MEFV and NLRP3 Inflammasome Expression Is Attributed to Immature Macrophages and Correlates with Serum Inflammatory Proteins in Crohn´s Disease Patients

Inflammation - Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet...     

Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

A 5-year follow-up study of adolescents who sought treatment for substance misuse in Sweden

Previous studies have shown that substance misuse in adolescence is associated with increased risks of hospitalizations for mental and physical disorders, convictions for crimes, poverty, and premature death from age 21 to 50. The present study examined 180 adolescent boys and girls who sought treatment for substance misuse in Sweden. The adolescents and their parents were assessed independently when the adolescents first contacted the clinic to diagnose mental disorders and collect information on maltreatment and antisocial behavior. Official criminal files were obtained. Five years later, 147 of the ex-clients again completed similar assessments. The objectives were (1) to document the prevalence of alcohol use disorders (AUD) and drug use disorders (DUD) in early adulthood; and (2) to identify family and individual factors measured in adolescence that predicted these disorders, after taking account of AUD and DUD in adolescence and treatment. Results showed that AUD, DUD, and AUD + DUD present in mid-adolescence were in most cases also present in early adulthood. Prediction models detected no positive effect of treatment in limiting persistence of these disorders. Thus, treatment-as-usual provided by the only psychiatric service for adolescents with substance misuse in a large urban center in Sweden failed to prevent the persistence of substance misuse. Despite extensive clinical assessments of the ex-clients and their parents, few factors assessed in mid-adolescence were associated with substance misuse disorders 5 years later. It may be that family and individual factors in early life promote the mental disorders that precede adolescent substance misuse.     

Does Bone Resorption Stimulate Periosteal Expansion? A Cross‐Sectional Analysis of β‐C‐telopeptides of Type I Collagen (CTX), Genetic Markers of the RANKL Pathway,and Periosteal Circumference as Measured by pQCT

We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β‐C‐telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMD_C). CTX and mid‐tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMD_C (β = –0.46 [–0.52,–0.40]) and cortical thickness [β = –0.11 (–0.18, –0.03)]. CTX was positively related to bone strength as reflected by the strength‐strain index (SSI) (β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single‐nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF‐κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p < 0.05 cut‐off) (n = 2379). Subsequently, we performed a meta‐analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938), and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p < 0.05 cut‐off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.     

Pattern of microbial translocation in patients living with HIV-1 from Vietnam,Ethiopia and Sweden

Introduction

The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.

Methods

Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay.

Results

All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.

Conclusions

Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.     

Serological reactivity to <Emphasis Type="Italic">Anaplasma phagocytophilum</Emphasis> in neoehrlichiosis patients

The tick-borne bacterium Candidatus (Ca.) Neoehrlichia (N.) mikurensis is a cause of “fever of unknown origin” because this strict intracellular pathogen escapes detection by routine blood cultures. Case reports suggest that neoehrlichiosis patients may display serological reactivity to Anaplasma (A.) phagocytophilum. Since Anaplasma serology is part of the diagnostic work-up of undetermined fever in European tick-exposed patients, we wanted to investigate (1) the prevalence of A. phagocytophilum seropositivity among neoehrlichiosis patients, (2) the frequency of misdiagnosed neoehrlichiosis patients among A. phagocytophilum seropositive patients, and (3) the frequency of A. phagocytophilum and Ca. N. mikurensis co-infections. Neoehrlichiosis patients (n?=?18) were analyzed for A. phagocytophilum IgM and IgG serum antibodies by indirect immunofluorescence assay. Serum samples from suspected anaplasmosis patients (n?=?101) were analyzed for bacterial DNA contents by singleplex PCR specific for A. phagocytophilum and Ca. N. mikurensis, respectively. One fifth of the neoehrlichiosis patients (4/18) were seropositive for IgM and/or IgG to A. phagocytophilum at the time of diagnosis. Among the patients with suspected anaplasmosis, 2% (2/101) were positive for Ca. N. mikurensis by PCR whereas none (0/101) had detectable A. phagocytophilum DNA in the serum. To conclude, patients with suspected anaplasmosis may in fact have neoehrlichiosis. We found no evidence of A. phagocytophilum and Ca. N. mikurensis co-infections in humans with suspected anaplasmosis or confirmed neoehrlichiosis.