubiquitous and often highly motile in aqueous environments. Vibrio swimming motility is driven by a polar flagellum covered with a membranous sheath, but this sheathed flagellum is not well understood at the molecular level because of limited structural information. Here, we use Vibrio alginolyticus as a model system to study the sheathed flagellum in intact cells by combining cryoelectron tomography (cryo-ET) and subtomogram analysis with a genetic approach. We reveal striking differences between sheathed and unsheathed flagella in V. alginolyticus cells, including a novel ring-like structure at the bottom of the hook that is associated with major remodeling of the outer membrane and sheath formation. Using mutants defective in flagellar motor components, we defined a Vibrio-specific feature (also known as the T ring) as a distinctive periplasmic structure with 13-fold symmetry. The unique architecture of the T ring provides a static platform to recruit the PomA/B complexes, which are required to generate higher torques for rotation of the sheathed flagellum and fast motility of Vibrio cells. Furthermore, the Vibrio flagellar motor exhibits an intrinsic length variation between the inner and the outer membrane bound complexes, suggesting the outer membrane bound complex can shift slightly along the axial rod during flagellar rotation. Together, our detailed analyses of the polar flagella in intact cells provide insights into unique aspects of the sheathed flagellum and the distinct motility of Vibrio species.


Clinical implication of monitoring rivaroxaban and apixaban by using anti-factor Xa assay in patients with non-valvular atrial fibrillation.
Although patients taking non-vitamin K antagonist oral anticoagulants (NOACs) do not require routine coagulation monitoring, high-risk patients require monitoring to assess pharmacodynamics. We measured (1) anti-factor Xa activity (AXA), using chromogenic assay with the HemosIL Liquid Heparin kit, (2) prothrombin time (PT), and (3) activated partial thromboplastin time (aPTT) in 188 blood samples from 70 patients with non-valvular atrial fibrillation, of whom 36 received rivaroxaban once daily and 34 received apixaban twice daily. After the rivaroxaban therapy, AXA ranged from 0 to 3.65 IU/mL; PT, from 9.6 to 44.5 s; and APTT, from 19.3 to 69.7 s. After the apixaban therapy, AXA ranged from 0.02 to 3.18 IU/mL; PT, from 10.2 to 20.8 s; and APTT, from 21.8 to 59.8 s. At peak time, the AXA of patients who received rivaroxaban and apixaban were almost the same (2.08±0.91 IU/mL vs. 1.71±0.57 IU/mL), but the PT and APTT of patients who received rivaroxaban were more prolonged than those of patients who received apixaban (18.1±5.6 s vs. 13.8±0.9 s, p<0.001 and 40.9±7.3 s vs. 35.5±7.5 s, p<0.01, respectively). At trough time, the AXA and PT of patients who received rivaroxaban were respectively lower and shorter than those of patients who received apixaban (0.28±0.31 IU/mL vs. 1.04±0.72 IU/mL, p<0.001 and 11.9±2.0 s vs. 13.7±2.4 s, p<0.01, respectively), but the APTT of patients who received rivaroxaban and apixaban did not significantly differ (32.3±4.3 s vs. 34.3±3.8 s). Measurement of AXA might be useful to assess the pharmacodynamics of high-risk patients, such as high age, low body weight, and/or low renal function, and to assess the intensity of anticoagulation by using different methods of administration, such as crushed tablet via the nasogastric tube.


Hair cortisol concentration reflects the life cycle and management of grey wolves across four European populations.
The grey wolf (Canis lupus) persists in a variety of human-dominated landscapes and is subjected to various legal management regimes throughout Europe. Our aim was to assess the effects of intrinsic and methodological determinants on the hair cortisol concentration (HCC) of wolves from four European populations under different legal management. We determined HCC by an enzyme-linked immune assay in 259 hair samples of 133 wolves from the Iberian, Alpine, Dinaric-Balkan, and Scandinavian populations. The HCC showed significant differences between body regions. Mean HCC in lumbar guard hair was 11.6 ± 9.7 pg/mg (range 1.6-108.8 pg/mg). Wolves from the Dinaric-Balkan and Scandinavian populations showed significantly higher HCC than Iberian wolves, suggesting that harvest policies could reflected in the level of chronic stress. A significant negative relationship with body size was found. The seasonal, sex and age patterns are consistent with other studies, supporting HCC as a biomarker of chronic stress in wolves for a retrospective time frame of several weeks. Our results highlight the need for standardization of sampling and analytical techniques to ensure the value of HCC in informing management at a continental scale.


Two forms of guanylate cyclase in mammalian tissues and possible mechanisms for their regulation.
All mammalian tissues examined to date have two forms of guanylate cyclase with apparently different properties. From the studies in several laboratories, we suggest the following mechanisms for the possible regulation of guanylate cyclase activity: (1) factors that could alter the apparent cooperative nature of the enzyme, (2) interactions of metal ions with the substrate or enzyme, (3) factors that could overcome inhibition by ATP, (4) mechanisms that could regulate the interconversion of latent and active forms of the enzyme, (5) possible translocation of particulate and soluble forms of the enzyme, and (6) induction or repression of the enzyme.


Combined continuous ultra low dose rate irradiation and radiofrequency hyperthermia in the C3H mouse.
Intradermally inoculated RIF tumors and normal skin of male C3H mice were implanted with variable activities of Iodine 125 seeds or dummy seeds enclosed in Vicryl sutures, and subjected to 0, 1, 2 or 3 local radiofrequency heat treatments for 30 minutes. Each treatment raised the tumor volume to 44 degrees C. Gastrointestinal toxicity (assessed by weight change), skin reaction, tumor growth delay, and tumor cure were assessed. Neither radiofrequency treatment alone or continuous ultra low dose rate irradiation up to 16,000 rad over 180 days alone was successful in curing these tumors; however, combined modality treatments employing doses as low as 8,000 rad over 180 days plus two radiofrequency treatments did effect cures. Gastrointestinal toxicity was best correlated with hyperthermia treatments, while skin reactions secondary to hyperthermia were prolonged by continuous ultra low dose rate irradiation. Implications for clinical usage are discussed.


Treatment planning with external beams. Introduction and historical overview.
In this first of a series of articles on Radiation Treatment Planning based on the Basic Physics Symposium of the American Association of Physicists in Medicine at the 73rd Annual meeting of the RSNA, an attempt has been made to provide a broad overview of the process of designing an optimal radiation therapy regimen. The essentials of treatment planning have been identified and essential terms have been defined. Variables to be selected have been identified and constraints in choosing treatment plans have been noted. The effect of combining multiple beams to achieve the most advantageous distribution of radiation dose within the patient has been discussed and the vital importance of appropriate quality control has been emphasized. Future articles will consider specific aspects of this discipline in detail.


Immunohistochemical demonstration of estrogen, progesterone, CEA and ferritin in breast cancer and their clinical value for the prediction of early postoperative recurrence.
The aim of this paper is to determine whether the incidence of estrogen-, progesterone-, CEA-, and ferritin- positive staining of primary tumors, by using the PAP method, is related to the prognosis of breast cancer status. A significantly higher incidence (71 per cent) of CEA-positive tumors was observed in patients who had a recurrence of breast cancer within 2 years after radical operation. Patients, whose tumors were positive in estrogen or negative in CEA, showed a relatively good prognosis, even after a recurrence of the disease. Distant metastases were seen in most of the patients positive in CEA (78 per cent). Before the recurrence of breast cancer, those patients positive in progesterone had a good prognosis. After the recurrence, however, there was no relationship between the prognosis of recurrent disease and the progesterone-staining of primary tumors. Our data suggest that the immunohistological staining of estrogen, progesterone and CEA might offer the effective prognostic indices in breast cancer patients.


