Stability of the Liquid Water Phase on Mars: A Thermodynamic Analysis Considering Martian Atmospheric Conditions and Perchlorate Brine Solutions.
The stability of the liquid water phase on Mars has been examined on the basis of fundamental thermodynamic principles. The analysis considers the atmospheric pressure and temperature conditions prevalent on Mars. Because of the very low atmospheric pressure on Mars, water cannot exist in the liquid form. However, salt dissolution can reduce the freezing point and elevate the boiling point of aqueous solutions. This is interesting in the light of the discovery of perchlorate, sulphate, sodium, potassium, and calcium ions over the Martian surface. The effect of different perchlorate salts on the freezing and boiling points of water while considering their saturation solubility under varying ionic conditions is key to this analysis. It is shown that under an average atmospheric pressure of 600 Pa, the saturated solution of sodium perchlorate (NaClO4) is stable in the liquid phase in the temperature range between 240 and 275 K. The triple point of water under this condition is shifted to 269 K with a saturation solubility of 14.4 mass % of the salt. However, a saturated solution of magnesium perchlorate (Mg(ClO4)2) renders this temperature range wider from 198 to 296 K, with the triple point being located at 269 K (salt saturation at 13.5 mass % salt). In case the water is contaminated with a mixture of these salts, an increased stability is predicted for liquid water down to 180 K and up to at least 298 K. This is caused by the increased ionic strength that enhances the freezing point depression and boiling point elevation of the solution. Thus, in the extreme and uneventful conditions of saturation by mixtures of salts, liquid water can be stable on Mars between 180 K and at least up to 298 K. Below this temperature, water exists as a glacier and above, as steam only.


The links between medical school of Bologna and Ionian Academy.
The Ionian Academy, on the British dominion island of Corfu (Kerkyra), was founded in 1824 and his Medical School functioned during two separate periods (1824-1828, 1844-1865). It was the first Greek University. Among the 15 professors of the Academy's Medical School, 12 studied at various Italian universities. In particular, three of them, G. Therianos, Professor of Comparative Anatomy and Experimental Physics, G. Grassetti, Professor of Physiology and S. Arvanitakis, Professor of Pathology and Hygiene, either studied or graduated at the Medical school of Bologna University. Another Bologna graduate, Rokkos Pylarios, was appointed to the chair of Professor in Surgery and Gynecology - though it is not known if he actually took up the position. It is concluded that the Medical School of Bologna, as a centre of original medical study, contributed significantly to the foundation and development of the Ionian Academy. Moreover, the Greek physicians who had studied either at the University of Bologna or at the Ionian Academy, contributed to the renaissance of neohellenic medicine during the 19th century.


Soluble IL2 receptor serum levels and epidermal cytokines in mycosis fungoides and related disorders.
We examined the immune activation in 20 patients with mycosis fungoides, 6 patients with erythrodermia of unknown origin (Pré-Sézary's syndrome), 5 with lymphomatoid papulosis, 4 with parapsoriasis, 2 with Sézary's syndrome, and 2 with actinic reticuloid, by measuring soluble interleukin-2 receptor levels in serum. In Mycosis fungoides we observed normal levels in 3 patients (less than 500 units/ml), between 500 and 1000 units/ml in 9 patients, and greater than 1000 units/ml in 5 patients. Four of these 5 patients died within one year after this observation, as did 2 patients with Pré-Sézary and Sézary's syndrome, respectively, who had a similarly large increase in sIL2R. Although sIL2R is not a specific parameter for cutaneous T-cell lymphoma, a value above 1000 units/ml is correlated with clinical disease activity and is a serious prognostic parameter. We also studied cytokine activity in epidermal homogenates from 9 patients with Mycosis fungoides and one patient with Sézary's syndrome. We observed interleukin-1-like activity within the normal range for healthy skin. However, we also observed in the same epidermal homogenates a T-lymphocyte chemotactic activity in patients with stage II, but not in stage I. The nature of this activity is not yet fully elucidated, but it may be an important biological factor for the epidermal T-cell accumulation in this disorder.


A histological and immunohistochemical study of the changes induced in the brains of white mice by infection with Toxoplasma gondii.
The topography and the severity of the brain lesions induced in male and female white mice 1-6 weeks following inoculation with Toxoplasma gondii were studied by conventional histological and peroxidase-antiperoxidase (PAP) immunohistochemical techniques. The medulla oblongata and fourth ventricle were the most severely damaged areas of the brain, while the cerebellum was only minimally involved in this only in the later stages of the disease. Toxoplasma cysts were revealed by the PAP method as early as 2 weeks after infection. The number of cysts and the severity of the lesions increased gradually each week following inoculation. The lymphoplasmacytic element in the lesions was less intense in male than in female mice. The significance of these findings in respect to the possible immunological pathogenesis of CNS toxoplasmic changes is discussed. A correlation of the experimental findings with the known neurologic manifestations of the disease is also attempted. The advantage of the PAP method in the study of toxoplasmic infection is stressed.


Oligomerization, conformational stability and thermal unfolding of Harpin, HrpZPss and its hypersensitive response-inducing c-terminal fragment, C-214-HrpZPss.
HrpZ-a harpin from Pseudomonas syringae-is a highly thermostable protein that exhibits multifunctional abilities e.g., it elicits hypersensitive response (HR), enhances plant growth, acts as a virulence factor, and forms pores in plant plasma membranes as well as artificial membranes. However, the molecular mechanism of its biological activity and high thermal stability remained poorly understood. HR inducing abilities of non-overlapping short deletion mutants of harpins put further constraints on the ability to establish structure-activity relationships. We characterized HrpZPss from Pseudomonas syringae pv. syringae and its HR inducing C-terminal fragment with 214 amino acids (C-214-HrpZPss) using calorimetric, spectroscopic and microscopic approaches. Both C-214-HrpZPss and HrpZPss were found to form oligomers. We propose that leucine-zipper-like motifs may take part in the formation of oligomeric aggregates, and oligomerization could be related to HR elicitation. CD, DSC and fluorescence studies showed that the thermal unfolding of these proteins is complex and involves multiple steps. The comparable conformational stability at 25°C (∼10.0 kcal/mol) of HrpZPss and C-214-HrpZPss further suggest that their structures are flexible, and the flexibility allows them to adopt proper conformation for multifunctional abilities.


Pre- and Intraoperative Predictors of Delirium after Open Abdominal Aortic Aneurysm Repair.
We reviewed our series of patients who underwent open abdominal aortic aneurysm (AAA) repair and constructed a prediction model for postoperative delirium. 397 patients who underwent open AAA repair at our institution between April 2005 and June 2013 were retrospectively reviewed. Postoperative delirium was diagnosed from the patients' medical records according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria. Mental alterations resulting from postoperative cerebrovascular events or preexisting mental disorders were excluded. Parameters with significant differences on univariate analysis were subjected to a logistic regression analysis. There were 46 patients (11.5%) diagnosed with postoperative delirium. The following parameters were significant in the univariate analysis: age, history of stroke, hyperlipidemia, forced expiratory volume in 1 s (FEV1), percent vital capacity (%VC), and blood urea nitrogen (BUN) level. A logistic regression analysis revealed that an age ≥70 years (odds ratio [95% confidence interval], 3.342 [1.437-7.774]), blood loss ≥1517 mL (2.707 [1.359-5.391]), and the absence of hyperlipidemia (2.154 [1.060-4.374]) were significant risk factors. Older patients with substantial intraoperative blood loss require highly vigilant postoperative care. Further studies are necessary to elucidate the relationship between cholesterol and delirium.


The 2019 Flemish consensus on screening for overt diabetes in early pregnancy and screening for gestational diabetes mellitus.
Screening for gestational diabetes mellitus (GDM) is important to improve pregnancy outcomes and to prevent type 2 diabetes after pregnancy. The 'International Association of Diabetes and Pregnancy Study Groups' (IADPSG) recommends a universal one-step approach with the 75 g oral glucose tolerance test (OGTT) for screening of GDM. The IADPSG recommendation remains controversial due to the important increase in GDM prevalence and increased workload. After review of the latest evidence and based on data from the 'Belgian Diabetes in Pregnancy' study, members of the Diabetes Liga, the Flemish associations of general physicians (Domus Medica), obstetricians (VVOG), midwives (VVOB), diabetes nurse educators (BVVDV) and clinical chemists (RBSLM) have reached a new consensus on screening for GDM in Flanders. This new consensus recommends universal screening for overt diabetes when planning pregnancy or at the latest at first prenatal contact, preferably by measuring the fasting plasma glucose by using the same diagnostic criteria as in the non-pregnant state. In women with impaired fasting glycaemia, but also in normoglycemic obese women and women with a previous history of GDM, lifestyle counselling is advised with screening for GDM with a 75 g OGTT at 24 weeks. In all other women, we recommend a two-step screening strategy with a 50 g glucose challenge test (GCT) at 24 weeks followed by a 75 g OGTT when the glucose level 1 hour after the GCT ≥130 mg/dl. Diagnosis of GDM is made using the IADPSG criteria for GDM. Postpartum screening for subsequent glucose abnormalities should be advocated and organized for every woman with GDM.


Negative dielectrophoresis spectroscopy for rare analyte quantification in biological samples.
We propose the use of negative dielectrophoresis (DEP) spectroscopy as a technique to improve the detection limit of rare analytes in biological samples. We observe a significant dependence of the negative DEP force on functionalized polystyrene beads at the edges of interdigitated electrodes with respect to the frequency of the electric field. We measured this velocity of repulsion for 0% and 0.8% conjugation of avidin with biotin functionalized polystyrene beads with our automated software through real-time image processing that monitors the Rayleigh scattering from the beads. A significant difference in the velocity of the beads was observed in the presence of as little as 80 molecules of avidin per biotin functionalized bead. This technology can be applied in the detection and quantification of rare analytes that can be useful in the diagnosis and the treatment of diseases, such as cancer and myocardial infarction, with the use of polystyrene beads functionalized with antibodies for the target biomarkers.


Structural diversity of metal-organic self-assembly assisted by chlorine.
From the combination of STM imaging and DFT calculations, we show that both alkali metal and halogens interact with different sites of the target molecules resulting in structural formation in a synergistic way. The elementary metal-organic motifs are connected by Cl in a variety of fashions demonstrating structural diversity.


