Current Concepts in Zika Research

Zika is an arboviral disease that has caused a significant impact, especially in the Americas after the epidemics in 2015 and 2016. The World Health Organization (WHO) declared it as a Public Health Emergency of International Concern (PHEIC) in 2016, linking it with the Guillain-Barré syndrome and especially the microcephaly and the Congenital Zika Syndrome. The multiple consequences, especially in the central and peripheral nervous system in the short and long term, are still to be better defined. Therefore research on Zika is crucial. This book presents an update of the significant epidemiological and clinical research of Zika over the last years in many aspects and from a multinational perspective

A Predictive Model for Guillain-Barré Syndrome Based on Single Learning Algorithms

Background. Guillain-Barré Syndrome (GBS) is a potentially fatal autoimmune neurological disorder. The severity varies among the four main subtypes, named as Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Acute Motor Axonal Neuropathy (AMAN), Acute Motor Sensory Axonal Neuropathy (AMSAN), and Miller-Fisher Syndrome (MF). A proper subtype identification may help to promptly carry out adequate treatment in patients. Method. We perform experiments with 15 single classifiers in two scenarios: four subtypes’ classification and One versus All (OvA) classification. We used a dataset with the 16 relevant features identified in a previous phase. Performance evaluation is made by 10-fold cross validation (10-FCV). Typical classification performance measures are used. A statistical test is conducted in order to identify the top five classifiers for each case. Results. In four GBS subtypes’ classification, half of the classifiers investigated in this study obtained an average accuracy above 0.90. In OvA classification, the two subtypes with the largest number of instances resulted in the best classification results. Conclusions. This study represents a comprehensive effort on creating a predictive model for Guillain-Barré Syndrome subtypes. Also, the analysis performed in this work provides insight about the best single classifiers for each classification case

Biopsy Characteristics, Subtypes, and Prognostic Features in 107 Cases of Feline Presumed Immune-Mediated Polyneuropathy

Inflammatory polyradiculoneuropathy (IMPN) is one of the causes of sudden onset of neuromuscular signs such as para-/tetraparesis in young cats. Even though most cases have a favorable outcome, persistent deficits, relapses, and progressive courses are occasionally seen. As clinical presentation does not always appear to predict outcome and risk of recurrence, this study was initiated to screen for prognostic biopsy findings in a large cohort of histologically confirmed IMPN cases with clinical follow-up. In total, nerve and muscle specimens of 107 cats with biopsy diagnosis of presumed autoreactive inflammatory polyneuropathy and 22 control cases were reviewed by two blinded raters for a set of 36 histological parameters. To identify patterns and subtypes of IMPN, hierarchical k-means clustering of 33 histologic variables was performed. Then, the impact of histological parameters on IMPN outcome was evaluated via an univariate analysis to identify variables for the final multivariate model. The data on immediate outcome and follow-up were collected from submitting neurologists using a purpose-designed questionnaire. Hierarchical k-means clustering sorted the tissues into 4 main categories: cluster 1 (44/129) represents a purely inflammatory IMPN picture, whereas cluster 2 (47/129) was accompanied by demyelinating features and cluster 3 (16/129) by Wallerian degeneration. Cluster 4 (22/129) reflects normal tissues from non-neuropathic control cats. Returned questionnaires provided detailed information on outcome in 63 animals. They were categorized into recovered and non-recovered. Thereby, fiber-invasive infiltrates by mononuclear cells and mild fiber loss in intramuscular nerve branches correlated with higher probabilities of recovery. Remyelination in semithin sections, on the other hand, is correlated with a less favorable outcome. Animals grouping in cluster 1 had a tendency to a higher probability of recovery compared to other clusters. In conclusion, diagnosis of feline IMPN from nerve and muscle biopsies allowed for the identification of histologic features that were positively or negatively correlated with outcome

Biopsy Characteristics, Subtypes, and Prognostic Features in 107 Cases of Feline Presumed Immune-Mediated Polyneuropathy

