Immune Evasion by Borrelia burgdorferi – With Special Reference to CD38-mediated Chemotaxis of Neutrophils and Dendritic Cells

Lyme borreliosis is a tick-transmitted infection caused by the spirochete bacterium Borrelia burgdorferi sensu lato. The tick injects bacteria into host skin, where a first line defence, mainly the complement system, neutrophils, dendritic cells and macrophages are ready to attack foreign intruders. However, in the case of Lyme borreliosis, the original immune response in the skin is untypically mild among bacterial infections. A further untypical feature is the ability of B. burgdorferi to disseminate to distant organs, where, in some patients, symptoms appear after years after the original infection. This study aimed at uncovering some of the immune evasion mechanisms utilized by B. burgdorferi against the complement system, neutrophils and dendritic cells. B. burgdorferi was shown to inhibit chemotaxis of human neutrophils towards nformyl- methyl-leucyl-phenylalanine (fMLP). Outer surface protein B (OspB) of B. burgdorferi was shown to promote resistance to the attack of the complement system and neutrophil phagocytosis at low complement concentrations. B. burgdorferi was shown to inhibit migration of dendritic cells in vitro towards CCL19 and CCL21 and also in an in vivo model. This effect was shown to be due to the absence of CD38 on the borrelia-stimulated dendritic cell surface. A defect in p38 mitogen-activated-protein-kinase (p38) signaling was linked to defective CD38 expression. A defect in CD38 expression on B. burgdorferi-stimulated neutrophils was also observed. In this study, a number of novel immune evasion strategies utilized by B burgdorferi were chracterized. However, further studies are needed as other immune evasion mechanisms await to be uncovered.Siirretty Doriast

The association of coronary heart disease risk factors from adolescence to adulthood with coronary artery calcification and epicardial fat: The Cardiovascular Risk in Young Finns Study

Background: Atherosclerosis and coronary heart disease (CHD) are leading causes of mortality that have their origins in childhood and may develop for decades without clinical symptoms. Coronary artery calcification (CAC) is a marker of subclinical atherosclerosis that confirms the presence of atherosclerotic plaque in the coronary arteries. Epicardial fat, adipose tissue surrounding the heart and coronary arteries, has been suggested to influence the development of CHD. Aims: The aim of this study was to investigate the associations of cardiovascular disease risk factor levels measured from adolescence to adulthood with CAC and epicardial fat volume (EFV) and the associations of EFV and CAC. Participants and Methods: This thesis is part of the Cardiovascular Risk in Young Finns Study (Young Finns Study). Cardiovascular disease risk factor levels were measured intermittently from 1980 to 2007 and a computed tomography study to quantify CAC and EFV was performed on 589 participants in 2008. Results: Higher low-density lipoprotein cholesterol measured in adolescence associated with CAC in adulthood independent of 27-year change in levels. In addition to this risk factor, mean longitudinal values of systolic blood pressure, apolipoprotein B and total cholesterol were also higher among those with, versus those without, CAC. EFV was most strongly associated with body-mass index, while most other risk factor associations were not statistically significant after adjustment for body-mass index. EFV was not independently associated with CAC. Conclusions: Risk factor levels measured in adolescence and throughout the life-course are associated with CAC. The association of EFV on development of CHD is at least partly explained by its strong relation with overall adiposity.Sepelvaltimotaudin riskitekijät nuoruudesta aikuisuuteen ja koronaarikalkki sekä sydämen ympärysrasva. Lasten Sepelvaltimotaudin Riskitekijät -projekti Tausta: Ateroskleroosi ja sepelvaltimotauti ovat merkittäviä kansantauteja, joiden kehitys alkaa jo lapsuudessa ja jatkuu oireettomana vuosikymmeniä. Sepelvaltimoiden kalkkeutuminen on osoitus ateroskleroottisten plakkien olemassaolosta. Sydäntä ympäröivä rasva on mahdollinen myötävaikuttaja sepelvaltimoplakkien syntymisessä. Tavoite: Tutkimuksen tavoitteena oli tutkia nuoruudessa mitattujen sepelvaltimotaudin riskitekijöiden yhteyttä aikuisiällä mitattuun sepelvaltimoiden kalkkeutumiseen ja sydämen ympärysrasvan määrään sekä niiden keskinäistä yhteyttä. Menetelmät: Väitöskirjatutkimus toteutettiin osana Lasten Sepelvaltimotaudin Riskitekijät (LASERI) –tutkimusta. Sepelvaltimotaudin riskitekijätasoja mitattiin vuodesta 1980 vuoteen 2007 toistuvasti ja vuonna 2008 589 tutkittavalle tehtiin sydämen tietokonetomografiatutkimus, jolla mitattiin sepelvaltimoiden kalkkeutumista sekä sydäntä ympäröivän rasvan määrää. Tulokset: Nuoruudessa mitattu LDL-kolesteroli oli yhteydessä sepelvaltimoiden kalkkeutumiseen aikuisuudessa. Sen lisäksi myös kokonaiskolesterolin ja apolipoproteiini B:n pitoisuudet sekä systolinen verenpaine olivat keskimäärin korkeammat seuranta-aikana niillä, joille kehittyi kalkkiplakkeja verrattuna niihin, joilla niitä ei todettu. Sydäntä ympäröivän rasvan määrä oli vahvimmin yhteydessä kehon painoindeksiin, jolla vakioimisen jälkeen yhteydet useimpien muiden riskitekijöiden kanssa menettivät tilastollisen merkitsevyytensä. Johtopäätökset: Nuoruudessa ja pitkin elämänkaarta mitatut riskitekijätasot ovat yhteydessä subkliiniseen valtimonkovettumautiin. Sydäntä ympäröivän rasvan vaikutusta valtimonkovettumataudin kehittymiseen selittää osaltaan sen vahva yhteys lihavuuteen