Interval-Valued Model Level Fuzzy Aggregation-Based Background Subtraction.
In a recent work, the effectiveness of neighborhood supported model level fuzzy aggregation was shown under dynamic background conditions. The multi-feature fuzzy aggregation used in that approach uses real fuzzy similarity values, and is robust for low and medium-scale dynamic background conditions such as swaying vegetation, sprinkling water, etc. The technique, however, exhibited some limitations under heavily dynamic background conditions, as features have high uncertainty under such noisy conditions and these uncertainties were not captured by real fuzzy similarity values. Our proposed algorithm is particularly focused toward improving the detection under heavy dynamic background conditions by modeling uncertainties in the data by interval-valued fuzzy set. In this paper, real-valued fuzzy aggregation has been extended to interval-valued fuzzy aggregation by considering uncertainties over real similarity values. We build up a procedure to calculate the uncertainty that varies for each feature, at each pixel, and at each time instant. We adaptively determine membership values at each pixel by the Gaussian of uncertainty value instead of fixed membership values used in recent fuzzy approaches, thereby, giving importance to a feature based on its uncertainty. Interval-valued Choquet integral is evaluated using interval similarity values and the membership values in order to calculate interval-valued fuzzy similarity between model and current. Adequate qualitative and quantitative studies are carried out to illustrate the effectiveness of the proposed method in mitigating heavily dynamic background situations as compared to state-of-the-art.


Low perinatal autopsy rate in Malaysia: time for a change.
Our objectives were to determine the perinatal autopsy rate in a tertiary hospital in Malaysia and to quantify the value of the perinatal autopsy. All stillbirths, miscarriages, therapeutic abortions, and neonatal deaths between January 1, 2004, and August 31, 2009, were identified from the archives. The autopsy findings were compared with the clinical diagnoses. The autopsy reports were also reviewed to determine if it would be possible to improve the quality of the autopsies. There were 807 perinatal deaths, of which 36 (4.5%) included an autopsy. There were ethnic differences in the rate of autopsy, with the lowest rate among the Malays. The autopsy provided the diagnosis, changed the clinical diagnosis, or revealed additional findings in 58.3% of cases. Ancillary testing, such as microbiology, chromosomal analysis, and biochemistry, could improve the quality of the autopsy. This study provides further data on the perinatal autopsy rate from an emerging and developing country. It reaffirms the value of the perinatal autopsy. Attempts must be made to improve on the low autopsy rate while recognizing that the performance of autopsies can be enhanced through the use of ancillary testing.


A novel monoclonal antibody dependent on domain 5 of the platelet-derived growth factor beta receptor inhibits ligand binding and receptor activation.
Platelet derived growth factor (PDGF) induces activation of the protein tyrosine kinase domain of the PDGF receptor, resulting in receptor dimerization and the initiation of mitogenesis in responsive cells. In order to identify domains of the receptor involved in these processes, a panel of monoclonal antibodies (MAbs) against the extracellular region of the human PDGF receptor was developed and screened to identify which of these specifically block PDGF binding. One of these, MAb 2A1E2, binds PDGF beta receptor with high affinity and blocks PDGF BB binding in a whole cell binding assay with an IC 50 of 0.1 nM. Inhibition of binding results in the inhibition of ligand-induced receptor phosphorylation, dimerization and mitogenesis in cells expressing the PDGF beta receptor. MAb 2A1E2 has been mapped to the fifth Ig domain of the PDGF beta receptor, implying that this domain is important for ligand binding, dimerization and/or activation. The potency of MAb 2A1E2 for inhibiting PDGF BB binding indicates that this antibody is ideally suited to identify and characterize PDGF BB-induced biological responses.


Influence of previous acid etching on bond strength of universal adhesives to enamel and dentin.
The objective of this study was to evaluate the effect of acid pretreatment on the bond strength of composite resin bonded to enamel and dentin with 2 different universal self-etching adhesives. The null hypothesis was that the acid treatment performed prior to adhesive application would not significantly change the bond strength to enamel or dentin for either universal adhesive tested. A sample of 112 bovine incisors were selected and embedded in acrylic resin. Half were ground until a flat enamel surface was obtained, and the other half were polished until a 6 × 6-mm area of dentin was exposed, resulting into 2 groups (n = 56). The enamel and dentin groups were divided into 2 subgroups according to the adhesive system applied: Futurabond U or Scotchbond Universal. Each of these subgroups was divided into 2 additional subgroups (n = 14); 1 subgroup received phosphoric acid pretreatment, and 1 subgroup did not. The bond strength was assessed with a microtensile test. Data from enamel and dentin specimens were analyzed separately using 1-way analysis of variance. The acid pretreatment did not significantly change the bond strength of the adhesives tested, either to enamel (P = 0.4161) or to dentin (P = 0.4857). The acid etching pretreatment did not affect the bond strength to dentin and enamel when the tested universal multipurpose adhesive systems were used.


Immunopathology of thrombocytopenia in experimental malaria.
An early thrombocytopenia was observed in CBA mice during acute infection with Plasmodium berghei. This was associated with an increase in bone marrow megakaryocytes and a reduction of normal syngeneic 111Indium-labelled platelet life span. Malaria-induced thrombocytopenia was thus considered to be the result of increased peripheral platelet destruction rather than central hypoproduction. The occurrence of thrombocytopenia was modulated by T-cell depletion. Indeed, thymectomized, irradiated or anti-CD4 monoclonal antibody-treated mice failed to develop thrombocytopenia, although they were infected to the same extent. Conversely, a significant thrombocytopenia was observed in thymectomized mice reconstituted with CD4+ T cells. During the course of infection, a significant inverse correlation was found between platelet counts and platelet-associated IgG. Normal mice passively transferred with serum from syngeneic malaria-infected mice developed thrombocytopenia. The possibility to raise monoclonal anti-platelet antibodies from P. berghei-infected animals further suggested a role for an antibody-mediated platelet destruction during acute murine malaria infection. These results indicate that in murine malaria, thrombocytopenia is mediated by immune mechanisms and that CD4+ T cells might be significantly involved.


Bioactive DOPA melanin isolated and characterised from a marine actinobacterium Streptomyces sp. MVCS6 from Versova coast.
The melanin pigment produced from Streptomyces sp., MVCS6 was isolated and dihydroxyphenyalanine (DOPA) melanin compound was biochemically identified and spectroscopically characterised (ultraviolet and FT-IR). DOPA melanin showed a promising activity as an antibacterial natural product against 12 pathogenic bacteria from hospital isolations, particularly, against Pseudomonas aeruginosa RMMH7 (inhibition zone of 18 ± 0.02 at 30 μg/disc, and MIC of 10 ± 0.02 μg/mL) and Vibrio parahaemolytics RMMH12 (inhibition zone of 15 mm ± 0.03 at 30 μg/disc, and MIC of 14 ± 0.02 μg/mL). Moreover, in vitro evaluation of reducing power (Ascorbic Acid Equivalent (160 μg/mL)), DPPH radical-scavenging (89%), NO-scavenging (72%) and lipid peroxidation activities (89.6%) were determined. Cytotoxicity of DOPA melanin against cervical cancer cell line showed a dose-response activity, and IC50 value was found to be 300 μg/mL. These results would open the way to propose Streptomyces sp. MVCS6 as a promising source of bioactive eumelanin with therapeutic potential in medicine.


Cholesteatoma induction. Consequences of external auditory canal ligation in gerbils, cats, hamsters, guinea pigs, mice and rats.
Surgical ligation of the external auditory canals of Mongolian gerbils produces aural cholesteatomas that are similar to spontaneous gerbilline cholesteatomas. These experimental cholesteatomas expand rapidly, medially displacing the tympanic membrane and eroding bone. Less than 2 months after ligation, half these cholesteatomas are in contact with the bony prominence of the cochlea. Ligation-induced formation of cholesteatomas may be unique to the gerbil. Keratin deposits are produced by similar ligations of the external auditory canals of cats, guinea pigs, hamsters, mice, and rats. However, in these animals there is no medial displacement of the tympanic membrane, no cholesteatoma formation, and no bone erosion. Cholesteatomas were not seen in cats, guinea pigs, hamsters, mice, and rats even after post-ligation intervals of 6 to 36 months.


Induction of herpes simplex virus type 1 immediate-early gene expression by a cellular activity expressed in Vero and NB41A3 cells after growth arrest-release.
Infected cell protein 0 (ICP0), a major immediate-early regulatory protein of herpes simplex virus type 1 (HSV-1), activates expression of all classes of HSV genes as well as a variety of heterologous viral and cellular genes. Previous studies have shown that a cellular activity expressed maximally in Vero cells 8 h after release from growth arrest in the G0/G1 phase of the cell cycle can enhance plaque formation and gene expression of a mutant virus (7134) lacking both copies of the gene encoding ICP0 (W. Cai and P. Schaffer, J. Virol. 65:4078-4090, 1991). This observation suggests that the cellular activity can substitute for ICP0 to activate viral gene expression. To further characterize this cellular activity, Vero and NB41A3 (mouse neuroblastoma) cells were transfected at various times after release from growth arrest with promoter-chloramphenicol acetyltransferase (CAT) constructs containing promoters representing the major kinetic classes of HSV genes, and CAT activity was measured from 2 to 24 h postrelease. The results of these tests demonstrate that CAT expression from immediate-early promoter-CAT plasmids was enhanced 10- and 3-fold when Vero and NB41A3 cells were transfected at 6 and 2 h postrelease, respectively. In contrast, only low levels of immediate-early promoter-driven CAT activity were apparent when cells were transfected at later times postrelease. No significant stimulation of CAT activity was observed from promoter-CAT plasmids containing representative early or late HSV promoters or a heterologous viral (simian virus 40 early) promoter. Differences in the efficiency of uptake of plasmid DNA by cells at various times postrelease did not account for the observed differences in CAT expression. Unlike Vero cells, in which cell division resumed after release from growth arrest, division of NB41A3 cells did not resume. Rather, these cells displayed morphological features suggestive of a differentiated phenotype. Collectively, these findings demonstrate that a cellular activity expressed in Vero and NB41A3 cells after release from growth arrest can activate HSV gene expression by enhancing immediate-early gene expression.


