Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of relaxin.

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation.

Families' experiences with patients who died after assisted suicide: a retrospective interview study in southern Switzerland.

BACKGROUND: In Switzerland, if certain conditions are met, assisted suicide is not prosecuted. International debate suggests that requests for hasten death are often altered by the provision of palliative care. Aims of the study were to explore patients' reasons for choice of assisted suicide and family perceptions of the interactions with health care professionals. PATIENTS AND METHODS: This is a qualitative study upon 11 relatives of 8 patients cared for by a palliative care team, deceased of assisted suicide. RESULTS: Pain and symptom burden were not regarded by patients as key reasons to seek assisted suicide: existential distress and fear of loss of control were the determinants. Most patients had made pre-illness decisions to use assisted suicide. A general need for perceived control and fear of dependency were reported as a common characteristic of these patients. Patients held misunderstandings about the nature and purpose of palliative care, and the interviewed indicated that patients did not regard provision of palliative care services as influential in preventing their decision. CONCLUSIONS: Assisted suicide was preferred despite provision of palliative care. Better understanding of the importance placed on perceived control and anticipated dependency is needed. Further research is needed to develop appropriate support for patients contemplating assisted suicide.

Anti-psoriatic drug anthralin activates JNK via lipid peroxidation: mononuclear cells are more sensitive than keratinocytes.

Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known, however, about differential sensitivities of targeted cell types and specific mechanisms of signaling pathway activation. We demonstrate that anthralin exerts potent effects on keratinocytes and mononuclear cells through strong induction of lipid peroxidation and JNK activation, a stress-induced signal transduction pathway. Lipid peroxidation was observed rapidly and half-maximal levels of lipid peroxidation were reached at a 10-fold lower concentration of anthralin for peripheral blood mononuclear cells vs normal keratinocytes. JNK activation was detected in peripheral blood mononuclear cells at a 40-fold lower anthralin dose compared with keratinocytes. For both cell types, selected inhibitors of lipid peroxidation prevented JNK activation. This study demonstrates that mononuclear leukocytes are markedly more sensitive than keratinocytes to anthralin-induced lipid peroxidation and JNK activation. We identify anthralin as a novel and potent inducer of JNK activation and demonstrate that this process is mediated, at least in part, by lipid peroxidation which is among the earliest and most proximate, membrane-related responses to anthralin yet described.

H2O2 is an important mediator of UVB-induced EGF-receptor phosphorylation in cultured keratinocytes.

Exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) radiation induces phosphorylation of the epidermal growth factor receptor (EGFR). We demonstrate that H2O2 generated by UVB mediates EGFR phosphorylation. Using dihydrorhodamine 123 as a specific fluorescent dye probe, we show that UVB irradiation (50-800 J per m2) of keratinocytes leads within minutes to concentration-dependent intracellular production of H2O2. A corresponding concentration-dependent increase in the release of extracellular H2O2 was measured by using Amplex, a derivative of dihydrophenoxazine. The levels of intracellular H2O2 that are induced by UVB irradiation and that stimulate EGFR phosphorylation correlate strongly with the response induced by exogenously added H2O2. UVB or H2O2 demonstrated concentration- and time-dependent stimulation of EGFR phosphorylation that was initially observed within 1-5 min and exhibited a proportionate delay for UVB-induced production of H2O2. EGFR phosphorylation induced by UVB or H2O2 declined significantly toward baseline levels by 4 h and could be restimulated after H2O2 but not after UVB exposure. Phosphorylation of EGFR was inhibited by the structurally unrelated antioxidants butylated hydroxyanisole, N-acetyl-L-cysteine, and pyrrolidine dithiocarbamate, or by the H2O2-degrading enzyme catalase. These data indicate that generation of H2O2 by UVB radiation of human keratinocytes participates in the rapid, ligand-independent phosphorylation of EGFR and implicate H2O2 as a biologic mediator in EGFR activation and regulation of the downstream signaling cascade. UVB-induced H2O2 has the potential to initiate or modulate early EGFR-mediated signaling events that could play an important role in the cellular response to oxidative stress.

Vitamin E analog modulates UVB-induced signaling pathway activation and enhances cell survival.

We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H(2)O(2) generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure-increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.

Attachment and culture. Security in the United States and Japan.

Attachment theorists maintain that cultural differences are relatively minor, and they focus on universals. Here the authors highlight evidence of cultural variations and note ways in which attachment theory is laden with Western values and meaning. Comparisons of the United States and Japan highlight the cultural relativity of 3 core hypotheses of attachment theory: that caregiver sensitivity leads to secure attachment, that secure attachment leads to later social competence, and that children who are securely attached use the primary caregiver as a secure base for exploring the external world. Attachment theorists use measures of sensitivity, competence, and secure base that are biased toward Western ways of thinking: The measures emphasize the child's autonomy, individuation, and exploration. In Japan, sensitivity, competence, and secure base are viewed very differently, calling into question the universality of fundamental tenets of attachment theory. The authors call for an indigenous approach to the psychology of attachment.

Immigrant-Chinese and Euro-American parents' physical closeness with young children: themes of family relatedness.

This study examined cultural differences in the expression and meaning of physical closeness. Findings indicated that immigrant-Chinese parents, as compared with Euro-American parents, sleep in closer proximity with their children; more often view independence as children growing with the family; are more likely to emphasize the family unit; and place greater importance on inhibition of expression, adherence to correct values, and hierarchy of relations. Euro-Americans, by contrast, are more accepting of nudity; place more emphasis on psychological benefits of physical closeness and on the child's expression of wants and feelings; more often view independence as celebrating the child's distinctiveness; and place greater importance on intimacy, pleasure, and spousal exclusiveness. The authors suggest that closeness is characterized by an overarching theme of harmony in immigrant-Chinese families and by an overarching theme of romance in Euro-American families.

