Anti-CD20 therapy in multiple sclerosis : clinical and paraclinical outcomes

Multiple sclerosis is a chronic inflammatory disease of the central nervous system and the most common non-traumatic cause of neurological disability in young adults. Rituximab is a B-cell depleting drug targeting the CD20 epitope on B-cells, which drive inflammation in relapsing-remitting multiple sclerosis by acting as antigen-presenting cells to activate T-cell responses against central nervous system autoantigens. Despite not being formally approved for this disease, rituximab is Sweden´s most common multiple sclerosis disease-modifying treatment. The objective of this thesis was to through observational studies increase the knowledge base for the risk-benefit of rituximab in multiple sclerosis by determining clinical and paraclinical outcomes, in comparison with drugs approved for this disease, in real-world cohorts. Study I is a multicentre retrospective study of 241 relapsing-remitting multiple sclerosis patients switching from interferon-β or glatiramer acetate to rituximab, natalizumab or fingolimod due to breakthrough disease. Our results indicate a superior efficacy with rituximab and natalizumab compared to fingolimod, a similar tolerability profile between treatments, but a significantly higher overall drug persistence with rituximab. Study II is a single-centre retrospective study of all 808 relapsing-remitting multiple sclerosis patients ever treated with rituximab at Karolinska. Data on reason for therapy stop, new therapies and clinical and radiological outcomes after rituximab termination were recorded. Rituximab was stopped in 92 (11%) cases, with 7 (< 1%) of all patients doing so due to lack of efficacy. Pregnancy plans and adverse events were the most frequent reasons for stopping therapy and disease activity remained low regardless if a new disease-modifying drug was started or not. The cross-sectional Study III surveyed frequency of anti-drug antibodies and their potential impact on efficacy and safety outcomes in 339 rituximab treated multiple sclerosis patients. Presence of anti-drug antibodies was high; 37% and 26% in patients with relapsing-remitting and progressive disease, respectively. High anti-drug antibody titres were associated with incomplete B-cell depletion, but not with reduced clinical effectiveness or tolerability. Study IV is a retrospective study comparing rates of regional atrophy and T1-weighted lesion volume accumulation on magnetic resonance imaging in relapsing-remitting multiple sclerosis patients starting rituximab (n = 15) or interferon-β (n = 67) as initial treatment. The rituximab group had lower rate of T1-weighted lesion volume accumulation, but higher volume loss in some brain regions compared to interferon-β, possibly due to pseudoatrophy. The results add to a growing body of evidence suggesting equal or better effectiveness and tolerability of rituximab compared to commonly used drugs in relapsing-remitting multiple sclerosis. Furthermore, rituximab interruption is not associated with a rebound effect and anti-drug antibodies, while frequent, do not seemingly impact on therapeutic effect or tolerability. Lastly, rituximab is associated with slower brain lesion volume accumulation compared to a first-line treatment. The finding of a higher rate of regional brain volume loss with rituximab treatment, however, warrants further studies conducted over longer time periods

