Enterovirus infections in type 1 diabetes and cystic fibrosis : antiviral defence and viral immune evasion strategies

Enteroviruses are common viruses which cause infections in humans that usually result in mild flu-like symptoms before viral clearance. However, in some cases these infections can progress to more severe diseases such as myocarditis, pancreatitis and hepatitis. Coxsackievirus induced hepatitis in infants may become so severe that the outcome is fatal. In addition, infections with enteroviruses belonging to the group B Coxsackieviruses have been implicated in the etiology of type 1 diabetes. Enterovirus infections are also commonly observed in patients with cystic fibrosis, resulting in lung exacerbations and morbidity. Proper antiviral response mechanisms are crucial for the prevention of viral replication and spread, as well as the inhibition of virus induced cellular damage. Recently a novel group of interferons, called type III interferons, were discovered and shown to have antiviral properties predominantly in cells of epithelial origin. In Paper I we show that type III interferons protect primary human hepatocytes from Coxsackievirus infection. Given the importance of interferons in preventing early viral replication, many viruses have developed mechanisms to inhibit their induction. In Paper II, we showed that Coxsackieviruses inhibit the induction of type III interferons in infected cells. In addition, we demonstrated that this inhibition was caused by the proteolytic activity of the viral protease 2Apro. The exact role of enterovirus infections in type 1 diabetes development is still under speculation. Coxsackieviruses encodes several viral proteins that have been shown to interfere with cellular function and signaling pathways. In Paper III, we used primary human pancreatic islets and an insulin-secreting cell line to identify mechanisms by which Coxsackeiviruses can cause beta cell dysfunction. We found that the viral proteins 2Apro, 3A and 3Cpro could, independently of one other, affect exocytosis with 2Apro and 3Cpro targeting calcium influx while 3A inhibited exocytosis via a calcium independent mechanism. An impaired antimicrobial defense has been observed in patients with cystic fibrosis. This could explain why common respiratory infections are often prolonged and more severe in these patients. By using a mouse model for cystic fibrosis, we showed in Paper IV that the most common mutation resulting in cystic fibrosis, F508del, caused an impaired adaptive immune response with a delayed production of neutralizing antibodies to Coxsackievirus. In conclusion, the studies performed in this thesis add to our understanding of innate and adaptive immune response mechanisms during Coxackievirus infections. In addition they demonstrate a role for viral proteins in circumventing host antiviral immune responses, thus causing cellular damage, which could contribute to disease pathology. Increasing the knowledge of host-pathogen interactions may help to develop new treatments that could prevent severe Coxsackievirus infections

Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essential for the induction of type 1 interferons after Coxsackievirus infection

AbstractCoxsackievirus infections are associated with severe diseases such as myocarditis, meningitis and pancreatitis. To study the contribution of the intracellular viral sensor melanoma differentiation-associated protein-5 (MDA-5) in the host immune response to Coxsackievirus B3 (CVB3) we infected C57BL/6 and 129/SvJ mice lacking mda-5. Mice deficient in MDA-5 showed a dramatically increased susceptibility to CVB3 infection. The loss of MDA-5 allowed the virus to replicate faster, resulting in increased liver and pancreas damage and heightened mortality. MDA-5 was not absolutely required for the induction of type 1 interferons (IFNs), but essential for the production of maximal levels of systemic IFN-α early after infection. Taken together, our findings indicate that MDA-5 plays an important role in the host immune response to CVB3 by preventing early virus replication and limiting tissue pathology

Patients' experience of communication difficulties due to stroke : a literature review