[When mothers get cancer: psychological effects on children and needs for prevention]. / Wenn Mütter an Krebs erkranken: Seelische Auswirkungen auf Kinder und präventiver Handlungsbedarf.

Children having a parent who suffers from a serious somatic disease are at increased risk for mental health problems. Mainly due to the high prevalence of breast cancer diseases children of mothers with cancer are the most studied subgroup of this risk population. In this review the sequelae of a cancer diagnosis on a patient's female identity with respect to the maternal role are illuminated. Then, children's fears, conflicts and stressors that may be typically associated with maternal cancer are differentiated by age groups from a developmental perspective. In several controlled studies children of cancer patients had increased scores in symptom scales. If there are psychic symptoms, these are likely to manifest themselves as anxiety, depression, psychosomatic complaints or social withdrawal. Adolescent daughters of mothers having cancer had an especially increased risk to develop symptoms. The possible impact of a maternal cancer disease on a developing girl's puberty is discussed. In addition, a case vignette of a nine-year-old daughter of a breast cancer patient illustrates psychotherapeutic procedures in a brief intervention, the goal of which was to facilitate talking about fears between mother and daughter. Perspectives of family oriented mental health prevention in the context of gynaecological care are discussed.

Comparison of MRI, CT and angiography in cerebral arteriovenous malformations.

Computed tomography (CT), magnetic resonance imaging (MRI) and cerebral angiography were performed in 30 patients with cerebral arteriovenous malformations (AVMs). Clinical data and radiographic findings are presented. The diagnostic values of CT and MRI are compared. 25 of 30 AVMs were seen on CT-scans, 27 on MR-images, 26 by angiography. Typical CT-findings were irregularly hyperdense areas with spotlike contrast enhancement. 4 out of 5 AVMs not depicted by CT were diagnosed for tumor, in one case the malformation was hidden by a hematoma. MRI mostly showed the AVM as round or oval lesions with spongelike structure of low signal intensity in T1-weighted sequences or as single enlarged vessels. The 26 AVM revealed by angiography presented typically enlarged vessels; in 2 cases angiography was without any pathological findings, 2 cases showed signs of a space occupying lesion. The results confirm that MRI is superior to CT in detecting and recognizing AVM. Its strength lies in the possibility to detect abnormal vessels even in presence of fresh or older hematoma, and in the precise information on size and location of the AVM. In our series, MRI and CT-scans together showed 28 of 30 AVMs, the remaining 2 cases were not seen with angiography either but only proven histologically. Although today MR-angiography is able to provide three dimensional images of blood vessels, it cannot yet replace angiography in the exact study of the vessels which is required for surgical planning.

The development of close relationships in Japan and the United States: paths of symbiotic harmony and generative tension.

Findings from research on parent-child and adult mate relationships suggest that there are different paths of development in Japan and the United States. In Japan, the path is one of symbiotic harmony, as seen in the emphasis on union in infancy, others' expectations in childhood, the stability of relationships with parents and peers in adolescence, and assurance about the mate relationship in adulthood. In the United States, the path is one of generative tension, as seen in the tug between separation and reunion in infancy, the emphasis on personal preferences in childhood, the transfer of closeness from parents to peers in adolescence, and the emphasis on trust-a faith and hope in new relationships-in adulthood. The notion that there are different paths of development challenges Western investigators' presumption that certain processes-separation-individuation, use of the relational partner as a secure base for exploration, and conflict between partners-are central in all relationships. The notion of different paths also challenges the assumption of many cross-cultural investigators that relationships in the United States are less valued or weaker than those in Japan; this article highlights cultural differences in the meaning and dynamics, as opposed to the importance and strength, of relationships. The model suggests a need to investigate the processes underlying, and the adaptive consequences of, these two alternative paths.

Trade-offs in the study of culture and development: theories, methods, and values.

The commentators are unanimous in their support for our general orientation to culture and development, and for the pathways we have identified, and they suggest ways to enrich our approach to theory, methods, and values. We view their main suggestions as relating to trade-offs: between theories that highlight generalizations or exceptions; between methods that rely on one-, two-, or multiculture studies; and between values involving individuation or accommodation. Here, we describe ways to find an optimal balance in each instance.

Immunocytochemical characterization of malignant mesothelioma and carcinoma metastatic to the pleura: IOB3--a new tumor marker.

We have tried to find a reliable panel of markers that would allow distinction between mesotheliomas and carcinomas metastatic to the pleura. In a prospective study, we evaluated 54 pleural effusions: In 27 of the patients, a diagnosis of histologically proven metastatic carcinoma was subsequently established, 7 patients had biopsy-proven malignant mesotheliomas and 20 had benign, reactive effusions whose benign etiologies were established by more than 2 years clinical follow-up. The MAb (monoclonal antibody) IOB3 proved to be diagnostic for carcinomas in all 27 cases (100%), whereas CEA (carcinoembryonic antigen) expression was found in only 22 out of 27 (81%). None of the malignant mesotheliomas, nor benign reactive mesothelial cells reacted with these two markers. All carcinomas, as well as one malignant mesothelioma, reacted with the MAb HEA125. Antibodies against 12 single cytokeratins, vimentin, and EMA (epithelial membrane antigen) were not helpful in the differentiation between malignant mesotheliomas and malignant carcinomatous pleural effusions. We conclude that adding the antibody IOB3 to the CEA assay should allow a reliable differentiation between these two entities.