Community-acquired pneumonia in children: Aetiology, clinical features, and complications

Pneumonia is an important cause of morbidity and hospitalization in children worldwide. Since the development of nucleic acid amplification techniques, rhinovirus (RV) is frequently detected in community-acquired pneumonia (CAP), but the causative role of RV in pneumonia is still questioned. Empyema is a severe complication of pneumonia, and the evaluation of its long-term consequences is necessary. We studied the viral aetiology of childhood CAP by searching for 18 respiratory viruses and six bacteria in sputum specimens (n = 76). The clinical characteristics and prevalence of RV pneumonia and its risk factors were evaluated by retrospectively comparing the medical record data of RV-positive (n = 82) and RV-negative (n = 231) children hospitalized for CAP. We also prospectively investigated viral and bacterial biomarker levels in children hospitalized for CAP (n = 24), focusing on RV pneumonia. Finally, we investigated the long-term outcome of childhood parapneumonic empyema (n = 26) at 3–19 years’ follow-up by a detailed interview, physical examination, lung imaging and lung function tests. Viruses were detected in 72%, bacteria in 91%, and both in 66% of children hospitalized for CAP. RV, human bocavirus, and human metapneumovirus were the most commonly found viruses. Treatment failures were documented in viral-bacterial co-infections. Young age and a history of preterm birth were associated with RV-positive pneumonia, but the clinical features of pneumonia were similar in RV-positive and RV-negative children. RV-positive children had elevated levels of bacterial biomarkers, but a viral biomarker myxovirus resistance protein A remained low. Lung magnetic resonance imaging showed abnormal findings in 92% and significant pleural scarring in 25% of the children recovered from empyema, but most patients had normal lung function, chest radiograph and clinical recovery. Viral-bacterial co-detections are common in childhood CAP and potentially associated with treatment failure. RV is commonly detected in young children with pneumonia and it is often associated with bacterial co-infection. Making the decision to withdraw antibiotics in children with pneumonia is challenging. Further studies and strategies are needed to differentiate viral from bacterial or mixed viral-bacterial pneumonia. The long-term recovery from parapneumonic empyema seems to be good with current treatment strategies.Lasten avosyntyinen keuhkokuume Keuhkokuume on maailmanlaajuisesti merkittävä lasten sairastavuuden ja sairaalahoidon aiheuttaja. Rinovirus (RV) on yleinen löydös lasten keuhkokuumeessa, mutta sen rooli keuhkokuumeen aiheuttajana on edelleen epäselvä. Empyeema on keuhkokuumeen vakava komplikaatio, jonka pitkäaikaisvaikutusten selvittäminen on tärkeää. Selvitimme