Smittskydd vid veterinär fältverksamhet i häststall

Smittsamma sjukdomar orsakar lidande för drabbade individer och kan ge stora ekonomiska konsekvenser, därför har ett aktivt smittskyddsarbete fördelar både ur ett djurvälfärdsperspektiv och ur ett ekonomiskt perspektiv. Tre av de viktigaste endemiska hästsjukdomarna i Sverige är hästinfluensa, ekvint herpesvirus-1 och kvarka. Alla tre sjukdomarna ger symptom i övre luftvägarna och ett smittsamt nosflöde. Sjukdomarna sprids direkt från häst till häst och indirekt via kontaminering av omgivning och personer som hanterar sjuka hästar. Åtgärder för att förhindra indirekt smittspridning verkar sällsynta i svenska häststall, endast ett fåtal stall erbjuder besökare möjlighet att tvätta händerna med varmt vatten och tvål. Hästar som flyttas mellan olika stall i samband med försäljning, avel, träning och tävling är den största risken för att smittsamma sjukdomar ska spridas. Människor som rör sig mellan stall, till exempel veterinärer, är också en riskfaktor men det finns åtgärder för smittskydd som minskar risken. Klädbyte mellan besök på olika stall eller skyddskläder, skobad vid stallets entré eller lånestövlar är åtgärder som visat sig förebygga att ett stall blir infekterat. Vidare är handtvätt med varmt vatten och tvål effektivt för att avlägsna både bakterier och virus från händer, vissa studier visar även att handdesinfektion fungerar lika bra och ibland bättre på nämnda smittämnen. Många veterinärer uppger att de utför ett antal åtgärder av vikt för smittskyddet mellan besök på olika gårdar. Det finns dock studier som visar att det är svårt att få människor att efterleva smittskyddsregler och att många människor också har en felaktig uppfattning om huruvida de har följt reglerna eller inte. Den psykosociala aspekten är en stor utmaning när det kommer till smittskydd. Hur stor roll veterinärens smittskydd och hygien har vid spridning av smittämnen kan diskuteras. Många stall besöks av flertalet privatpersoner varje dag och stallets egna smittskyddsåtgärder är mest troligt av större betydelse än den enskilda veterinärens. Hästägare verkar dock ha stort förtroende för sin veterinär när det gäller smittskyddsåtgärder och veterinären kan minska risken för smittspridning inte endast genom att själv följa hygienrutiner utan även genom att ge adekvat information till hästägare.Contagious diseases causes suffering for the affected individuals and may result in large economic consequences. Hence, an active approach for disease control and prevention has advantages both from an animal welfare perspective and an economic perspective. Three of the most important endemic diseases among horses in Sweden are equine influenza, equine herpesvirus-1 and strangles. All three diseases cause symptoms in the upper respiratory tract and a contagious nasal shedding. They spread directly from horse to horse and indirectly via contamination of the environment and people who are handling affected horses. Actions to prevent indirect contamination seem rare in Swedish stables, only a few stables offer facilities for washing their hands with warm water and soap. Horses that are moved between different stables in relation to selling, breeding, training and competing constitute the greatest risk for the spread of contagious diseases. People that are moving between stables, for example veterinarians, also constitute a risk but there are preventive measures which limit the risk. Changing clothes between visits to different stables or using protective clothing, footbath at the entrance of the stable or providing boots for visitors are measures which haves proven useful in preventing a stable from infection. Moreover, washing hands in warm water and soap is effective in order to remove both bacteria and virus from hands. Some studies indicate that hand disinfection might be as effective or sometimes even more effective against the viruses and bacteria mentioned. Many veterinarians state that they undertake a number of preventative measures between their visits to different farms. However, some studies show that it is difficult to make people follow biosecurity rules and many people have an inaccurate perception regarding whether or not they follow the rules. How important the veterinarian’s biosecurity and hygiene are for the spread of infectious agents can be discussed. Many stables are visited by numbers of different persons during one day and the stables’ own routines for biosecurity are probably more important than what the individual veterinarian does. However horse owners seem to have a high confidence in their own veterinarian according to biosecurity measures and the veterinarian may hence contribute to the infection control not only by following good routines for hygiene but also by giving adequate information to horse owners

