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De facon etonnante pulse pressure 20 generic 100 mg aldactone amex, cet acide amine passe sans probleme la barriere hematoencephalique (chez des rats adultes blood pressure medication overdose treatment buy aldactone 100 mg on-line, elle est non detectable et elle passe a 1 blood pressure medication zanidip buy discount aldactone 25mg online,5 mM apres 5 jours de complementation en citrulline) (156) blood pressure log chart pdf generic aldactone 25mg visa. Ainsi, il a ete demontre qu’une complementation orale en citrulline pendant 3 mois chez des rats ages permet d’ameliorer les changement lies a l’age des rafts lipidiques au niveau de l’hippocampe (157). Or, la complementation en citrulline est capable de modifier la structure de ces rafts, se rapprochant de celle d’un rat adulte avec la citrulline. Cette augmentation pourrait etre un mecanisme protecteur des cellules mais cela reste a demontrer. Ainsi, les donnees restent parcellaires et ne permettent pas a ce jour de determiner le vrai impact des changements cellulaires au niveau de l’hippocampe par la citrulline. Par ailleurs, il a ete demontre recemment que la citrulline est capable de stimuler la voie dopaminergique dans le cerveau. Or, cette augmentation de la motricite avec la citrulline pourrait etre 39 liee a une action sur le systeme nerveux central notamment via une stimulation de la voie dopaminergique. Il a ainsi ete demontre que l’augmentation de la motricite par la citrulline est associee a une augmentation de la forme totale et de la forme phosphorylee de la tyrosine hydroxylase (+125%), l’enzyme limitante de la voie dopaminergique (156). En revanche, de facon surprenante, au niveau de la jonction neuromusculaire, il a ete demontre chez le rat que la citrulline inhibe la liberation d’acetylcholine, neurotransmetteur implique dans le signal nerveux induisant la contraction musculaire (163). Ainsi, la citrulline pourrait affecter le systeme vasculaire cerebral et ameliorer l’oxygenation. Cependant, les mecanismes precis d’action de la citrulline restent encore a explorer. Ainsi, l’effet stimulateur de la synthese proteique musculaire a ete mis en evidence pour la premiere fois en 2006 par Osowska et al. Ce modele de malnutrition proteino-energetique consiste a nourrir les rats avec seulement 50% des ingesta spontanes pendant 12 semaines. Puis, les rats sont renourris une semaine avec un regime correspondant a 90% de leur ingesta spontanes et enrichis en citrulline ou en acides amines non essentiels (afin que les regimes soient isoazotes). Il a ainsi ete demontre que les rats recevant le regime enrichi en citrulline ont une synthese proteique musculaire augmentee de 80% et un gain proteique musculaire net de 20% (Fig. En utilisant le meme modele, il a ete demontre que l’accretion proteique liee a la prise de citrulline s’accompagne d’une augmentation de la force maximale ainsi que d’une augmentation de la motricite des animaux permettant d’etablir un continuum entre une action metabolique et un retentissement clinique (162). Les effets de la citrulline sur la synthese proteique musculaire et sur la force ne se limitent pas au rat age puisque ces resultats ont ete confirmes par Ventura et al. En effet, chez les rats complementes en citrulline, la synthese des proteines myofibrillaires est plus importante et la force musculaire est preservee contrairement aux rates restreintes sans complementation en citrulline. Les trois groupes ont ete subis une restriction alimentaire (50% des ingesta spontanes) pendant 12 semaines. Cependant, l’action de la citrulline sur la synthese proteique musculaire ne se limite pas au rat age, car dans un modele de jeune court chez des rats adultes (mis a jeun pendant 18 heures), le jeune se traduit par une chute de 40% de la synthese proteique musculaire qui est totalement restauree par un bolus oral de citrulline (171). Enfin, dans un modele de restriction de croissance intra-uterine induite par une restriction alimentaire maternelle chez le rat, Bourdon et al. Il a egalement ete montre que cette capacite de la citrulline a moduler la synthese proteique musculaire existe chez l’Homme : en effet, une complementation orale en citrulline (10 g vs placebo isoazote) permet d’ameliorer la synthese proteique musculaire de 25% chez des adultes sains soumis a un regime hypo-proteine (8%) durant 3 jours (173). De plus, cette amelioration de la synthese proteique musculaire semble insuline-independante puisque l’insulinemie n’est pas differente entre les differents groupes. Enfin, l’effet de la citrulline sur la synthese proteique semble specifique au muscle puisque 3 etudes cliniques ont etudie les effets d’une complementation en citrulline dans differentes conditions sur la synthese proteique au niveau corps entier et aucune d’entre-elles n’a pu montrer un effet positif de la citrulline (122,173,175). Cependant, si la capacite de la citrulline a moduler la synthese proteique musculaire a ete prouvee, les mecanismes precis de son action restent peu connus. Enfin, bien que la citrulline stimule la synthese proteique musculaire globale, elle agit de facon plus complexe sur l’expression des proteines. En effet, la citrulline est capable de stimuler l’expression de proteines specifiques et d’inhiber l’expression d’autres proteines. La modulation specifique par la citrulline de certaines proteines a ete recemment repertoriee dans une revue generale par Bourgoin-Voillard et al. Plus precisement, la citrulline stimule plus particulierement l’expression de