Translational protein RpsE as an alternative target for novel nucleoside analogues to treat MDR Enterobacter cloacae ATCC 13047: network analysis and molecular dynamics study.
The pathogenic Enterobacter cloacae subsp. cloacae str. ATCC 13047 has contemporarily emerged as a multi-drug resistant strain. To formulate an effective treatment option, alternative therapeutic methods need to be explored. The present study focused on Gene Interaction Network study of 46 antimicrobial resistance genes to reveal the densely interconnecting and functional hub genes in E. cloacae ATCC 13047. The AMR genes were subjected to clustering, topological and functional enrichment analysis, revealing rpsE (RpsE), acrA (AcrA) and arnT (ArnT) as novel therapeutic drug targets for hindering drug resistance in the pathogenic strain. Network topology further indicated translational protein RpsE to be exploited as a promising drug-target candidate for which the structure was predicted, optimized and validated through molecular dynamics simulations (MDS). Absorption, distribution, metabolism and excretion screening recognized ZINC5441082 (N-Isopentyladenosine) (Lead_1) and ZINC1319816 (cyclopentyl-aminopurinyl-hydroxymethyl-oxolanediol) (Lead_2) as orally bioavailable compounds against RpsE. Molecular docking and MDS confirmed the binding efficacy and protein-ligand complex stability. Furthermore, binding free energy (Gbind) calculations, principal component and free energy landscape analyses affirmed the predicted nucleoside analogues against RpsE protein to be comprehensively examined as a potential treatment strategy against E. cloacae ATCC 13047.


Interactive combining of functional images.
A technique of interactively combining digital images using virtual color tables is presented. The general combination algorithm, a particular implementation of this algorithm, and an interactive approach to combining functional images are described. Combined phase and amplitude images derived from gated blood-pool studies are presented to illustrate the method, and other applications of the technique in nuclear medicine are suggested.


Adsorbed solution model for prediction of normal-phase chromatography process with varying composition of the mobile phase.
The adsorbed solution model has been used to predict competitive adsorption equilibria of the solute and the active component of mobile phase in a normal-phase liquid chromatography system. The inputs to the calculations were the single adsorption isotherms accounting for energetic heterogeneity of the adsorbent surface and non-ideality of the mobile phase solution. The competitive adsorption model has been coupled with a model of the column dynamics and used for simulating of chromatography process at different mobile phase composition. The predictions have been verified by comparing the simulated and experimental chromatograms. The model allowed quantitative prediction of chromatography process on the basis of the pure-species adsorption isotherms.


Difference between tortoise and hen lysozymes in the mode of association with N-acetyl D-glucosamine as revealed by proton magnetic resonance spectroscopy.
Tortoise lysozyme, unlike hen lysozyme, does not distinguish between the alpha- and beta-anomeric forms of N-acetyl D-glucosamine. This indicates that alpha- and beta-anomeric forms of the inhibitor have the same affinities and experience identical magnetic environments in tortoise lysozyme. The dissociation constant of tortoise lysozyme-inhibitor complex was calculated from chemical shift data and found to be 3.5 X 10(-2) M. The enthalpy of dissociation was calculated to be 5.0 kcal/mol.


Mechanically induced scission and subsequent thermal remending of perfluorocyclobutane polymers.
Perfluorocyclobutane (PFCB) polymer solutions were subjected to pulsed ultrasound, leading to mechanically induced chain scission and molecular weight degradation. (19)F NMR revealed that the new, mechanically generated end groups are trifluorovinyl ethers formed by cycloreversion of the PFCB groups, a process that differs from thermal degradation pathways. One consequence of the mechanochemical process is that the trifluorovinyl ether end groups can be remended simply by subjecting the polymer solution to the original polymerization conditions, that is, heating to >150 °C. Stereochemical changes in the PFCBs, in combination with radical trapping experiments, indicate that PFCB scission proceeds via a stepwise mechanism with a 1,4-diradical intermediate, offering a potential mechanism for localized functionalization and cross-linking in regions of high stress.


Management of dysphonic patients by otolaryngologists.
To investigate common treatment approaches of general otolaryngologists for adult dysphonic patients without obvious laryngeal anatomic abnormalities. Cross-sectional survey. General otolaryngology community. One thousand randomly chosen American Academy of Otolaryngology-Head and Neck Surgery general otolaryngologists were mailed a survey. The response rate was 27.8%. Mean years in practice was 19.5. The most common treatments were proton pump inhibitor (PPI), referral to speech pathology, and stroboscopy. Muscle tension dysphonia, vocal fold nodules, and dysphonia of uncertain etiology were the most common reasons for voice therapy referral. Various forms of supraglottic compression and tender extralaryngeal muscles were identified as findings of muscle tension dysphonia. Response to once-daily PPI, laryngeal signs, and throat symptoms were the most common determinants for laryngopharyngeal reflux. When patients failed initial treatment, 58.2% refer for voice therapy, 46.9% obtain stroboscopy, and 33.3% extend or increase duration of PPI treatment. Varied treatment approaches to adult dysphonic patients were identified. How practice patterns vary from best practice guidelines, affect patient outcome, and influence health care costs needs examination.


SlMYC2 mediates jasmonate-induced tomato leaf senescence by promoting chlorophyll degradation and repressing carbon fixation.
Leaf senescence occurs as the last developmental phase of leaf. The initiation and progression of leaf senescence is highly regulated by a plethora of internal developmental signals and environmental stimuli. Being an important class of phytohormones, jasmonates (JAs) are shown to induce premature leaf senescence in tomato (Solanum lycopersicum), nevertheless, the underlying mechanisms remain enigmatic. Here, we report that tomato MYC2, a key factor in the JA signal transduction, functions in JA-induced tomato leaf senescence by promoting chlorophyll degradation and inhibiting photosynthetic carbon fixation. We found that exogenous application of MeJA reduced chlorophyll content, decreased carbon assimilation rates and disrupted membrane integrity. We further demonstrated using SlMYC2-RNAi tomato plants that SlMYC2 enhanced the expression of SlPAO, which encodes a chlorophyll degradation enzyme, but suppressed the expression of SlRCA and SlSBPASE, both of which are required for photosynthesis and growth in plants. Dual-luciferase assay confirmed that SlMYC2 activated the transcription of SlPAO, but inhibited the transcription of SlRCA and SlSBPASE. Furthermore, repression of SlRCA led to typical features associated with leaf senescence in tomato. Taken together, these results favor that tomato MYC2 acts positively in the regulation of JA-dependent tomato leaf senescence. The results extend our mechanistic understanding of JA-induced senescence in an important horticultural crop.


Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors.
Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. Here we demonstrate that VEGF is induced in vivo by exposing mice to systemic hypoxia. VEGF induction was highest in brain, but also occurred in kidney, testis, lung, heart, and liver. In situ hybridization analysis revealed that a distinct subset of cells within a given organ, such as glial cells and neurons in brain, tubular cells in kidney, and Sertoli cells in testis, responded to the hypoxic stimulus with an increase in VEGF expression. Surprisingly, however, other cells at sites of constitutive VEGF expression in normal adult tissues, such as epithelial cells in the choroid plexus and kidney glomeruli, decreased VEGF expression in response to the hypoxic stimulus. Furthermore, in addition to VEGF itself, expression of VEGF receptor-1 (VEGFR-1), but not VEGFR-2, was induced by hypoxia in endothelial cells of lung, heart, brain, kidney, and liver. VEGF itself was never found to be up-regulated in endothelial cells under hypoxic conditions, consistent with its paracrine action during normoxia. Our results show that the response to hypoxia in vivo is differentially regulated at the level of specific cell types or layers in certain organs. In these tissues, up- or down-regulation of VEGF and VEGFR-1 during hypoxia may influence their oxygenation after angiogenesis or modulate vascular permeability.


Adrenergic regulation of the plasma levels of purine metabolites in the rat.
The effects of i.v. infusions of catecholamines on the plasma levels of uric acid and allantoin were investigated in the conscious rat. Isoproterenol and epinephrine, in this decreasing order of potency, remarkably elevated both uric and allantoin levels. Norepinephrine did not affect these purine metabolite levels. These effects of isoproterenol and epinephrine were completely abolished by propranolol. Phentolamine, on the contrary, slightly potentiated the effects of epinephrine. In contrast to i.v. fusion, s.c. injection of epinephrine had no effect, but, after prior treatment of animals with phentolamine, elicited striking increases in the plasma purine metabolite levels. Catecholamines thus caused hyperuricemia with a rise in plasma allantoin, both effects being mediated via beta-adrenoceptors and alpha-adrenergic mechanism sometimes functions in such a manner as to mask or inhibit this beta-mediated response.