Inflammatory polyradiculoneuropathy (IMPN) is one of the causes of sudden onset of neuromuscular signs such as para-/tetraparesis in young cats. Even though most cases have a favorable outcome, persistent deficits, relapses, and progressive courses are occasionally seen. As clinical presentation does not always appear to predict outcome and risk of recurrence, this study was initiated to screen for prognostic biopsy findings in a large cohort of histologically confirmed IMPN cases with clinical follow-up. In total, nerve and muscle specimens of 107 cats with biopsy diagnosis of presumed autoreactive inflammatory polyneuropathy and 22 control cases were reviewed by two blinded raters for a set of 36 histological parameters. To identify patterns and subtypes of IMPN, hierarchical k-means clustering of 33 histologic variables was performed. Then, the impact of histological parameters on IMPN outcome was evaluated via an univariate analysis to identify variables for the final multivariate model. The data on immediate outcome and follow-up were collected from submitting neurologists using a purpose-designed questionnaire. Hierarchical k-means clustering sorted the tissues into 4 main categories: cluster 1 (44/129) represents a purely inflammatory IMPN picture, whereas cluster 2 (47/129) was accompanied by demyelinating features and cluster 3 (16/129) by Wallerian degeneration. Cluster 4 (22/129) reflects normal tissues from non-neuropathic control cats. Returned questionnaires provided detailed information on outcome in 63 animals. They were categorized into recovered and non-recovered. Thereby, fiber-invasive infiltrates by mononuclear cells and mild fiber loss in intramuscular nerve branches correlated with higher probabilities of recovery. Remyelination in semithin sections, on the other hand, is correlated with a less favorable outcome. Animals grouping in cluster 1 had a tendency to a higher probability of recovery compared to other clusters. In conclusion, diagnosis of feline IMPN from nerve and muscle biopsies allowed for the identification of histologic features that were positively or negatively correlated with outcome

Neuropathogenic flaviviruses : isolation and characterization of Zika and tick-borne encephalitis viruses from human brains

