Bouncing off Ove: Old men's readings of the novel A Man Called Ove as a cultural representation of ageing masculinity.

In recent years, there has been a rise in portrayals of greying protagonists in popular fiction, often featuring older people in humorous and heart-warming stories. An emerging genre within this literature is the "geezer and grump lit", a genre where older people are active protagonists, and while often portrayed as grumpy "'usually turn out to have a heart of gold'" (Swinnen, 2019). A notable example of a book in this genre is the internationally bestselling novel A Man Called Ove (2012) by the Swedish author Fredrik Backman. Telling the story of the 59-year-old Ove who sets out to take his own life, the novel can be understood not only as a cultural representation of ageing, but more specifically a cultural representation of ageing masculinity. But how is this popular novel read and responded to by old men themselves? This article builds on a focus group study with Swedish men aged 65-92 who read and discussed A Man Called Ove. The aim of this article is thus to explore how men read the novel and how these readings function as ways of constructing, negotiating and challenging ageing masculinity and the old man as a gendered and aged position. Findings of the study show how discussion of the novel generated a variety of "imaginary positions" through which the participants made sense of what it means to be an old man in contemporary Sweden, including positions such as the active aspiring ageing man, the passive lonely old man, the embodied and vulnerable old man, and the dutiful old man. Future research should explore how other literary genres may provide ways of understanding how old men's gendered and aged subjectivities are constructed.

CTLA4-Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats.

INTRODUCTION: Immunogenicity causing development of anti-drug antibodies (ADAs) are major challenges in the treatment of haemophilia, as well as other diseases where proteins are used for treatment. Furthermore, it is a complication for preclinical testing of such therapies in animal models. AIM: To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4-Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment. METHODS: Two different prophylactic rhFVIII compounds were given intravenously to HA rats for 4 weeks. Both rhFVIII compounds were co-administered with commercially available CTLA4-Ig or human IgG subclass 4 (hIgG4) as control, and blood samples were collected. To functionally test if pharmacological efficacy was retained, rats were subjected to a bleeding experiment under anaesthesia at end of study. RESULTS: The mean inhibitory level after 4 weeks in rats receiving rhFVIII and hIgG4 was 85.7 BU for octocog alfa and 37.4 BU for rurioctocog alfa pegol. In contrast, co-administration with CTLA4-Ig during rhFVIII therapy prevented the formation of ADAs (both binding and inhibitory) in 14/14 rats receiving octocog alfa and in 7/7 rats receiving rurioctocog alfa pegol. Moreover, we were able to show that the pharmacological efficacy of rhFVIII was preserved. CONCLUSION: In a rat model with spontaneous bleeding, co-administration of CTLA4-Ig with rhFVIII prevented antibody formation. No FVIII antibodies were detected, demonstrating that CTLA4-Ig co-administration can be applicable as a method to prevent immunogenicity, when evaluating human proteins in preclinical systems permitting continuous pharmacokinetic and pharmacodynamic assessment.

FVIII activity following FVIII protein infusion or FVIII gene transfer predicts the bleeding risk in hemophilia A rats.

BACKGROUND: Prophylactic replacement therapy in hemophilia A (HA) patients does not adequately prevent bleeds and arthropathic complications. A more refined understanding of the relationship between coagulation factor VIII (FVIII) levels and bleeding risk during protein prophylaxis, or with gene therapy, is needed to improve patient care. OBJECTIVES: Investigate this relationship in the HA rat, a model exhibiting spontaneous bleeds and development of arthropathy similar to HA patients. METHODS: Human B domain-deleted FVIII was delivered to HA rats via adeno-associated virus (AAV)-mediated gene transfer or multiple intravenous protein injections. RESULTS AND CONCLUSIONS: After 12 weeks of observation, both approaches significantly reduced bleeds per animal and increased the proportion of bleed-free animals compared with controls (43% vs 0%, respectively [AAV]; 75% vs 8%, respectively [injection]). Both approaches resulted in an anti-FVIII inhibitory response in 20% to 37% of treated animals, similar to HA patients. Inhibitory antibodies were refractory to clinical improvement (reduction of bleeds) only in the AAV-based prophylaxis. An integrated model-based analysis of data on FVIII exposure and bleeding events was performed. This predicted the bleeding risk at any given circulating FVIII activity. Specifically, 4.8 or 10 IU/dL FVIII (0.048 and 0.1 IU/mL, respectively) were predicted to reduce bleeding risk by 90% or 95%, respectively, compared with untreated controls. Our data establish the utility of the HA rat model in FVIII prophylaxis studies and describe how FVIII activity affects bleeding risk in this setting. These enable further studies on FVIII prophylaxis focusing on disease complications for an optimized treatment of HA patients.