Effect of HLA matching in simultaneous pancreas-kidney transplantation.
Simultaneous pancreas-kidney (SPK) transplantation has become the therapy of choice for type 1 diabetic patients with end-stage renal disease. The current analysis examined the impact of HLA matching on graft outcome following SPK transplantation. The study population was obtained from patients enrolled in the Euro-SPK 001 study. The effect of HLA matching on graft function and survival was assessed in 180 SPK recipients in whom complete donor-recipient HLA data were available. A group of 45 patients with 0 to 3 HLA mismatches (MM) was compared to 135 patients with 4 to 6 MM. There were no differences in 3-year kidney, pancreas, or patient survival rates between the 0 to 3 and 4 to 6 MM groups. Biological parameters of kidney and pancreas graft function were similar in both groups. Significantly more patients with 0 to 3 MM (66%) were rejection free at 3 years than those with 4 to 6 MM (41%; P = .003). The relative risk of acute rejection was 2.6 times higher among patients with 4 to 6 MM than among those with 0 to 3 MM. In conclusion, there was no evidence that HLA matching was associated with improved kidney or pancreas survival. However, a higher rate of acute rejection was observed with poor HLA matches, which may impact long-term survival.


Immunological function of tubular epithelial cells: the functional implications of CD40 expression.
Tubulo-interstitial inflammation in the kidney is characterized by the presence of activated T cells. Both by the local production of cytokines, as well as by direct cell-cell interactions, these activated T cells might affect the immune and inflammatory response. Recently it has been demonstrated that these kidney-infiltrating T cells express CD40 ligand and that tubular epithelial cells (TECs) express CD40. In the present review we will discuss the potential implications of CD40-CD40L interactions for the activation of TECs and its immunological function.


Uncertainty in Genomics Impacts Precision Medicine.
As exacting as genetic and genomic testing have become, health professionals continue to encounter uncertainty in their applications to medical practice. As examining the human genome at more refined levels increases, so is the likelihood of encountering uncertainty about the meaning of the information. The history of this concept informs how we might confront and deal with uncertainty, and what the future might hold. Precision medicine holds great promise for establishing more accurate diagnoses, directing specific therapy to patients who will most benefit from it, and avoiding treatments in patients who are most likely to suffer adverse consequences, or at best not benefit. But its application depends importantly on the proper interpretation of a person's genotype.


Newer combination therapies in the management of hypertension: an update.
A panel was convened to discuss current combination therapy for hypertension. Alan H. Gradman, MD, of the Western Pennsylvania Hospital, Temple University School of Medicine (Clinical Campus), Pittsburgh, PA, moderated the discussion. Participants included Matthew R. Weir, MD, University of Maryland School of Medicine, Baltimore, MD, and George L. Bakris, MD, University of Chicago, Chicago, IL.


Functions of CXCL12 and CXCR4 in breast cancer.
The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 were first identified in the context of trafficking and homeostasis of immune cells, such as T lymphocytes. Subsequently, it has been determined that CXCR4 regulates several key processes in a wide variety of cancers. Functions of CXCL12 and CXCR4 in cancer first were described in metastatic breast cancer, and more recent studies also have identified roles for this signaling pathway in primary breast tumors. This review focuses on functions of CXCR4 and CXCL12 in primary and metastatic breast cancer, including molecular mechanisms of action and relationships of this pathway to other key regulators of breast cancer progression. We also describe pre-clinical studies indicating the potential to exploit CXCR4 as a new molecular target for diagnosis and treatment of breast cancer in patients.


A novel polyethylene glycol mediated lipid nanoemulsion as drug delivery carrier for paclitaxel.
A novel polyethylene glycol 400 (PEG400) mediated lipid nanoemulsion as drug-delivery carrier for paclitaxel (PTX) was successfully developed. The formulation comprised a PEG400 solution of the drug (25mg/mL) that would be mixed with commercially 20% lipid emulsion to form PTX-loaded nanoemulsion (1mg/mL) prior to use. This two-vial formulation of PTX-loaded lipid nanoemulsion (TPLE) could significantly reduce extraction of reticuloendothelial system (RES) organs and increase tumor uptake, and exhibited more potent antitumor efficacy on bearing A2780 or Bcap-37 tumor nude mice compared to conventional PTX-loaded lipid nanoemulsion (CPLE). TPLE did not cause haematolysis and intravenous irritation response yet, and showed the same cytotoxicity against HeLa cells as Taxol®, and its LD50 was 2.7-fold higher than that of Taxol®, suggesting its good safety and druggability. In addition, TPLE displayed distinctly faster release of PTX, a greater proportion of PTX in phospholipids layer and a smaller share in oil phase than CPLE. From the Clinical Editor: This study demonstrates the feasibility and potential advantage of a novel PEG400-mediated two-vial formulation of lipid nanoemulsion as drug carrier for PTX in clinical application for the cancer therapy. This team of investigators convincingly demonstrates the feasibility and potential advantage of a PEG400-mediated two-vial formulation of lipid nanoemulsion as drug carrier for PTX in cancer therapy, documenting superior safety and faster release of PTX compared to commercially available formulations.


Low-intensity pulsed ultrasound increases bone ingrowth into porous hydroxyapatite ceramic.
Synthetic porous ceramic made of hydroxyapatite (HA) has been used as a bone graft substitute. In the present study we investigated whether low-intensity pulsed ultrasound (LIPUS) accelerates bone ingrowth into the pores of HA ceramic. Application of LIPUS did not mechanically weaken porous ceramic that was immersed in water in vitro. In vivo experiments using rabbits showed that LIPUS application for 2 weeks significantly increased osteoblast number and bone area in the central part of the porous HA ceramic implanted in the femoral condyle in comparison with similarly implanted HA ceramic that was not exposed to LIPUS. LIPUS application for 3 weeks significantly increased mineralized tissue volume and mineral content in the porous HA ceramic. Wound healing assays revealed increased migration of MC3T3-E1 cells as a result of LIPUS treatment, partly accounting for the increased osteoblast number. Use of porous HA ceramic combined with LIPUS may be a promising treatment for filling large bone defects in a clinical setting.


Histological Changes in Pancreatic Islets of Animals with Experimental Diabetes Caused by Xanthurenic Acid under Condition of Suppression of Its Endogenous Synthesis.
Long-term administration of pyridoxine to rats kept on a diabetogenic diet stimulating endogenous synthesis of xanthurenic acid resulted in minimal glycemia, less pronounced decrease in insulin content in β-cells, and more intensive excretion of xanthurenic acid with urine. Histological changes were observed in 23% pancreatic islets, whereas in rats not treated with pyridoxine, destruction and necrosis of 40-45% β-cells were found in 38% of studied islets.


Management of Skull Base Defects After Surgical Resection of Sinonasal and Ventral Skull Base Malignancies.
Over the past 2 decades, there has been a significant increase in the resection of larger and more complex ventral skull base malignancies. The resection of these lesions has resulted in the creation of larger and more difficult to repair skull base defects. There are many available options for ventral skull base reconstruction. Despite the variety of reconstructive options, the key objective is to eliminate any communication between the intracranial space and the sinonasal cavity. This article discusses some of the more common techniques currently used for repair of these skull base defects.


Sensory nerve conduction study in forearm segment of superficial radial nerve: standardization of technique.
Sensory nerve conduction velocity (SNCV) over the forearm segment of the superficial radial nerve was studied by an antidromic method in 76 nerves of 50 normal volunteers ranging in age from 16 to 70 years. The mean SNCVs were 53.3 +/- 3.6 m/sec (1 SD) and the mean amplitudes of sensory nerve action potentials were 15.2 +/- 9.8 microV (1 SD). This method of obtaining SNCV over the forearm segment of the superficial radial nerve is easily performed and the findings are consistent.