proteines myofibrillaires et module des enzymes du metabolisme energetique (voir chapitre 8). Concernant les effets de la citrulline sur la proteolyse, a ce jour peu de donnees sont disponibles dans la litterature. En effet, ces auteurs montrent qu’une complementation en citrulline pendant 5 jours permet de diminuer le proteasome activator complex subunit 1. Cependant, malgre des donnees interessantes mais fragmentaires, la regulation de la proteolyse musculaire par la citrulline reste encore a explorer. En effet, afin d’explorer les mecanismes d’action de la citrulline, une etude proteomique differentielle a montre, dans le meme modele de malnutrition proteino-energetique precedemment decrit qu’une renutrition enrichie en citrulline chez des rat ages entraine, au niveau musculaire, une surexpression des enzymes impliquees dans la glycogenolyse. Dans ce meme travail, les auteurs ont observe une fonte massive du tissu adipeux chez les animaux ages (pres de -50% de la masse grasse abdominale). Ce travail a suggere que la modulation du metabolisme energetique ne se limitait pas au muscle puisque Joffin et al. Ces resultats ont ete confirmes dans des explants adipeux de rats adultes obeses (8) (Fig. Ces effets de la citrulline pourraient ainsi expliquer la diminution de la masse adipeuse de souris obeses complementees avec de citrulline (11) (et qui a egalement ete observee chez l’Homme). De plus dans cette etude, l’homeostasie glucidique est restauree avec une amelioration de la tolerance au glucose et de la sensibilite a l’insuline, et l’activite lipogenique hepatique est diminuee. Malgre un role evident de la citrulline sur le metabolisme energetique, les donnees restent parcellaires et il n’est pas possible de comprendre de facon integree comment la citrulline agit sur ce metabolisme. Cependant, peu d’etudes ont a ce jour etudier les effets d’une complementation en citrulline sur la performance. De facon surprenante, la complementation en citrulline a diminue la performance des athletes en comparaison avec le placebo. Par consequent, ces deux etudes n’ont montre aucun effet benefique d’une complementation aigue en citrulline sur la performance. En revanche, les resultats semblent differents lorsque la citrulline est ingeree de facon chronique. En effet, deux etudes ont evalue la complementation en citrulline pendant 7 jours. La seconde etude a demontre, avec une complementation chronique en citrulline inferieure (2,4g/jour), une reduction du temps necessaire pour effectuer 4 km en velo de 1,5% (180). De plus, dans cette etude, au niveau de la fatigue musculaire, le ressenti des sujets etait meilleur apres la complementation en citrulline. Les effets de la citrulline ne se limitent pas a la performance puisque la citrulline permet d’augmenter la perfusion musculaire et egalement de preserver la perfusion splanchnique. En effet, une hypoperfusion splanchnique apparait durant un exercice physique intense, due a une redistribution sanguine de l’aire splanchnique aux muscles actifs et au systeme cardio- pulmonaire (181). Cette hypoperfusion splanchnique est associee a une diminution de la fonction de barriere de l’intestin et ainsi a une performance athletique pouvant etre diminuee (182). Cependant, la citrulline est souvent consommee sous forme de malate de citrulline par les athletes. Pour cette raison ; plusieurs auteurs ont utilises ce sel de citrulline pour evaluer les proprietes de la citrulline lors d’un exercice. Une autre etude a montre qu’une unique ingestion de malate de citrulline (8g) augmente la capacite de travail de 19% (mesure par le nombre de repetitions effectuees jusqu’a epuisement lors d’une exercice en resistance) (184). Des resultats similaires sur la performance en filiere anaerobie ont ete retrouves par Wax et al. Ainsi le malate de citrulline semble etre interessant pour ameliorer la performance, en particulier lors d’exercice en resistance. Cependant, ces resultats doivent etre consideres avec precaution puisqu’il n’est pas possible de determiner si les effets sont lies a la citrulline ou au malate (qui est notamment implique dans la production d’energie en tant qu’intermediaire du cycle de Krebs (178,188)). Par consequent, bien que les resultats d’une complementation en citrulline soient plutot prometteurs lors d’un exercice, d’autres etudes sont necessaires pour confirmer l’effet ergogenique de la citrulline. Par ailleurs, concernant les autres etudes disponibles, elles n’ont generalement pas de placebo isoazote ce qui en limite la portee clinique. Dans une premiere etude (Publication n°1), nous avons etudie in vivo la relation entre les metabolismes proteique et energetique, et l’action de la citrulline sur ces derniers. En parallele et au vu de proprietes qui semblent communes, nous avons evalue les potentiels effets synergiques d’un entrainement physique et d’une complementation en citrulline. Pour se faire, nous avons explore les metabolismes proteique (notamment la synthese proteique musculaire) et energetique (notamment le metabolisme mitochondrial) et evalue la performance chez des rats Wistar adultes sains sedentaires ou entraines pendant 4 semaines. Ces rats ont ete complementes en citrulline (1g/kg/jour) durant cette meme periode. Par ailleurs, concernant la citrulline, si son action sur la synthese proteique a bien ete prouvee, en revanche l’impact de cet acide amine sur le secretome musculaire est totalement meconnu et une augmentation de la synthese proteique par la citrulline dans la cellule musculaire pourrait moduler certaines proteines secretees.