lasten avosyntyisen keuhkokuumeen virusetiologiaa tutkimalla 18 viruksen ja kuuden bakteerin esiintyvyyttä yskösnäytteistä (n = 76). RV-keuhkokuumeen taudinkuvaa, esiintyvyyttä ja riskitekijöitä tutkittiin vertailemalla retrospektiivisesti keuhkokuumeen vuoksi sairaalahoitoon joutuneiden RV-positiivisten (n = 82) ja RV-negatiivisten (n = 231) lasten potilaskertomustietoja. Tutkimme myös virus- ja bakteerimerkkiaineiden tasoja lasten sairaalahoitoa vaativassa keuhkokuumeessa (n = 24), erityisesti RV-keuhkokuumeessa. Lasten empyeeman pitkäaikaisvaikutuksia selvitettiin 3–19 vuoden kuluttua sairastamisesta kliinisellä tutkimuksella sekä keuhkojen toimintakokeilla ja kuvantamisella (n = 26). Viruksia löydettiin 72 %:lta, bakteereja 91 %:lta ja molempia 66 %:lta lapsista, jotka tarvitsivat sairaalahoitoa keuhkokuumeen vuoksi. RV, bokavirus ja metapneumovirus olivat yleisimmin löydetyt virukset. Hoidon epäonnistumista havaittiin virus-bakteeriseka-infektioissa. Lapsen nuori ikä ja keskosuustausta olivat yhteydessä RV-positiiviseen keuhkokuumeeseen, mutta keuhkokuumeen taudinkuva oli samankaltainen RV-positiivisilla ja RV-negatiivisilla lapsilla. Bakteeri-infektion merkkiaineiden tasot olivat koholla mutta virusmerkkiaineen, myksovirusresistenssiproteiini A:n, pitoisuus veressä oli matala RV-positiivisilla lapsilla. Keuhkojen magneettikuvauksella havaittiin poikkeavia löydöksiä 92 %:lla ja merkittävää arpea keuhkopussissa 25 %:lla empyeeman sairastaneista lapsista, mutta kliininen paraneminen, keuhkojen toiminta ja keuhkokuva olivat valtaosalla normaalit. Virus-bakteerisekainfektiot ovat yleisiä lasten avosyntyisessä keuhkokuumeessa ja ovat mahdollisesti yhteydessä hoidon epäonnistumiseen. RV löytyy usein nuorilta keuhkokuumetta sairastavilta lapsilta ja usein yhdessä bakteeri-infektion kanssa. Päätös antibioottihoidon aloittamatta jättämisestä on haastava. Lisää tutkimuksia ja toimintasuunnitelmia tarvitaan virusinfektion erottamiseksi bakteeri- tai virus-bakteerisekainfektioista. Pitkäaikaisseurannassa empyeemasta paraneminen vaikuttaa hyvältä nykyisillä hoitokäytännöillä

Lymphangiogenesis and Lymphangiogenic Growth Factors

Lymphedema is a progressive disease caused by damage to the lymphatic network. Recent development in the fields of preclinical growth factor research and lymphedema microsurgery promise new hope for lymphedema patients. In this article, we review the latest results on basic research and highlight the role of specific growth factors in normal lymphatic development and several disease states. Lymph node transfer, a new promising method in reconstructive lymphatic microsurgery, is also dependent on the lymphatic vascular regrowth and lymphangiogenic growth factors. We discuss the scientific basis of lymph node transfer and therapeutic potential of lymphangiogenic growth factors in the treatment of lymphedema.Peer reviewe