Bakgrund: En av de största orsakerna till funktionsnedsättningar i världen är stroke. Stroke kan orsaka ett flertal komplikationer varav en av de vanligaste är svårigheter med kommunikation. Kommunikation är en viktig del i mötet mellan patient och vårdare och det är centralt för sjuksköterskan att ha kunskap om olika sätt att kommunicera med patienter som har kommunikationssvårigheter. Sjuksköterskan behöver ha kunskap om dessa kommunikationssvårigheter och patientens upplevelse av kommunikation under och efter vårdtiden för att kunna ge en god personcentrerad vård där patientens behov uppfylls.  Syfte: Syftet var att belysa patienters upplevelse av kommunikationssvårigheter till följd av stroke.  Metod: Denna icke-systematiska litteraturöversikt inkluderade 15 vetenskapliga artiklar, av dessa bestod 13 av kvalitativ ansats och två av en mixad metod. Med hjälp av olika kombinationer av sökord inhämtades samtliga artiklar från PubMed och CINAHL. Dessa har sedan utifrån Sophiahemmet Högskolas bedömningsunderlag för vetenskaplig klassificering och kvalitet genomgått en kvalitetsgranskning. En integrerad dataanalys har använts för att analysera och sammanställa resultatet.  Resultat: Resultatet delades upp i två huvudkategorier; kommunikation i vården och kommunikation efter vårdtiden. Även fem underkategorier har identifierats; tillit och bemötande, självständighet och stöd, sociala aktiviteter och interaktion, hopp och känslor till följd av kommunikationssvårigheter. Resultatet visade både positiva och negativa upplevelser kring kommunikationssvårigheter. Ett mönster som upptäcktes var att negativa känslor var kopplat till den akuta fasen och att positiva känslor uppstod i ett senare skede.  Slutsats: Studien visar att sjuksköterskor behöver bemöta och stötta strokeöverlevare och använda sig av god kommunikation genom att prata direkt till patienten, låta personen tala till punkt, samt lyssna på patienten och anpassa informationen till patienten. Detta kommer stärka patientens tillit till vården, självständighet, sociala förmåga, känsla av hopp samt minska de negativa känslorna som uppstår efter en stroke.Background: One of the major causes of disability in the world is stroke. Stroke can cause a number of complications, one of the most common of which is difficulties with communication. Communication is an important part of the meeting between patient and carer, and it is cnetral for the nurse to have knowledge of different ways of communicating with patients that have communication difficulties. The nurse needs to have knowledge of these communication barriers and the patients’ experience of communication during and after the period of care in order to provide good person-centred care where the patients' needs are met.  Aim: The aim of this study was to illuminate patients' experience of communication difficulties due to stroke.  Method: This non-systematic literature review included 15 scientific articles, of which 13 consisted  of a qualitative approach and two of a mixed method. Using different combinations of search terms, all articles were obtained from PubMed and CINAHL. These have then undergone a quality review based on Sophiahemmet University's assessment basis for scientific classification and quality. An integrated data analysis has been used to analyze and compile the results.  Results: The results were divided into two main categories; communication in care and communication after the care period. Five subcategories have also been identified; trust and treatment, independence and support, social activities and interaction, hope and feelings as a result of communication difficulties. The results showed both positive and negative experiences regarding communication difficulties. A pattern that was discovered was that negative emotions were linked to the acute phase and that positive emotions emerged at a later stage. Conclusion: The study shows that nurses need to meet and support stroke survivors and use good communication by talking directly to the patient, letting the person speak to the end, as well as listening to the patient and adapting the information to the patient. This will strengthen the patient's trust in care, independence, social ability, sense of hope and reduce the negative feelings that arise after a stroke

How to create a logotype based on core values - A study of how craft companies can visually strengthen their brand identity

DIY- \u93Do it Yourself\u94 är en ny trend som går ifrån konsumtionssamhället för att istället värna om det genuina hantverket. Få studier har presenterat hur en visuell varumärkesidentitet bör utformas för att förtydliga dessa typer av verksamheter. Rapporten syftar till att undersöka hur en logotyp kan utformas för ett Hantverksföretag utifrån verksamhetens kärnvärden, för att skapa önskvärda associationer och därmed stärka varumärkets identitet. Under studien har arbetet genomförts utifrån ett \u93case-företag\u94 vid namn Hantverksgården. Genom företagets kärnvärden, genuint, lantligt och idylliskt har rapporten undersökt hur en logotyp bör utformas för att reflektera verksamheten. Genom att identifiera verksamheten och söka inspiration utifrån kärnvärdena togs två logotyper fram. För att besvara syftet värderades vardera logotyp med åtta respondenter. Logotyperna undersöktes utifrån sex kriterier minnesvärd, meningsfull, älskvärd, originalitet, skalbarhet/mångsidighet/överförbarhet och utförande. Studiens visade genom att framhäva verksamhetens ursprung skapades associationer till begreppet genuint. Kärnvärdet lantligt reflekterades genom avbildade objekt kopplade till verksamheten. Genom dekorativa illustrationer kunde logotypen uppfattas som idyllisk. Kriterierna älskvärd och meningsfull visades vara de viktigaste kriterierna för att uppfylla önskvärda associationer

Patients' experience of communication difficulties due to stroke : a literature review