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To determine the outbreak blood pressure medication good for acne purchase 25 mg aldactone with amex, cases of confirmed or probable Legionnaires’ disease identified before July 31 blood pressure 78 over 48 discount aldactone 25mg mastercard, 1994 toprol xl arrhythmia generic 100mg aldactone, were enrolled into a matched case-control study enrique heart attack buy cheap aldactone 25 mg online. Water and environmental swabs were collected from 28 sites on board the ship, sites visited by passengers in Bermuda and from the ship’s source of water in New York, United States. The case-control study 92 Water Recreation and Disease showed that case-passengers were significantly more likely than control- passengers to have been in the hot tub water. Among the passengers who did not enter the hot tub water, case passengers were significantly more likely to have spent time around the hot tub (Anonymous 1994). The hot tubs seem to have been a persistent source of infection for at least nine separate week-long cruises during the spring and summer of 1994. No further cases of Legionnaires’ disease were identified after the hot tubs were closed on July 16, 1994 (Jernigan et al. The illness is considered to be severe with a high risk of death, severe acute symptoms generally lasting more than seven days. There are a number of documented cases of persons suffering sequelae as a consequence of infection. Taxonomy the family Leptospiraceae are of the order Spirochaetales and are divided into three genera: Leptospira, Leptonema and Turneria. All recognised species have been classified as pathogens, intermediate or saprophytes (Plank and Dean 2000). Although most leptospires are associated with mild illness, these serovars are frequently fatal if untreated. Reservoir the primary source of leptospires is the surface of the renal tubes in the kidney of an excreting carrier animal. Carrier animals pass urine containing leptospires into the surrounding environment. The highest prevalence rates are in tropical, developing countries although epidemiological studies show infection in temperate zones is more frequent than previously thought (Plank and Dean 2000). Charactersitics Pathogenic leptospires are aerobic, motile, helicoidal, flexible spirochaetes, usually between 6 µm and 20 µm long and 0. Severe forms are frequently fatal if untreated; symptoms include jaundice, haemorrhage, potentially fatal kidney and liver failure. Aseptic meningitis is estimated to complicate between 5% and 24% of cases (Arean 1962; De Brito et al. Sequelae include psychiatric illness such as depression and psychoses, prolonged listlessness and joint pains lasting from weeks to months. Results showed that liver and renal disease had resolved but headache and ophthalmic sequelae persisted. Delirium, hallucinations, encephalitis, grand mal seizures and coma have been reported (Torre et al. An association between antiphospholipid syndrome and leptospirosis has been proposed by Tattevin et al. The authors describe a case in a 63- year-old man who was admitted to hospital with fever, acute renal failure, lymphocytic meningitis, hepatitis, and alveolar meningitis. However, the patient was also showing pulmonary hypertension which has not been reported in leptospirosis but is associated with antiphospholipid syndrome (Karmochkine et al. Once the patient was treated with amoxicillin the pulmonary hypertension resolved and kaolin clotting time, which was slower than normal in the patient, also returned to normal. Levels of antibodies to antiphospholipid returned to normal suggesting that antiphospholipid syndrome and leptospirosis were associated. In a retrospective study of 16 patients with documented leptospirosis, IgG anticardiolipin antibody concentrations were increased in all patients with severe leptospirosis but in none of the patients with uncomplicated leptospirosis (Rugman et al. Erythroid hypoplasia has been found to be associated with leptospirosis but is rarely reported. Thrombocytopenia in a patient with serological findings indicative of acute leptospira infection is reported by Wenz et al. Disease manifestations are not necessarily due to direct tissue damage by the organism, but due to the host’s immune response. Leptospira may persist in the brain – in one report 4 out of 11 patients had persistent headaches for between 6 and 34 years post-infection. Ophthalmic involvement with blurred vision has Bacteria 95 been reported to persist for decades following acute infection (Shpilberg et al. Cardiac involvement is common in severe disease and can manifest as myocarditis, congestive heart failure, non-specific electrocardiogram abnormalities and sudden death. Uncommon sequelae are acalculous cholecystitis, pancreatitis, and hypermylasemia (Plank and Dean 2000). This may be caused by adult respiratory distress syndrome or profuse pulmonary bleeding. Exposure/mechanism of infection Leptospires enter the host from contaminated urine, water, soil or mud, by penetrating abrasions in the skin or body surfaces and possibly by inhalation of aerosols containing leptospires. Disease incidence the incidence of human infection is higher in the tropics than in temperate regions but transmission occurs in both industrialised and developing countries. Incidence rates are underestimated due to lack of awareness of the disease and relatively inaccessible and insufficiently rapid diagnostics (Bharti et al. Farr (1995) estimated that an average of between 100 and 200 cases are identified annually in the United States with about 50% of cases occurring in Hawaii. Data collected in 1999 concerning number of deaths and mortality rates are provided in Table 4. Patients suffer a very sudden onset of severe headache, fever, muscle pain and sometimes red eyes and photophobia. Infectivity A very small number (one to ten) of leptospires can cause a fatal infection in a susceptible host. Leptospires enter a host from urine, water, soil or mud, by penetrating small abrasions in the skin or body surfaces, possibly by inhalation of aerosols containing leptospires, and possibly through the conjunctival sac. Drinking or inhalation of contaminated water following immersion has also caused