Substituent effects in aqueous solutions of carboxylate salts studied by x-ray absorption spectroscopy at the oxygen K-edge.
The present study aims at probing the influence of different substituents of sodium carboxylate salts R-COO-:Na+ in aqueous solutions, with R = H, CH3, C2H5, CH2Cl, CF3, and C6H5. X-ray absorption spectroscopy was used in the oxygen K-edge region to highlight the effect of R on the energy position of the O1s-to-πCOO* resonance of the carboxylate ion. Ab initio static exchange and ΔSCF calculations are performed and confirm the experimental observations. We qualitatively discuss the results on the basis of the polar properties of these groups as well as on the basis of the πCOO* orbital energy in the ground states, the oxygen 1s orbital ionization energy, and the O1s-to-πCOO* resonance energy.


Elovl3: a model gene to dissect homeostatic links between the circadian clock and nutritional status.
The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues. Circadian expression of the Elovl3 gene in the liver is perturbed in mutant CLOCK mice but persists in mice with severe hepatic dysfunction. A reliance on an intact clock, combined with the refractoriness to liver decompensation and the finding of a robust sexually dimorphic pattern of expression, evince a particularly complex mode of transcriptional control. The Elovl3 gene upstream region was repressed by RevErbalpha and activated by sterol-regulatory element binding protein-1 (SREBP1) transcription factors. We propose that the temporal coordination of RevErbalpha and SREBP1 activities integrates clock and nutrition signals to drive a subset of oscillatory transcripts in the liver. Proteolytic activation of SREBP1 is circadian in the liver, and because the cycle of SREBP1 activation was reversed after restricting meals to the inactive phase of the day, this factor could serve as an acute sensor of nutritional state. SREBP1 regulates many known lipogenic and cholesterogenic circadian genes; hence, our results could explain how feeding can override brain-derived entraining signals in the liver. This mechanism would permit a rapid adjustment in the sequence of key aspects of the absorptive and postabsorptive phases in the liver.


A novel approach for the improvement of stress resistance in wine yeasts.
During wine production yeast cells are affected by several stress conditions that could affect their viability and fermentation efficiency. In this work we describe a novel genetic manipulation strategy designed to improve stress resistance in wine yeasts. This strategy involves modifying the expression of the transcription factor MSN2, which plays an important role in yeast stress responses. The promoter in one of the genomic copies of this gene has been replaced by the promoter of the SPI1 gene, encoding for a cell wall protein of unknown function. SPI1 is expressed at late phases of growth and is regulated by Msn2p. This modification allows self-induction of MSN2 expression. MSN2 gene transcription, Msn2p protein levels and cell viability increase under several stress conditions in the genetically modified strain. The expression of stress response genes regulated by Msn2p also increases under these situations. Cells containing this promoter change are able to carry out vinifications at 15 and 30 degrees C with higher fermentation rates during the first days of the process compared to the control strain.


Impact of current and past blood pressure on retinal arteriolar diameter in an older population.
To examine the effects of current and past blood pressure on retinal arteriolar diameter in a general older population. Cross-sectional and longitudinal studies. Population-based cohort study of older residents from an area west of Sydney, Australia. Two thousand three hundred and thirty-five individuals (n = 2335) (aged > or = 54 years) who attended the 5-year follow-up Blue Mountains Eye Study during 1997-99. A computer-assisted method measured vessel diameters from digitized right eye retinal photographs. The narrowest quintile of central retinal arteriolar equivalent or arteriole-to-venule ratio (AVR) defined generalized arteriolar narrowing. Blood pressure was measured using a mercury sphygmomanometer. After simultaneous adjustment for age, sex, body mass index, smoking and current or past blood pressure, elevated levels of both current and past blood pressure were associated with narrower retinal arterioles [Ptrend = 0.009 and 0.007 for current and past systolic blood pressure (SBP), respectively] and lower AVR [Ptrend = 0.001 and 0.0009 for current and past diastolic blood pressure (DBP), respectively]. Generalized arteriolar narrowing was associated with both current blood pressure [adjusted odds ratio (OR) 2.4, 95% confidence interval (CI) 1.5-3.8 for the highest versus lowest quintile of current DBP] and past blood pressure (adjusted OR 1.7, 95% CI 1.1-2.6, for the highest versus lowest quintile of past DBP). Hypertension duration or control status at baseline had no additional effect on arteriolar diameter after adjusting for current blood pressure. Our data document the independent effects of both current and past blood pressure on small vessel calibre in the retina, suggesting that retinal arteriolar narrowing may result from the cumulative effects of long-standing hypertension.


Naloxone exacerbates memory impairments and depressive-like behavior after mild traumatic brain injury (mTBI) in mice with upregulated opioid system activity.
The neuroprotective role of the endogenous opioid system in the pathophysiological sequelae of brain injury remains largely ambiguous. Noteworthy, almost no data is available on how its genetically determined activity influences the outcome of mild traumatic brain injury. Thus, the aim of our study was to examine the effect of opioid receptor blockage on cognitive impairments produced by mild traumatic brain injury in mice selectively bred for high (HA) and low (LA) swim-stress induced analgesia that show innate divergence in opioid system activity. Mild traumatic brain injury was induced with a weight-drop device on anaesthetized mice. Naloxone (5mg/kg) was intraperitoneally delivered twice a day for 7days to non-selectively block opioid receptors. Spatial memory performance and manifestations of depressive-like behavior were assessed using the Morris Water Maze and tail suspension tests, respectively. Mild traumatic brain injury resulted in a significant deterioration of spatial memory performance and severity of depressive-like behavior in the LA mouse line as opposed to HA mice. Opioid receptor blockage with naloxone unmasked cognitive deficits in HA mice but was without effect in the LA line. The results suggest a protective role of genetically predetermined enhanced opioid system activity in suppression of mild brain trauma-induced cognitive impairments. Mice selected for high and low swim stress-induced analgesia might therefore be a useful model to study the involvement of the opioid system in the pathophysiology and neurological outcome of traumatic brain injury.


Evidence for defective skeletal mineralization in low-birthweight infants: the absorption of calcium and fat.
Using serial metabolic balance techniques, the absorption and retention of calcium and the absorption of fat have beem measured over the first 30 to 70 days of life in 11 preterm and 2 full-term light-for-dates infants. They were fed either full-cream cow's milk, half-skimmed cow's milk, the proprietary filled milk S.M.A., or breast milk. The values for calcium intake, absorption and retention were compared with the rate of accumulation of calcium by the fetus in utero, which was calculated from published data on the chemical composition of fetal bodies. Infants fed breast milk had an absolute dietary deficiency of calcium. Those fed other milks ingested sufficient but they did not absorb enough. Though calcium absorption increased with increasing postnatal age, intrauterine rates of calcium retention were never achieved on any of the milks. The average retention of calcium by preterm infants as a percentage of intrauterine accumulation was, for cow's milk 38%, for S.M.A. 27%, and for breast milk 17%. The full-term light-for- dates infants absorbed and retained more calcium than the preterm infants; it was on average 52% of the amount accumulated by the human fetus for an equivalent weight gain. The average absorption of fat by preterm infants was, from the cow's milk preparations 55%, from S.M.A. 61%, and from breast milk 84%. The light-for-dates infants absorbed on average 87% of the breast milk fat. There was no evidence that the amount of calcium absorbed was materially influenced by fat malabsorption. The principal determinants of the amount of calcium absorbed were the length of gestation and postnatal age of the infant.


Carbenoxolone prevents chemical eye ischemia-reperfusion-induced cell death via 11β-hydroxysteroid dehydrogenase type 1 inhibition.
Glaucoma is one of the leading causes of preventable blindness diseases, affecting more than 2 million people in the United States. Recently, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors were found to exert preventive effects against glaucoma. Therefore, we investigated whether carbenoxolone (CBX), an 11β-HSD1 inhibitor, prevents chemical ischemia-reperfusion-induced cell death in human trabecular meshwork (HTM) cells. The present study demonstrated that CBX inhibited cell death caused by iodoacetic acid (IAA)-induced ischemia-reperfusion, and its effect was associated with the inhibition of 11β-HSD1 expression and activity. Furthermore, CBX reversed the IAA-induced structural damage on filamentous actin in HTM cells. In IAA-treated cells, the levels of 11β-HSD1 and the apoptosis-related factors Bax and FASL were increased throughout the reperfusion period, and CBX was able to attenuate the expression of 11β-HSD1 and the apoptosis-related factors. CBX also effectively suppressed IAA-induced intracellular ROS formation and cytochrome c release, which are involved in the mitochondrial apoptosis pathway. In addition, IAA-induced chemical ischemia-reperfusion stimulated TNF-α expression and NF-κB p65 phosphorylation, and these effects were attenuated by CBX. 11β-HSD1 RNAi also suppressed IAA-induced cell apoptosis via reduction of oxidative stress and inhibition of the pro-inflammatory pathway. Taken together, the present study demonstrated that the inhibition of 11β-HSD1 protected the TM against chemical ischemia-reperfusion injury, suggesting that the use of 11β-HSD1 inhibitors could be a useful strategy for glaucoma therapy.


Gene Set Enrichment Analyses: lessons learned from the heart failure phenotype.
Genetic studies for complex diseases have predominantly discovered main effects at individual loci, but have not focused on genomic and environmental contexts important for a phenotype. Gene Set Enrichment Analysis (GSEA) aims to address this by identifying sets of genes or biological pathways contributing to a phenotype, through gene-gene interactions or other mechanisms, which are not the focus of conventional association methods. Approaches that utilize GSEA can now take input from array chips, either gene-centric or genome-wide, but are highly sensitive to study design, SNP selection and pruning strategies, SNP-to-gene mapping, and pathway definitions. Here, we present lessons learned from our experience with GSEA of heart failure, a particularly challenging phenotype due to its underlying heterogeneous etiology. This case study shows that proper data handling is essential to avoid false-positive results. Well-defined pipelines for quality control are needed to avoid reporting spurious results using GSEA.


