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.     

Influence of rate of administration of raclopride on akathisia and prolactin response

The D₂-dopamine receptor antagonist raclopride was administered to eight healthy male subjects, who had previously experienced akathisia following antipsychotic drugs. The influence of administration rate on onset, severity and duration of akathisia and on prolactin response was studied. Raclopride 3,5 or 9 mg or placebo (P) was administered as single IV infusions during 10 min (R10 min/3 mg), 1 h (R1h/5 mg) or 4 h (R4h/9 mg) according to a randomized double-blind design. Despite a 24-fold difference in administration rate a similar peak raclopride concentration of about 350 nmol/l was obtained after all three infusions. Three of the eight subjects experienced akathisia following R10 min/3 mg and R1h/5 mg, respectively. After R4h/9 mg seven subjects experienced akathisia of longer duration but not more severe than after the short infusions. The incidence and duration of akathisia seem to be mainly related to the plasma raclopride concentrations over time, whereas the rate of administration might be more important for the severity. A maximal prolactin response was induced which was not markedly affected by the rate of administration.     

Electron Microscopy and Computed Microtomography Studies of in Vivo Implanted Mini-Tl Dosimeters

The need for direct methods of measuring the absorbed dose in vivo increases for systemic radiation therapy, and in more sophisticated methodologies developed for radioimmunotherapy. One method suggested is the use of mini-thermoluminescent dosimeters (TLD). Recent reports indicate a marked loss of signal when the dosimeters are used in vivo. We investigated the exterior surface of the dosimeters with scanning electron microscopy and the interior dosimeter volume with computed microtomography. The results show that the dosimeters initially have crystals uniformly embedded in the teflon matrix, with some of them directly exposed to the environment. After incubation in gel, holes appear in the dosimeter matrix where the crystals should have been. The computed microtomographic images show that crystals remain in the interior of the matrix, producing the remaining signal. We conclude that these dosimeters should be very carefully handled, and for practical use of mini-TLDs in vivo the dosimeters should be calibrated in equivalent milieus. An alternative solution to the problem of decreased TL efficiency, would be to coat the dosimeters with a thin layer, of Teflon, or other suitable material.     

Logics and Logistics of Community Intervention Against Osteoporosis: An Evidence Basis

Under designations like small areas action research and intervention, directed ‘ground-up’ health promotion and prevention in the population form an important part of the ongoing medical systems development. There is recent evidence of the success of community intervention against cardiovascular disease. In osteoporosis, however, there is still a lack of conclusive data on both the logics and logistics of such an approach. Since 1988, a county health policy program has been formulated and implemented in Östergötland, Sweden, following the principles and guidelines of the WHO HFA 2000 declaration. Vadstena (n ? 7,600) was chosen for a local and generalizable osteoporosis prevention project mediated by the primary care organization by means of health promotion and education in the community. In the present report we emphasize that community intervention is an important new advancement of the medical systems, where the basic research questions include operational and management aspects as equally vital and measurable requisites and results as other performance and outcome variables. We found that a community intervention trial against osteoporosis is both motivated and feasible and in this report wish to provide evidence on these crucial issues of logics and logistics.     

Rate and predictability of pulp revascularization in therapeutically reimplanted permanent incisors

Abstract The aim of the present investigation was to study the frequency of pulp revascularization in therapeutically reimplanted incisors as well; is its relationship with the following factors: width of apical foramen, duration of extra-alveolar lime, storage conditions and postoperative administration of antibiotics. Out of 72 immature teeth (width of apical foramen 1.1–5.0 mm) the pulp was revascularized in 13 (18%), while in 88 mature teeth (width of apical foramen 1.0 mm or less) no revascularization occurred. Among parameters tested statistically in immature teeth, a significantly increased frequency of revascularization (p < 0.05) was only found in teeth reimplanted within 45 minutes after avulsion, when compared with teeth reimplanted after a longer extra-alveolar time, and in mandibular incisors when compared with maxillary incisors (p < 0.01). All teeth in which revascularization did not occur exhibited a periapical radiolucency and/or external inflammatory root resorption.     

Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus.

Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens.     

Children with deficits in attention,motor control and perception (DAMP) almost grown up: The contribution of various background factors to outcome at age 16 years

Fifty-six children with and forty-five children without deficits in attention, motor control and perception (DAMP) had been recruited from the general population at age 7 years. They were followed up neuropsychiatrically at age 16 years after intermediate term follow up at age 10 and 13 years. Cases were subdivided into those with good and not good outcome on the basis of absence or presence of psychiatric and personality disorders, multiple traumatic accidents and speech and language problems at age 16 years. The presence of DAMP in itself was the strongest predictor of poor outcome. High scores for minor neurological dysfunction, low performance IQ, autistic features at age 7 years and poor reading skills at age 10 and/or 13 years were important background factors in cases with poor outcome. In the small subgroup with poor outcome among those without DAMP at age 7 years, major life events was the most important background factor.

---

Zusammenfassung 56 Kinder mit und 45 Kinder ohne Störungen der Aufmerksamkeit, der motorischen Kontrolle und der Wahrnehmung (DAMP) waren aus einer Gesamtpopulation 7jÄhriger rekrutiert worden. Sie wurden neuropsychiatrisch im Alter von 16 jahren nachuntersucht, nachdem zwischenzeitliche Untersuchungen im Alter von 10 und 13 Jahren erfolgt waren. Die Probanden wurden in solche mit gutem und nicht gutem Ausgang unterteilt, in AbhÄngigkeit vom Vorliegen psychiatrischer AuffÄlligkeiten, Persönlichkeitsstörungen, multiplen Traumata und Sprech- und Sprachproblemen im Alter von 16 Jahren. Das Vorhandensein von DAMP war der stÄrkste PrÄdiktor für einen schlechten Ausgang. Hohe Werte für leichte neurologische AuffÄlligkeiten, ein niedriger Handlungs-IQ, autistische Züge im Alter von 7 Jahren und schlechte LesefÄhigkeiten im Alter von 10 und/oder 13 Jahren waren wichtige Hintergrundfaktoren bei den Probanden mit einem schlechten Ausgang. In der kleinen Untergruppe mit einem schlechten Ausgang bei den Kindern, die im Alter von 7 Jahren kein DAMP ausgewiesen hatten, bildeten schwerwiegende Lebensereignisse den wichtigsten Hintergrundfaktor.

---

Résumé Cinquante-six enfants atteints et quarante-cinq enfants non atteints de déficits de l'attention, du contrÔle moteur et de la perception (DAMP), ont été recrutés en population générale à l'âge de 7 ans. Ils ont été évalués sur la plan neuropsychiatrique à l'âge de 16 ans, après des évaluations intermédiaires à l'âge de 10 et 13 ans. Les cas ont été subdivisés entre bons et mauvais devenir sur la base de la présence ou de l'absence de troubles de la personnalité, l'importance du nombre d'accidents traumatiques, les difficultés d'élocution et de langage à 16 ans. La présence de DAMP était en soi, le facteur prédictif le plus important de mauvais devenir. Des scores élevés à des dysfonctionnements neurologiques mineurs, un QI bas, des traits autistiques à l'âge de 7 ans, et de mauvaises capacités en lecture à l'âge de 10 ou 13 ans ont été des facteurs importants dans les cas de mauvais devenir. Dans le petit sous-groupe à mauvais devenir caractérisé par une absence de DAMP à l'âge de 7 ans, des événements de vie marquants ont semblé Être des antécédents importants.

     

Thrombin activatable fibrinolysis inhibitor and hemostatic changes in patients with type I diabetes mellitus with and without microvascular complications.