Neoadjuvant chemo-radiotherapy for cT3N0 rectal cancer: any benefit over upfront surgery? A propensity score-matched study.
Benefits of neoadjuvant chemo-radiotherapy (CRT) are well known for locally advanced and/or node-positive rectal cancer, but the best timing for CRT has been less explored for cT3N0 patients. The aim of the present study was to compare the 5-year disease-free survival (DFS) probability between neoadjuvant CRT and upfront surgery in patients affected by cT3N0 rectal cancer. A retrospective review of 105 patients affected by cT3N0 rectal cancer, staged by pelvic magnetic resonance imaging and treated at the National Cancer Institute of Milan between 2011 and 2017, was performed: 42 (40.0%) were treated by neoadjuvant CRT and 63 (60.0%) by upfront surgery. Propensity score matching was performed to avoid selection bias, and Cox multivariate regression was used to analyze outcomes. The 5-year DFS probability was 87.5% in neoadjuvant CRT patients vs. 90.0% in upfront surgery cases (Log-rank p = 0.76). The 5-year loco-regional recurrence-free survival probability was respectively 96.8% vs. 96.3% (Log-rank p = 0.954). On multivariate analysis, neoadjuvant CRT had no impact on DFS when compared to upfront surgery (adjusted HR 0.71, 95%CI 0.18-2.70, p = 0.613), but 61.9% of upfront surgery cases were treated by adjuvant chemo-radiation (adjusted HR 0.41, 95%CI 0.11-1.57, p = 0.196). The only independent predictor of improved DFS was age at diagnosis (adjusted HR 0.95, p = 0.017). CRT should be considered for cT3N0 patients, but its timing (neoadjuvant vs. adjuvant) seems not to affect the disease-free survival in the present cohort of patients.


Influence of different posts and cores on marginal adaptation, fracture resistance, and fracture mode of composite resin crowns on human mandibular premolars. An in vitro study.
To evaluate marginal adaptation, fracture modes, and loads to failure of composite crowns with different substructures on root-canal-treated premolars. Forty-eight mandibular teeth with single root canals were selected and assigned to six equal groups: group I, untreated; group II, root-canal-treated (RCT), access cavity restored with composite resin; group III, RCT, ferrule (2 mm), no post, standardized composite resin crown (SRCC); group IV, RCT, ferrule, glass fiber post, SRCC; group V, RCT, ferrule, zirconium post, SRCC; group VI, RCT, ferrule, cast gold post, SRCC. All teeth were subjected to thermocycling and mechanical loading (TCML) in a computer-controlled masticator (1,200,000 loads, 49N, 1.7Hz, 3000 temperature cycles of 5-50-5 degrees C). Marginal adaptation was evaluated before and after TCML with scanning electron microscopy at x200 at the tooth-to-luting-composite (IF1) and the luting-composite-to-crown (IF2) interfaces. After TCML, all specimens were loaded to failure in a universal testing machine at 0.5mm/min. A significant decrease in marginal adaptation was found in groups III and IV after TCML at IF1. A significant decrease was observed at IF2 in group V. Mean loads to failure did not differ significantly between the groups with SRCCs. Those of groups II, III, and IV did not differ from that of unrestored teeth. Half the specimens exhibited partial root fractures, independent of the substructures used. No deep or vertical root fractures were observed in any group. All studied posts had a positive effect on marginal adaptation at IF1, but not on failure modes or loads to failure of composite resin crowns.


Acid-sensing ion channels (ASICs) in the taste buds of adult zebrafish.
In detecting chemical properties of food, different molecules and ion channels are involved including members of the acid-sensing ion channels (ASICs) family. Consistently ASICs are present in sensory cells of taste buds of mammals. In the present study the presence of ASICs (ASIC1, ASIC2, ASIC3 and ASIC4) was investigated in the taste buds of adult zebrafish (zASICs) using Western blot and immunohistochemistry. zASIC1 and zASIC3 were regularly absent from taste buds, whereas faint zASIC2 and robust zASIC4 immunoreactivities were detected in sensory cells. Moreover, zASIC2 also immunolabelled nerves supplying taste buds. The present results demonstrate for the first time the presence of zASICs in taste buds of teleosts, with different patterns to that occurring in mammals, probably due to the function of taste buds in aquatic environment and feeding. Nevertheless, the role of zASICs in taste remains to be demonstrated.


Risk Factors of Extended Hospital Stay After One-Level Anterior Cervical Discectomy Fusion or Disc Replacement: Results from 1004 Patients in Food and Drug Administration Trials.
Extended length of stay (LOS) after surgery is costly to the health care system and can be distressing to the patient and family. Previous studies have shown conflicting data on factors associated with increased LOS and are limited by using multiple different surgeries. Our study seeks to analyze factors that are associated with extended LOS. The objective of this study was to analyze data from 2 Food and Drug Administration trials of one-level cervical surgery to identify risk factors that are associated with extended LOS in the hospital. Extended LOS was defined to be >1 day. Patients with LOS ≤1 day were compared with those with LOS >1 day. Data from the BRYAN and Prestige ST Trial (n = 1004) were analyzed. Subjects with LOS ≤1 day were compared with those with LOS >1 day. Variables analyzed for their effect on LOS included demographic characteristics, patient-reported outcome measures, preoperative medical conditions, preoperative neurologic status, and intraoperative factors. A total of 912 patients (90.84%) had an LOS ≤1 day and 92 patients (9.16%) had an extended LOS >1 day. Weak narcotic medication use (P = 0.021; odds ratio [OR], 1.72), Nurick gait (P = 0.019; OR, 1.796), and operative time (P < 0.0001; OR, 2.062) were found to significantly affect LOS. Nurick gait, operative time, and history of weak narcotic use are associated with extended hospital stay. These data may be useful in preoperatively counseling patients, developing quality metrics for hospitals, and helping create financial models for cost/diagnosis-related group reimbursement for single-level anterior cervical surgery.


Flow in the left anterior descending coronary artery in patients with migraine headache.
Migraine is a common neurovascular disorder characterized by attacks of severe headache, autonomic and neurologic symptoms. Migraine can affect many systems in the body, yet its effects on cardiovascular system are unclear. We hypothesized that migraine and coronary microvascular angina may be manifestations of a common systemic microvascular dysfunction and clinically associated. Forty patients with migraine and 35 healthy volunteers were included into the study. Using transthoracic Doppler echocardiography, coronary flow was visualized in the middle or distal part of the left anterior descending artery. Coronary diastolic peak flow velocities were measured with pulse wave Doppler at baseline and after dipyridamole infusion (0.56 mg/kg/4 min). Coronary flow reserve of <2 was considered normal. In addition, thorough 2-dimensional and Doppler echocardiographic examinations were also performed. Fifty-two women and 23 men were included. Coronary flow reserve was significantly lesser in the migraine group than in the control group (1.99 ± 0.3 vs 2.90 ± 0.5, p <0.05). In addition, mitral annular velocities were lower and the ratio of early mitral inflow velocity to early mitral annular velocity (E/E' lateral and E/E' septal) was higher in migraineurs than in the control group (p <0.05 for all), indicating diastolic function abnormalities in the migraine group. In conclusion, these findings suggest that there is an association between coronary microvascular dysfunction and migraine independently of the metabolic state of the patients. A common pathophysiologic pathway of impaired endothelial vasodilatation, vasomotor dysfunction, and increased systemic inflammatory factors may play a role in these 2 clinical conditions and could be the underlying cause of subclinical systolic and diastolic left ventricular dysfunction in migraineurs.


Severe food allergy reactions are associated with α-tryptase.
Increased TPSAB1 copy numbers encoding ⍺-tryptase are associated with severe reactions in adults with Hymenoptera venom allergy, systemic mastocytosis, and idiopathic anaphylaxis. The primary objective was to assess the association between ⍺-tryptase and severity of food allergy. A total of 119 subjects underwent tryptase genotyping; 82 of them were from an observational food allergy cohort at the National Institute of Allergy and Infectious Disease (NIAID), and 37 were from a cohort of children who reacted to peanut oral food challenge (OFC) at Lurie Children's Hospital of Chicago. The primary predictor was presence or absence of ⍺-tryptase. The primary outcomes for both cohorts were measures of severity of food allergy reaction. Secondary outcomes included OFC symptom scores (Bock/Practical Allergy [PRACTALL] and Severity Grading Score for Acute Reactions [SGSAR]). Correlation between total α-tryptase isoforms and OFC scores was also assessed to account for gene dosage effects. Among the subjects in the NIAID cohort, the presence of ⍺-tryptase was associated with a higher prevalence of food-triggered anaphylaxis than in those with only β-tryptase (P = .026). Similarly, only 1 of 6 subjects in the OFC cohort with only β-tryptase (17%) had a severe reaction, whereas 20 of 31 of subjects with α-tryptase (65%) had a severe reaction (P = .066). Subjects with ⍺-tryptase also had higher total SGSAR scores than did the subjects with no ⍺-tryptase (P = .003). In addition, there were also significant positive correlations between ⍺-tryptase isoform copy numbers and both higher total SGSAR and Bock/PRACTALL OFC scores (P = .008 and P = .003, respectively). The presence of α-tryptase in subjects is correlated with a higher prevalence of anaphylaxis or severe reaction to food than in subjects without any α-tryptase.


