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.     

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...     

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.     

Drying properties of bloodstains on common indoor surfaces

When blood reaches an extracorporeal surface, a drying process is initiated. Properties of this drying process may be crucial for the correct assessment of case-specific time lapses, however, there is a lack of systematic studies concerning the drying times of blood. We present a study on drying properties of small blood droplets with a standardized size of 25?μl (resembling droplets originating from pointed and sharp objects, e.g. the tip of a knife) under different environmental conditions to elucidate the effect of different ambient temperatures, indoor surfaces and anticoagulant treatment. As a rule of thumb, wiping a typical small blood droplet will not lead to a macroscopically visible smear after a time period of approximately 60?min (time(min)?=?45?min; time(max)?=?75?min) at an average room temperature of 20?°C. Alteration of the ambient temperature has a remarkable effect, as the time needed for the drying process leading to wipe resistance of the droplets decreases to 30?min (time(min)) at an ambient temperature of 24?°C, and is prolonged up to >120?min (time(max)) at an ambient temperature of 15?°C. As for the surface materials in our study, significant differences in drying periods were only found between wood and linoleum (80th percentile 45 vs. 75?min). Treatment with anticoagulants did not influence extracorporeal drying times. In synopsis, the present study shows that ambient temperature is a major determinant of the drying process of blood droplets and should always be documented accurately and continuously on a crime scene. In certain situations, an estimation of the time elapsed since bloodstain origination may be of importance to answer questions related to the time course of actions. However, further systematic studies are needed to clarify the effect of other properties such as droplet size, humidity, or evaporation.     

Severe QTc prolongation under mild hypothermia treatment and incidence of arrhythmias after cardiac arrest--a prospective study in 34 survivors with continuous Holter ECG

Background

Mild hypothermia treatment (32-34 °C) in survivors after cardiac arrest (CA) is clearly recommended by the current guidelines. The effects of cooling procedure towards QT interval have not been evaluated so far outside of case series. In a prospective study 34 consecutive survivors after cardiac arrest were continuously monitored with Holter ECG over the first 48 h.

Patients and methods

A total of 34 patients were analysed and received mild therapeutic hypothermia treatment (MTH) according to the current guidelines and irrespective of the initial rhythm. At admission to hospital and in the field in case of OHCA, a 12-lead ECG was performed in all patients.

Results

During cooling the incidence of ventricular tachycardia was low (8.8%) and in none of the patients Torsade de pointes occurred. The QTc interval was within normal range at first patient contact with EMS in the field (440.00 ms; IQR 424.25-476.75; n = 17) but during hypothermia treatment the QTc interval was significantly prolonged at 33 °C after 24 h of cooling (564.47 ms; IQR 512.41-590.00; p = 0.0001; n = 34) and decreased after end of hypothermia to baseline levels (476.74 ms; 448.71-494.97; p = 0.15).

Conclusion

The QTc interval was found to be significantly prolonged during MTH treatment, and some severe prolongations >670 ms were observed, without a higher incidence of life-threatening arrhythmias, especially no Torsade des pointes were detected. However, routine and frequent ECG recording with respect to the QTc interval should become part of any hypothermia standard operation protocol and should be recommended by official guidelines.