Rapid inflammation and early degeneration of bone and cartilage revealed in a time-course study of induced haemarthrosis in haemophilic rats.

OBJECTIVES: Detailed knowledge of the sequential cell and tissue responses following haemarthrosis is important for a deep understanding of the pathological process initiated upon extensive bleeding into the joint causing haemophilic arthropathy (HA). The underlying pathobiology driving haemarthrosis towards HA has been difficult to establish in detail, although animal models have shed light on some processes. Previous studies have focused on a single or a few distant time points and often only characterizing one tissue type of the joint. The objective of this study was, therefore, to carefully map early onset of synovitis and HA following induced haemarthrosis. METHODS: One hundred and thirty haemophilia A rats were subjected to induced haemarthrosis or a sham procedure in full anaesthesia and euthanized from 30 min to 7 days after the procedure. Pathological changes of the joints were visualized using micro-computed tomography, histology and immunohistochemistry. RESULTS: Synovitis developed within 24 h and was dominated by myeloid cell infiltrations. Cartilage and bone pathology were evident as early as 48-96 h after haemarthrosis, and the pathology rapidly progressed with extensive periosteal bone formation and formation of subchondral cysts. CONCLUSION: Fast, extensive and simultaneous cartilage and bone degeneration developed shortly after haemarthrosis, as shown by the detailed mapping of the early pathogenesis of HA. The almost immediate loss of cartilage and the pathological bone turnover suggest a direct influence of blood on these processes and are unlikely to be attributed simply to an indirect effect of inflammation.

Acute Haemarthrosis in the Haemophilia A Rat Generates a Local and Systemic Proinflammatory Response.

Background Replacement therapy with coagulation factor VIII (FVIII) concurrent with bleeds (on-demand) in haemophilia A (HA) patients has been hypothesized to increase the risk for antidrug antibodies (inhibitors). A danger signal environment, characterized by tissue damage and inflammation at the site of a bleed, is thought to contribute to the anti-FVIII response. The nature of this inflammatory reaction is, however, not fully known, and new insights will be valuable for both managing inhibitors and understanding arthropathy development. Objective To characterize the inflammatory response, locally and systemically, during the first 24 hours following a joint bleed in the HA rat. Methods HA rats received a needle-induced knee joint bleed (n = 83) or a sham procedure (n = 41). Blood samples were collected at selected time points from 0 to 24 hours post injury/sham. Synovial fluid, intra-articular knee tissue and popliteal lymph nodes were collected at 24 hours. Cytokine/chemokine concentrations and gene expression were measured. Results Gene expression analysis revealed a rapid inflammatory response in the injured knees, accompanied by significantly increased levels of specific gene products in the synovial fluid; IL-1ß, TNFα, KC/GRO, IL-6, Eotaxin, MCP-1, MCP-3, MIP-1α, MIP-2, RANTES, A2M and AGP. Plasma analysis demonstrated significantly increased systemic levels of KC/GRO and IL-6 in injured rats already after 5 to 6 hours. Conclusion A rapid proinflammatory response, locally and systemically, characteristic of innate immunity, was demonstrated. Results reveal a more comprehensive inflammatory picture than previously shown, with resemblance to human haemophilic arthropathy, and with unique correlation between gene expression level, synovial concentration and plasma concentration in individual rats.