In vitro acaricidal activity of 1,8-cineole against Sarcoptes scabiei var. cuniculi and regulating effects on enzyme activity.
1,8-Cineole found in many essential oils is a monoterpene and acts as a repellent against Sarcoptes scabiei var. cuniculi. In the present study, the acaricidal activity of 1,8-cineole against S. scabiei var. cuniculi was evaluated and the acaricidal mechanism was also investigated by assaying enzyme activities. The results showed that the lethal concentration of 50% (LC50) value (95% confidence limit (CL)) and the lethal time of 50% (LT50) value (95% CL) of 1,8-cineole were 2.77 mg/mL and 3.606 h, respectively. The pathological changes under transmission electron microscopy showed that the morphology of the mitochondria was abnormal, the cell nuclear membrane was damaged, and the nuclear chromatin was dissoluted. The activities of superoxide dismutase (SOD), glutathione-s-transferases (GSTs), monoamine oxidase (MAO), nitric oxide synthase (NOS), and acetylcholinesterase (AChE) were significantly changed after treatment with 1,8-cineole for 4, 8, 12, and 24 h. SOD and GSTs are associated with the protection mechanism of scabies mites. And, the activities of SOD and GSTs were increased as compared with the control group. MAO, AChE, and NOS are associated with the nervous system of scabies mites. The activity of MAO was increased whereas the AChE was suppressed. The activity of NOS was suppressed in the high-dose group whereas increased in the middle-dose group and low-dose group. These results indicated that the mechanism of 1,8-cineole mainly attributed to the changes of these enzyme activities related to the nervous system of scabies mites.


What does the public think of placebo use? The Canadian experience.
Part of the National Placebo Initiative in Canada included public consultations, based on the belief that the views of the public should inform Canadian policy development on what constitutes appropriate placebo use. Public consultations took place nationally in 2003. A deliberative dialogue approach was used, or a structured discussion format designed to facilitate the consideration of complex issues and build consensus. The placebo debate was characterized as having 3 distinct approaches and each were explored. The first approach "Maximize Patient Protection" identified the need for experts to determine appropriate placebo use and that placebos should only be allowed under very restricted conditions. The second approach "Maximize Medical Knowledge" identified that placebos give essential information about the safety and efficacy of new drugs, and are appropriate when the rights, safety and well-being of research participants are ensured. The third approach "Maximize Patient Autonomy" identified that the current system of regulating placebo use is paternalistic and that patients should be able to define what is in their best interests and have more leeway to determine for themselves if they wish to participate in a placebo-controlled trial. Advantages and disadvantages of each approach were considered and feedback on what constitutes appropriate placebo use was sought. The major findings were that: PCTs were considered a valuable and acceptable part of advancing medical knowledge, research using placebos must be valid and justifiable; a patient-centred approach needs to be fostered; patient autonomy (choice) should be a first consideration and take clear precedence in trials of low to medium risk, patient protection (or health) may need to "trump" patient autonomy at higher levels of risk and/or patient vulnerability; placebos are not a violation of the duty of care as duty of care is best met by identifying a choice for patients, whenever a choice is available. These consultations clearly were not designed to produce conclusive evidence, but rather to provide some useful insights into what the public may think about placebo use; additional studies are indicated.


Postorthodontic lower incisor and canine inclination and labial gingival recession in adult patients : A prospective study.
The goal was to determine whether changes in the inclination of lower incisors and canines upon orthodontic treatment with fixed appliances poses a threat for labial gingival recession in adult patients. The sample of this prospective clinical trial consisted of 32 adult patients (mean age 25.08 ±6.50 years) treated with fixed appliances. Plaque and bleeding indices, probing pocket depth, clinical attachment level, gingival recession height (GR) and width (GRW), gingival thickness (GT), and keratinized tissue width were clinically recorded, while cone beam computed tomography (CBCT) was used to evaluate teeth inclination before (T1) and after treatment (T2). Oral hygiene, brushing habits, and smoking were controlled. During orthodontic treatment on 15 (8.33%) teeth (10 incisors and 5 canines), spontaneous complete improvement of pre-existing GR was observed. On 2 incisors, GR decreased and on 3 teeth GR did not change. Moreover, 1 incisor presented an increased GR, while 2 teeth developed new defects. Mean GR, GRW, and GT decreased significantly only on the incisors. Proclination of incisors and canines during treatment (compared with retroclination of the teeth) implicated a lower reduction in GR at T2: 0.19 mm (p = 0.034) and 0.18 mm (p = 0.037), respectively. Multiple regression analysis confirmed that more tooth proclination was associated with a higher risk for an increase in GR (p < 0.00). Properly planned changes in lower incisor and canine inclination can be carried out in adult patients without posing a high risk to labial gingival recessions if the individual periodontal biotype is respected. The reported outcomes underscore the orthodontic principle to keep tooth roots inside the alveolar bone.


Investigation on the microbial community of an accelerating stabilization landfill by aeration engineering.
The microbial community of the landfill undergoing aerobic stabilization process by aeration engineering was investigated. The municipal solid wastes (MSWs) were sampled from two aeration well sites with different landfill temperatures (65.5°C and 41.7°C) under higher and lower stabilization level. The physical component, chemical property, and microbial population of MSWs were analyzed and compared. The result showed that the phylum Firmicutes was dominant in the aerobic landfill; and the genus Weissella and Syntrophaceticus were more abundant in high, and low temperature site, respectively. The bacterial distribution showed difference on two temperature sites and four landfill depths, mainly affected by the ammonia-nitrogen and moisture content of MSWs. The ecological profiles of the microorganisms responded the aeration engineering were predicted. The anaerobic hydrolytic and acetogenic microorganisms were decreased in abundance, while the facultative Lactobacillus increased when the landfill under a higher stabilization level. The function abundances of methane oxidation, sulfide oxidation, and aerobic chemoheterotrophy were enriched by aeration engineering, which was the microbial mechanism for accelerating the stabilization process of landfill.


Mechanisms of psychopharmacological effects of granulocytic colony-stimulating factor during severe hypoxia.
Granulocytic colony-stimulating factor produced a strong therapeutic effect during encephalopathy of different genesis. The preparation improved the psychoneurological status and increased the number of neural precursors in the paraventricular area of cerebral hemispheres in animals.


Microbiological quality of ayib, a traditional Ethiopian cottage cheese.
One-hundred samples of ayib, a traditional Ethiopian cottage cheese, were purchased from Awassa market and analysed for their aerobic mesophilic counts, psychrotrophic counts, yeasts and molds, coliforms, spore-formers, enterococci, lactic acid bacteria. Listeria monocytogenes, staphylococci and Bacillus cereus. The majority of the samples showed counts of mesophilic aerobic bacteria, yeasts and enterococci of 10(8), 10(7) and 10(7) cfu/g. About 55% of the samples were positive for coliforms and faecal coliforms. Listeria spp. were not detected in any of the samples. B. cereus and S. aureus were isolated at varying frequencies but at low numbers (10(2)-10(3)). The pH value of the samples varied between 3.3 and 4.6 with about 40% having pH lower than 3.7.