Hybrid formation between endogenous mouse and transfected human tyrosine kinase-deficient (A/K1018) insulin receptors leads to decreased insulin sensitivity in 3T3-L1 adipocytes.
Swiss Mouse 3T3-L1 cells provide a unique model for insulin-sensitive primary fat cells. Under defined conditions this fibroblast cell line can be converted to fully differentiated adipocytes, characterized by increased insulin receptor number and induction of adipogenic-specific proteins. 3T3-L1 cells were therefore transfected with the cDNA for the A/K1018 insulin receptor (alanine substituted for lysine at amino acid 1018 in the ATP binding region of the kinase domain). The cell lines in which the dominant inhibitory effects of the A/K1018 receptor had been previously demonstrated [Rat 1 fibroblasts and Chinese Hamster Ovary cells] have relatively few endogenous insulin receptors; however, the 3T3-L1 cell line has about 200,000 insulin receptors when differentiated. In this study we have used this cell line to explore the molecular mechanisms for the dominant inhibitory effect of a tyrosine kinase-defective insulin receptor on insulin action. The A/K1018 receptor was inhibitory in the 3T3-L1 cells as shown by decreased glucose transport. Further, altered differentiation in the transfected cell implicates the insulin receptor as an important downstream regulator in this process. We were able to demonstrate the presence of numerous hybrid receptors, composed of endogenous mouse heterodimers and human kinase-deficient heterodimers in these cells. Trans phosphorylation did occur within these hybrids as evidenced by autophosphorylation of human beta-subunits; however, these hybrids are unable to phosphorylate substrates. These results establish hybrid formation as an important determinant in the dominant negative nature of the A/K1018 insulin receptor.


Safety and efficacy of semiextended field intensity-modulated radiation therapy and concurrent cisplatin in locally advanced cervical cancer patients: An observational study of 10-year experience.
Patients with locally advanced cervical cancer (LACC) are at risk of para-aortic lymph node (PALN) metastasis. Pelvic concurrent chemoradiotherapy, the current standard treatment for LACC, has a PALN failure rate of 9% according to the Radiation Therapy Oncology Group Trial 90-01, suggesting that it may not completely eliminate all microscopic tumors in the PALNs. To minimize the toxicities associated with conventional prophylactic extended-field radiotherapy, our institute use prophylactic semiextended field radiotherapy that includes only the PALNs below the level of the renal vessels. Use of intensity-modulated radiotherapy (IMRT) is another means of reducing the incidence of toxicity. This study evaluated the safety and efficacy of prophylactic semiextended field IMRT (SEF-IMRT) and concurrent cisplatin chemotherapy in patients with LACC.We retrospectively assessed survival and toxicity in 76 patients with stage IB2-IVA cervical cancer and negative PALNs who received prophylactic SEF-IMRT and concurrent weekly cisplatin (40 mg/m) between 2004 and 2013. The region targeted by SEF-IMRT included the PALNs below the level of the renal vessels, and the prescribed dose was 50.4 Gy in 28 fractions. Brachytherapy was administered at a dose of 30 Gy in 6 fractions. Survival outcomes were calculated by using the Kaplan-Meier method, and acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 3.0.All patients completed the planned SEF-IMRT, as well as brachytherapy. Acute grade ≥3 gastrointestinal, genitourinary, and hematologic toxicities were observed in 2, 0, and 41 patients, respectively. The median follow-up time after SEF-IMRT was 55 (range, 11-124) months. Eight patients developed out-field distant recurrences without PALN failure, and 1 patient experienced out-field PALN failure with simultaneous distant metastasis. No patients had late genitourinary toxicities, and 3 patients had late grade 3 gastrointestinal toxicities. The 5-year overall survival, disease-free survival, local failure-free survival, regional failure-free survival, PALN failure-free survival, and distant metastasis-free survival rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively.For patients with LACC, prophylactic PALN irradiation up to the level of the renal vessels reduced PALN recurrence and resulted in favorable outcomes with few severe toxicities.


Substrate preferences in biodesulfurization of diesel range fuels by Rhodococcus sp. strain ECRD-1.
The range of sulfur compounds in fuel oil and the substrate range and preference of the biocatalytic system determine the maximum extent to which sulfur can be removed by biodesulfurization. We show that the biodesulfurization apparatus in Rhodococcus sp. strain ECRD-1 is able to attack all isomers of dibenzothiophene including those with at least four pendant carbons, with a slight preference for those substituted in the alpha-position. With somewhat less avidity, this apparatus is also able to attack substituted benzothiophenes with between two and seven pendant carbons. Some compounds containing sulfidic sulfur are also susceptible to desulfurization, although we have not yet been able to determine their molecular identities.


Salivary tannin-binding proteins are a pervasive strategy used by the folivorous/frugivorous black howler monkey.
Dietary tannins can affect protein digestion and absorption, be toxic, and influence food selection by being astringent and bitter tasting. Animals that usually ingest tannins may regularly secrete tannin-binding salivary proteins (TBSPs) to counteract the negative effects of tannins or TBSPs production can be induced by a tannin-rich diet. In the wild, many primates regularly eat a diet that contains tannin-rich leaves and unripe fruit and it has been speculated that they have the physiological ability to cope with dietary tannins; however, details of their strategy remains unclear. Our research details the salivary protein composition of wild and zoo-living black howler monkeys (Alouatta pigra) feeding on natural versus manufactured low-tannin diets, and examines differences in TBSPs, mainly proline-rich proteins (PRPs), to determine whether production of these proteins is dependent on the tannin content of their food. We measured the pH, flow rate, and concentration of total protein and trichloroacetic acid soluble proteins (an index of PRPs) in saliva. Howler monkeys produced slightly alkaline saliva that may aid in the binding interaction between tannin and salivary proteins. We used gel electrophoresis to describe the salivary protein profile and this analysis along with a tannin-binding assay allowed us to detect several TBSPs in all individuals. We found no differences in the characteristics of saliva between wild and zoo-living monkeys. Our results suggest that black howler monkeys always secrete TBSPs even when fed on foods low in tannins. This strategy of constantly using this salivary anti-tannin defense enables them to obtain nutrients from plants that sometimes contain high levels of tannins and may help immediately to overcome the astringent sensation of their food allowing howler monkeys to eat tanniferous plants.


An insertion/deletion ACE polymorphism and kidney size in Polish full-term newborns.
The number of nephrons is a multifactorial trait controlled by the interaction of environmental factors and genetic variants that influence the extent of branching nephrogenesis during foetal life. A correlation between renal mass and nephron number in newborns allows the use of the total kidney volume at birth as a surrogate for congenital nephron number. Since the renin-angiotensin system plays an important role in renal development we hypothesized that the common, functional insertion/deletion (I/D) polymorphism in the ACE gene might be responsible for the variation in kidney size amongst healthy individuals. We recruited 210 healthy Polish full-term newborns born to healthy women with uncomplicated pregnancies. The kidney volume was measured sonographically. Total kidney volume (TKV) was calculated as the sum of left kidney volume and right kidney volume. TKV was normalized to body surface area (TKV/BSA). The I and D alleles were identified using polymerase chain reaction. TKV/BSA in newborns carrying at least one insertion ACE allele was significantly reduced by approximately 8% as compared with homozygous newborns for the D allele (DD genotype) (105.1±23.6 vs. 114.2±28.2 cm(3)/m(2), p<0.05). The results of this study suggest that I/D ACE polymorphism may account for subtle variation in kidney size at birth, which reflects congenital nephron endowment.


Promoting effects of carminic acid-enriched cochineal extracts on capsular invasive thyroid carcinomas through targeting activation of angiogenesis in rats.
Cochineal extracts (CE) is a coccid-derived natural food colorant containing carminic acid (CA) as an active ingredient that potentiates inhibition of tissue proteolysis mediated by activation of plasma hyaluronan-binding protein (PHBP). In our previous study, dietary administered CE (CA: 28.5% in CE) has shown to promote the macroscopic development of capsular invasive carcinomas (CICs) associated with up-regulation of angiogenesis-related genes in an intracapsular invasion model of experimental thyroid cancers using rats. However, the promoting effect of CE could not be confirmed histopathologically. The purpose of the present study was to confirm the promoting effect of CE through direct injections to animals on the development of CICs using this cancer invasion model. One week after initiation with N-bis(hydroxypropyl)nitrosamine, male F344/NSlc rats were administered CA-enriched CE (CA: 52.6% in CE) by intraperitoneal injections every other day (10 mg/kg body weight) during the promotion with 0.15% sulfadimethoxine in the drinking water for 8 weeks. The multiplicities of macroscopical CICs and the mean area of early capsular invasive foci estimated by Tenascin (TN)-C-immunoreactivity in the thyroid significantly increased with CE-treatment, while the number of TN-C-positive foci did not change with CE. Transcript level of Phbp and downstream genes unchanged; however, transcript level of angiogenesis-related genes, i.e, Vegfb and its transcription factor gene, Hif1a, those being downstream of phosphatase and tensin homolog (PTEN)/Akt signaling, up-regulated in the thyroid tissue with CE-administration. These results suggest that CE potentiates promotion activity by facilitating angiogenesis through activation of PTEN/Akt signaling without accompanying modification of PHBP-related proteolysis.


Mutations of CCNF gene is rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia from Mainland China.
Mutations of the cyclin F (CCNF) gene were recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Western and Japanese populations. The rare protein-altering variants frequency is 0.6 to 3.3% in ALS and FTD from these diverse geographic populations while no systematic analysis of CCNF variants were conducted in the Chinese population. We screened all exons of CCNF in a cohort of 269 cases (including 181 ALS and 88 FTD) from Mainland China using Sanger sequencing. A rare heterozygous variant (c.481G > A, p.G161R) was detected in a sporadic ALS case with a frequency of 0.6%, while no mutation was identified in patients with FTD. The same variant was also found in a sporadic ALS patient from America. Our result indicates that the mutation of CCNF is rare in patients with ALS and FTD from Mainland China.


Uncovering patterns of consumers' interest for beer: A case study with craft beers.
To uncover patterns of consumer interest in craft beers, the authors explored the quality perception of craft beers in a panel of industrial mass-marketed beer drinkers (n=150) and examined the differences in interest for this beer segment between men and women. The authors adopted a conjoint rating experiment in which the respondents were given forty-nine beer profiles to evaluate and were asked to score the degree of interest in each profile on a 9-point scale. Each profile was described on eight attributes (type of brewery, brewing technology, characterizing raw materials, brewhouse equipment, location of the brewery, type of container, retail price, where to buy) varied at different levels. Results showed that Italian consumers placed greatest importance on type of container (30.49%) and on brewing technology (17.64%). Characterizing raw materials (13.44%) and type of brewery (12.64) rank 3 and 4 and were placed in the same band some way below brewing technology. Retail price (9.87%) and where to buy (8.73%) were of far less importance. The least importance of all was attached to brewhouse equipment (4.44%) and to location of the brewery (2.75%). As far as utility values are concerned, the factor level glass bottle+crown cap and the factor level microfiltration are the utilities that most increased the interest of consumers. They were followed by the factor level local grains, stainless steel keg and monastery. In contrast, the factor level PET Keg, aluminum can and large scale corporate brewery showed the greatest negative impact on interest. Men and women shared similar patterns of interest. However, men placed more importance than women on retail price, location of the brewery and where to buy. Women attached more importance than men on type of container, brewing technology and type of brewer. These findings are relevant to understanding consumers'behavior in the beer market and to translating consumer needs, wants and expectations into manufacturing designed to produce the best possible, cost-competitive, widely accepted product in a relatively short period.


