Does Prolonged Education Causally Affect Dementia Risk When Adult Socioeconomic Status Is Not Altered? A Swedish Natural Experiment in 1.3 Million Individuals.

Intervening on modifiable risk factors to prevent dementia is of key importance, since progress-modifying treatments are not currently available. Education is inversely associated with dementia risk, but causality and mechanistic pathways remain unclear. We aimed to examine the causality of this relationship in Sweden using, as a natural experiment, data on a compulsory schooling reform that extended primary education by 1 year for 70% of the population between 1936 and 1949. The reform introduced substantial exogenous variation in education that was unrelated to pupils' characteristics. We followed 18 birth cohorts (n = 1,341,842) from 1985 to 2016 (up to ages 79-96 years) for a dementia diagnosis in the National Inpatient and Cause of Death registers and fitted Cox survival models with stratified baseline hazards at the school-district level, chronological age as the time scale, and cohort indicators. Analyses indicated very small or negligible causal effects of education on dementia risk (main hazard ratio = 1.01, 95% confidence interval: 0.98, 1.04). Multiple sensitivity checks considering only compliers, the pre-/post- design, differences in health-care-seeking behavior, and the impact of exposure misclassification left the results essentially unaltered. The reform had limited effects on further adult socioeconomic outcomes, such as income. Our findings suggest that without mediation through adult socioeconomic position, education cannot be uncritically considered a modifiable risk factor for dementia.

'And Eden from the Chaos rose': utopian order and rebellion in the Oxford Physick Garden.

Abel Evans's poem Vertumnus (1713) celebrates Jacob Bobart the Younger, second keeper of the Oxford Physick Garden (now the Oxford University Botanic Garden), as a model monarch to his botanical subjects. This paper takes Vertumnus as a point of departure from which to explore the early history of the Physick Garden (founded 1621), situating botanical collections and collecting spaces within utopian visions and projects as well as debates about order more widely in the turbulent seventeenth-century. Three perspectives on the Physick Garden as an ordered collection are explored: the architecture of the quadripartite Garden, with particular attention to the iconography of the Danby Gate; the particular challenges involved in managing living collections, whose survival depends on the spatial order regulating the microclimates in which they grow; and the taxonomic ordering associated with the hortus siccus collections. A final section on the ideal 'Botanick throne' focuses on the metaphor of the state as a garden in the period, as human and botanical subjects resist being order and can rebel, but also respond to right rule and wise cultivation. However, the political metaphor is Evans's; there is little to suggest that Bobart himself was driven by utopian, theological and political visions.

A CRISP(e)R view on kidney organoids allows generation of an induced pluripotent stem cell-derived kidney model for drug discovery.

Development of physiologically relevant cellular models with strong translatability to human pathophysiology is critical for identification and validation of novel therapeutic targets. Herein we describe a detailed protocol for generation of an advanced 3-dimensional kidney cellular model using induced pluripotent stem cells, where differentiation and maturation of kidney progenitors and podocytes can be monitored in live cells due to CRISPR/Cas9-mediated fluorescent tagging of kidney lineage markers (SIX2 and NPHS1). Utilizing these cell lines, we have refined the previously published procedures to generate a new, higher throughput protocol suitable for drug discovery. Using paraffin-embedded sectioning and whole-mount immunostaining, we demonstrated that organoids grown in suspension culture express key markers of kidney biology (WT1, ECAD, LTL, nephrin) and vasculature (CD31) within renal cortical structures with microvilli, tight junctions and podocyte foot processes visualized by electron microscopy. Additionally, the organoids resemble the adult kidney transcriptomics profile, thereby strengthening the translatability of our in vitro model. Thus, development of human nephron-like structures in vitro fills a major gap in our ability to assess the effect of potential treatment on key kidney structures, opening up a wide range of possibilities to improve clinical translation.

Residential area and physical activity: A multi-level study of 68,000 adults in Stockholm County.