[Acoustic neurinoma with preserved inner ear function. Interesting audiologic constellation of findings].
Neurofibromatosis (NF) is a syndrome with multiple neuromas. With the central form or NF2 very often bilateral acoustic neuromas are found. Tumours derive from Schwann cells of the eighth cranial nerve; symptoms are tinnitus, hearing loss and vertigo. Therapy is surgical, if possible with the protection of remaining hearing function. We report the case of a 28 year old female patient with neurofibromatosis type 2. After complete resection of the left AN and partial resection of the right AN the patient suffered from bilateral complete deafness, although almost normal DPOAE can be recorded on one side. Therefore we find the classical neural deafness with intact function of outer haircells (OHC).


Combined spinal-epidural anesthesia using epidural volume extension leads to faster motor recovery after elective cesarean delivery: a prospective, randomized, double-blind study.
Epidural volume extension (EVE) via a combined spinal-epidural (CSE) technique is the enhancement of a small-dose intrathecal block by epidural saline boluses. In this prospective, randomized, double-blind study, we compared the EVE technique with single-shot spinal anesthesia with respect to its sensory and motor block profile and hemodynamic stability. Sixty-two parturients (n = 31 in each group) undergoing elective cesarean deliveries were administered either spinal anesthesia with hyperbaric 0.5% bupivacaine 9 mg and fentanyl 10 microg or CSE comprising intrathecal hyperbaric 0.5% bupivacaine 5 mg with fentanyl 10 microg, followed by 0.9% saline 6.0 mL through the epidural catheter 5 min thereafter. In each group, the lowest systolic blood pressure (SBP), sensory block level to loss of pain from pinprick, and modified Bromage scores were recorded at 2.5-min intervals. The visual analog pain score (VAS), peak sensory block height, highest modified Bromage motor score, time for sensory regression to the tenth thoracic dermatome (T10), and motor block recovery were compared between groups. Both groups were comparable in demographic data, VAS scores, peak sensory block height, time for sensory regression to T10, and lowest SBP recorded. Patients in the EVE group demonstrated significantly faster motor recovery to modified Bromage 0 (73 +/- 33 min versus 136 +/- 32 min, P < 0.05). When compared with conventional, single-shot spinal anesthesia, epidural volume extension of a small-dose spinal block provides satisfactory anesthesia for cesarean delivery with only 55% of the bupivacaine dose required and is associated with faster motor recovery of the lower limbs.


A qualitative study of paramedics' attitudes to providing prehospital thrombolysis.
To explore paramedics' attitudes to administering prehospital thrombolysis (PHT). In-depth interviews with 20 paramedics were recorded and transcribed and analysed for emergent themes using the constant comparative method. Although there was a will to provide PHT because of its benefits to patients, its associated risks, aspects of pay and working conditions, and certain organisational factors undermined the willingness of some paramedics to administer thrombolysis. The eight minute response time standard is a competing imperative which can delay thrombolysis. A minority of paramedics are likely to be unwilling to deliver PHT unless countervailing imperatives are addressed.


Real-time Ultrasound Assessment of Astronaut Spinal Anatomy and Disorders on the International Space Station.
Back pain is one of the most common conditions of astronauts during spaceflight and is hypothesized to be attributed to pathologic anatomic changes. Ultrasound (US) represents the only available imaging modality on the International Space Station, but a formal US protocol for imaging the structures of the spinal column does not exist. This investigation developed a method of acquiring diagnostic-quality images of the anterior lumbar and cervical regions of the spine during long-duration spaceflight. Comprehensive spinal US examinations were conducted on 7 long-duration spaceflight astronauts before flight, in flight, and after flight and compared to preflight and postflight magnetic resonance imaging data. In-flight scans were conducted after just-in-time training assisted by remote expert tele-US guidance. Novice users were able to obtain diagnostic-quality spinal images with a 92.5% success rate. Thirty-three anomalous or pathologic findings were identified during the preflight US analysis, and at least 14 new findings or progressions were identified during the postflight US analysis. Common findings included disk desiccation, osteophytes, and qualitative changes in the intervertebral disk height and angle. Ultrasound has proven efficacy as a portable and versatile diagnostic imaging modality under austere conditions. We demonstrated a potential role for US to evaluate spinal integrity and alterations in the extreme environment of space on the International Space Station. Further investigations should be performed to corroborate this imaging technique and to create a larger database related to in-flight spinal conditions during long-duration spaceflight.


Validation of active surveillance criteria for pathologically insignificant prostate cancer in Asian men.
To validate the ability of contemporary active surveillance protocols to predict pathologically insignificant prostate cancer among Asian men undergoing radical prostatectomy. We retrospectively reviewed data on 132 patients eligible for any active surveillance criteria out of 450 patients that underwent radical prostatectomy at several institutions between 2006 and 2013. We validated the ability of seven contemporary active surveillance protocols to predict pathologically insignificant prostate cancer. Traditional and updated criteria to define pathologically insignificant prostate cancer were used. Predictive factors for pathologically insignificant prostate cancer were determined by logistic regression analysis. The predictive rate for updated pathologically insignificant prostate cancer of respective active surveillance criteria was 51% for Johns Hopkins Medical Institution, 41% for Prostate Cancer Research International: Active Surveillance Study, 39% for University of Miami, 32% for University of California, San Francisco, 32% for Memorial Sloan-Kettering Cancer Center, 31% for Kakehi and 27% for University of Toronto. Predictive rates for pathologically insignificant prostate cancer in Asian men were far lower than in USA men. On multivariate analysis, predictive factors of updated pathologically insignificant cancer was prostate volume (odds ratio 1.07, P = 0.004). By adding prostate volume to Prostate Cancer Research International: Active Surveillance Study criteria, the predictive rate for updated insignificant prostate cancer was improved up to 66.7%. Active surveillance can be carried out considering the clinical characteristics of prostate cancers depending on ethnicity, as current active surveillance criteria seem to have a lower predictive ability value of insignificant prostate cancer in Asian men compared with men in Western countries.


Life events and their impact on bladder control in children.
To investigate the relationship between incidence and nature of life events within families and age of bladder control acquisition in healthy children. Thirty-five parents of 36, 6-year-old children were interviewed using the Coddington life events questionnaire. The children had experienced a total of 185 life events (mean 5, median 4.5, range 1-12) before the time of dryness. The most common were related to childcare/occupation of parent (51%), illness/injury/death (24%), family composition (16%) and living conditions (9%). There was a strong correlation between the number of life events and the age of dryness; the more life events and the older the child was when experiencing them, the later the child became dry. The only single event that was significantly associated with a later age of dryness was the birth of a sister or brother. In general, children had reacted positively (39%) or neutrally, but to 30% of events there was a negative reaction. There was a correlation between the reaction of the child and adaptation to the life event, and if the child had difficulty adapting to an event, that child became day dry at a later age. Although life events are a natural part of daily life, this study supports the conclusion that a large number of events and events to which the child has difficulty adapting can be of importance for the age of acquisition of bladder control.


Pyrogenic action of endothelin in conscious rabbit.
Injection of 0.3 nmol/kg endothelin(ET)-1 into the ear vein of conscious rabbits induced a significant increase in body temperature. ETB receptor specific agonist, namely 4-Ala-ET-1, also caused an elevation of the body temperature in a dose-dependent manner by injection into the ear vein of rabbit. These results suggest that ET play important roles in regulation of body temperature through selective stimulation of ETB receptor.


Does an intracanal composite anchorage replace posts?
This study aims to assess the effectiveness of an intracanal composite anchorage to replace conventionally cemented titanium or bonded glass fibre posts. Post space preparation was performed up to depths of 6 mm (groups 1 and 2) and 3 mm (group 3) in root filled mandibular premolars. In group 1, titanium posts were cemented with zinc phosphate cement. Glass fibre posts were adhesively cemented in group 2 using a dual-cure composite resin. In group 3, intracanal anchorage was solely performed with a dual-cure composite. All teeth were restored with standardised direct composite crowns without a ferrule. After thermo-mechanical loading, static load was applied until failure. Fracture patterns were assessed, and a microscopic analysis was performed to analyse the occurrence of additional cracks. Group 2 revealed a significantly higher median fracture value (408 N) than groups 1 and 3, while no difference was detected between group 1 (290 N) and group 3 (234 N) (p = .1417). In group 3, the more favourable fracture patterns were observed. However, the majority of teeth within this fracture category revealed additional minor cracks of the root. Within the limitations of this study, adhesive intracanal anchorage to a depth of 3 mm with resin composite only has the same fracture resistance as titanium posts conventionally cemented to a depth of 6 mm. Even teeth with repairable main fractures exhibited additional dentinal cracks on the root. Additional dentinal root cracks in the teeth with repairable main fractures may considerably impair their longevity.