Distinct phospholipases A2 regulate the release of arachidonic acid for eicosanoid production and superoxide anion generation in neutrophils.
Arachidonic acid (AA) released from membrane phospholipids by phospholipase A2 (PLA2) is important as a substrate for eicosanoid formation and as a second messenger for superoxide anion (O2-) generation in neutrophils. Different isoforms of PLA2 in neutrophils might mobilize AA for different functions. To test this possibility, we sought to characterize the PLA2s that are activated by the neutrophil stimuli, Aroclor 1242, a mixture of polychlorinated biphenyls, and A23187, a calcium ionophore. Both Aroclor 1242 and A23187 caused release of [3H]AA; however, O2- production was seen only in response to Aroclor 1242. Eicosanoids accounted for >85% of the radioactivity recovered in the supernatant of A23187-stimulated cells but <20% of the radioactivity recovered from cells exposed to Aroclor 1242. Omission or chelation of calcium abolished A23187-induced AA release, but did not alter AA release in Aroclor 1242-stimulated neutrophils. AA release and O2- production in response to Aroclor 1242 were inhibited by bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2. BEL, however, did not alter Calcium-independent activity was inhibited >80% by BEL, whereas calcium-dependent activity was inhibited <5%. Furthermore, calcium-independent, but not calcium-dependent, PLA2 activity was significantly enhanced by Aroclor 1242. These data suggest that Aroclor 1242 and A23187 activate distinct isoforms of PLA2 that are linked to different functions: Aroclor 1242 activates a calcium-independent PLA2 that releases AA for the generation of O2-, and A23187 activates a calcium-dependent PLA2 that mobilizes AA for eicosanoid production.


A Case of AML Characterized by a Novel t(4;15)(q31;q22) Translocation That Confers a Growth-Stimulatory Response to Retinoid-Based Therapy.
Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-trans retinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving the TMEM154 and RASGRF1 genes. Analysis of primary cells from the patient revealed the expression of TMEM154-RASGRF1 mRNA and the resulting fusion protein, but no expression of the reciprocal RASGRF1-TMEM154 fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML.


Chickpea (Cicer arietinum L.).
Chickpea is one of the most important leguminous, cool-season, food crops, cultivated prevalently in the Asian Pacific region. In spite of its nutritional importance, its area of cultivation has been low, with virtually no increase. Conventional breeding has resulted in several important improvements in this crop, and recent advances in biotechnology such as plant tissue culture and genetic transformation can significantly contribute to better sustainability of this important food crop. Here, we describe an efficient Agrobacterium-mediated transformation protocol for chickpea using axillary meristem explants, which results in a high frequency of genetic transformation (70%) and recovery of valuable transgenic plants. The protocol is significant owing to its high reproducibility and recovery of the transgenics in a relatively short period (90-100 days).


Similar alterations in brain function for phonological and semantic processing to visual characters in Chinese dyslexia.
Dyslexia in alphabetic languages has been extensively investigated and suggests a central deficit in orthography to phonology mapping in the left hemisphere. Compared to dyslexia in alphabetic languages, the central deficit for Chinese dyslexia is still unclear. Because of the logographic nature of Chinese characters, some have suggested that Chinese dyslexia should have larger deficits in the semantic system. To investigate this, Chinese children with reading disability (RD) were compared to typically developing (TD) children using functional magnetic resonance imaging (fMRI) on a rhyming judgment task and on a semantic association judgment task. RD children showed less activation for both tasks in right visual (BA18, 19) and left occipito-temporal cortex (BA 37), suggesting a deficit in visuo-orthographic processing. RD children also showed less activation for both tasks in left inferior frontal gyrus (BA44), which additionally showed significant correlations with activation of bilateral visuo-orthographic regions in the RD group, suggesting that the abnormalities in frontal cortex and in posterior visuo-orthographic regions may reflect a deficit in the connection between brain regions. Analyses failed to reveal larger differences between groups for the semantic compared to the rhyming task, suggesting that Chinese dyslexia is similarly impaired in the access to phonology and to semantics from the visual orthography.


The trinucleotide repeat expansion on chromosome 6p (SCA1) in autosomal dominant cerebellar ataxias.
Affected members of 73 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCAs) were investigated for the trinucleotide (CAG) repeat expansion which is found in pedigrees exhibiting linkage to the SCA1 locus on chromosome 6. Most of the families were too small for linkage analysis. The mutation was only found in ADCA type I, in 19 out of 38 such kindreds investigated (50%). It was slightly more common in Italian (59%) than British (50%) families, and was also found in Malaysian, Bangladeshi and Jamaican kindreds. Overall, ADCA type I patients with the expansion had a lower incidence of hyporeflexia and facial fasciculation than those without. The trinucleotide expansion was not found in eight families with ADCA and maculopathy or 24 kindreds with a pure type of ADCA, confirming that these syndromes are genetically distinct. It was also not detected in 12 patients with sporadic degenerative ataxias. DNA analysis for the SCA1 mutation is useful diagnostically in single patients or small families, and can be used for presymptomatic testing where appropriate.


[The principles of mechanical ventilation in ARDS].
Acute respiratory distress syndrome (ARDS) is a real challenge for the pulmonary and critical care physicians. Although it is quite frequently encountered in intensive care clinics, its diagnosis and treatment bare many variations among the clinicians. Since ARDS is a fully dynamic process, there is no uniform application of mechanical ventilation (MV) being one of the inevitable components of ARDS management. This situation makes the clinicians very prone to make mistakes during setting and subsequent adjustments of mechanical ventilation parameters. In this review, we aimed to clarify the most common issues of discussion by presenting the principles of MV in ARDS with regard to some recent modifications.


3D Monolayer Silanation of Porous Structure Facilitating Multi-Phase Pollutants Removal.
Activated carbon (AC) is widely used to removing hazardous pollutants from air and water, owing to its exceptional adsorption properties. However, the high affinity of water molecules with the surface oxygen-containing functional groups can adversely affect the adsorption performance of AC. In this study, a facile and efficient method is presented for fabrication of hydrophobic AC through surface monolayer silanation. Compared to initial AC, the hydrophobic AC improves the water contact angle from 29.7° to 123.5° while maintaining high specific surface area and enhances the removal capacity of multi-phase pollutants (emulsified oil and toluene). Additionally, the hydrophobic AC exhibits excellent adsorption capability to harmful algal bloom species (Chlorella) (97.56%) and algal organic matter (AOM) (96.23%) owing to electrostatic interactions and surface hydrophobicity. The study demonstrates that this method of surface monolayer silanation can effectively weaken the effect of water molecules on AC adsorption capacity, which has significant potential for practical use in air and water purification, as well as in the control of harmful algal blooms.


Sheehan's syndrome of hypothalamic origin in a woman with juvenile diabetes mellitus.
A 25-year-old woman with severe diabetes mellitus since the age of 7 developed anterior pituitary insufficiency after pregnancy toxaemia with hypofunction of the thyroid, ovaries and adrenal cortex. Following the development of Sheehan's syndrome, her insulin requirment decreased dramatically. I.v. administration of TRH, LRH and vasopressin induced nearly normal pituitary response levels of TSH, LH and plasma cortisol, indicating a hypothalamic damage as the primary aetiological factor.


Motion compensation strategies in magnetic resonance imaging.
Image quality in magnetic resonance imaging (MRI) is considerably affected by motion. Therefore, motion is one of the most common sources of artifacts in contemporary cardiovascular MRI. Such artifacts in turn may easily lead to misinterpretations in the images and a subsequent loss in diagnostic quality. Hence, there is considerable research interest in strategies that help to overcome these limitations at minimal cost in time, spatial resolution, temporal resolution, and signal-to-noise ratio. This review summarizes and discusses the three principal sources of motion: the beating heart, the breathing lungs, and bulk patient movement. This is followed by a comprehensive overview of commonly used compensation strategies for these different types of motion. Finally, a summary and an outlook are provided.


Two Ce3+-Substituted Selenotungstates Regulated by N, N-Dimethylethanolamine and Dimethylamine Hydrochloride.
Two multi-Ce3+-substituted selenotungstates (STs), [HDMEA][H2N(CH3)2]4H3Na4[Ce2(H2O)6(DMEA)W4O9(α-SeW9O33)3]·26H2O (1) and [H2N(CH3)2]10H4Na10[Ce2W4O9(H2O)7(α-SeW9O33)3]2·63H2O (2), were prepared by the one-pot approach of sodium tungstate, sodium selenite, and lanthanide nitrate in an acidic water solution in the presence of N, N-dimethylethanolamine (DMEA) or dimethylamine hydrochloride (DMAHC). 1 was obained in the presence of DMEA, whereas 2 was synthesized in the presence of DMAHC. The trimeric polyoxoanion of 1 contains an unusual V-shaped [Se3W29O103]20- group embracing a prominent heterometal oxide fragment, [Ce2(H2O)6(DMEA)W2O5]8+, and the hexameric polyoxoanion of 2 is constructed from two equivalent trimeric [Ce2W4O9(H2O)7(SeW9O33)3]224- subunits through two -O-W-O-Ce-O- linkages. The most worthy of attention is that the polyoxoanion of 1 can be approximatively viewed as a half of the polyoxoanion of 2 because of the coordination and blocking effect of DMEA. The stability of 1 and 2 in different water pH values was studied by electrospray ionization mass spectroscopy (ESI-MS), and the results manifest that 1 and 2 are stable in pH = 3.5-7.5 and 3.5-7.0, respectively. The oxidation reactions of aromatic sulfides catalyzed by H2O2 were studied when 1 or 2 worked as a catalyst, and experimental results reveal that 1 or 2 can serve as available catalysts for the oxidation of aromatic sulfides under mild conditions.


Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is characterized by exercise performance impairment. Although airflow limitation is common, no previous studies have evaluated the prevalence and impact of dynamic hyperinflation (DH) in LAM. To investigate the dynamic responses during maximal exercise and the prevalence, predictors, and repercussions of DH in LAM. Forty-two patients with LAM performed symptom-limited incremental cycle exercise and pulmonary functions tests (PFTs) and were compared with 10 age-matched healthy women. Dyspnea intensity, inspiratory capacity, oxygen saturation, and cardiac, metabolic, and respiratory variables were assessed during exercise. Patients with LAM also performed a 6-minute walk test (6MWT). Patients with LAM had higher baseline dyspnea, poorer quality of life, obstructive pattern, air trapping, and reduced diffusing capacity of carbon monoxide in PFTs. Although they had the same level of regular physical activity, their maximal exercise performance was reduced and was associated with ventilatory limitation, greater desaturation, and dyspnea. The prevalence of DH was high in LAM (55%), even in patients with mild spirometric abnormalities, and was correlated with airflow obstruction, air trapping, and diffusing capacity of carbon monoxide. Compared with the non-DH subgroup, the patients who developed DH had a ventilatory limitation contributing to exercise cessation on cycling and higher desaturation and dyspnea intensity during the 6MWT. Ventilatory limitation and gas exchange impairment are important causes of exercise limitation in LAM. DH is frequent in LAM, even in patients with mild spirometric abnormalities. DH was associated with the severity of disease, higher dyspnea, and lower oxygen saturation. In the 6MWT, desaturation and dyspnea were greater in patients with DH.


Isolated relapse in the oral cavity of a child with T-lineage acute lymphoblastic leukemia.
Despite high cure rates, approximately 20% of patients with acute lymphoblastic leukemia (ALL) have disease relapse. Isolated recurrence in oral cavity is extremely unusual. The aim of this paper is to report a case of an isolated relapse occurred in a child with T-lineage ALL. Clinical picture included swelling and pain in the right upper gingiva of the oral cavity, with no other clinical or hematological alterations. Diagnosis was confirmed by biopsy and immunohistochemical staining. Bone marrow aspiration was normal. Five months later leukemic infiltration of the bone marrow was detected and systemic chemotherapy was reintroduced. This case report highlights the relevance of dental care during and after chemotherapy, not only to treat lesions in the oral cavity resulting from the disease itself or from treatment side effects, but also to detect unusual sites of ALL relapse.


Developing a surveillance system for HIV/AIDS in Pakistan.
Apart from other interventions, surveillance remains a major focus of the national response to HIV/AIDS. However, with a shift in the epidemic pattern, the existing surveillance strategies are barely insufficient and long-term structural changes are desirable. This article provides a conceptual framework for developing a scientific system for HIV surveillance in Pakistan. Second generation surveillance system including repeated cross-sectional surveys in high risk population groups are suggested to collect behavioral and serological data at regular intervals on an annual basis to monitor the epidemic trend as well as the associated behaviors. In addition, multiple data resources have been highlighted, which could be coordinated to describe the epidemic pattern in the country. This information should form the basis for national prevention planning and ought to be used for making sensible choices through which prevention efforts are most likely to reduce new infections.


Enhanced Reactive Oxygen Species Production, Acidic Cytosolic pH and Upregulated Na+/H+ Exchanger (NHE) in Dicer Deficient CD4+ T Cells.
MicroRNAs (miRNAs) negatively regulate gene expression at a post-transcriptional level. Dicer, a cytoplasmic RNase III enzyme, is required for the maturation of miRNAs from precursor miRNAs. Dicer, therefore, is a critical enzyme involved in the biogenesis and processing of miRNAs. Several biological processes are controlled by miRNAs, including the regulation of T cell development and function. T cells generate reactive oxygen species (ROS) with parallel H+ extrusion accomplished by the Na+/H+-exchanger 1 (NHE1). The present study explored whether ROS production, as well as NHE1 expression and function are sensitive to the lack of Dicer (miRNAs deficient) and could be modified by individual miRNAs. CD4+ T cells were isolated from CD4 specific Dicer deficient (DicerΔ/Δ) mice and the respective control mice (Dicerfl/fl). Transcript and protein levels were quantified with RT-PCR and Western blotting, respectively. For determination of intracellular pH (pHi) cells were incubated with the pH sensitive dye bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) and Na+/H+ exchanger (NHE) activity was calculated from re-alkalinization after an ammonium pulse. Changes in cell volume were measured using the forward scatter in flow cytometry, and ROS production utilizing 2',7' -dichlorofluorescin diacetate (DCFDA) fluorescence. Transfection of miRNA-control and mimics in T cells was performed using DharmaFECT3 reagent. ROS production, cytosolic H+ concentration, NHE1 transcript and protein levels, NHE activity, and cell volume were all significantly higher in CD4+ T cells from DicerΔ/Δ mice than in CD4+ T cells from Dicerfl/fl mice. Furthermore, individual miR-200b and miR-15b modify pHi and NHE activity in Dicerfl/fl and DicerΔ/Δ CD4+ T cells, respectively. Lack of Dicer leads to oxidative stress, cytosolic acidification, upregulated NHE1 expression and activity as well as swelling of CD4+ T cells, functions all reversed by miR-15b or miR-200b.


Assessing the Taxonomic Status of the Gray Brocket Mazama simplicicornis argentina Lönnberg, 1919 (Artiodactyla: Cervidae).
Mazama simplicicornis argentina is the name that was given to describe a gray brocket collected by Lönberg in 1919 in the central Chaco region of Argentina. Subsequent authors, based on morphological similarities, considered this name to be a synonym for the species Subulo gouazoubira Fischer, 1814 from Paraguay. In the absence of genetic analyses to compare the Argentinian and Paraguayan gray brockets, we aimed to clarify the taxonomy of M. simplicicornis argentina through an integrative assessment using morphological, cytogenetical, and molecular data from its holotype and a current topotype. Qualitative skull features and cranio-morphometric results of M. simplicicornis argentina showed a great similarity with the S. gouazoubira neotype characters. The diploid chromosome number of M. simplicicornis argentina topotype corresponded with the karyotypical pattern of S. gouazoubira with 2n = 70 and FN = 70, showing a great similarity in all classic and molecular cytogenetic results and revealing the homologies between karyotypes. The phylogenetic analysis of mitochondrial genes used in this study (concatenated partial ND5 and Cytb gene) allocated the M. simplicicornis argentina specimens in the monophyletic clade of S. gouazoubira with a branch value of 100%. These results show that there is no discontinuity between the Argentinian and Paraguayan gray brockets. Therefore, the individuals originally described as M. simplicicornis argentina should be recognized as S. gouazoubira.


Mitochondrial function in normal and genetically altered cells and tissues.
The impact upon oxidative metabolism of normal and pathological variations of oxidative capability is just beginning to be understood, based upon the few examples of human and animal subject survivals and the relatively few cell systems in which the impact of molecular pathologies on function has been studied. On the one hand, difficulties of isolation of systems containing altered oxidases are significant because of ineffective assembly or small amounts of surviving isoenzymes, and on the other hand, unexpected fragilities of the oxidase system may lead to low yields when subjected to the preparative stresses appropriate to the wild types. To circumvent these problems, this paper describes the application, in vivo, of noninvasive, nondestructive techniques to study the function of cytochrome oxidase and other components of the respiratory chain, particularly cytochromes b-c1 in human subjects on the one hand, and in isolated cells on the other, principally mutants of Saccharomyces cerevisiae in which the subunit content is varied. Two principal spectroscopic approaches are employed: optical and phosphorus magnetic resonance spectroscopy (P MRS). Optical spectroscopy of the near red region of the spectrum provides effective analysis of brain and muscle, as does the surface coil of space-resolved phosphorus magnetic resonance. Both techniques are applicable to suspensions of single cells such as yeast. The optical method yields essential information on oxygen delivery to tissues by hemoglobin and myoglobin and oxygen utilization by cytochrome oxidase. P MRS affords essential information on the efficiency of ATP generation and the extent to which oxidative metabolism meets the needs of cell function in terms of the ratio of phosphocreatine to inorganic phosphate (PCr/Pi). This in turn enables the calculation of the velocity of oxidative metabolism, V, in relation to its maximum capability, Vm, according to a Michaelis-Menten relationship that involves control not only by ADP (Pi/PCr) and Pi, but also by oxygen and substrate deliveries. Thus, an overview of the functionality of mitochondria in cells and tissues is uniquely provided by this combined approach and thereby deficiencies of components of the respiratory chain are quantified.


Epigenetic Regulation: A New Frontier for Biomedical Engineers.
Gene expression in mammalian cells depends on the epigenetic status of the chromatin, including DNA methylation, histone modifications, promoter-enhancer interactions, and noncoding RNA-mediated regulation. The coordinated actions of these multifaceted regulations determine cell development, cell cycle regulation, cell state and fate, and the ultimate responses in health and disease. Therefore, studies of epigenetic modulations are critical for our understanding of gene regulation mechanisms at the molecular, cellular, tissue, and organ levels. The aim of this review is to provide biomedical engineers with an overview of the principles of epigenetics, methods of study, recent findings in epigenetic regulation in health and disease, and computational and sequencing tools for epigenetics analysis, with an emphasis on the cardiovascular system. This review concludes with the perspectives of the application of bioengineering to advance epigenetics and the utilization of epigenetics to translate bioengineering research into clinical medicine.


Role of Serum Follicle Stimulating Hormone, Luteinizing Hormone, Testosterone and Prolactin Levels in Azoospermic Male Partner of Subfertile Couple.
This cross sectional study was carried out in the Infertility Unit, Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from January 2011 and June 2013. Eighty one (81) consecutive azoospermic male partner of married couple, aged 20-50 years with at least two years of subfertility and no known endocrinopathy and ejaculatory dysfunction were included in this study to find out their abnormal hormonal pattern. None of them had received any form of treatment within the last 3 months prior to hormonal evaluation. Men with hypertension, recent fever, chemo or radiation exposure were excluded from the study. Eight weeks interval two semen analyses were done in the Andrology Laboratory of above department following standard WHO guideline, 2004. Using standard ELISA technique, serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone and prolactin were measured/assayed/estimated. The results of this study demonstrated that 40 (49.4%) men had normal endocrine pattern against 51 (50.6%) with endocrinopathy. The former may be related to obstructive azoospermia, which needs further analyses. Both the increased FSH (>11.1mIU/ml) and LH (>7.6mIU/ml) were observed in 25 (30.9%) men, only elevated FSH (>11.1mIU/ml) in 9(11.1%), and only elevated LH (>7.6mIU/ml) in 7(8.6%). Low testosterone level (<270ng/dl) was observed in 11(13.6%), low TSH (<0.4μIU/ml) in 1(1.2%) and low prolactin (<2.5ng/dl) in 5(6.2%).