leptospirosis. Once in the body the leptospires spread very quickly and 96 Water Recreation and Disease can be found in the blood minutes after entering the body of the host. Around 90% of recognised cases of leptospirosis are mild and self-limited (Plank and Dean 2000). The relative importance of such occupational risks has decreased since protective measures have been implemented. Many cases occur in association with conditions of slum living or with recreational activities involving immersion in water (Anonymous 1998; Haake et al. In tropical environments, occupational exposure such as rice farming and other agricultural activities is still significant, as well as exposure of the general population during activities of daily living, and especially is associated with high seasonal rainfall. Leptospirosis is the only epidemic-prone infection which can be transmitted directly from contaminated water. Of significance is the potential for large, multinational, point-source outbreaks after recreational events (Bharti et al. Farmers, sewer workers, miners, fishermen and meat workers have historically been at highest risk of infection. Recently, however, a number of outbreaks have been associated with recreational water contact – the majority associated with fresh open water accessible to animals; recreational exposure to natural water sources is reported as a common route of transmission (Jackson et al. In the United States, for example, prior to 1970 it was suggested that 66% of cases were from occupational exposure (Heath et al. In 1971, however, 60% of reported cases were in children, students, and housewives while only 17% occurred among occupational workers, suggesting the epidemiology had moved to home and recreational settings (Thiermann 1977). Of 237 confirmed cases in the Netherlands between 1987 and 1991, 14% were diagnosed in travellers, all except one who had had surface water exposure overseas (Van Crevel et al. In June and August 1964, in the State of Washington, United States, 61 cases of leptospirosis occurred in teenagers who reported swimming in a local irrigation canal. When the canal was inspected it was found that a herd of cattle 98 Water Recreation and Disease had access to the water upstream of the swimming area. Although no leptospires were found in water samples taken from the suspected area in which a herd of cows were present with access to the water, possibly indicating the source of infection. In September 1987, 22 United States military personnel were infected with leptospires on the island of Okinawa, Japan.

Although he enjoyed this work blood pressure medication harmful order aldactone 100 mg online, he decided he was more interested in solving problems that he felt were more biomedically relevant blood pressure zone generic 25mg aldactone with mastercard. In 1974 blood pressure medication for asthmatics buy aldactone 100mg with mastercard, Smith took a job as a senior scientist at Mead Johnson in Evansville blood pressure 7850 discount aldactone 100mg, Indiana where he spent his time studying platelet aggregation, prostaglandin formation, and arachidonic acid mobilization. A year later, he accepted a position in the Department of Biochemistry at Michigan State University where he remained for 28 years and served as chair for the last 8 years of his time there. Work in other laboratories suggested that aspirin was acetylating a serine residue on the enzyme (10, 11). They concluded that the Ser-O-acetyl protrudes into the cyclooxygenase active site thereby interfering with arachidonic acid binding. This is the most definitive biochemical work on how aspirin works at the molecular level to interfere with cyclooxygenase activity. Smith later showed that substitu- tions of Ser-530 with bulkier residues such as threonine and asparagine gradually reduced cyclooxygenase activity (13). In 2002 Smith decided to step down as Chair of Biochemistry at Michigan State, saying “My opinion is that administrators should serve no longer than American presidents. Still at the University of Michigan today, he continues to work on prostaglandins. In recognition of his many contributions to science, Smith has received several awards and honors. These include the 1991 Treadwell Award from George Washington University, the 1992 Distinguished Faculty Award from Michigan State University, the 1996 Abraham White Distinguished Scientific Achievement Award from George Washington University, the 1997 Senior Aspirin Award from Bayer Corporation, the 1999 Michigan Universities Association of Governing Boards Award, the 2004 State of Michigan Scientist of the Year Award, the 2004 Berzelius Lectureship from the Karolinska Institute, the 2004 Avanti Award from the Amer- ican Society for Biochemistry and Molecular Biology, the 2006 William C. Rose Award from the American Society for Biochemistry and Molecular Biology, and the 2006 Hayaishi Lectureship 1 from Hamamatsu University. Lands, was a young faculty member at the University of Michigan when Smith joined his laboratory. Lands subsequently left Mich- igan in 1980 to become Chair of Biochemistry at the University of Illinois, Chicago, and later moved to the National Institutes of Health in 1990, where he served as the Senior Scientific Advisor to the Director of the National Institute on Alcohol Abuse and Alcoholism. Lands is the discoverer of the “retailoring” pathway for membrane phospholipid synthesis. He is an au- thority on essential fatty acids and is credited with recognizing the beneficial effects of balancing excess -6 fatty acids with dietary -3 fatty acids. In recognition of his work, the University of Michigan’s Department of Biological Chemistry endowed a lectureship in nutri- tional biochemistry in honor of Lands. Bradshaw 125 Properties of the Specific Binding of I-Nerve Growth Factor to Responsive Pe- ripheral Neurons (Frazier, W. During his senior year at Colby, he took a course in biochem- istry taught by Wilmon B. Chipman, a recent graduate of the University of Illinois and a new addition to the Colby faculty. Chipman was young and enthusiastic about biochemis- try, and less than 2 weeks into the course Bradshaw decided that he would go to graduate school to pur- sue studies in biochemistry. He ap- plied to