Immuunijärjestelmän solut ja elimet

Tiivistelmä. Tämä tutkielma käsittelee immuunijärjestelmän soluja ja elimiä. Immuunijärjestelmä toimii puolustusmuurina ulkoisia ja sisäisiä tekijöitä vastaan. Vaste pitää pystyä muodostamaan nopeasti laajaa yhtäaikaista infektoivaa joukkoa vastaan kaikkialla kehossa. Haasteena on muodostaa riittävä vaste taudinaiheuttajia vastaan. Vaste pitää kuitenkin pystyä kohdentamaan ja skaalaamaan, jotta toleranssi hyödylliselle mikrobistolle toteutuu. Puolustuksen lisäksi immuunijärjestelmällä on tehtäviä mm. kasvainten kehittymisen estossa ja kehon homeostaasin ylläpidossa, kuten kuolleiden solujen poistossa ja kudosten korjauksessa. Tutkielman ensimmäisessä osassa esitellään immuunijärjestelmän solutyypit, niiden alkuperä, ominaisuuksia ja toiminnallisuutta tulehdusvasteissa. Näiden solujen järjestäytyminen kehossa ja kyky siirtyä veren, imunesteen ja kudosten välillä muodostaa immuunijärjestelmän perustan. Immuunijärjestelmä jaetaan toiminnallisuuden mukaan luontaiseen ja adaptiiviseen osaan. Luontainen immuniteetti välittyy mekanismien avulla, jotka ovat nimensä veroisesti paikallaan jo ennen infektion sattumista, ja mahdollistaa nopean vasteen hyökkääviä mikrobeja vastaan. Adaptiivinen immuunijärjestelmä tunnistaa ja reagoi suureen määrään mikrobisia ja myös ei-mikrobisia aineita. Vaikka moni taudinaiheuttaja on kehittynyt sietämään luontaisia immuunivasteita, adaptiivinen immuunivaste kykenee hävittämään niitä, sillä se on vahvempi ja erikoistuneempi hyökkääjää kohtaan. Luontaisten ja adaptiivisten immuunivasteiden välillä on lukuisia yhteyksiä ja ne tukevat toistensa toimintaa. Koordinoitu immuunivaste vaatii immuunijärjestelmän solujen keskeistä yhteistyötä ja myös yhteistyötä kehon muiden solujen kanssa. Tutkielman toisessa osassa käsitellään immuunijärjestelmän toimintaan ja kehittymiseen osallistuvia elimiä ja kudoksia. Kaikki käsiteltävät eivät ole varsinaisia immuunijärjestelmän elimiä, mutta niillä on olennainen rooli vasteiden muodostuksessa. Tällainen on esimerkiksi maksa, jonka sijainti kehossa ja immuunisolupopulaatio tukevat myös toleranssin muodostusta harmittomia antigeenejä kohtaan. Immuunijärjestelmän elimet ja kudokset jaetaan kolmeen osaan niiden toiminnallisuuden mukaan. Primääristen elinten tärkeät tehtävät ovat immuunisolujen kasvattaminen ja kypsyvien solujen toleranssin varmistaminen. Sekundääriset elimet ja kudokset sijaitsevat optimaalisilla paikoilla immuunivasteen tehokkaan käynnistämisen kannalta. Ne tarjoavat ympäristöt immuunisolujen vasteiden muodostumiselle ja kehittymiselle niin omia kuin vierasperäisiäkin antigeenejä kohtaan. Tertiääriset kudokset kehittyvät muista tyypeistä poiketen vasta syntymän jälkeen. Ne ovat jatkuvasti riippuvaisia tulehduksellisista ärsykkeistä ja poistuvat, kun tulehdus on ratkaistu. Tutkielman toisessa osassa käsitellään elinten ja kudosten yhteydessä myös hermoston roolia immuunivasteiden hallinnassa ja generoinnissa. Vaikka hermostoa ja immuunijärjestelmää on perinteisesti pidetty toiminnallisesti ja anatomisesti erillisinä, on olemassa yhä enemmän näyttöä tarttuvien taudinaiheuttajien aiheuttamasta aistihermosolujen suorasta aktivoinnista. Rajapintakudoksissa olevien reseptorien on mm. osoitettu havaitsevan bakteerituotteita. Lisäksi yhä enemmän tiedetään siitä, miten kaksisuuntainen viestintä ääreishermoston ja immuunijärjestelmän välillä mm. pernassa, luuytimessä, suolistossa, hengitysteissä, keuhkoissa ja ihossa moduloi immuuni- ja tulehdusprosesseja

Human Noroviruses in Swine and Cattle

Detection of GII.4 norovirus sequences in animal fecal samples and retail meats demonstrates that noroviruses may be transmitted zoonotically

Monitoring of Salmonella, Campylobacter, Yersinia enterocolitica, E. coli 0157, and Listeria monocytogenes on a subset of Canadian swine farms