AIM: To determine whether there are systematic differences in physical activity between residential areas after extensive control for sociodemographic factors at the individual level. METHODS: Multi-level regressions of walking/bicycling, sedentary activities, household work and exercise were carried out in a representative sample of 68,303 adults in 39 residential areas in Stockholm County, first adjusting at the individual level for country of birth, sex, age, education, occupational class and income. The type of housing was then considered at the individual level or, for walking/bicycling and exercise, at both the individual and area levels (as a measure of area density). RESULTS: After adjustment for sociodemographic factors, differences between residential areas remained in walking/bicycling, corresponding to 0.27 SD, or 50 min/week between the most and least active areas. Forty per cent of this difference could be explained by the type of housing at the area level. For sedentary activities and household work, respectively, much of the variation that remained after adjustment for sociodemographic factors was, in turn, explained by the type of housing at the individual level, leaving a difference of 0.16 SD (80 min/week) and 0.13 SD (60 min/week), respectively. For exercise, the corresponding difference was 0.11 SD (11 min/week, not sensitive to housing). CONCLUSIONS: Area level factors may influence walking/bicycling. High area density was associated with more activity. However, high density also comes with a type of housing (apartments) that is associated with less household work and, surprisingly, more sedentary activities, introducing a challenging trade-off. The differences in exercise were smaller than for all other types of activities.

The role of social capital in explaining mental health inequalities between immigrants and Swedish-born: a population-based cross-sectional study.

BACKGROUND: Social capital may theoretically explain health inequalities between social groups, but empirical evidence is lacking. Some studies indicate that social capital may be particularly important for immigrant health. Nearly 16% of Sweden's population are foreign-born immigrants and research has shown them to be susceptible to psychological distress, though significant variation has been found between groups. In this study, we investigate the following hypotheses: 1) if non-refugees have better mental health than Swedish-born, and refugees experience worse mental health than Swedish-born; 2) if mental health status converges with that of Swedish-born with longer duration of residence; and 3) if social capital mediates the effect of immigrant status on psychological distress for different immigrant groups as compared to Swedish-born. METHODS: This cross-sectional study uses baseline data from the Stockholm Public Health Cohort and includes 50,498 randomly-selected individuals from Stockholm County in 2002, 2006, and 2010. Mental health was measured as psychological distress, using the 12-item General Health Questionnaire. Social capital was measured using indicators of bonding, bridging, and linking social capital. Both cognitive and structural aspects were measured for the latter two indicators. Mediation was tested using logistic regression and the Sobel test. RESULTS: The results show that refugees generally had greater odds of psychological distress than non-refugees compared to their respective Swedish-born counterparts. Among immigrant men, both refugees and non-refugees had significantly greater odds of psychological distress than Swedish-born men. Only refugee women in Sweden 10 years or more had significantly greater odds of psychological distress compared to Swedish-born women. The mediation analysis demonstrated that indicators of social capital mediated the association for all immigrant men (except non-refugees in Sweden 3-9 years) and for refugee women in Sweden 10 years or more. While bonding social capital showed the greatest mediatory role among the three social capital types, adding them together had the strongest explanatory effect. CONCLUSIONS: Social capital explains differences in mental health for some immigrant groups, highlighting its role as a potentially important post-migration factor. Increased investment from policy-makers regarding how social capital can be promoted among new arrivals may be important for preventing psychological distress.

Exposure to maternal smoking during pregnancy as a risk factor for tobacco use in adult offspring.