Bakgrund: En av de största orsakerna till funktionsnedsättningar i världen är stroke. Stroke kan orsaka ett flertal komplikationer varav en av de vanligaste är svårigheter med kommunikation. Kommunikation är en viktig del i mötet mellan patient och vårdare och det är centralt för sjuksköterskan att ha kunskap om olika sätt att kommunicera med patienter som har kommunikationssvårigheter. Sjuksköterskan behöver ha kunskap om dessa kommunikationssvårigheter och patientens upplevelse av kommunikation under och efter vårdtiden för att kunna ge en god personcentrerad vård där patientens behov uppfylls.  Syfte: Syftet var att belysa patienters upplevelse av kommunikationssvårigheter till följd av stroke.  Metod: Denna icke-systematiska litteraturöversikt inkluderade 15 vetenskapliga artiklar, av dessa bestod 13 av kvalitativ ansats och två av en mixad metod. Med hjälp av olika kombinationer av sökord inhämtades samtliga artiklar från PubMed och CINAHL. Dessa har sedan utifrån Sophiahemmet Högskolas bedömningsunderlag för vetenskaplig klassificering och kvalitet genomgått en kvalitetsgranskning. En integrerad dataanalys har använts för att analysera och sammanställa resultatet.  Resultat: Resultatet delades upp i två huvudkategorier; kommunikation i vården och kommunikation efter vårdtiden. Även fem underkategorier har identifierats; tillit och bemötande, självständighet och stöd, sociala aktiviteter och interaktion, hopp och känslor till följd av kommunikationssvårigheter. Resultatet visade både positiva och negativa upplevelser kring kommunikationssvårigheter. Ett mönster som upptäcktes var att negativa känslor var kopplat till den akuta fasen och att positiva känslor uppstod i ett senare skede.  Slutsats: Studien visar att sjuksköterskor behöver bemöta och stötta strokeöverlevare och använda sig av god kommunikation genom att prata direkt till patienten, låta personen tala till punkt, samt lyssna på patienten och anpassa informationen till patienten. Detta kommer stärka patientens tillit till vården, självständighet, sociala förmåga, känsla av hopp samt minska de negativa känslorna som uppstår efter en stroke.Background: One of the major causes of disability in the world is stroke. Stroke can cause a number of complications, one of the most common of which is difficulties with communication. Communication is an important part of the meeting between patient and carer, and it is cnetral for the nurse to have knowledge of different ways of communicating with patients that have communication difficulties. The nurse needs to have knowledge of these communication barriers and the patients’ experience of communication during and after the period of care in order to provide good person-centred care where the patients' needs are met.  Aim: The aim of this study was to illuminate patients' experience of communication difficulties due to stroke.  Method: This non-systematic literature review included 15 scientific articles, of which 13 consisted  of a qualitative approach and two of a mixed method. Using different combinations of search terms, all articles were obtained from PubMed and CINAHL. These have then undergone a quality review based on Sophiahemmet University's assessment basis for scientific classification and quality. An integrated data analysis has been used to analyze and compile the results.  Results: The results were divided into two main categories; communication in care and communication after the care period. Five subcategories have also been identified; trust and treatment, independence and support, social activities and interaction, hope and feelings as a result of communication difficulties. The results showed both positive and negative experiences regarding communication difficulties. A pattern that was discovered was that negative emotions were linked to the acute phase and that positive emotions emerged at a later stage. Conclusion: The study shows that nurses need to meet and support stroke survivors and use good communication by talking directly to the patient, letting the person speak to the end, as well as listening to the patient and adapting the information to the patient. This will strengthen the patient's trust in care, independence, social ability, sense of hope and reduce the negative feelings that arise after a stroke

Calcium Current Inactivation Rather than Pool Depletion Explains Reduced Exocytotic Rate with Prolonged Stimulation in Insulin-Secreting INS-1 832/13 Cells

Impairment in beta-cell exocytosis is associated with reduced insulin secretion and diabetes. Here we aimed to investigate the dynamics of Ca2+-dependent insulin exocytosis with respect to pool depletion and Ca2+-current inactivation. We studied exocytosis, measured as increase in membrane capacitance (ΔCm), as a function of calcium entry (Q) in insulin secreting INS-1 832/13 cells using patch clamp and mixed-effects statistical analysis. The observed linear relationship between ΔCm and Q suggests that Ca2+-channel inactivation rather than granule pool restrictions is responsible for the decline in exocytosis observed at longer depolarizations. INS-1 832/13 cells possess an immediately releasable pool (IRP) of ∼10 granules and most exocytosis of granules occurs from a large pool. The latter is attenuated by the calcium-buffer EGTA, while IRP is unaffected. These findings suggest that most insulin release occurs away from Ca2+-channels, and that pool depletion plays a minor role in the decline of exocytosis upon prolonged stimulation

Demonstration of the double-pulse protocol.

<p>Single cells were depolarized from a holding potential of −70 mV to 0 mV during 50 ms. This was followed by a resting period of 100 ms and a second 50-ms depolarization from −70 mv to 0 mV (top trace). The evoked Ca²⁺ currents were measured and the charges for the first (Q₁) and second (Q₂) pulses were estimated (middle trace). In addition, the increases in membrane capacitance evoked by the first (ΔC_m1) and second (ΔC_m2) depolarizations were measured.</p

Mixed-effects analysis of the pulse-length data from the second pulse, following a 50 ms prepulse, in the control and EGTA groups.

<p>Capacitance data (ΔCm) plotted against Ca²⁺ influx measured as charge (Q) from individual cells with single-cell fits indicated by solid lines, while group fits (fixed-effects) are given by the dashed lines. Ctrl (panel 1–14); EGTA (panel 15–32).</p

Mixed-effects analysis of the train protocol.

<p>Cumulative capacitance data is plotted against cumulative Ca²⁺ influx measured as charge, for individual cells with single-cell fits indicated by solid lines, while group fits (fixed-effects) are given by the dashed lines. Model fit to all cumulative data from all 10 pulses is given in gray, while the fit to the first three pulses is given in black.</p