Svenska och norska hästar med mugg och rasp

Mugg och rasp är ett vanligt förekommande hudproblem på häst. Det är snarare ett syndrom än en sjukdom då benämningen mugg och rasp beskriver lesioner på hästens distala ben. På engelska går syndromet oftast under namnet ”Pastern dermatitis” men fler benämningar kan förekomma. Lesionerna kan bl.a. visa sig i form av krustor, sår och svullnader. Den drabbade hästen kan bli halt och lesionerna kan leda till kroniska besvär. Det finns flera olika underliggande orsaker finns till att mugg och rasp uppstår, bl.a. omnämns Chorioptes bovis, Trombicula alfreddugesi, fotosensibilitet och vaskulit i litteraturen. 2017 inledde Statens veterinärmedicinska anstalt och Sveriges lantbruksuniversitet tillsammans med Norges veterinärinstitut ett forskningsprojekt finansierat av Stiftelsen hästforskning. Målet med projektet är att hitta bättre diagnostik och behandling för mugg och rasp. En del av projektet består av en enkät som nått svenska och norska hästägare och det är denna enkät som detta arbete handlar om. Frågor som ställs är bland annat: Vilka symtom är vanliga? Vilka ben drabbas? Spelar mängden hovskägg någon roll för hur sjukdomsbilden ser ut? Målsättningen med detta arbete är att kartlägga symtombild och sjukdomsförlopp vid mugg och rasp hos nordiska hästar. Resultatet av detta arbete bekräftar det som står beskrivet i litteraturen om att bakben verkar drabbas oftare än framben. Hästar får samma typ av symtom oavsett hur mycket behåring de har på benen. De absolut vanligaste symtomen är krustor följt av sår, smärta, svullnad, klåda och hudvalkar. Det är vanligt förekommande med kroniska och/eller återkommande besvär. Blött/lerigt väder är en försvårande omständighet oavsett vilken typ av behåring hästen har. Ett intressant resultat är att hästar med tunnare behåring i högre utsträckning drabbas sommartid medan en del hästar med kraftigare behåring snarare drabbas vintertid. Detta kan indikera att beroende på typ av behåring är hästen mer eller mindre mottaglig för de olika underliggande orsakerna till mugg och rasp. Bland de hästar som i högre grad insjuknar på vintern finns en stor representation av rasen nordsvensk brukshäst och dölehäst. Detta skulle kunna tyda på att det finns en genetisk faktor som gör dessa hästar mer mottagliga för underliggande orsaker som är vanligare vintertid, t.ex. benskabb.Pastern dermatitis is a regularly occurring skin-problem in horses that affects the distal limbs. The syndrome is also named greasy heel, cracked heel, scratches, mud fever, verrucous pododermatitis and grapes. Crusts, wounds and swellings are typical symptoms. Lameness is not an uncommon complication and the problems can get chronic. There are several underlying reasons for pastern dermatitis described in the litterature, for example Chorioptes bovis, Trombicula alfreduggesi, photosensitivity and vasculitis. In 2017 a joint research project between National veterinary institute of Sweden, Swedish university of veterinary sciences and the Norwegian veterinary institute, financed by The Swedish-Norwegian Fund for Equine Research was launched. The project’s goal is to identify better diagnostic tools and treatments for pastern dermatitis. The project partly consists of a survey addressed to horse owners in Sweden and Norway. The survey includes questions concerning any eventual skin problems in the distal limbs of the horse, what limbs are affected and what time of the year these problems occur. This thesis will study the answers of the survey. Questions asked will be: What symptoms are common? Which legs are more often affected? Does it matter whether the horse is feathered or non-feathered for how pastern dermatitis will occur? The aim with this thesis is to map the symptoms and the disease course for pastern dermatitis in Swedish and Norwegian horses. The result of this thesis confirms what is earlier described in the literature, the hindlimbs are more frequently affected than the forelimbs. The symptoms seem to be the same whether the horse have feathered legs or not. The most common symptoms are crusts followed by wounds, pain, swelling, pruritus and thickened skin. It is common with chronic and/or reoccurring problems. Wet and muddy weather seems to make the problems worse for all types of horses. An interesting finding is that non-feathered horses have more problems during summer while some feathered horses have more problems during winter. This could indicate that pastern dermatitis can be caused through different pathogenesis depending on what type of coat the horse has. Among those horses that are more disposed during winter there is a large proportion of Nordsvensk brukshäst and Dölehäst. This could indicate that there is some genetic factor that makes these horses more adoptive for the underlaying causes that are more common during the winter, for example Chorioptes bovis

Venous bicarbonate as a prognostic biomarker and proposed proxy for vital capacity to be used as an eligibility criterion in amyotrophic lateral sclerosis clinical trials