Carboxylated short single-walled carbon nanotubes but not plain and multi-walled short carbon nanotubes show in vitro genotoxicity.
Long carbon nanotubes (CNTs) resemble asbestos fibers due to their high length to diameter ratio and they thus have genotoxic effects. Another parameter that might explain their genotoxic effects is contamination with heavy metal ions. On the other hand, short (1-2 µm) CNTs do not resemble asbestos fibers, and, once purified from contaminations, they might be suitable for medical applications. To identify the role of fiber thickness and surface properties on genotoxicity, well-characterized short pristine and carboxylated single-walled (SCNTs) and multi-walled (MCNTs) CNTs of different diameters were studied for cytotoxicity, the cell's response to oxidative stress (immunoreactivity against hemoxygenase 1 and glutathione levels), and in a hypoxanthine guanine phosphoribosyltransferase (HPRT) assay using V79 chinese hamster fibroblasts and human lung adenocarcinoma A549 cells. DNA repair was demonstrated by measuring immunoreactivity against activated histone H2AX protein. The number of micronuclei as well as the number of multinucleated cells was determined. CNTs acted more cytotoxic in V79 than in A549 cells. Plain and carboxylated thin (<8 nm) SCNTs and MCNTs showed greater cytotoxic potential and carboxylated CNTs showed indication for generating oxidative stress. Multi-walled CNTs did not cause HPRT mutation, micronucleus formation, DNA damage, interference with cell division, and oxidative stress. Carboxylated, but not plain, SCNTs showed indication for in vitro DNA damage according to increase of H2AX-immunoreactive cells and HPRT mutation. Although short CNTs presented a low in vitro genotoxicity, functionalization of short SCNTs can render these particles genotoxic.


[Differentiation of geographic biovariants of smallpox virus by PCR].
Comparative analysis of amino acid and nucleotides sequences of ORFs located in extended segments of the terminal variable regions in variola virus genome detected a promising locus for viral genotyping according to the geographic origin. This is ORF O1L of VARV. The primers were calculated for synthesis of this ORF fragment by PCR, which makes it possible to distinguish South America-Western Africa genotype from other VARV strains. Subsequent RFLP analysis reliably differentiated Asian strains from African strains (except Western Africa isolates). This method has been tested using 16 VARV strains from various geographic regions. The developed approach is simple, fast and reliable.


[Laryngeal paraganglioma].
A case of laryngeal paraganglioma in a 65-year-old male was treated by supraglotic laryngectomy. This controversial tumor is analyzed and guidelines are given for its clinical and histological (immunohistochemical) diagnosis and treatment.


INITIAL SYMPTOMATIC PITUITARY METASTASIS IN A PATIENT WITH PROSTATE FOAMY GLAND CARCINOMA: TAILORING SAFE AND EFFECTIVE THERAPY.
Metastases to pituitary gland are unusual and mostly asymptomatic, presenting with local symptoms in one of ten patients, and only 3%-5% of them are of prostate origin. Here we report and evaluate the effectiveness and safety of multimodal treatment in a patient with pituitary metastasis of a prostate foamy gland carcinoma. A 78-year-old male patient presented with blurred vision and headache without a previous history of malignancy. Magnetic resonance imaging scans revealed a large sellar mass, with infiltration of the surrounding structures. Maximal transsphenoidal reduction of pituitary metastasis was performed, with a histologic finding of metastatic prostate foamy gland adenocarcinoma. Evaluation of the prostate specific antigen revealed a very high level (1461 ng/mL) and foamy gland carcinoma was found on prostate needle biopsy. The patient received 3D conformal external beam radiotherapy with 6 MV photons to the sellar and parasellar region with a tumor dose of 44 Gy, followed by androgen deprivation therapy. Follow up magnetic resonance imaging done after radiotherapy showed shrinkage of the tumor process, with rapid prostate specific antigen decline to 0.3 ng/mL. The visual function was fully established and headache resolved. On the last follow up 14 months after the diagnosis, the patient was alive and free from clinical signs of disease. Tailored treatment, including limited radiotherapy in a higher palliative dose, in a patient with foamy gland symptomatic pituitary metastatic disease resulted in good local and systemic control of the disease. In older male patients with clinical and/or radiologic characteristics suggestive of metastatic pituitary disease, the prostate specific antigen test should be included as part of the work-up.


Color weight photometry.
We study the "color weight" for a number of rather different paradigms. In well researched heterochromatic photometry methods we find that the "weights" determined by settings of naive observers are closely determined by the CIE luminance functional. This is very different for tasks that involve mid- and high-level aspects of perception. In several cases we find equipollence for the display red, green and blue channels. Moreover, in such cases the very nonlinear maximum-rule fits the data rather better than a linear functional. These findings are of interest when photometry needs to be applied for stimuli that are different from the high temporal and low spatial frequency gratings typical for flicker photometry. These results are relevant for science, ergonomics and art.


Being moved by meaningfulness: appraisals of surpassing internal standards elicit being moved by relationships and achievements.
People can be moved and overwhelmed, a phenomenon typically accompanied by goose-bumps and tears. We argue that these feelings of being moved are not limited to situations that are appraised as pro-social but elicited when someone surpasses an internal standard. In line with these predictions, people were moved by relationships and success (Study 1), by reunion, separation, success and failure (Study 2) and by social, environmental and sports achievements (Study 3). In all three studies, the elicitation of these feelings was partially mediated by appraisals of surpassing social or achievement standards. In line with this, ratings of meaningfulness were closely associated with feelings of being moved and moving stimuli elicited behavioural intentions such as spending time with family and friends, helping others and/or achieving something in life. Thus, moving situations may remind us about what we perceive as meaningful and thereby help us to act accordingly.


Statistical characteristics of under-ice noise on the Arctic Chukchi Plateau.
In the context of global warming leading to rapidly changing Arctic sea ice and the environment, it is necessary to understand the statistical characteristics of noise under existing Arctic ocean environmental conditions. The data recorded from August 1, 2018 to November 2, 2019, on the Arctic Chukchi Plateau, have been studied to analyze the relationship between the ice transient events and the non-Gaussian statistics of under-ice noise. The ice-generated transient noise largely contributes to the under-ice noise environment, and the total under-ice noise exhibits non-Gaussian statistics due to the occurrence of these ice transients. The number of ice transients has a strong negative correlation with the characteristic index α, meaning that the higher the occurrence of transient events, the stronger the non-Gaussian statistics of under-ice noise. Stronger non-Gaussian noise with full ice coverage is observed compared to partial ice coverage. The under-ice noise in 0.5-1 kHz exhibits the strongest non-Gaussian statistics, followed by 1-4 kHz, while it is weakest in 20-500 Hz. The statistics of ice transients and under-ice noise have been provided in this paper, which can be used in sonar detection algorithms and have important significance for the performance prediction and optimization of sonar processors.


To err or to guess: an ERP study on the source of errors.
Given the large contribution of human error in the failure of complex systems, understanding the source of errors is an important issue. It has been proposed that, in speeded situations, responses biases induce subjects to guess which response will be required. When the guess turns out to be wrong, a fast guess error occurs. In unbiased conditions the possible contribution of fast guess errors remains an open question. We used a response-locked event-related potential (N-40), assumed to reveal the presence of a response selection process during the reaction time, to probe the presence of a response selection in biased and unbiased situations. The N-40 was present without response bias but absent in biased situations. This lends physiological support to the idea that, in a priming paradigm as used here, most errors in biased conditions are fast guesses whereas most errors result from inappropriate response selections in unbiased conditions. This reveals different sources of errors.


Photocatalytic Reverse Semi-Combustion Driven by Ionic Liquids.
The simple photolysis of CO2 in aqueous solutions to generate CO and/or hydrocarbons and derivatives in the presence of a catalyst is considered to be a clean and efficient approach for utilizing CO2 as a C1 building block. Despite the huge efforts dedicated to this transformation using either semiconductors or homogeneous catalysts, only small improvements of the catalytic activity have been achieved so far. This article reports that simple aqueous solutions of organic salts-denominated as ionic liquids-can efficiently photo-reduce CO2 to CO without using photosensitizers or sacrificial agents. The system relies on the formation of the [CO2 ].- intermediate through homolytic C-C bond cleavage in a cation-CO2 adduct of imidazolium-based ionic liquids (ILs). The system continuously produced CO up to 2.88 mmol g-1 of IL after 40 h of irradiation by using an aqueous solution of 1-n-butyl-3-methylimidazolium-2-carboxylate (BMIm.CO2 ) IL, representing an apparent quantum yield of 3.9 %. The organophotocatalytic principles of our system may help to develop more simple and efficient organic materials for the production of solar fuels from CO2 under mild conditions, which represents a real alternative to those based on semiconductors and homogeneous metal-based catalysts.


The regulation of muscle glycogen: the granule and its proteins.
Despite decades of studying muscle glycogen in many metabolic situations, surprisingly little is known regarding its regulation. Glycogen is a dynamic and vital metabolic fuel that has very limited energetic capacity. Thus its regulation is highly complex and multifaceted. The stores in muscle are not homogeneous and there appear to be various metabolic pools. Each granule is capable of independent regulation and fundamental aspects of the regulation appear to be associated with a complex set of proteins (some are enzymes and others serve scaffolding roles) that associate both with the granule and with each other in a dynamic fashion. The regulation includes altered phosphorylation status and often translocation as well. The understanding of the roles and the regulation of glycogenin, protein phosphatase 1, glycogen targeting proteins, laforin and malin are in their infancy. These various processes appear to be the mechanisms that give the glycogen granule precise, yet dynamic regulation.