Comfortable and leisurely: Old women on style and dress.

This article uses wardrobe interviews with women in the ages of 62-94 to explore transitions and continuities during the life course. During interviews the women have defined their style preferences. One categorization favored by several of them was comfortable. Different meanings were attached to this concept. Practical and convenient outfits were described as increasingly important when aging. Garments that did not expose the body-and its changes with aging-were preferred. The informants talked about the importance of feeling at ease, appropriately dressed for the occasion and situation. They were concerned with feeling nice in their outfits but also stressed becoming more laid-back and prioritizing convenience in their later years. All of these examples had to do with comfort and being comfortable. Uncomfortable clothes were too tight, deemed wrong for the occasion, and unwanted sources of self-consciousness and visibility. Transitions in their style of dress had been gradual, slowly adapting to changes in everyday life as well as in their bodies.

Sensitive methods for evaluation of antibodies for host cell protein analysis and screening of impurities in a vaccine process.

BACKGROUND: Host cell proteins (HCP) should be carefully monitored in vaccine production. To achieve a reliable HCP estimation, a mixture of polyclonal antibodies (pAbs) with broad affinity would be of preference. Sensitive evaluations of the pAbs are therefore of value. METHODS: Column purification of specific HCPs with affinity to the anti-HCP pAbs was compared with Western blotting of the anti-HCP pAbs binding to filter bound total lysate. The anti-HCP pAbs were used in an HCP quantification analysis using surface plasmon resonance (SPR). Host cell derived impurities from an influenza vaccine process were analyzed using 2-D DIGE analysis. RESULTS: The Western blotting showed a similar HCP binding pattern of anti-HCP pAbs from immunizations using two adjuvants: CFA/IFA and AbISCO(®). From the column purification of HCPs, total proteins detectable were similar for all anti-HCP pAbs; however the immune response pattern differed significantly for the anti-HCP pAbs from the AbISCO(®) immunization. In the SPR HCP quantification assay the standard curve ranged from 0.3 to 40 µg/ml. The advantage of SPR compared with ELISA was the decreased hands on time and that the sample number was not limiting. The 2-D DIGE showed that most of the HCPs were removed at the clarification and virus capture step. DISCUSSION: Column purification of HCPs with affinity to the anti-HCP pAbs increased the sensitivity of affinity analysis compared with Western blotting and opened the possibility of further analysis. The anti-HCP pAbs did not interact with proteins in the virus; simplifying analysis of process samples using SPR. 2-D DIGE analysis gave a direct study of the impurity profile with the advantage of independence from antibody performance.

The Swedish tant: a marker of female aging.

This article presents and analyzes findings from interviews with women aged 45-65; popular magazines targeting women in this age category, and popular books and blogs on a Swedish age-sensitive concept, tant. The term can be used in many different senses, ranging from polite to derogatory, connoting "aunt," or "granny," but also "little old lady" and "biddy"; the term tantig translating to "frumpish." The article discusses different representations of tant, how she is used as a symbol of invisibility and no longer being seen as a sexual being, but outdated. The concept is used as a warning, indicating an unwanted way to grow old, when addressing middle-aged and older women. As of recently, tant has come to be celebrated by young women, praised for moral courage, for thrift and being represented as free from the male gaze, no longer aiming to please or fretting about appearances. The article sheds light on the different uses of the concept, where who is categorizing whom is of utmost importance. The tant is used as a symbol for doing age either by derogation or by celebration.

A novel non-toxic combined CTA1-DD and ISCOMS adjuvant vector for effective mucosal immunization against influenza virus.

