Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: A phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy

Background  

In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3–4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established.     

Opioids bind to the amino acids 84 to 118 of UDP-glucuronosyltransferase UGT2B7

The UDP-glucuronosyltransferase UGT2B7 is an important human UGT isoform that catalyzes the conjugation of many endogenous and exogenous compounds, among them opioids, resulting in the formation of D-glucuronides. The binding site of the aglycone is located in the N-terminal half of the protein. Using NMR analysis, we demonstrate that the opioid binding site in UGT2B7 is within the 84 to 118 N-terminal amino acids. Three maltose binding protein-UGT2B7 fusion proteins, 2B7F3 and 2B7F4 incorporating the amino acids 24 to 118 and 24 to 96 of UGT2B7, respectively, and 2B7F5 incorporating amino acids 84 to 118 of UGT2B7 were expressed in Escherichia coli and purified by affinity chromatography. NMR analysis showed that morphine was bound to the fusion protein 2B7F3 with a K(D) value similar to the K(D) values obtained for the previously produced fusion proteins, which included amino acids 24 to 180. Morphine did not bind to 2B7F4, but it did bind to 2B7F5. Both NMR 1-D spectra and NOESY experiments indicated that the 2B7F5 protein was mediating magnetization transfer within the morphine. These results allowed us to predict and model a binding site within the amino acids 96 to 101 of UGT2B7. A mutant fusion protein 2B7F3 with the substitution D99A was produced, and the NMR spectroscopy analysis of the protein supported the model. A marked reduction of morphine binding was observed when the charged aspartate was substituted with alanine.     

Protein kinase C and phosphoinositol-3-kinase mediate differentiation or proliferation of slice-derived rat microglia

Granulocyte-macrophage colony-stimulating factor plays an important role in the activation of microglia in the central nervous system. We have recently shown (see text) that granulocyte-macrophage colony-stimulating factor activates the proliferation and subsequent migration of microglia from organotypic cortex brain slices. The aim of this study was to investigate whether this activation is modulated by different putative intracellular pathway inhibitors. Our data show that the protein kinase C inhibitor staurosporine enhanced the proliferation as well as the differentiation of slice-derived microglia, while the phosphoinositol-3-kinase inhibitor LY294002 markedly suppressed the proliferative activity. In conclusion, proliferation, migration, as well as differentiation of rat microglia are highly regulated by intracellular signaling cascades.     

Linking actions and their perceivable consequences in the human brain

Voluntary action is goal-directed and therefore depends on the ability to learn associations between movements and their perceivable consequences. The neural substrate of this ability was investigated with H2(15O) positron emission tomography (PET). Healthy adults first learned that self-initiated keypresses were consistently followed by certain tones (i.e., action effects). During PET imaging, participants listened to varied ratios of action-effect tones and neutral tones without performing any movement. The caudal supplementary motor area and the right hippocampus increased their activity with the frequency of action-effect tones, suggesting that both cortical areas play a role in linking the consequences of an action and the action itself. This integration process represents a highly flexible mechanism that helps to promote the learning, automatization, and control of voluntary     

Time for a "vision zero" concerning premature death from ischaemic heart disease?

OBJECTIVE: To study the trend in premature mortality (before 75 years of age) from ischaemic heart disease (IHD) in a Swedish primary health care district compared to communities of similar demographic situation and all Sweden. DESIGN: Mortality from IHD in men and women was compared between the community of Habo and other Swedish communities of similar size and all Sweden for the period 1984-96. SETTING: The community of Habo in Sweden with about 9600 inhabitants. INTERVENTION: Intensified efforts by the local primary health care organisation, in co-operation with the community, in respect of primary and secondary cardiovascular prevention since the beginning of the 1980s. RESULTS: Mortality from IHD has decreased significantly both in Habo and in Sweden during these years. The decrease has been more prominent in Habo than in Sweden as a whole and other Swedish communities of similar demographic situation. CONCLUSION: With increased and purposeful efforts in primary and secondary prevention, in co-operation between the community and primary health care, it is possible to substantially decrease mortality from IHD in the community.     