Interventions for emergency contraception.
In emergency contraception a drug or IUD is used to prevent pregnancy shortly after unprotected intercourse. Except for some Western-European countries and China, emergency contraception is largely under-utilised worldwide. In many developing countries lack of access to emergency contraception may subject women to unsafe abortions, which contribute significantly to maternal mortality and morbidity. Currently, several interventions (IUD, the Yuzpe regimen, levonorgestrel, mifepristone, danazol and some combination regimens) are available for emergency contraception. Information on the comparative efficacy, safety and convenience of these methods is crucial for reproductive health care providers and the women they serve. To determine which emergency contraceptive method following unprotected intercourse is the most effective, safe and convenient to prevent pregnancy. The search included the Cochrane Controlled Trials Register, Popline, MEDLINE, Chinese biomedical databases and UNDP/UNFPA/WHO/World Bank Special Programme on Human Reproduction (HRP) emergency contraception database (July 2003). Content experts and pharmaceutical companies were contacted. Randomised controlled trials and controlled clinical trials including women attending services for emergency contraception following a single act of unprotected intercourse were eligible. Data on outcomes and trial characteristics were extracted in duplicate and independently by two reviewers. Quality assessment was also done by two reviewers independently. Meta-analysis results are expressed as relative risk (RR) using a fixed-effects model with 95% confidence interval (CI). In the presence of significant heterogeneity a random-effect model was applied. Forty-eight trials with 33110 women were included. Most trials were conducted in China (37/48). Levonorgestrel is more effective than the Yuzpe regimen in preventing pregnancy (2 trials, RR: 0.51; 95% CI: 0.31 to 0.83). Single dose (1.5 mg) administration seems to have similar effectiveness as the standard 12 hours apart split-dose (0.75 mg twice) of levonorgestrel (2 trials, RR: 0.77, 95% CI: 0.45 to 1.30). Levonorgestrel has similar effectiveness to mid-dose (8 trials, RR: 1.64; 95% CI: 0.82 to 3.25) or low-dose (7 trials, RR: 1.38; 95% CI: 0.93 to 2.05) mifepristone. Low-dose (=< 10 mg) mifepristone is similarly effective as mid doses (25-50 mg) when only high quality trials are considered. Delay in the onset of subsequent menses is the main unwanted effect of mifepristone and seems to be dose-related. The Yuzpe regimen can be used when levonorgestrel and mifepristone are not available. Half-dose Yuzpe with single administration is associated with fewer side-effects but it is not clear whether it is as effective as the standard Yuzpe regimen (RR: 1.41; 95% CI: 0.76 to 2.61). Levonorgestrel 1.5 mg (two split doses or a single dose) and low and mid-doses (25-50 mg) of mifepristone offer high efficacy with an acceptable side-effect profile. Single dose simplifies the use of levonorgestrel for emergency contraception without an increase in side-effects. However, mifepristone might delay the following menstruation, which could increase anxiety, particularly in higher doses. The Yuzpe regimen could be used if levonorgestrel or mifepristone are not available. The intrauterine device (IUD) is another effective emergency contraceptive, and can be kept for ongoing contraception.


Different domains of Pseudomonas aeruginosa exoenzyme S activate distinct TLRs.
Some bacterial products possess multiple immunomodulatory effects and thereby complex mechanisms of action. Exogenous administration of an important Pseudomonas aeruginosa virulence factor, exoenzyme S (ExoS) induces potent monocyte activation leading to the production of numerous proinflammatory cytokines and chemokines. However, ExoS is also injected directly into target cells, inducing cell death through its multiple effects on signaling pathways. This study addresses the mechanisms used by ExoS to induce monocyte activation. Exogenous administration resulted in specific internalization of ExoS via an actin-dependent mechanism. However, ExoS-mediated cellular activation was not inhibited if internalization was blocked, suggesting an alternate mechanism of activation. ExoS bound a saturable and specific receptor on the surface of monocytic cells. ExoS, LPS, and peptidoglycan were all able to induce tolerance and cross-tolerance to each other suggesting the involvement of a TLR in ExoS-recognition. ExoS activated monocytic cells via a myeloid differentiation Ag-88 pathway, using both TLR2 and the TLR4/MD-2/CD14 complex for cellular activation. Interestingly, the TLR2 activity was localized to the C-terminal domain of ExoS while the TLR4 activity was localized to the N-terminal domain. This study provides the first example of how different domains of the same molecule activate two TLRs, and also highlights the possible overlapping pathophysiological processes possessed by microbial toxins.


PET imaging of CCND1 mRNA in human MCF7 estrogen receptor positive breast cancer xenografts with oncogene-specific [64Cu]chelator-peptide nucleic acid-IGF1 analog radiohybridization probes.
Treatment of breast cancer is hampered by a large unmet need for rapid, sensitive, specific staging and stratification of palpable and nonpalpable abnormalities. Mammography and physical examination miss many early breast cancers, yet detect many benign lesions. Cyclin D1, encoded by CCND1 messenger RNA (mRNA), and insulin-like growth factor 1 receptor (IGF1R) are key regulators of cell proliferation that are overexpressed in most breast cancers. Therefore, we hypothesized that malignant breast masses could be imaged and quantitated externally by PET with a dual-specificity probe that targets both CCND1 mRNA and IGF1R. We designed a CCND1-specific peptide nucleic acid (PNA) hybridization sequence (CTGGTGTTCCAT), separated by a C-terminal spacer to a cyclized IGF1 peptide analog (d-Cys-Ser-Lys-Cys), for IGF1R-mediated endocytosis. On the N-terminus we attached a chelator (1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl [DO3A]) for the positron-emitting nuclide (64)Cu. We administered the [(64)Cu]CCND1-IGF1 analog radiohybridization probes, as well as sequence controls, by tail vein to immunocompromised female NCr mice bearing human MCF7 estrogen-dependent, receptor-positive xenografts. We imaged the mice by PET and CT 4 and 24 h later, and measured tissue distribution of the radiohybridization probes. We observed 8 +/- 2-fold higher PET intensity in the center of the breast cancer xenografts than in the contralateral tissues at 24 h after injection of the [(64)Cu]CCND1-IGF1 analog radiohybridization probe. IGF1 blocking yielded significantly weaker images (P < 0.05) relative to the tumor-free side at 24 h after injection, as did a PNA mismatch probe, a peptide mismatch probe, and free (64)CuCl(2). These results are consistent with our hypothesis for radiohybridization PET of overexpressed CCND1 mRNA, dependent on IGF1R-mediated endocytosis, in suspect masses. Early noninvasive detection of initial cancerous transformation, as well as invasive or recurrent breast cancer, with dual-specificity radiohybridization probes, might enable molecularly targeted staging, stratification, and choice of therapy.


[Evidence-Based Indication for Proton Pump Inhibitors - a Group Practice Perspective].
Evidence-Based Indication for Proton Pump Inhibitors - a Group Practice Perspective Abstract. Little is known about the extent of non-evidence-based proton pump inhibitor (PPI) prescriptions in the general practice setting in Switzerland. A recommendation for long-term therapy was included in the "Top 5 list" of "smarter medicine" for the outpatient internal medicine in 2014. The observational study recorded the proportion of patients without evidence-based indication for PPI in a practice with six general practitioners retrospectively over three months. Of 2225 patients analysed, 11.1 % (n = 248) took a PPI. The percentage of patients without a clear evidence-based indication was 46.8 %. Almost every second patient did not have a clear evidence-based indication for PPI. The results could be an incentive for general practitioners to reconsider the indication when prescribing PPI, also in the sense of "smarter medicine".


Functional and Cognitive Impairments Increased Risks of Outcomes of Healthcare Utilization in Patients With Stroke Receiving Home and Community-Based Care in Taiwan.
Aim: Stroke is a leading cause of disability; however, little is known about the outcomes of the utilization of long-term care (LTC) recipients in Taiwan. This study aimed to quantify the burdens of disease of stroke survivors receiving LTC by evaluating the outcomes of their utilization including mortality, readmissions, and re-emergency within 1 year after diagnoses of strokes. Methods: By interlinkages among the national mortality registry, LTC dataset (LTC-CM), and the National Health Insurance Research Dataset (NHIRD), the outcomes and the factors associated with receiving LTC up to 1 year were explored. Patients were aged 50 years and over with an inpatient claim of the first diagnosis of stroke of intracerebral hemorrhage (ICH) and ischemic stroke during 2011-2016. Outcomes of the healthcare utilization include rehospitalization and re-emergency. Results: There were 15,662 patients with stroke who utilized the LTC services in the dataset among the stroke population in NHIRD. Stroke survivors receiving LTC showed no difference in clinical characteristics and their expected years of life loss (EYLL = 7.4 years) among those encountered in NHIRD. The LTC recipients showed high possibilities to be rehospitalized and resent to emergency service within 1 year after diagnosis. Apart from the comorbidity and stroke severity, both the physical and mental functional disabilities and caregiving resources predicted the outcomes of the utilization. Conclusions: For stroke survivors, both severe functional impairments and cognitive impairments were found as important factors for healthcare utilizations. These results regarding reserving functional abilities deserve our consideration in making the decision on the ongoing LTC policy reform in the aged society of Taiwan.


The role of milk and lactose intolerance in Ethiopian patients with non-ulcer dyspepsia: a case control study.
Milk intolerance, lactose intolerance and non-ulcer dyspepsia are common among Ethiopians. This study, therefore, was designed to find out if milk intolerance associated with lactase deficiency account for non-ulcer dyspepsia. Ninety-eight patients with non-ulcer dyspepsia and 95 controls were examined and interviewed for demographic data and milk drinking habits. Then each had a lactose tolerance test (LTT), stool examination for pH, ova and parasites. The demographic characteristics and the number of milk drinkers were comparable in the 2 groups. However, milk intolerance and lactose intolerance were significantly higher among the patients with non-ulcer dyspepsia than among the control group (p less than 0.01, p less than 0.05 respectively). The combination of milk intolerance, lactose intolerance and LTT was also significantly different (p less than 0.01). The mean stool pH was markedly reduced after lactose ingestion and there were more ova and parasites in the stools of the control group. These observations suggest that milk intolerance and/or lactose intolerance account significantly for the symptoms of the patients with non-ulcer dyspepsia. However, since lactose intolerance and abnormal LTT are very common among adult Ethiopians symptoms related to the drinking of milk should be interpreted with caution vis-a-vis the results of the lactose loading test.


Kinetics of the surface hydrolysis of raw starch by glucoamylase.
The hydrolysis of raw starch catalyzed by glucoamylase has been studied with starch granules of different sizes by use of an amperometric glucose sensor by which the direct and continuous observation of the concentration of glucose can be achieved even in a thick raw starch suspension. The initial rate of the enzymatic hydrolysis in the raw starch suspension increased with increasing concentration of the enzyme to approach a saturation value and was proportional to the amount of substrate. Also, the rate was proportional to the specific surface area of the substrate. The experimental results can be explained well by the rate equations derived from a three-step mechanism, which consists of adsorption of the free enzyme onto the surface of the substrate, reaction of the adsorbed enzyme with the substrate, and liberation of the product.