several schools but settled on Duke University because of the prominent faculty in the biochemis- try department and because Duke offered the most financial support. Hill had only come to Duke the year before Brad- shaw arrived, but he already had a sizable research group that focused on the structure- function relationships of proteins. From the biochemistry course taught by Chipman, Brad- shaw knew that this was where his interests lay and he “was thrilled beyond words” (2) when Hill accepted him into his group. Working with Hill, Bradshaw characterized hemoglobin from four species of lemur, defined active site residues in fumarase using chemical modifications, and used cysteine-mixed disulfide derivatives to define aspects of disulfide bond formation in lysozyme. In 1969, Bradshaw was offered a position on the faculty of the Department of Biological Chemistry at Washington University School of Medicine in St. He accepted the offer knowing that the position would provide ample opportunity for productive collaborations. In the second Classic, Bradshaw and his colleagues continue their binding studies, this time using embryonic heart and brain tissues from chickens, and report that binding in these tissues is very similar to that in the sympathetic and sensory nervous systems. Immediately, many other substances such as platelet-derived growth factor, the somatomedins (now insulin-like growth factors), the transforming growth factors, and the fibroblast growth factors shot to center stage, and the growth factor field, as an expansion of endocrinology, was born with a vengeance. In 1982, Bradshaw moved to California where he became Professor and Chair of the Department of Biological Chemistry at the University of California, Irvine. He is currently Professor Emeritus in the Department of Physiology & Biophysics at the University of California, Irvine as well as Professor in the Department of Pharmaceutical Chemistry and Deputy Director of the Mass Spectrometry Facility at the University of California, San Francisco. Bradshaw has been very active in the American Society for Biochemistry and Molecular Biology, serving on the Committee on Equal Opportunities for Minority Groups, the Nomi- nating Committee, and the Membership Committee and also acting as Society Treasurer and Councilor. Bradshaw was also the President of the Federation of American Societies for Experimental Biology, Treasurer of the Keystone Symposia, and the founding President of the Protein Society. He has served on many editorial boards and was an Associate Editor of the Journal of Biological Chemistry. In recognition of his contributions to science, Bradshaw has received many awards and honors including the Passano Foundation Young Scientist Award (1976), the American Chem- ical Society St. Louis Section Award (1979), the Italian National Research Council Gold Medal 1,2 (1987), and the Australia Society of Medical Research Gold Medal (1999). At the time the papers were published, Frazier was a predoctoral student in Bradshaw’s laboratory. A few years later, he became an Assistant Professor in the Department of Biological Chemistry at Washington University School of Medicine. He remains there today and is currently a Professor of Cell Biology and Physiology 1 Biographical information on Ralph Bradshaw was taken from Ref. Robbins Temperature-sensitive Yeast Mutants Deficient in Asparagine-linked Glycosylation (Huffaker, T. This discovery made a large contribution to the general un- derstanding of the global sulfur cycle, and as a result Robbins received the Eli Lilly Award in Biochemistry in 1956. The next year, Lipmann moved to the Rockefeller Institute, and Rob- bins joined him as Assistant Professor where he continued his work on sul- fur activation. The formation of N-glycosidic linkages of eukaryotic glycoproteins was known to involve the transfer of a common precursor oligosaccharide from a lipid carrier (dolichol) to an asparagine residue in the nascent polypeptide chain. Robbins set out to identify and characterize the genes involved in the early steps of the dolichol-linked oligosaccharide assembly. These results indicated that the algl-1 mutant was blocked at the addition of the fist mannose residue to the oligosaccharide-lipid. Robbins subsequently identified and characterized several other genes in this pathway. The enzymology and genetics of the dolichol pathway enzymes represent classical pieces of glycobiology history. Robbins’ later research turned to the dynamics of yeast cell wall synthesis and remodeling, focusing on chitin synthesis. In recognition of his contributions to science, Robbins has received many awards and honors. These include the Karl Meyer Award for Lifetime Achievement in Glycobiology (2000) and election to the National Academy of Sciences (1986). After do- ing a postdoctoral fellowship from 1966 to 1968 with Gordon Hammes at Cornell University, Pace joined the faculty of the Department of Biochem- istry and Biophysics at Texas A&M University. As an independent researcher, Pace used the ideas and techniques he learned in Tanford’s laboratory to study protein folding and denatur- ation. The method is the most widely used method for Nick Pace measuring protein stability, and the paper has been cited more than 370 times. By analyzing the proteins’ denaturation curves, they were able to make linear plots of the free energy of unfolding ( G) versus denaturant concentration. The plot’s intercept gave a measure of the protein’s stability whereas the slope gave an “m value” that measured how strongly G depended on urea concentration. Pace’s follow-up paper on m values (2) is the third most cited paper in the history of Protein Science with about 800 citations. Today, Pace remains at Texas A&M where he is a distinguished professor at the Health Science Center. He has received many awards and honors for his contributions to science, including a Texas A&M University Association of Former Students Faculty Distinguished this paper is available on line at. In 1970, Stenflo pub- lished a paper that showed that admin- istration of the vitamin K antagonist dicumarol leads to the biosynthesis of an abnormal prothrombin that is chemically similar to prothrombin but is biologically inactive (6).