Advanced Behavioural Research Method

Outbreak of Puumala Virus Infection, Sweden

An unexpected and large outbreak of Puumala virus infection in Sweden resulted in 313 nephropathia epidemica patients/100,000 persons in Västerbotten County during 2007. An increase in the rodent population, milder weather, and less snow cover probably contributed to the outbreak

Repeated cognitive assessments show stable function over time in patients with ALS

Multivariate analysis of psychological dat

First Human Isolate of Hantavirus (Andes virus) in the Americas

We isolated Andes virus (formal name: Andes virus [ANDV], a species in the genus Hantavirus), from serum of an asymptomatic 10-year-old Chilean boy who died 6 days later of hantavirus pulmonary syndrome (HPS). The serum was obtained 12 days after his grandmother died from HPS and 2 days before he became febrile. No hantavirus immunoglobulin (Ig) G or IgM antibodies were detected in the serum sample. After three blind passages, ANDV antigens were detected in Vero E6 cells by immunofluorescence assay and enzyme-linked immunosorbent assay, and ANDV RNA was detected by reverse transcription-polymerase chain reaction. A fragment of the virus genome showed 96.2% nucleotide identity with that of prototype ANDV. To our knowledge, this is the first isolation of any agent of hemorrhagic fever with renal syndrome from a human and the first such isolation of hantavirus before symptoms of that syndrome or HPS began

Demographic Factors Associated with Hantavirus Infection in Bank Voles (Clethrionomys glareolus)

The bank vole (Clethrionomys glareolus) is the natural reservoir of Puumala virus (PUUV), a species in the genus Hantavirus. PUUV is the etiologic agent of nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome. Factors that influence hantavirus transmission within host populations are not well understood. We evaluated a number of factors influencing on the association of increased PUUV infection in bank voles captured in a region in northern Sweden endemic for the virus. Logistic regression showed four factors that together correctly predicted 80% of the model outcome: age, body mass index, population phase during sampling (increase, peak, or decline/low), and gender. This analysis highlights the importance of population demography in the successful circulation of hantavirus. The chance of infection was greatest during the peak of the population cycle, implying that the likelihood of exposure to hantavirus increases with increasing population density

Human Hantavirus Infections, Sweden

The prevalent human hantavirus disease in Sweden is nephropathia epidemica, which is caused by Puumala virus and shed by infected bank voles (Clethrionomys glareolus). To evaluate temporal and spatial patterns of this disease, we studied 2,468 reported cases from a highly disease-endemic region in northern Sweden. We found that, in particular, middle-aged men living in rural dwellings near coastal areas were overrepresented. The case-patients were most often infected in late autumn, when engaged in activities near or within manmade rodent refuges. Of 862 case-patients confident about the site of virus exposure, 50% were concentrated within 5% of the study area. The incidence of nephropathia epidemica was significantly correlated with bank vole numbers within monitored rodent populations in part of the region. Understanding this relationship may help forestall future human hantavirus outbreaks

Background radiation and individual dosimetry in the costal area of Tamil Nadu, India.

South coast of India is known as the high-level background radiation area (HBRA) mainly due to beach sands that contain natural radionuclides as components of the mineral monazite. The rich deposit of monazite is unevenly distributed along the coastal belt of Tamil Nadu and Kerala. An HBRA site that laid in 2×7 m along the sea was found in the beach of Chinnavillai, Tamil Nadu, where the maximum ambient dose equivalent reached as high as 162.7 mSv y(-1). From the sands collected at the HBRA spot, the high-purity germanium semi-conductor detector identified six nuclides of thorium series, four nuclides of uranium series and two nuclides belonging to actinium series. The highest radioactivity observed was 43.7 Bq g(-1) of Th-228. The individual dose of five inhabitants in Chinnavillai, as measured by the radiophotoluminescence glass dosimetry system, demonstrated the average dose of 7.17 mSv y(-1) ranging from 2.79 to 14.17 mSv y(-1)