Rationale: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear. Objective: To study the effect of CF ablation on cardiac remodeling. Methods and Results: We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome–transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy. Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

Introduction-Laser lithotripsy of bile duct stones has become a widely accepted endoscopic treatment modality for giant, impacted, or very hard stones. The procedure is usually carried out under direct endoscopic control in view of the potential risk of bile duct injuries in "blind" laser application. Aims-To investigate the use of a rhodamine 6G laser lithotriptor with an integrated optical stone tissue detection system (oSTDS). Methods-From 1 September 1991 to 7March 1997, 60 patients with giant or impacted common bile duct stones refractory to endoscopic papillotomy stone extraction, and mechanical lithotripsy were treated via the endoscopic retrograde route using a rhodamine 6G dye laser (595 nm, 2.5 µs, 80-150 mJ pp, Lithognost Telemit/Baasel Corp., Germany) with integrated oSTDS. In case of tissue contact oSTDS cuts oV the laser pulse after 190 ns (transmission of 5-8% of the total pulse energy). 47 patients (78.3%) were subjected to x ray targeting (oSTDS) alone, five (8.3%) to choledochoscope targeting alone, and eight (13.3%) to both techniques. Results-At the end of treatment 52 (87%) patients were completely stone-free. The only major complications included transient haemobilia, cholangitis, and pancreatitis in five patients. All five were successfully treated by conservative methods. Conclusions-Laser lithotripsy using the described rhodamine 6G dye laser with oSTDS seems to be safe and eVective and allows "blind" fragmentation of diYcult common bile duct stones under radiological control only. (Gut 1998;43:823-829)

Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery.

Interoception describes the ability to perceive internal bodily signals. Previous research found a relationship between interoceptive accuracy (IAcc) and cardiovascular outcomes during or after acute stress. So far, the association between IAcc and long‐term stress has not been investigated, although this would be important to identify a starting point to prevent long‐term stress. To address this idea in the current study, we examined the relationship between IAcc and long‐term stress, which was assessed with different questionnaires and biological markers, including cortisol and dehydroepiandrosterone (DHEA). Furthermore, we investigated self‐regulation as a mechanism linking IAcc to long‐term stress. The sample consisted of 98 participants. To measure IAcc, participants completed the heartbeat perception task. Perceived long‐term stress and self‐regulation were assessed via an online questionnaire. Moreover, hair samples were taken from 65 participants to determine long‐term stress with cortisol and DHEA as well as the ratio of both. Results showed that IAcc was positively related to DHEA and weakly negatively related to the other indicators of long‐term stress, except for the nonsignificant relationships to the indicators cortisol and stress experiences due to negative events. Furthermore, these relationships were mediated by participants' enhanced self‐regulation. Thus, our results suggest that enhanced self‐regulation could be a mechanism explaining why IAcc is associated with long‐term stress.

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As pheochromocytoma sometimes is accompanied by medullary thyroid carcinoma (in the sense of multiple endocrine adonomatosis type II = Sipple-Syndrome), serum calcitonin (CT) was measured by radioimmunoassay in 4 patients with pheochromocytoma. Before extirpation of the adreno-medullary tumor, serum CT was distinctly increased to 3 and 30 ng/ml in 2 of 4 patients, respectively. After removal of the tumor, serum CT was normal in the patients and pentagastrin stimulation produced no exaggerated CT response. In hydrochloric acid extracts from the two corresponding pheochromocytoma tissues, immunoreactive-Calcitonin (IR-CT) was detected, the concentrations amounting 1 and 4 ng/mg wet tissue. These findings suggest that hypercalcitonism in patients with pheochromocytoma cannot always be ascribed to the thyroid, i.e. increased calcitonin levels do not necessarily indicate a medullary carcinoma of this organ.

Short-term fluctuations in plasma cortisol were determined overnight in twelve patients with Cushing's syndrome: eight patients with bilateral adrenal hyperplasia of hypothalamic-pituitary orgin, three patients with a cortisol producing adenoma and one patient with a carcinoma of the adrenal cortex. While either secretory episodes in plasma cortisol or a fixed pattern of cortisol secretion were observed both in patients with pituitary dependent and in those with pituitary independent hypercorticism, a typical night-day variation in plasma cortisol was only found in one of the eight patients with Cushing's syndrome of hypothalamic-pituitary origin. The patient with a cortisol producing carcinoma showed only minor fluctuations in plasma cortisol throughout the test period. The results indicate that no discrimination can be made between patients with pituitary dependent or independent Cushing's syndrome by demonstrating an episodic or a fixed secretion of cortisol. It seems, however, that the finding of a typical night-day variation in hormone secretion points to hypercorticism of hypothalamic-pituitary orgin.

This chapter introduces the concept of visitor affinity to the visitor management (VM) literature. It illustrates the basic possibilities and limits of segmentation by visitor affinity, within the framework of visitor monitoring in protected areas. For this purpose, different methodological procedures are identified and discussed in order to allow a better comparison between protected areas. Hereupon, guiding strategies for a target group-oriented VM are formulated. The Hohe Tauern National Park, Austria, is used as a case study for empirical research.