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Twenty-one of the 24 women treated with bromocriptine conceived: 18 had a live birth (85 sinus arrhythmia icd 10 discount aldactone 25 mg otc. In addition hypertension 14090 generic aldactone 100 mg mastercard, serum prolactin levels during early pregnancy (5–10 weeks of gestation) were significantly higher in women who miscarried (31 hypertension bradycardia buy aldactone 100 mg on line. However blood pressure medication over the counter discount 100 mg aldactone overnight delivery, this conclusion is based on a single small study, and hence should be confirmed. Furthermore, vitamin D deficiency during pregnancy adversely affects health, growth and development of the child (McAree et al. Vitamin D status is affected by factors that regulate its production in the skin, including skin pigmentation, latitude, season, dressing codes, aging, sunscreen use and air pollution (De-Regil et al. A recent review combining trials on vitamin D supplementation in pregnancy, which cumulatively involved more than 2000 pregnant women, reported that there were no adverse events observed attributable to vitamin D supplementation (De-Regil et al. Regarding the benefit of vitamin D supplementation on pregnancy related outcomes, evidence is scarce and inconsistent. Vitamin D supplementation during pregnancy seems to reduce the risk of preterm birth (three trials) and low birth weight (four trials). Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. Effect of metformin on early pregnancy loss in women with polycystic ovary syndrome. Major malformation risk, pregnancy outcomes, and neurodevelopmental outcomes associated with metformin use during pregnancy. Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss. Aspirin and low- molecular weight heparin combination therapy effectively prevents recurrent miscarriage in hyperhomocysteinemic women. Modulatory effects of vitamin D on peripheral cellular immunity in patients with recurrent miscarriage. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Recurrent spontaneous abortion and polycystic ovarian disease: comparison of two regimens to induce ovulation. Current challenges in the pharmacological management of thyroid dysfunction in pregnancy. Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study. Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases. Use of human menopausal gonadotropins in the treatment of endometrial defects associated with recurrent miscarriage: preliminary report. McAree T, Jacobs B, Manickavasagar T, Sivalokanathan S, Brennan L, Bassett P, Rainbow S, Blair M. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity. Vitamin supplementation and pregnancy outcome in women with recurrent early pregnancy loss and hyperhomocysteinemia. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. Treatment of thyroid disorders before conception and in early pregnancy: a systematic review. Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications. Relationship between abnormal glucose tolerance test and history of previous recurrent miscarriages, and beneficial effect of metformin in these patients: a prospective clinical study. Septate uterus For a septate uterus, hysteroscopic metroplasty has become the indicated treatment of choice (Valle and Ekpo, 2013). Older studies have discussed abdominal metroplasty, but based on lower morbidity, ease of the procedure and the reduced risk of intrauterine adhesions, hysteroscopic metroplasty is the preferred option, and widely applied (Grimbizis et al. There were no significant differences in preterm birth, low birth weight or caesarean section. Non-controlled and observational studies have suggested a beneficial effect of surgery (Homer et al. A few studies have also reported on the live birth rate, and found an increase after surgery (Choe and Baggish, 1992, Valli et al. They found that surgery had a negative impact on fertility, with only 52% becoming pregnant in the first year after surgery. For those becoming pregnant, they found a reduction in the miscarriage rate (Venturoli et al. Hysteroscopic treatment of a symptomatic septate uterus can be accomplished via various methods including hysteroscopic scissors, and electrosurgical electrodes fitted through the hysteroscope (or resectoscope), which are the most common used methods. However, in cases of hemi-uterus with rudimentary horn and cavity, laparoscopic removal of the rudimentary horn should be considered to avoid “ectopic” pregnancy in this cavity and, in some cases, hematocavity (obstructive symptoms). Metroplasty (transabdominal or laparoscopically) is the only option for a bicornuate uterus (Papp et al. Justification Women with (untreated) congenital uterine malformations have significantly impaired pregnancy outcome (see also chapter 8) (Grimbizis et al. For Mullerian malformations other than septate uterus, there are currently no high quality studies to support surgery for improving the live birth rate or decreasing the miscarriage rate. Existing studies are difficult to summarize as they use different diagnostic criteria, various techniques, different endpoints, and a wide range of therapeutic options (transabdominal, hysteroscopic metroplasty by using monopolar, bipolar, loop, or scissors). For other Mullerian malformations, good quality randomized trials with carefully classified patients are urgently needed (Sugiura-Ogasawara et al. The size-limit is derived from the observation that a significant proportion (27%) of endometrial polyps regressed spontaneously within one year, and that this was specifically seen in smaller polyps (<1 cm) (Lieng et al. In subfertile women with submucosal fibroids, myomectomy did not significantly improve live birth rate or miscarriage rate, as compared to controls with fibroids that did not have myomectomy (based on two observational studies) (Pritts et al. Pregnancy rates, live birth rates and miscarriage rates after myomectomy were similar to those in infertile patients without fibroids, indicating a benefit for surgery (based on three studies). Furthermore, women with fibroids not distorting the uterine cavity can achieve high live birth rates without intervention (Saravelos et al. There is insufficient evidence to Conditional recommend removing fibroids that distort the uterine cavity. Hysteroscopic myomectomy for fibroids may be associated with postoperative complications that can affect future pregnancies, including the formation of intrauterine adhesions and the risk of uterine rupture during pregnancy (Di Spiezio Sardo et al. In the absence of controlled trials, this conclusion is based on small observational studies comparing miscarriage rates before and after adhesiolysis. Recommendation There is insufficient evidence of benefit for surgical removal of intrauterine adhesions for pregnancy outcome. For severe adhesions, benefits with regard to pregnancy and pain symptoms may outweigh the potential harms of surgery In any case, uterine surgery is a known cause for adhesions, and treatment should attempt to prevent recurrence of adhesions. Additional information Non-surgical techniques for the removal of intrauterine adhesions (f. Cervical cerclage has been used in the prevention of preterm birth in women with previous second trimester pregnancy loss or risk factors such as short cervix revealed at ultrasound examination. Another recent review on cerclage (not specifically on pregnancy loss) concluded that the actual groups that benefit of cerclage are limited, but include women with three prior adverse events, and those with a short cervix (<25 mm) who have had a prior preterm birth (Story and Shennan, 2014). With regard to the technical aspects, a review reported no difference in the reproductive outcomes when the cerclage was performed before or during pregnancy.

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Investigation of the uterine and umbilical arteries gives information on the perfusion of the uteroplacental and fetoplacental circulations blood pressure chart over 65 discount aldactone 25 mg free shipping, respectively blood pressure categories generic 25 mg aldactone, while Doppler studies of selected fetal organs are valuable in detecting the hemodynamic rearrangements that occur in response to fetal hypoxemia blood pressure 300200 purchase aldactone 100mg amex. This minimizes the risk of developing supine hypotension syndrome due to caval compression blood pressure reduction generic aldactone 25mg free shipping. Fetal Heart Rate There is an inverse relation between fetal heart rate and length of cardiac cycle and, therefore, fetal heart rate influences the configuration of the arterial Doppler waveform. When the heart rate drops, the diastolic phase of the cardiac cycle is prolonged and the end-diastolic frequency shift declines. Although the Doppler indices are affected by the fetal heart rate, the change is of no clinical significance when the rate is within the normal range. Fetal breathing movements During fetal breathing movements, there are variations in the shape of the flow velocity waveforms from fetal vessels and, therefore, Doppler examinations should be conducted only during fetal apnea and in the absence of fetal hiccup or excessive movement. Blood viscosity Animal studies have demonstrated that increased blood viscosity is associated with reduced cardiac output and increased peripheral resistance, and vice versa. These vessels anastomose at the cornu of the uterus and give rise to arcuate arteries that run circumferentially round the uterus. The radial arteries arise from the arcuate vessels and penetrate at right angles into the outer third of the myometrium. These vessels then give rise to the basal and spiral arteries, which nourish the myometrium and decidua and the intervillous space of the placenta during pregnancy, respectively. There are about 100 functional openings of spiral arteries into the intervillous space in a mature placenta, but maternal blood enters the space in discrete spurts from only a few of these 2,3. Physiological changes in pregnancy Physiological modification of spiral arteries is required to permit the ten-fold increase in uterine blood flow which is necessary to meet the respiratory and nutritional requirements of the fetus and placenta. Basal arteries showed no changes, but spiral arteries were invaded by cytotrophoblastic cells and were converted into uteroplacental arteries. These have a dilated and tortuous lumen, a complete absence of muscular and elastic tissue, no continuous endothelial lining, mural thrombi and fibrinoid deposition. This conversion of the spiral arteries to uteroplacental arteries is termed ‘physiological change’. It has been reported to occur in two stages: the first wave of trophoblastic invasion converts the decidual segments of the spiral arteries in the first trimester and the second wave converts the myometrial segments in the second trimester 5. As a result of this ‘physiological change’, the diameter of the spiral arteries increases from 15–20 to 300–500 mm, thus reducing impedance to flow and optimizing fetomaternal exchange in the intervillous space. Browne and Veall injected 24 Na tracer directly into the choriodecidual space of women with anterior placentae and used a Geiger counter to construct decay curves for the falling levels of radioactivity 7. Although this method was beset by technical failures, it established the commonly quoted figure of 600 ml/min for uterine blood flow at term. The placental site was located using real-time ultrasound and the Doppler probe was then pointed at the center of the placental bed and ‘searched’ until characteristic waveforms were obtained. Validation of the method was performed by directing a pulsed wave Doppler facility along the same line and obtaining identical waveforms from subplacental vessels. The Doppler probe was directed into the parauterine area in the region of the lower uterine segment and rotated until a characteristic waveform pattern was recognized. In the early stages of the study, the methodology was validated with Duplex equipment or by in vivo measurements obtained during Cesarean section. They found that patterns of uterine, arcuate and iliac vessels could be differentiated from each other and from other vessels in the pelvis. The presence of an early diastolic notch was noted and was found to disappear between 20 and 26 weeks. The two lower ‘uterine’ sites were insonated in a similar way to that described by Schulman et al. The two upper ‘arcuate’ sites were halfway between the fundus of the uterus and its most lateral point. Color flow imaging was used to visualize the flow through the main uterine artery medial to the external iliac artery (Figure 2) and the Doppler sample gate was placed at the point of maximal color brightness. Color flow imaging was found to allow a higher number of reliable recordings to be obtained, to shorten the observation time, and to reduce the intra- and interobserver coefficients of variation. Normal flow velocity waveforms from the uterine artery at 24 weeks of gestation demonstrating high diastolic flow (right). The initial fall until 24–26 weeks is thought to be due to trophoblastic invasion of the spiral arteries, but a continuing fall in impedance may be explained in part by a persisting hormonal effect