We investigated thrombin activatable fibrinolysis inhibitor (TAFI) and its influence on fibrinolysis by measuring pro-TAFI activity and total TAFI antigen in 38 patients with type I diabetes mellitus (18 with and 20 without microvascular complications), as well as in 20 healthy controls. The pro-TAFI levels in the two groups of patients did not differ from those in the control group. Total TAFI antigen [i.e. pro-TAFI, TAFI and inactive carboxypeptidase U (TAFIi)] tended to decrease in both the patient groups (59.7 +/- 7.2 and 73.4 +/- 8.9% with and without microvascular complications, respectively) compared with controls (91.9 +/- 12.2%) (P = 0.12). We also assessed the overall hemostatic potential (OHP) in plasma, the clot lysis time and the overall fibrinolytic potential. The OHP was significantly higher in patients with complications compared with controls (8.9 +/- 0.9 versus 6.7 +/- 0.4; P < 0.05) and also higher in the diabetics without complications (7.8 +/- 0.6), although the latter difference did not reach statistical significance. Levels of clot lysis time and overall fibrinolytic potential were similar in the two groups of patients and the controls. The increased OHP in plasma from diabetic patients with microvascular complications indicates an imbalance of the hemostatic system towards a prothrombotic state. No signs of impaired fibrinolysis were observed in patients with diabetes. Using the OHP method for estimation of overall hemostasis, it seems that TAFI does not influence either fibrinolysis or the increased thrombotic potential observed in patients with type I diabetes mellitus.     

The influence of cytochrome P-450 induction on the disposition of carcinogenic benzo[a]pyrene 7, 8-dihydrodiol 9, 10-epoxide in isolated cells

The disposition of the carcinogenic (+)-7ß, 8-dihydroxy-9,10-epoxy-7, 8, 9, 10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE]has been studied in isolated hepatocytes obtained from 3-methylcholanthrene-pretreatedrats. In these cells different routes are acting in concertand contribute to diol-epoxide elimination. Conjugation of (+)-anti-BPDEwith glutathione (GSH) and cytochrome P-450c-mediated metabolismof the diol-epoxide to 1- and 3-hydroxy-anti-BPDE (triol-epoxides)appears to be equally important. The reactive triol-epoxidesundergo a number of secondary reactions, including covalentbinding to cellular constituents, e.g. protein and GSH, andhydrolysis to pentahydroxyderivatives. The effective intracellularlifetime of (+)-anti-BPDE is 1 min and comparable to that previouslyobserved in hepatocytes obtained from uninduced animals.     

Currently used nucleic acid amplification tests for the detection of viruses and atypicals in acute respiratory infections

For the detection of respiratory viruses conventional culture techniques are still considered as the gold standard. However, results are mostly available too late to have an impact on patient management. The latest developments include appropriate DNA- and RNA-based amplification techniques (both NASBA and PCR) for the detection of an extended number of agents responsible for LRTI. Real time amplification, the latest technical progress, produces, within a considerable shorter time, results with a lower risk of false positives. As results can be obtained within the same day, patient management with appropriate therapy or reduction of unnecessary antibiotic therapy in LRTI will be possible. A number of technical aspects of these amplification assays, and their advantages are discussed.The availability and use of these new diagnostic tools in virology has contributed to a better understanding of the role of respiratory viruses in LRTI. The increasing importance of the viral agents, Mycoplasma pneumoniae and Chlamydophila pneumoniae in ARI is illustrated. A great proportion of ARI are caused by viruses, but their relative importance depends on the spectrum of agents covered by the diagnostic techniques and on the populations studied, the geographical location and the season. The discovery of new viruses is ongoing; examples are the hMPV and the increasing number of coronaviruses. Indications for the use of these rapid techniques in different clinical situations are discussed. Depending on the possibilities, the laboratory could optimize its diagnostic strategy by applying a combination of immunofluorescence for the detection of RSV an IFL, and a combination of real-time amplification tests for other respiratory viruses and the atypical agents. When implementing a strategy, a compromise between sensitivity, clinical utility, turn around time and cost will have to be found.