The objective of the present study was to investigate the occurrence of major bacterial foodborne pathogens in swine on a subset of Ontario swine farms between 2005 and 2007 In total, 359 samples from manure storage tanks and fresh pooled feces obtained from finisher pigs, sows, and weanlings were collected and tested Campylobacter, Salmonella, Y. enterocolitica, E coli 0157 and L monocytogenes were isolated from 36.5%, 31.5%, 5.8%, 3 3%, and 33% of samples, respectively. All E. coli O157 isolates were tested but none were determined to be E. coli O157:H7 Salmonella and Campylobacter were more likely to be detected from stored manure rather than fresh fecal samples. Y. enterocolitica tended to be detected more commonly from fresh samples than from manure pits

Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial

Importance: Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission. Objective: To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent. Design, Setting, and Participants: Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017. Interventions: Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline. Main Outcomes and Measures: The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A1c (HbA1c). Results: Among 126 participants who were randomized (mean [SD] age, 55.3 years [14.9 years]; 78 women [61.9%]), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P \u3c .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, -0.01 to 0.10), high-density lipoprotein cholesterol (-0.01 mg/dL; 95% CI, -0.03 to 0.01), triglyceride (-0.153 mg/dL; 95% CI, -0.306 to 0.004), glucose (-0.02 mg/dL; 95% CI, -0.12 to 0.08), or HbA1c levels (-0.0002 mg/dL; 95% CI, -0.0021 to 0.0016). Conclusions and Relevance: Among patients with psychotic depression in remission, continuing sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks. This benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain. Trial Registration: ClinicalTrials.gov Identifier: NCT01427608

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

Cu-II(atsm) Attenuates Neuroinflammation

Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex Cu-II(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of Cu-II(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). Cu-II(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of Cu-II(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.Peer reviewe

A review of hyperfibrinolysis in cats and dogs

The fibrinolytic system is activated concurrently with coagulation; it regulates haemostasis and prevents thrombosis by restricting clot formation to the area of vascular injury and dismantling the clot as healing occurs. Dysregulation of the fibrinolytic system, which results in hyperfibrinolysis, may manifest as clinically important haemorrhage. Hyperfibrinolysis occurs in cats and dogs secondary to a variety of congenital and acquired disorders. Acquired disorders associated with hyperfibrinolysis, such as trauma, cavitary effusions, liver disease and Angiostrongylus vasorum infection, are commonly encountered in primary care practice. In addition, delayed haemorrhage reported in greyhounds following trauma and routine surgical procedures has been attributed to a hyperfibrinolytic disorder, although this has yet to be characterised. The diagnosis of hyperfibrinolysis is challenging and, until recently, has relied on techniques that are not readily available outside referral hospitals. With the recent development of point‐of‐care viscoelastic techniques, assessment of fibrinolysis is now possible in referral practice. This will provide the opportunity to target haemorrhage due to hyperfibrinolysis with antifibrinolytic drugs and thereby reduce associated morbidity and mortality. The fibrinolytic system and the conditions associated with increased fibrinolytic activity in cats and dogs are the focus of this review article. In addition, laboratory and point‐of‐care techniques for assessing hyperfibrinolysis and antifibrinolytic treatment for patients with haemorrhage are reviewed

Validation of computerized diagnostic information in a clinical database from a national equine clinic network

BACKGROUND: Computerized diagnostic information offers potential for epidemiological research; however data accuracy must be addressed. The principal aim of this study was to evaluate the completeness and correctness of diagnostic information in a computerized equine clinical database compared to corresponding hand written veterinary clinical records, used as gold standard, and to assess factors related to correctness. Further, the aim was to investigate completeness (epidemiologic sensitivity), correctness (positive predictive value), specificity and prevalence for diagnoses for four body systems and correctness for affected limb information for four joint diseases. METHODS: A random sample of 450 visits over the year 2002 (nvisits=49,591) was taken from 18 nation wide clinics headed under one company. Computerized information for the visits selected and copies of the corresponding veterinary clinical records were retrieved. Completeness and correctness were determined using semi-subjective criteria. Logistic regression was used to examine factors associated with correctness for diagnosis. RESULTS: Three hundred and ninety six visits had veterinary clinical notes that were retrievable. The overall completeness and correctness were 91% and 92%, respectively; both values considered high. Descriptive analyses showed significantly higher degree of correctness for first visits compared to follow up visits and for cases with a diagnostic code recorded in the veterinary records compared to those with no code noted. The correctness was similar regardless of usage category (leisure/sport horse, racing trotter and racing thoroughbred) or gender.For the four body systems selected (joints, skin and hooves, respiratory, skeletal) the completeness varied between 71% (respiration) and 91% (joints) and the correctness ranged from 87% (skin and hooves) to 96% (respiration), whereas the specificity was >95% for all systems. Logistic regression showed that correctness was associated with type of visit, whether an explicit diagnostic code was present in the veterinary clinical record, and body system. Correctness for information on affected limb was 95% and varied with joint. CONCLUSION: Based on the overall high level of correctness and completeness the database was considered useful for research purposes. For the body systems investigated the highest level of completeness and correctness was seen for joints and respiration, respectively