on elasticity of arterial walls. Impedance in the uterine artery on the same site as the placenta is lower, which is thought to be due to the trophoblastic invasion only taking place in placental spiral arteries and the fall in impedance engendered by this being transmitted to other parts of the uterine circulation through collaterals. The intra- and interobserver coefficients of variation in the measurement of impedance to flow from the uterine arteries are both 5–10%. Flow velocity waveforms from the umbilical cord have a characteristic saw-tooth appearance of arterial flow in one direction and continuous umbilical venous blood flow in the other. The transducer, usually a pencil-shaped probe, is placed on the mother’s abdomen overlying the fetus and is systematically manipulated to obtain the characteristic waveforms from the umbilical artery and vein. With a pulsed wave Doppler system, an ultrasound scan is first carried out, a free-floating portion of the cord is identified and the Doppler sample volume is placed over an artery and the vein (Figure 4). Normal Pregnancy - Development of the umbilcal artery Normal impedance to flow in the umbilical arteries and normal pattern of pulsatility at the umbilical vein in 1 trimester Normal impedance to flow in the umbilical arteries and umbilical vein in early 2 trimester Normal impedance to flow in the umbilical arteries and umbilcal vein in late 2 and 3 trimester the location of the Doppler sampling site in the umbilical cord affects the Doppler waveform and the impedance indices are significantly higher at the fetal end of the cord than at the placental end. A possible explanation for this finding is that the fetal placental vascular bed is a low impedance system associated with minimal wave reflection, which explains the presence of continuing forward flow in the umbilical artery during diastole. The closer the measurement site is to the placenta, the less is the wave reflection and the greater the end-diastolic flow. Consequently, the Doppler waveform that represents arterial flow velocity demonstrates progressively declining pulsatility and the indices of pulsatility from the fetal to the placental end of the cord13. Figure 4a: Ultrasound image with color Doppler showing the umbilical cord, red umbilical artery and blue umbilical vein (left). Normal flow velocity waveforms from the umbilical vein (bottom) and artery (top) at 32 weeks of gestation (right). Figure 4b: Normal flow velocity waveforms from the umbilical vein (top) and artery (bottom) at 32 weeks of gestation. There are no appreciable diurnal changes or significant day-to-day variations in pregnancies with normal umbilical arterial Doppler waveforms. Umbilical venous blood flow increases with fetal inspiration (during which the fetal abdominal wall moves inward) and decreases with expiration (during which the wall moves outward). There is also a breathing-related modulation of arterial pulsatility, and umbilical artery Doppler studies should be avoided during fetal breathing. Maternal exercise may cause an increase in fetal heart rate but mild to moderate exercise does not affect flow impedance in the umbilical artery. Umbilical arterial flow waveforms are not affected by fetal behavioral states (sleep or wakefulness). Although, in certain pregnancy disorders (such as pre-eclampsia), fetal blood viscosity is increased, the contribution to the increased impedance in the umbilical artery from viscosity is minimal compared to the coexisting placental pathology. Therefore, the viscosity of fetal blood need not be considered when interpreting the umbilical Doppler indices. With advancing gestation, umbilical arterial Doppler waveforms demonstrate a progressive rise in the end-diastolic velocity and a decrease in the impedance indices (Figure 5). When the high-pass filter is either turned off or set at the lowest value, end-diastolic frequencies may be detected from as early as 10 weeks and in normal pregnancies they are always present from 15 weeks. Human placental studies have demonstrated that there is continuing expansion of the fetoplacental vascular system throughout the pregnancy. Furthermore, the villous vascular system undergoes a transformation, resulting in the appearance of sinusoidal dilatation in the terminal villous capillaries as pregnancy approaches term, and more than 50% of the stromal volume may be vascularized. The intra- and interobserver variations in the various indices are about 5% and 10%, respectively 14. Figure 5: Pulsatility index in the umbilical artery with gestation (mean, 95th and 5th centiles). It may be difficult to obtain a low angle because the aorta runs anterior to the fetal spine and, therefore, parallel to the surface of the maternal abdomen. This problem can be overcome, by moving the transducer either toward the fetal head or toward its breech and then tilting the transducer. Flow velocity waveforms in the descending aorta represent the summation of blood flows to and resistance to flow in the kidneys, other abdominal organs, femoral arteries (lower limbs) and placenta. Approximately 50% of blood flow in the descending thoracic aorta is distributed to the umbilical artery. The mean blood velocity increases with gestation up to 32 weeks and then remains constant up to 40 weeks, when there is a small fall (Figure 7) 15. Figure 6: Parasagittal view of the fetal trunk with superimposed color Doppler showing the descending aorta (left).

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