Nicotine from maternal smoking during pregnancy can cross the placental barrier, possibly resulting in fetal brain sensitization, as indicated by studies in which prenatal exposure to maternal smoking was associated with an increased risk of tobacco use among adolescent offspring. We investigated whether this association persists beyond adolescence by studying cigarette smoking and the use of snus (Swedish oral moist snuff) among 983 young adults from a prospective cohort study conducted in Stockholm, Sweden, between 2006 and 2010. Self-reported questionnaire data were linked with data from national population-based registers from 1983 onward. Maternal smoking during pregnancy was consistently associated with snus use in offspring (e.g., for lifetime daily snus use, adjusted odds ratio = 2.04, 95% confidence interval: 1.32, 3.16; for use of >3 cans of snus per week vs. less, odds ratio = 3.85, 95% confidence interval: 1.57, 10.15). No association was apparent with offspring's smoking, age at onset of tobacco use, or changes in use between 2006 and 2010. These findings indicate that prenatal exposure to maternal smoking is associated with regular and heavy nicotine intake from smokeless tobacco rather than from smoking. This should be further explored in epidemiologic studies that simultaneously address the roles of genetics and social environments.

HTLV in Sweden.

Sweden is a country with a low prevalence of human lymphotropic T-cell virus (HTLV) infection, estimated at < 0.005%, but the infection rate is notably higher in specific risk groups such as HTLV-2 among intravenous drug users (IVDU) and people originating from HTLV-1 highly endemic areas. Thus, in the most recent study from 2012, the prevalence of HTLV-2 among IVDU in Stockholm was 3.2%. However, much of the epidemiological data on HTLV in Sweden stems from studies conducted primarily between the 1990s and 2007, and the impact of migration to Sweden during the past 15 years has not been evaluated. Despite Sweden's status as a country with generally low prevalence of HTLV, it is prudent to anticipate and prepare for several potential challenges associated with HTLV infection in the future. Proactive measures to enhance awareness, alongside strategies to curtail transmission and mitigate complications, are crucial for addressing this relatively rare, but significant health issue. In this work, we review the current epidemiological knowledge about HTLV in Sweden and discuss future Swedish perspectives.

Surgery for carpal tunnel syndrome in patients with and without diabetes-Is there a difference in the frequency of surgical procedures?

Carpal tunnel syndrome (CTS) occurs more often among individuals with diabetes. The aim of this retrospective observational registry study was to examine whether individuals with diabetes and CTS are treated surgically to the same extent as individuals with CTS but without diabetes. Data on CTS diagnosis and surgery were collected from the Skåne Healthcare Register (SHR). A total of 35,105 individuals (age ≥ 18 years) diagnosed with CTS from 2004-2019 were included. Data were matched to the Swedish National Diabetes Register (NDR. Cox regression models were used to calculate the risk of the use of surgical treatment. Of the 35,105 included individuals with a CTS diagnosis, 17,662 (50%) were treated surgically, and 4,966 (14%) had diabetes. A higher number of individuals with diabetes were treated surgically (2,935/4,966, 59%) than individuals without diabetes (14,727/30,139, 49%). In the Cox regression model, diabetes remained a significant risk factor for surgical treatment (PR 1.14 (95% CI 1.11-1.17)). Individuals with type 1 diabetes were more frequently treated surgically (490/757, 65%) than individuals with type 2 diabetes (2,445/4,209, 58%). There was no difference between the sexes and their treatment. The duration of diabetes was also a risk factor for surgical treatment in diabetes type 2, but high HbA1c levels were not. Individuals with diabetes are more likely to be treated surgically for CTS than individuals without diabetes. Individuals with type 1 diabetes are more likely to be treated surgically for CTS than individuals with type 2 diabetes.

Assessment of glial fibrillary acidic protein and anti-glial fibrillary acidic protein autoantibody concentrations and necrotising meningoencephalitis risk genotype in dogs with pug dog myelopathy.

BACKGROUND: Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM. METHODS: The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility. RESULTS: This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036). LIMITATIONS: The study was limited by the lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME. CONCLUSIONS: The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM.

Maternal and fetal genetic contributions to postterm birth: familial clustering in a population-based sample of 475,429 Swedish births.

This study examines the familial clustering and relative influence of genetic and environmental effects on postterm birth in the Swedish population by considering all full- and half-siblings born in Sweden between 1992 and 2004. Of the eligible 475,429 births, 21% occurred after 41 completed weeks and 5.5% occurred after 42 completed weeks of gestation. Odds of postterm birth increased if mothers were older, heavier, more educated, primiparous, or carrying a male fetus. The highest odds increase was seen in women with a previous postterm birth, both with the same partner (odds ratio = 4.4, 95% confidence interval: 4.0, 4.6) and after a partner change (odds ratio = 3.4, 95% confidence interval: 2.9, 3.9). Sisters of women with a postterm birth were also at increased odds of postterm birth (odds ratio = 1.8, 95% confidence interval: 1.6, 2.0) while brothers' partners were not. Half of the variation in postterm birth could not be explained by factors shared in families, and the remaining half was explained by genetic factors, namely fetal (26%) and maternal (21%) genetic factors. Familial clustering of postterm birth is attributed to genetic effects, and fetal genetic effects have a considerable influence on the liability of postterm birth.

Fetal and maternal genes' influence on gestational age in a quantitative genetic analysis of 244,000 Swedish births.

Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.

A new interactive computer simulation system for violence risk assessment of mentally disordered violent offenders.

BACKGROUND: Assessment of risk of future violence has developed from reliance on static indicators towards a more dynamic approach. In the latter context, however, the offender is seldom confronted with real life situations. AIMS: The aim of this study is to evaluate a computer-based system--Reactions on Display, which presents human interactions based on real-life situations--for its effectiveness in distinguishing between potentially violent offenders with mental disorder and a healthy comparison group. METHODS: Male offenders with autism spectrum disorders or psychosis were recruited from specialist forensic psychiatric units in Sweden and healthy participants from the local communities. Each consenting participant was presented with film clips of a man in neutral and violent situations, which at critical moments stopped the story to ask him to predict the thoughts, feelings and actions of the actor. RESULTS: Offender patients, irrespective of diagnosis, detected fewer emotional reactions in the actor in the non-violent sequence compared with controls. When asked to choose one of four violent actions, the offender patients chose more violent actions than did the controls. They also reported fewer physical reactions in the actors when actors were being violent. There were also some examples of incongruent or deviant responses by some individual patients. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The use of interactive computer simulation techniques is not only generally acceptable to offender patients, but it also helps to differentiate their current response style to particular circumstances from that of healthy controls in a way that does not rely on their verbal abilities and may tap more effectively into their emotional reactions than standard verbal questions and answer approaches. This may pave the way for Reactions on Display providing a useful complement to traditional risk assessment, and a training route with respect to learning more empathic responding, thus having a role in aiding risk management.

APOL1 promotes endothelial cell activation beyond the glomerulus.

Apolipoprotein L1 (APOL1) high-risk genotypes are associated with increased risk of chronic kidney disease (CKD) in people of West African ancestry. Given the importance of endothelial cells (ECs) in CKD, we hypothesized that APOL1 high-risk genotypes may contribute to disease via EC-intrinsic activation and dysfunction. Single cell RNA sequencing (scRNA-seq) analysis of the Kidney Precision Medicine Project dataset revealed APOL1 expression in ECs from various renal vascular compartments. Utilizing two public transcriptomic datasets of kidney tissue from African Americans with CKD and a dataset of APOL1-expressing transgenic mice, we identified an EC activation signature; specifically, increased intercellular adhesion molecule 1 (ICAM-1) expression and enrichment in leukocyte migration pathways. In vitro, APOL1 expression in ECs derived from genetically modified human induced pluripotent stem cells and glomerular ECs triggered changes in ICAM-1 and platelet endothelial cell adhesion molecule 1 (PECAM-1) leading to an increase in monocyte attachment. Overall, our data suggest the involvement of APOL1 as an inducer of EC activation in multiple renal vascular beds with potential effects beyond the glomerular vasculature.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial.

BACKGROUND: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration. METHODS: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 µg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery. RESULTS: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly. CONCLUSION: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).

Migration and autism spectrum disorder: population-based study.

BACKGROUND: Migration has been implicated as a risk factor for autism, but evidence is limited and inconsistent. AIMS: To investigate the relationship between parental migration status and risk of autism spectrum disorder, taking into consideration the importance of region of origin, timing of migration and possible discrepancies in associations between autism subtypes. METHOD: Record-linkage study within the total child population of Stockholm County between 2001 and 2007. Individuals with high- and low-functioning autism were defined as having autism spectrum disorder with and without comorbid intellectual disability, and ascertained via health and habilitation service registers. RESULTS: In total, 4952 individuals with autism spectrum disorder were identified, comprising 2855 children with high-functioning autism and 2097 children with low-functioning autism. Children of migrant parents were at increased risk of low-functioning autism (odds ratio (OR) = 1.5, 95% CI 1.3-1.7); this risk was highest when parents migrated from regions with a low human development index, and peaked when migration occurred around pregnancy (OR = 2.3, 95% CI 1.7-3.0). A decreased risk of high-functioning autism was observed in children of migrant parents, regardless of area of origin or timing of migration. Parental age, income or obstetric complications did not fully explain any of these associations. CONCLUSIONS: Environmental factors associated with migration may contribute to the development of autism presenting with comorbid intellectual disability, especially when acting in utero. High- and low-functioning autism may have partly different aetiologies, and should be studied separately.

Familial aggregation of schizophrenia: the moderating effect of age at onset, parental immigration, paternal age and season of birth.

AIMS: An abundance of evidence has firmly established the familial aggregation of schizophrenia. The aim of this study was to examine how age at onset, parental characteristics and season of birth modify the familiality in schizophrenia. METHODS: A population-based cohort was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. Among 5,075,998 full siblings born between 1932 through to 1990, 16,346 cases of schizophrenia were identified. Familial aggregation was measured by the sibling recurrence-risk ratio, defined as the risk of schizophrenia among full siblings of schizophrenia patients compared with the risk among siblings of unaffected people. RESULTS: We found a statistically significantly lower recurrence-risk ratio in siblings of later onset cases (7.2; 95% confidence interval (95% CI) 6.7-7.9) than of early onset cases (10.8; 95% CI 9.4-12.2). A lower recurrence-risk ratio was observed among offspring to fathers above 40 years (6.3; 95% CI 5.3-7.3) as compared with offspring of younger fathers (8.6; 95% CI 8.0-9.3). Further, among offspring to parents born outside Sweden the recurrence-risk ratio was statistically significantly lower (maternal immigrants 4.8; 95% CI 4.0-5.7, paternal immigrants 5.7; 95% CI 4.6-6.9) than among offspring to parents born in Sweden. CONCLUSIONS: The familial aggregation of schizophrenia was reduced by higher age at onset, advancing paternal age and immigrant status of parents.

Quantification of normetanephrine in canine urine using ELISA: evaluation of factors affecting results.

Catecholamine release increases in dogs with pheochromocytomas and in situations of stress. Although plasma catecholamines degrade rapidly, their metabolites, normetanephrine (NME) and metanephrine (ME), are stable in acidified urine. Our aim was to verify a human urine ELISA kit for the quantification of NME and ME in canine urine and to determine the effects on metabolite stability of sampling time (morning or midday) and day (ordinary or day spent in a clinic). We analyzed 179 urine samples from 17 healthy dogs. For NME, the mean intra-assay CV was 6.0% for all samples and 4.3% for the canine control; inter-assay CVs were 3.3, 3.8, and 12% for high and low concentration human urine positive controls supplied in the ELISA kit and a positive canine control, respectively; spike-recovery was 90-101%. For ME, mean intra-assay CV was 6.5% for samples and 9.0% for the canine control; inter-assay CVs were 12.7, 7.2, and 22.5% for high and low concentration human urine positive controls supplied in the ELISA kit and a positive canine control, respectively; spike-recovery was 85-89%. Dilution recovery was unsatisfactory for both metabolites. Based on our verification results, NME was selected for remaining analyses. We found no effect on NME concentrations of acidification or room temperature storage for up to 24 h. The NME:creatinine ratio was higher after the first of 3 clinic days compared to the same morning (111.2 ± 5.5 vs. 82.9 ± 5.3; p < 0.0001), but not on the other days. NME verification results were generally superior to ME. Dilution studies were unsatisfactory for both metabolites. Given that NME was stable without acidification at room temperature, urine samples can be collected at home. The clinic environment can cause higher NME:creatinine ratios, especially in unaccustomed dogs.

Longitudinal study of the immune response and memory following natural bovine respiratory syncytial virus infections in cattle of different age.

Human and bovine respiratory syncytial virus (HRSV and BRSV) are closely genetically related and cause respiratory disease in their respective host. Whereas HRSV vaccines are still under development, a multitude of BRSV vaccines are used to reduce clinical signs. To enable the design of vaccination protocols to entirely stop virus circulation, we aimed to investigate the duration, character and efficacy of the immune responses induced by natural infections. The systemic humoral immunity was monitored every two months during two years in 33 dairy cattle in different age cohorts following a natural BRSV outbreak, and again in selected individuals before and after a second outbreak, four years later. Local humoral and systemic cellular responses were also monitored, although less extensively. Based on clinical observations and economic losses linked to decreased milk production, the outbreaks were classified as moderate. Following the first outbreak, most but not all animals developed neutralising antibody responses, BRSV-specific IgG1, IgG2 and HRSV F- and HRSV N-reactive responses that lasted at least two years, and in some cases at least four years. In contrast, no systemic T cell responses were detected and only weak IgA responses were detected in some animals. Seronegative sentinels remained negative, inferring that no new infections occurred between the outbreaks. During the second outbreak, reinfections with clinical signs and virus shedding occurred, but the signs were milder, and the virus shedding was significantly lower than in naïve animals. Whereas the primary infection induced similar antibody titres against the prefusion and the post fusion form of the BRSV F protein, memory responses were significantly stronger against prefusion F. In conclusion, even if natural infections induce a long-lasting immunity, it would probably be necessary to boost memory responses between outbreaks, to stop the circulation of the virus and limit the potential role of previously infected adult cattle in the chain of BRSV transmission.

Expression of IL-23 in gilt endometrium and oviduct after insemination with seminal plasma, spermatozoa or semen extender.

OBJECTIVE: Insemination with spermatozoa, seminal plasma and extender, cause a rapid inflammatory response in pig endometrium, characterized by an influx of neutrophils into the uterus. The transient inflammatory response to semen involves cytokine induction. Potential functions for Interleukin-23 (IL-23) in the inflammatory response to different insemination treatments were examined by studying mRNA expression and immunostaining in gilt oviduct and endometrium 35-40 h after insemination. Insemination was performed with seminal plasma (SP), spermatozoa (SPZ) without SP in the extender Beltsville thawing solution (BTS), or BTS alone. In control gilts an insemination catheter was inserted without anything being inseminated. RESULTS: Results showed that IL-23 mRNA was expressed in oviduct and endometrium after insemination regardless of treatment. There was an approximate two- to fourfold increase in expression of IL-23 mRNA in catheter-insertion control compared with SPZ, SP and BTS treatment groups. IL-23 immunolabelling was detected in a small number of separate cells and in the sub-epithelial connective tissue of the endometrium, the endosalpinx of isthmus and infundibulum. CONCLUSION: In conclusion, insemination with SP, SPZ in BTS, and BTS alone decreased the expression of IL-23 mRNA in the endometrium compared to catheter-insertion control, indicating a possible role for IL-23 in the inflammatory response after insemination in gilts.

Exploring the GLP-1-GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans. RESEARCH DESIGN AND METHODS: GLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract. RESULTS: High homogenous uptake of 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of 68Ga-exendin-4 in pigs scanned by PET. CONCLUSION: We identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.