A previously unreported syndrome of multiple scalp whorls and associated anomalies.
A 13-month-old male infant with 14 hair whorls in the scalp, sparse frontal hair, wide forehead, ectropion, abnormal implantation of eyelashes, peculiar face and depigmented nipples is reported. Other aspects of his physical and mental development were within normal limits. The constellation of clinical features in this patient appear to represent a previously undescribed syndrome.


Neutrophil chemotaxis and receptor expression in clinical septic shock.
To examine the hypothesis that neutrophil chemotaxis to interleukin-8 (IL-8) is reduced in septic shock. Surface expression of neutrophil CXC chemokine receptors and the adhesion molecule CD11b were also examined and associations between disease severity, gas exchange and receptor expression were studied. Prospective cohort clinical study. SETTING. Intensive care unit in a tertiary referral teaching hospital. Patients with septic shock ( n=15) and healthy controls ( n=8) were studied. Daily (for 5 consecutive days) flow cytometric measurements of chemokine and beta integrin surface expression. "In vitro" neutrophil chemotaxis to IL-8 was also compared between patients with sepsis and healthy controls. CXCR2 expression significantly fell, CD11b expression increased and CXCR1 expression was unchanged throughout the study in the septic group compared with healthy controls. CD11b positively correlated with increasing APACHE II scores ( p<0.0001) and worsening PaO(2)/FIO(2) ratios ( p<0.0001). CXCR2 expression negatively correlated with both APACHE II scores ( p=0.016) and PaO(2)/FIO(2) ratios ( p=0.01). There was no correlation between CXCR1 expression and either APACHE II score or PaO(2)/FIO(2) ratios. Chemotaxis to IL-8 was reduced in patients with sepsis compared with healthy volunteers. Surface expression of the chemokine receptor CXCR2 and the beta-integrin CD11b, but not CXCR1, were reduced on neutrophils isolated from patients with septic shock compared with healthy controls. Chemotaxis to IL-8 was also reduced in neutrophils from septic patients compared with healthy controls. The changes in receptor expression correlated with measures of disease severity.


The Old Supracondylar Fracture of Femur Treated by Gradual Deformity Correction Using the Ilizarov Technique Followed by the Second-Stage Internal Fixation in an Elderly Patient With Osteoporosis.
The supracondylar nonunion of femur in elderly individuals is rare and challenging to manage. Nothing in English literatures or guidelines is available regarding this particular fracture characterized by osteoporosis, soft-tissue contracture, shortening, and joint stiffness. We report a case of an elderly patient with a supracondylar nonunion of the femur, which was successfully treated using staged Ilizarov techniques and dual plating. An 84-year-old female patient was admitted to our orthopedic department for her pain and soft-tissue swelling around the right knee with claudication and shortening deformity of the affected extremity. She denied any specific history of trauma and had sought traditional Chinese medical attention for 6 months before she presented to our hospital. Diagnosis of the right femoral supracondylar nonunion was made based on the X-ray and computed tomography. Ilizarov external fixator was carried out for successive and slow distraction and gradual correction of the shortening deformity, in consideration of the nonunion was still present. Subsequently, internal fixation with dual plating of the distal femur was performed. Excellent function and patient satisfaction were observed at 6 months of follow-up. The protocol of Ilizarov technique with subsequent internal fixation of dual plating seems to be an efficient solution to the supracondylar nonunion of femur in elderly patients with osteoporosis. The advantage of the protocol is that it allows knee joint motion, avoids neurovascular complications, and gentle correction of soft-tissue contractures.


Stroke inpatient rehabilitation: a comparison across age groups.
To examine and compare the inpatient stroke rehabilitation experience of older adults (> or = 75 years) with that of young adults (< 65 years) and young-old adults (65-74 years). Cross-sectional descriptive study. A large university-affiliated free-standing rehabilitation hospital. 260 adults who were admitted to inpatient stroke rehabilitation with a primary diagnosis of recent (< 120 days) stroke (ICD9 430-436). Demographic data, diagnosis, time between stroke onset and rehabilitation admission, discharge disposition, and functional status on admission and discharge were obtained from the patient's medical record. Treatment intensity and type, length of stay, and primary payment source data were obtained from the patient's billing record. Three-month mortality data were available from the hospital's routine follow-up survey. Compared with the younger adults (< 65 yrs and 65-75 years), the older adults (> or = 75 years) were admitted to rehabilitation earlier and with comparable cognitive but poorer motor function. Rehabilitation treatment intensity (per day) and type were similar across age groups, but the older adults (> or = 75 years) had significantly shorter rehabilitation stays. Three-month survival was comparable across age groups, but the older adults (> or = 75 years) had poorer motor function at discharge and were more often discharged to a nursing home or required a paid caregiver. Age-associated factors may influence inpatient stroke rehabilitation referral, treatment, and outcome, particularly for patients over age 75. The cumulative effects of frailty and co-morbid disease upon stroke disability and treatment are possible explanations for the findings. The study provides evidence of a need for further investigation of stroke rehabilitation strategies for adults over 75 years old.


Evaluation of L6, an anti-carcinoma murine monoclonal antibody, in tumor-bearing nude mice.
L6 is a murine monoclonal antibody (MAb) binding to cells of most human carcinomas, mediating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and inhibiting tumor growth in nude mice [10]. Fab and F(ab')2 fragments of L6, as well as intact MAb, have been evaluated for immunospecific localization in nude mice xenografted with a human lung carcinoma. They were compared with preparations of an isotype-matched control immunoglobulin, P1.17, after labelling with 125I or 131I. L6 Fab fragments prepared from MAb L6 and labelled with 67Ga via desferrioxamine were also tested. The data suggest that MAb L6 may be useful for in vivo detection of human carcinomas.


Opioids for non-operable osteoarthritis and soft-tissue rheumatism.
Reviews of oral opioid trials have shown that many side-effects need to be considered when treating patients with non-operable osteoarthritis and soft-tissue problems. European and American guidelines recommend their use with or without paracetamol. The controversy surrounding the use of non-steroidal anti-inflammatory drugs/cyclo-oxygenase-2 inhibitors is limiting physician and patient choices. There is a great need for alternative medication or ways of using current compounds.


Improved treatment completion for tuberculosis patients: The case for a dedicated social care team.
The increasing social needs of people with Tuberculosis (TB), and the poor adherence to anti-TB therapy (ATT) associated with homelessness, drug or alcohol abuse, and prison history, led us to introduce a social care team (SCT) to support patient engagement with care within this low TB incidence setting. Using a risk assessment, patients with social risk factors (SRF) for non-adherence to ATT are identified and a referral made to the SCT, who then provide intensive casework support for areas including homelessness, housing, benefits, debt and immigration. Retrospective data analysis of the social care database from 2017 to 2019 was conducted. Patients who were (n = 170) and were not referred to the SCT (n = 734) were compared. Patients referred were significantly more likely to complete treatment for TB than those not (88.2% versus 77.7% respectively, p = 0.0025), irrespective of receipt of Directly/Video Observed Therapy and adjusting for confounders. This paper demonstrates important evidence for the positive impact of a dedicated SCT within a TB service, and these improved treatment outcomes provide a strong argument for development of similar SCTs within UK TB services and similar healthcare settings.