Asynkronisuus JavaScriptissä

Tässä työssä käydään läpi web-kehityksen historian vaiheita synkronisista HTML-sivuista kohti asynkronista ohjelmointia. Asynkronisen web-ohjelmoinnin johdosta käyttäjän ei tarvitse odottaa toimeettomana esimerkiksi datahakua palvelimelta, vaan voi käyttää sovellusta samanaikaisesti. Työssä tarkastellaan eri tapoja toteuttaa asykronisuutta JavaScriptissä, näiden tapojen kehitysvaiheet, sekä niiden mukanaan tuomat ongelmat ja ratkaisut. Työ keskittyy eri toteutustapojen luettavuuteen, ymmärrettävyyteen ja muokattavuuteen. Lisäksi työssä käydään vielä läpi virheiden käsittelyä näissä toteutustavoissa. Työssä toteutetaan sama demo-ohjelma kolmella eri asynkronisella tavalla JavaScriptissä ja vertaillaan näiden luettavuutta, muokattavuutta ja virheiden käsittelyä. Tämän lisäksi pureudutaan vielä async/await:in mukanaan tuomiin ongelmiin toisella demo-ohjelmalla. Työssä todetaan, että asynkronisuuden toteutus callback-metodin avulla JavaScriptissä muuttuu erittäin vaikealukuiseksi ja vaikeasti muokattavaksi ohjelman monimutkaistuessa, sillä se ajaa koodin rakenteen pyramidimaiseksi sisäkkäisyydeksi. Tähän ongelmaan kehitetty promise toimii erinomaisena ratkaisuna lohkojakonsa ja ketjutettavuutensa ansiosta. Promisen lisäksi kehitetty async/await-metodi tuo vielä keinon kirjoittaa promise-pohjaista asynkronista koodia ikään kuin se olisi synkronista, mutta työssä todetaankin, että tämän metodin kanssa täytyy olla tarkka missä ja miten sitä käytetään. Väärin käytettynä metodi vain hidastaa koodin suoritusta

The birth and development of clinical physiology in Finland

The specialty of clinical physiology was established in Finland about 20 years later than in Sweden. In the early 1960s, six physicians working mainly in preclinical departments of physiology were certified as specialists in clinical physiology. Many of the first specialists working in hospitals received specialist training in Sweden. The first hospital laboratories of clinical physiology were established in Tampere Central Hospital and Turku University Hospital in 1968. Thereafter, laboratories of clinical physiology were also established in Helsinki University Hospital and in Kuopio University Hospital and later also in most central hospitals. After clinical physiology laboratories were set up in hospitals and the number of specialists increased, the specialty gradually had more impact in clinical work. In the 1999 reform, nuclear medicine, which had previously been a subspecialty, was combined with clinical physiology. Arto Uusitalo was nominated the first professor of clinical physiology in Tampere University in 1984. The first professor in Helsinki University was Anssi Sovijarvi (1994), in Kuopio University Esko Lansimies (1998), and in Turku University Jaakko Hartiala (2003). Today, at four universities professors of clinical physiology and nuclear medicine lead research and medical education in this specialty. The hospital laboratories have modern equipment, which promotes multidisciplinary research with clinicians in fruitful collaboration. The Finnish Society of Clinical Physiology was founded in 1975. Today, it has about 160 members, about half of whom are specialists in the field. On its 40th anniversary, the Society decided to publish the history of clinical physiology in Finland.Peer reviewe

Risk of donor-site lymphatic vessel dysfunction after microvascular lymph node transfer