Here we demonstrate that by using non-toxic fractions of saponin combined with CTA1-DD we can achieve a safe and above all highly efficacious mucosal adjuvant vector. We optimized the construction, tested the requirements for function and evaluated proof-of-concept in an influenza A virus challenge model. We demonstrated that the CTA1-3M2e-DD/ISCOMS vector provided 100% protection against mortality and greatly reduced morbidity in the mouse model. The immunogenicity of the vector was superior to other vaccine formulations using the ISCOM or CTA1-DD adjuvants alone. The versatility of the vector was best exemplified by the many options to insert, incorporate or admix vaccine antigens with the vector. Furthermore, the CTA1-3M2e-DD/ISCOMS could be kept 1 year at 4°C or as a freeze-dried powder without affecting immunogenicity or adjuvanticity of the vector. Strong serum IgG and mucosal IgA responses were elicited and CD4 T cell responses were greatly enhanced after intranasal administration of the combined vector. Together these findings hold promise for the combined vector as a mucosal vaccine against influenza virus infections including pandemic influenza. The CTA1-DD/ISCOMS technology represents a breakthrough in mucosal vaccine vector design which successfully combines immunomodulation and targeting in a safe and stable particulate formation.

The combined CTA1-DD/ISCOMs vector is an effective intranasal adjuvant for boosting prior Mycobacterium bovis BCG immunity to Mycobacterium tuberculosis.

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains one of the leading causes of mortality worldwide. The current "gold standard" vaccine Mycobacterium bovis BCG has a limited efficacy that wanes over time. The development of a vaccine to boost BCG-induced immunity is therefore a highly active area of research. Mucosal administration of vaccines is believed to provide better protection against pathogens, such as M. tuberculosis, that invade the host via mucosal surfaces. In this study we demonstrate that an intranasal vaccine, comprising the antigenic fusion protein Ag85B-ESAT-6 and the mucosal combined adjuvant vector CTA1-DD/ISCOMs, strongly promotes a Th1-specific immune response, dominated by gamma interferon-secreting CD4-positive T cells. Mucosal administration of Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs strongly boosted prior BCG immunity, leading to a highly increased recruitment of antigen-specific cells to the site of infection. Most importantly, we observed a significantly (P < 0.001) reduced bacterial burden in the lung compared to nonboosted control animals. Thus, the results demonstrate the effectiveness of mucosal vaccination with Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs as adjuvant for stimulating TB-specific protective immunity in the lung.

The combined CTA1-DD/ISCOM adjuvant vector promotes priming of mucosal and systemic immunity to incorporated antigens by specific targeting of B cells.

The cholera toxin A1 (CTA1)-DD/QuilA-containing, immune-stimulating complex (ISCOM) vector is a rationally designed mucosal adjuvant that greatly potentiates humoral and cellular immune responses. It was developed to incorporate the distinctive properties of either adjuvant alone in a combination that exerted additive enhancing effects on mucosal immune responses. In this study we demonstrate that CTA1-DD and an unrelated Ag can be incorporated together into the ISCOM, resulting in greatly augmented immunogenicity of the Ag. To demonstrate its relevance for protection against infectious diseases, we tested the vector incorporating PR8 Ag from the influenza virus. After intranasal immunization we found that the immunogenicity of the PR8 proteins were significantly augmented by a mechanism that was enzyme dependent, because the presence of the enzymatically inactive CTA1R7K-DD mutant largely failed to enhance the response over that seen with ISCOMs alone. The combined vector was a highly effective enhancer of a broad range of immune responses, including specific serum Abs and balanced Th1 and Th2 CD4(+) T cell priming as well as a strong mucosal IgA response. Unlike unmodified ISCOMs, Ag incorporated into the combined vector could be presented by B cells in vitro and in vivo as well as by dendritic cells; it also accumulated in B cell follicles of draining lymph nodes when given s.c. and stimulated much enhanced germinal center reactions. Strikingly, the enhanced adjuvant activity of the combined vector was absent in B cell-deficient mice, supporting the idea that B cells are important for the adjuvant effects of the combined CTA1-DD/ISCOM vector.