A multi-centre survey on hospital malnutrition: result of PNSI study.
Disease-related malnutrition is associated with adverse outcomes such as increased rates of morbidity and mortality, prolonged hospital stay, and extra costs of health care. This study was conducted to assess nutritional status among patients and to determine the risk factors for malnutrition in Iran university f. Persian Nutritional Survey In Hospitals (PNSI) was a cross-sectional study that conducted in 20 university hospitals across Iran. All the patients with age range of 18 to 65 years, who were admitted or discharged, were assessed by subjective global assessment (SGA). In total, 2109 patients were evaluated for malnutrition. Mean values of age and body mass index were 44.68 ± 14.65 years and 25.44 ± 6.25 kg/m2, respectively. Malnutrition (SGA-B & C) was identified in 23.92% of the patients, 26.23 and 21% of whom were among the admitted and discharged patients, respectively. The highest prevalence of malnutrition was in burns (77.70%) and heart surgery (57.84%) patients. Multivariate analysis presented male gender (OR = 1.02, P < 0.00), malignant disease (OR = 1.40, P < 0.00), length of hospital stay (OR = 1.20, P < 0.00), and polypharmacy (OR = 1.06, P < 0.00) as independent risk factors for malnutrition. Malnutrition was not associated with age (P = 0.10). This study provides an overall and comprehensive illustration of hospital malnutrition in Iran university hospitals, finding that one out of four patients were malnourished; thus, appropriate consideration and measures should be taken to this issue.


A competitive ELISA for the detection of group-specific antibodies to African horse sickness virus.
A competition enzyme-linked immunosorbent assay (ELISA) has been developed for the rapid identification and quantification of antibodies against African horse sickness (AHS) in sera from solipeds. The data showed the ELISA to be sensitive, specific and reliable. More than 1600 sera from 37 different countries were examined and results compared with those obtained by agar gel immuno-diffusion (AGID) tests. In no case did any of 775 sera from countries where AHS has never been reported and where AHS vaccines are not used, record an ELISA titre greater than 4. A titre equal to or greater than 8 was considered positive. Using this criterion, 96.3% of sera tested in both assays were in agreement. Doubtful results by AGID (1.7%) were clearly defined in terms of positivity and negativity by ELISA. This ELISA is suited for the rapid laboratory confirmation of AHS and should be considered as a replacement for the traditional AGID test.


High fat diet attenuates glucose-dependent facilitation of 5-HT3 -mediated responses in rat gastric vagal afferents.
Glucose regulates the density and function of 5-HT3 receptors on gastric vagal afferent neurones. Diet-induced obesity compromises the excitability and responsiveness of vagal afferents. In this study, we assessed whether exposure to a high fat diet (HFD) compromises the glucose-dependent modulation of 5-HT responses in gastric vagal afferents prior to the development of obesity. We show that HFD does not alter the response of gastric vagal afferent nerves and neurones to 5-HT but attenuates the ability of glucose to amplify 5-HT3-induced responses. These results suggest that glucose-dependent vagal afferent signalling is compromised by relatively short periods of exposure to HFD well in advance of the development of obesity or glycaemic dysregulation. Glucose regulates the density and function of 5-HT3 receptors on gastric vagal afferent neurones. Since diet-induced obesity attenuates the responsiveness of gastric vagal afferents to several neurohormones, the aim of the present study was to determine whether high fat diet (HFD) compromises the glucose-dependent modulation of 5-HT responses in gastric vagal afferents prior to the development of obesity. Rats were fed control or HFD (14% or 60% kilocalories from fat, respectively) for up to 8 weeks. Neurophysiological recordings assessed the ability of 5-HT to increase anterior gastric vagal afferent nerve (VAN) activity in vivo before and after acute hyperglycaemia, while electrophysiological recordings from gastric-projecting nodose neurones assessed the ability of glucose to modulate the 5-HT response in vitro. Immunocytochemical studies determined alterations in the neuronal distribution of 5-HT3 receptors. 5-HT and cholecystokinin (CCK) induced dose-dependent increases in VAN activity in all rats; HFD attenuated the response to CCK, but not 5-HT. The 5-HT-induced response was amplified by acute hyperglycaemia in control, but not HFD, rats. Similarly, although 5-HT induced an inward current in both control and HFD gastric nodose neurones in vitro, the 5-HT response and receptor distribution was amplified by acute hyperglycaemia only in control rats. These data suggest that, while HFD does not affect the response of gastric-projecting vagal afferents to 5-HT, it attenuates the ability of glucose to amplify 5-HT effects. This suggests that glucose-dependent vagal afferent signalling is compromised by short periods of exposure to HFD well in advance of obesity or glycaemic dysregulation.


Polymorphisms in the MDM2 gene and risk of malignant bone tumors: a meta-analysis.
There are several studies published to assess the associations of murine double minute 2 (MDM2) genetic polymorphisms with risk of malignant bone tumors, but they reported contradictory results and failed to confirm a strong and consistent association. To assess the evidence regarding the associations of MDM2 genetic polymorphisms with the risk of malignant bone tumors, we conducted a meta-analysis of epidemiological studies. The pooled odds ratio (OR) with its 95% confidence intervals (95% CI) was used to assess these possible associations. Four studies with a total of 3,958 individuals were finally included the meta-analysis. Meta-analysis of two studies on MDM2 SNP309 polymorphism showed that MDM2 SNP309 polymorphism was associated with an increased risk of malignant bone tumors (G versus T: OR = 1.72, 95% CI 1.35-2.20, P < 0.001; GG versus TT: OR = 2.64, 95% CI 1.59-4.39, P < 0.001; GG/GT versus TT: OR = 1.87, 95% CI 1.33-2.62, P < 0.001; GG versus TT/GT: OR = 2.20, 95% CI 1.38-3.51, P = 0.001). Meta-analysis of those two studies on MDM2 rs1690916 polymorphism showed that MDM2 rs1690916 minor allele A was associated with decreased risk of malignant bone tumors (OR = 0.60, 95% CI 0.46-0.77, P < 0.001). Meta-analyses of available data show that there are significant associations of MDM2 SNP309 polymorphism and MDM2 rs1690916 polymorphism with malignant bone tumors.


CAD/CAM fabricated complete dentures: concepts and clinical methods of obtaining required morphological data.
The clinical impression procedures described in this article provide a method of recording the morphology of the intaglio and cameo surfaces of complete denture bases and also identify muscular and phonetic locations for the prosthetic teeth. When the CAD/CAM technology for fabricating complete dentures becomes commercially available, it will be possible to scan the denture base morphology and tooth positions recorded with this technique and import those data into a virtual tooth arrangement program where teeth can be articulated and then export the data to a milling device for the fabrication of the complete dentures. A prototype 3-D tooth arrangement program is described in this article that serves as an example of the type of program than can be used to arrange prosthetic teeth virtually as part of the overall CAD/CAM fabrication of complete dentures.


Accurate Proteoform Identification and Quantitation Using pTop 2.0.
The remarkable advancement of top-down proteomics in the past decade is driven by the technological development in separation, mass spectrometry (MS) instrumentation, novel fragmentation, and bioinformatics. However, the accurate identification and quantification of proteoforms, all clearly-defined molecular forms of protein products from a single gene, remain a challenging computational task. This is in part due to the complicated mass spectra from intact proteoforms when compared to those from the digested peptides. Herein, pTop 2.0 is developed to fill in the gap between the large-scale complex top-down MS data and the shortage of high-accuracy bioinformatic tools. Compared with pTop 1.0, the first version, pTop 2.0 concentrates mainly on the identification of the proteoforms with unexpected modifications or a terminal truncation. The quantitation based on isotopic labeling is also a new function, which can be carried out by the convenient and user-friendly "one-key operation," integrated together with the qualitative identifications. The accuracy and running speed of pTop 2.0 is significantly improved on the test data sets. This chapter will introduce the main features, step-by-step running operations, and algorithmic developments of pTop 2.0 in order to push the identification and quantitation of intact proteoforms to a higher-accuracy level in top-down proteomics.


Research methods from social science can contribute much to the health sciences.
Research methods from social science, such as social network analysis, random coefficient modeling, and advanced measurement techniques, can contribute much to the health sciences. There is, however, a slow rate of transmission of social science methodology into the health sciences. This paper identifies some of the barriers for adoption and proposes ideas for the future. Commentary. Contributions of social science to the health sciences are not always recognized as such. It may help if the professional profile of social science in the health sciences would be higher and if its focus would be more on making useful predictions. Clinical epidemiologists may assume that their discipline includes all relevant methods and that social science is largely based on qualitative research. These perceptions need to be challenged in order to widen the scope of clinical epidemiology and include relevant methods from other sciences. New methods help to ask new research questions and to provide better to old questions. This paper has sketched challenges for both social science researchers and clinical epidemiologists.