Epithelial–myoepithelial carcinoma of the submandibular gland with symptomatic lung metastases treated with chemotherapy

This report concerns a patient with symptomatic lung metastases from an epithelial–myoepithelial carcinoma of the submandibular gland. Although the efficacy of chemotherapy is unknown in this disease, our patient was treated with cisplatin combined with 5-fluorouracil and later with paclitaxel and cyclophosphamide. Chemotherapy allowed disease stabilization and relief of the pulmonary symptoms. This is the first report on the use of chemotherapy in this very rare salivary gland carcinoma.     

Psychophysiological correlates of peritraumatic dissociative responses in survivors of life-threatening cardiac events

The psychophysiological startle response pattern associated with peritraumatic dissociation (DISS) was studied in 103 survivors of a life-threatening cardiac event (mean age 61.0 years, SD 13.95). Mean time period since the cardiac event was 37 (79 IQD) months. All patients underwent a psychodiagnostic evaluation (including the Peritraumatic Dissociative Experiences Questionnaire) and a psychophysiological startle experience which comprised the delivery of 15 acoustic startle trials. Magnitude and habituation to trials were measured by means of electromyogram (EMG) and skin conductance responses (SCR). Thirty-two (31%) subjects were indexed as patients with a clinically significant level of DISS symptoms. High-level DISS was associated with a higher magnitude of SCR (ANOVA for repeated measures p = 0.017) and EMG (p = 0.055) and an impaired habituation (SCR slope p = 0.064; EMG slope p = 0.005) in comparison to subjects with no or low DISS. In a subgroup analysis, high-level DISS patients with severe post-traumatic stress disorder (PTSD; n = 11) in comparison to high-level DISS patients without subsequent PTSD (n = 19) exhibited higher EMG amplitudes during all trials (repeated measures analysis of variance F = 5.511, p = 0.026). The results demonstrate exaggerated startle responses in SCR and EMG measures - an abnormal defensive response to high-intensity stimuli which indicates a steady state of increased arousal. DISS patients without PTSD exhibited balanced autonomic responses to the startle trials. DISS may, therefore, unfold malignant properties only in combination with persistent physiological hyperarousability.     

GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain

The delta subunit is a novel subunit of the pentameric gamma-aminobutyric acid (GABA)(A) receptor that conveys special pharmacological and functional properties to recombinant receptors and may be particularly important in mediating tonic inhibition. Mice that lack the delta subunit have been produced by gene-targeting technology, and these mice were studied with immunohistochemical and immunoblot methods to determine whether changes in GABA(A) receptors were limited to deletion of the delta subunit or whether alterations in other GABA(A) receptor subunits were also present in the delta subunit knockout (delta-/-) mice. Immunohistochemical studies of wild-type mice confirmed the restricted distribution of the delta subunit in the forebrain. Regions with moderate to high levels of delta subunit expression included thalamic relay nuclei, caudate-putamen, molecular layer of the dentate gyrus, and outer layers of the cerebral cortex. Virtually no delta subunit labeling was evident in adjacent regions, such as the thalamic reticular nucleus, hypothalamus, and globus pallidus. Comparisons of the expression of other subunits in delta-/- and wild-type mice demonstrated substantial changes in the alpha4 and gamma2 subunits of the GABA(A) receptor in the delta-/- mice. gamma2 Subunit expression was increased, whereas alpha4 subunit expression was decreased in delta-/- mice. Importantly, alterations of both the alpha4 and the gamma2 subunits were confined primarily to brain regions that normally expressed the delta subunit. This suggests that the additional subunit changes are directly linked to loss of the delta subunit and could reflect local changes in subunit composition and function of GABA(A) receptors in delta-/- mice.