Flavivirus is a genus that consists of small RNA viruses transmitted by arthropod vectors, mosquitos and ticks. Flaviviruses cause human diseases of global concern, such as dengue fever, Yellow fever, West Nile disease and Japanese encephalitis, with hundreds of millions of infections every year. Zika virus (ZIKV), a mosquito-borne flavivirus, recently caused a major epidemic with severe and unexpected consequences. Circulating in sylvatic cycles for decades and traditionally causing only mild self-limiting disease, ZIKV quickly spread through the Americas between 2015 and 2016, leading to an unforeseen epidemic that affected hundreds of thousands of people. Following this outbreak of acute ZIKV infections, the number of microcephaly cases reported in neonates accumulated; a causal relationship was suspected and the World Health Organization declared a Public Health Emergency of International Concern in February 2016. We were able to provide a key piece of evidence in proving the causal relationship between ZIKV infection and microcephaly. We described a case of prolonged maternal viremia from an expectant mother infected with ZIKV at the 11th week of gestation, which led to brain damage in the fetus. Subsequently, we isolated the virus FB-FWUH-2016 from the brain tissue of the fetus in human neuroblastoma cells. There is no specific anti-viral treatment for ZIKV infections nor is there a fully effective vaccine. Thus, we screened several anti-cancer compounds known to possess anti-viral activities to determine their anti-Zika virus effectivity. We found that gemcitabine, saliphenylhalamide and obatoclax, the latter of which is a novel compound, inhibited ZIKV replication and virus production in retinal pigment epithelial cells. Furthermore, we found that the compounds differentially affect the metabolism of infected cells. These data provide novel information for anti-virus drug development, as these compounds affect the functions of infected cells instead of the virus itself. We further characterized the new epidemic virus isolate and conducted a study on cell tropism. In this study, we compared four ZIKV isolates, three of which were from the epidemic Asian lineage and the other was a prototypic virus of the African lineage. We found differences in cell susceptibility that favored the new strain and a closely related French Polynesian strain, particularly in cell lines originating from the placenta, umbilical veins, kidney and brain. Tick-borne encephalitis virus (TBEV), another flavivirus that affects the central nervous system, is endemic in many parts of Europe and in the Northern parts of Asia. Three subtypes of the virus, namely, the European, Siberian and Far Eastern subtypes, can cause encephalitis with different degrees of severity. The European subtype is most prominent in most of Europe, but the Siberian subtype is also found in the Baltic countries and Finland. Fatalities are rare, which made the Kotka Archipelago in Finland a new focus after the report of two fatal TBE cases in 2015 from the same island in the archipelago along with two other infected individuals. We isolated the virus from the brain of one of the deceased patients in human neuroblastoma cells and obtained sequence data on both fatal cases. Surprisingly, the viruses were the Siberian and European subtypes. During this and previous studies, we also found both viruses in ticks from the archipelago, which shows that the subtypes coexist in the same focus.Flavivirukset (suku Flavivirus, heimo Flaviviridae) ovat zoonoottisia viruksia, joista suurin osa tarttuu niveljalkaisten, hyttysten ja puutiaisten, välityksellä. Maailmanlaajuisesti flavivirusten aiheuttamia lievempiä ihottuma- ja kuumetauteja, sekä vakavampia keskushermostoinfektioita todetaan vuosittain satoja miljoonia. Denguekuume, Japanin aivotulehdus eli enkefaliitti, Länsi-Niilin kuume ja keltakuume ovat esimerkkejä flavivirusinfektioista. Hyttysvälitteiset flavivirukset säilyvät luonnossa kädellisten ja hyttysten välillä. Ne voivat myös vaihtaa urbaaniin kiertokulkuun ihmisten ja hyttysten välille, luoden näin mahdollisuuden epidemioille. Viime vuosina Zikavirus (ZIKV) on aiheuttanut laajan epidemian Etelä- ja Väli-Amerikassa. Tätä epidemiaa karakterisoivat erityisesti sikiöillä ja vastasyntyneillä esiintyneet infektiot aiheuttaen eriasteisia keskushermoston kehityshäiriöitä, kuten mikrokefaliaa. Puutiaisten välittämistä flaviviruksista puutiaisaivokuumevirus (TBEV) on kotoperäinen useassa Euroopan maassa. Suomessa sitä esiintyy rannikolla ja itäisessä Suomessa, pohjoisessa aina Simoon asti. Viime vuosina tautitapausten määrä on ollut kasvussa, ja myös kuolemaan johtaneita tapauksia on raportoitu. Tässä väitöskirjatutkimuksessa keskitytään näiden kahden keskushermostoinfektioita aiheuttavien flavivirusten, ZIKV ja TBEV, karakterisointiin. Väitöskirjatyössä kuvailemme raskaana olevan naisen zikavirusinfektion ja sen aiheuttaman vakavan seurauksen sikiölle. Zikavirusinfektion todettiin aiheuttavan potilaalla poikkeuksellisen pitkittyneen viruserityksen. Eristimme zikaviruksen sikiön aivokudoksesta, ja osoitimme näin osaltaan zikaviruksen ja sikiön aivovaurion yhteyden. Uuden sukupolven sekvensointitekniikkaa hyödyntäen selvitimme viruksen perimän. Zikavirusinfektion hoitoon ei ole vielä tehokasta viruslääkettä. Testasimme valikoitujen, jo tunnettujen antiviraalisina yhdisteinä vaikuttavien lääkkeiden tehoa zikavirusinfektioon soluviljelymallissa eristetyn viruksen avulla. Löysimme kolme solun omiin toimintoihin vaikuttavaa lääkeainetta, obatoclax, SaliPhe ja gemsitabiini, jotka estivät tehokkaasti zikaviruksen aiheuttaman solukuoleman. Nämä yhdisteet vaikuttivat viruksen ja isäntäsolun vuorovaikutuksiin viruksen elinkierron eri vaiheissa. Tutkimuksen kohteena olevaa vakavan tautimuodon aiheuttamaa zikaviruskantaa verrattiin soluviljelymallissa muihin lievempiä epidemioita aiheuttaneisiin zikaviruskantoihin. Tutkimuksessa osoitettiin aivokudoksesta eristetyn viruksen lisääntyvän tehokkaasti kohdusta, napasuonista, munuaisista ja aivoista peräisin olevissa solulinjoissa. Kotkan saaristossa on viimeisen vuosikymmenen aikana todettu uusi puutiaisaivokuumefokus. Erityisen merkittävän siitä tekee siellä esiintyneet vakavat TBEV-infektiot. Vuonna 2015 Kuutsalon saaressa esiintyi useita puutiaisaivokuumetapauksia, joista kaksi johtivat kuolemaan. Eristimme viruksen toisen tapauksen aivokudoksesta soluviljelmässä, ja virus osoittautui TBE-viruksen siperialaiseksi alatyypiksi. Aiemmassa tutkimuksessa Kotkan saaristosta on löydetty saman alatyypin TBE-virusta puutiaisita. Toinen tapauksista osoittautui täten hieman yllättäen viruksen eurooppalaisen alatyypin aiheuttamaksi. Löysimme saaristosta myös tätä alatyyppiä puutiaisesta, mikä osoittaa, että kaksi viruksen alatyyppiä esiintyvät poikkeuksellisesti samassa fokuksessa

Campylobacter Infection and Guillain-Barré Syndrome in Bangladesh: Clinical epidemiology and comparative microbial genomics

__Abstract__ Campylobacter spp. are small motile, microaerophilic, S-shaped or spiral rods (0.2-0.5 μm wide by 0.5-5 μm long), gram-negative bacteria. Campylobacter was first described in 1886 by Theodore Escherich (1) in the colon of children who had died of ‘cholera infantum’. The name Campylobacter is derived from a Greek word, which means curved. In 1962, Campylobacter, then still known as ‘related Vibrio’ was described as a rare and opportunistic human pathogen that was isolated from blood culture of humans (2). In 1972, Campylobacter jejuni was first isolated from human diarrheal stools by applying a filtration technique (3). The subsequent development of selective Campylobacter stool culture techniques (4) led to the recognition that C. jejuni was a more common cause of human diarrheal illness