BACKGROUND: Microvascular lymph node transfer has been used to improve lymphatic function in patients with lymphoedema. We previously reported changes in the lymphatic function of the donor limb after lymph node transfer. For this reason, we modified our surgical method to be more conservative. SUBJECTS AND METHODS: Microvascular lymph node transfer was performed in 13 patients using the previously reported original method. Sixteen patients were operated upon using the more conservative modified method. Lymphatic function in the donor limb was evaluated using volumetry, lymphoscintigraphy and tissue water percentage. RESULTS: In the original method group, the donor-limb volume was on average greater (199 ± 540 ml) than in the non-operated control limb. The volume difference between the limbs was smaller (151 ± 463 ml) in the modified method group. Two patients in the original method group had abnormal transport index (Ti) values in lymphoscintigraphy indicating decreased lymphatic function of the donor limb. In the modified method group, the Ti-values remained normal. The tissue water percentage of the donor limb was on average 40% ± 4% in the original method group and 40% ± 3% in the modified method group. Importantly, none of the patients in either group developed clinical lymphoedema in the donor limb during the 11-84-month follow-up. CONCLUSIONS: Even with the more conservative lymph node transfer method, we can observe slight, subclinical signs of lymphatic dysfunction in the donor limb. These results highlight the importance of minimizing the surgical exploration in the inguinal area and avoiding damage to the lymphatic vessels or sentinel nodes draining the lower limb.</p

Unidirectional heterologous receptor desensitization between both the fMLP and C5a receptor and the IL‐8 receptor

During inflammation neutrophils receive multiple signals that are integrated, allowing a single modified response. One mechanism for this discrimination is receptor desensitization, a process whereby ligand‐receptor binding is disassociated from cell activation. We examined the effect of heterologous receptor desensitization on neutrophil Chemotaxis, calcium mobilization, and arachidonic acid production, using interleukin‐8 (IL‐8), C5a, and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP). We observed reciprocal inhibition with respect to Chemotaxis. We demonstrated that homologous desensitization, with respect to the mobilization of intracellular calcium stores, lasted approximately 15 min. Heterologous desensitization between the fMLP receptor and the C5a receptor was reciprocal; either stimulant would diminish the cells9 response to stimulation by the other for approximately 3–5 min. However, we observed a unidirectional heterologous desensitization of the IL‐8 receptor by both the fMLP and the C5a receptor. This unidirectional heterologous desensitization was observed with respect to both calcium mobilization and arachidonic acid production (i.e., prestimulation of the IL‐8 receptor had no effect on subsequent stimulation by either fMLP or C5a).Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141009/1/jlb0088.pd

Phase 1 Lymfactin (R) Study : Short-term Safety of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

Objective: To study the safety and tolerability of Lymfactin (R) treatment combined with microvascular lymph node transfer surgery in patients with upper limb lymphedema. Background: Upper limb lymphedema is a common clinical challenge after breast cancer surgery and/or radiotherapy. Lymfactin (R) is an adenovirus type 5-based gene therapy involving expression of human vascular endothelial growth factor C (VEGF-C) in the damaged tissue. It aims to correct deficient lymphatic flow by promoting the growth and repair of lymphatic vessels. Methods: In Phase I, Lymfactin (R) was combined with microvascular lymph node transfer surgery to study the safety and tolerability of Lymfactin (R) and the biodistribution of the viral vector in patients with upper limb lymphedema. Results: Fifteen patients with breast cancer-associated secondary lymphedema of the upper arm were recruited between December 2016 and February 2018. Three patients received a lower dose (1 x 10(10)) and 12 a higher dose (1 x 10(11)) of viral particles, respectively. No dose-limiting toxicities were observed, and the study was completed with the pre-determined maximum dose. Commonly reported adverse events during the 12-month follow-up were common cold, fever, gastroenteritis, pain in the operation area, headache, muscle ache and elevated liver enzymes. Serious adverse events consisted of two erysipelas infections in the lymphedema arm (requiring hospitalization) and one hematoma of the flap donor site. Conclusions: After 12 months' follow-up, results indicate that Lymfactin (R) is well tolerated. The study continues with a 36-months efficacy and 5 years safety follow-up of the patients. The oncological safety aspects of Lymfactin (R) will require a longer follow-up period. (c) 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Pub-lished by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe