Early-life exposures associated with antibiotic use and risk of subsequent Crohn's disease

Objective. An inappropriate immune response to normal bowel flora is implicated in the etiology of Crohn's disease. Tolerance to bowel flora develops in infancy, so factors disrupting normal patterns of bowel colonization may increase the risk of Crohn's disease. The aim of this study was to test the hypothesis that antibiotic therapy between birth and age 5 years may disrupt the pattern of bowel colonization and increase the risk of Crohn's disease. Material and methods. Some 1098 patients with Crohn's disease and 6550 controls matched by delivery unit, year of birth, sex, and born between 1973 and 1997 were identified through the Swedish population registers. Seven inpatient diagnoses between birth and age 5 years associated with antibiotic therapy were identified by prospectively recorded data. Results. Of the seven diagnoses, only pneumonia and otitis media were sufficiently common for use in the analyses. Pneumonia and otitis media were not independent of each other in their association with Crohn's disease and the more important association was with pneumonia. Pneumonia by age 5 years was statistically significantly associated with both pediatric- and adult Crohn's disease, with odds ratios (and 95% CI) of 2.74 (1.04–7.21) and 4.94 (1.83–13.23), respectively. Pneumonia after age 5 years was not statistically significantly associated with Crohn's disease. Conclusions. Pneumonia prior to age 5 years, but not later, was associated with subsequent Crohn's disease and this may represent either susceptibility or causation. The results are consistent with early exposures influencing immune function, such as through disruption of bowel colonization, and thus increasing the risk of Crohn's disease.     

Sensitivity of regression calibration to non‐perfect validation data with application to the Norwegian Women and Cancer Study

Measurement error occurs when we observe error‐prone surrogates, rather than true values. It is common in observational studies and especially so in epidemiology, in nutritional epidemiology in particular. Correcting for measurement error has become common, and regression calibration is the most popular way to account for measurement error in continuous covariates. We consider its use in the context where there are validation data, which are used to calibrate the true values given the observed covariates. We allow for the case that the true value itself may not be observed in the validation data, but instead, a so‐called reference measure is observed. The regression calibration method relies on certain assumptions.This paper examines possible biases in regression calibration estimators when some of these assumptions are violated. More specifically, we allow for the fact that (i) the reference measure may not necessarily be an ‘alloyed gold standard’ (i.e., unbiased) for the true value; (ii) there may be correlated random subject effects contributing to the surrogate and reference measures in the validation data; and (iii) the calibration model itself may not be the same in the validation study as in the main study; that is, it is not transportable. We expand on previous work to provide a general result, which characterizes potential bias in the regression calibration estimators as a result of any combination of the violations aforementioned. We then illustrate some of the general results with data from the Norwegian Women and Cancer Study. Copyright © 2015 John Wiley & Sons, Ltd.     

Sex-related differences in diabetic kidney disease: A review on the mechanisms and potential therapeutic implications

Sexual dimorphism may play a key role in the pathogenesis of diabetic kidney disease (DKD) and explain differences observed in disease phenotypes, responses to interventions, and disease progression between men and women with diabetes. Therefore, omitting the consideration of sex as a biological factor may result in delayed diagnoses and suboptimal therapies. This review will summarize the effects of sexual dimorphism on putative metabolic and molecular mechanisms underlying DKD, and the potential implications of these differences on therapeutic interventions. To successfully implement precision medicine, we require a better understanding of sexual dimorphism in the pathophysiologic progression of DKD. Such insights can unveil sex-specific therapeutic targets that have the potential to maximize efficacy while minimizing adverse events.     

Relationships between inflammation,hemodynamic function and RAAS in longstanding type 1 diabetes and diabetic kidney disease

The renin angiotensin aldosterone system (RAAS) is associated with renal disease and inflammation in a diabetes setting, however, little is known about the implicated mechanisms in individuals with long standing diabetes. Accordingly, our aim was to perform an observational study to quantify urinary excretion of inflammatory biomarkers in participants with long standing type 1 diabetes (T1D) (with and without diabetic kidney disease [DKD]) and controls, at baseline and in response to RAAS activation. GFR_INULIN, ERPF_PAH, and 42 urine inflammatory biomarkers were measured in 74 participants with T1D for ≥50 years (21 with DKD and 44 without DKD [DKD resistors]) and 73 healthy controls. Additionally, inflammatory biomarkers were measured before and after an angiotensin II infusion (ANGII, 1 ng?kg^?1?min^?1). Significantly lower urinary excretion of cytokines (IL-18, IL-1RA, IL-8), chemokines (MCP1, RANTES) and growth factors (TGF-α, PDGFAA, PDGFBB, VEGF-A) was observed in participants with T1D at baseline compared to controls. Urinary IL-6 was higher in DKD than in DKD resistors in an exploratory analysis unadjusted for multiple comparisons. In T1D only, lower GFR_INULIN correlated with greater excretion of proinflammatory biomarkers (IL-18, IP-10, & RANTES), growth factors (PDGF-AA & VEGFAA), and chemokines (eotaxin & MCP-1). ANGII increased 31 of 42 inflammatory biomarkers in T1D vs controls (p < 0.05), regardless of DKD resistor status. In conclusion, lower GFR and intra-renal RAAS activation were associated with increased inflammation even after longstanding T1D. The increased urinary IL-6 in patients with DKD requires further investigation to determine whether IL-6 is a candidate protective biomarker for prognostication or targeted therapy in DKD.     

Asphyxia homicides in Denmark 1992–2016

In this retrospective study , we present the findings in 250 homicides by asphyxia in Denmark in a 25-year period, with a particular focus on the autopsy findings in strangulation. Our intention is for the results to be used in future death investigations, where difficulties in interpretation of findings in potential asphyxial deaths arise. Asphyxia homicides showed a strong bias with respect to sex, age, and homicide type. The frequent female victim was typically an adult, whereas the rarer male victim was most often a child. Female offenders most often killed their children, and male offenders most often killed their female partner. Generally, most asphyxia homicides took place in a domestic setting. Manual strangulation and ligature strangulation were the most common mechanisms of asphyxia homicides (81.6%). A lack of petechial hemorrhages, especially in the conjunctiva, was rare in homicidal strangulation, but there were exceptions, especially when there was postmortem decomposition, making it impossible to verify them. Most victims of strangulation had skin lesions in the face (including the jawline) or on the neck, with accompanying hemorrhages in muscle and connective tissue, but the findings could be subtle or compounded by decomposition. Fractures of the laryngo-hyoid complex were common in strangulation, particularly in manual strangulation (chi-sq = 4.0993, df = 1, P < 0.05) and were clearly related to the age of the victim (chi-sq = 82.193, df = 4, P < 0.001). In children and young adults dying from homicidal strangulation, a lack of fractures is to be expected, while a lack of fractures is unusual, but not entirely unexpected, for adults and aged people.

     

Exposure of chromatin and not high affinity for dsDNA determines the nephritogenic impact of anti-dsDNA antibodies in (NZB×NZW)F1 mice

Recent studies have demonstrated that the nephritogenicity of antibodies to dsDNA and nucleosomes confers to binding of glomerular membrane-associated nucleosomes, and not to cross-reacting glomerular antigens. There is no known parameter that determines antibody pathogenicity aside from specificity for dsDNA/nucleosomes, and systemic lupus erytheomatosus (SLE) patients may have high titer anti-dsDNA antibodies irrespective whether they have lupus nephritis or not. One parameter may be antibody affinity, as theoretically only high affinity antibodies may bind in vivo in a stable way. This was analyzed in (NZB × NZW)F1 mice with full-blown lupus nephritis. These mice had serum antibodies to dsDNA, and IgG autoantibodies bound in situ in glomerular membrane-associated electron dense structures as determined by immune electron microscopy (IEM). Intrinsic affinity of purified circulating and glomerular IgG anti-dsDNA antibodies was determined by surface plasmon resonance. The results demonstrate that affinity of glomerular-bound anti-dsDNA antibodies was higher than for those in circulation. However, affinity of glomerular in situ-bound antibodies from different mice varied considerably, from K_D in the range from 10^{? 8} to 10^{? 13}. These results indicate that antibody affinity is not a decisive pathogenic factor, but rather that availability of chromatin fragments may be the factor that determines whether an anti-dsDNA antibody binds in glomeruli or not.     

Swedish Universities Scales of Personality: Relation to Other Personality Instruments

ObjectiveTo investigate associations between Swedish universities Scales of Personality (SSP) and scales of the following personality instruments: Structured Clinical Interview for DSM-III-R axis II screening questionnaire (SCID-II screen), revised NEO personality inventory (NEO-PI-R), revised Chapman scales (Chapman) and the psychotic traits questionnaire (STQ). MethodsHealthy individuals (n=406) completed self-report personality questionnaires including SSP and at least one more personality inventory. Correlations were calculated between the 13 different SSP subscales as well as SSP’s three factors and factors and scales/subscales in SCID-II screen, NEO-PI-R, Chapman and STQ. The main factors of the various instruments were factor analysed. ICC were calculated. ResultsSSP Neuroticism factor correlated with SCID-II cluster C (r=0.71), NEO Neuroticism (r=0.80) and Chapman Social anhedonia (r=0.62). SSP Extraversion factor correlated with NEO Extraversion (r=0.63) and SSP Aggressiveness factor with NEO Agreeableness (r=-0.62). Strong correlations between SSP factors and scales and scales of the other instruments were sparse, although weaker correlations were common. ConclusionSSP is a useful investigation tool when measuring personality traits related to temperament-like features. SSP partly correlates well to especially three of the NEO-PI-R factors. The different personality inventories are not completely comparable to each other. Instead, they measure personality aspects in partly different ways.