Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels.

BACKGROUND AND PURPOSE: The cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion-induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents. EXPERIMENTAL APPROACH: A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca(2+) levels. The lead compound SAR7334 was further characterized by whole-cell patch-clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated. KEY RESULTS: SAR7334 inhibited TRPC6, TRPC3 and TRPC7-mediated Ca(2+) influx into cells with IC50 s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5-mediated Ca(2+) entry was not affected. Patch-clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6-dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short-term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR). CONCLUSIONS AND IMPLICATIONS: Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.

[Gerontology--Multi-, inter- and transdisciplinarity in theory and practise?]. / Gerontologie--Multi-, Inter- und Transdisziplinarität in Theorie und Praxis?

Given the suggestion to establish gerontology as an independent scientific discipline, the paper discusses the options for further development. It is argued that multidisciplinarity, interdisciplinarity and transdisciplinarity are the only alternatives that should be explicitly highlighted as a special feature of gerontology and that advantages and disadvantages of these alternatives should be discussed further.

Stability and biological activity of wild blueberry (Vaccinium angustifolium) polyphenols during simulated in vitro gastrointestinal digestion.

Wild blueberries are rich in polyphenols and have several potential health benefits. Understanding the factors that affect the bioaccessibility and bioavailability of polyphenols is important for evaluating their biological significance and efficacy as functional food ingredients. Since the bioavailability of polyphenols such as anthocyanins is generally low, it has been proposed that metabolites resulting during colonic fermentation may be the components that exert health benefits. In this study, an in vitro gastrointestinal model comprising sequential chemostat fermentation steps that simulate digestive conditions in the stomach, small intestine and colon was used to investigate the breakdown of blueberry polyphenols. The catabolic products were isolated and biological effects tested using a normal human colonic epithelial cell line (CRL 1790) and a human colorectal cancer cell line (HT 29). The results showed a high stability of total polyphenols and anthocyanins during simulated gastric digestion step with approximately 93% and 99% of recovery, respectively. Intestinal digestion decreased polyphenol- and anthocyanin- contents by 49% and 15%, respectively, by comparison to the non-digested samples. During chemostat fermentation that simulates colonic digestion, the complex polyphenol mixture was degraded to a limited number of phenolic compounds such as syringic, cinnamic, caffeic, and protocatechuic acids. Only acetylated anthocyanins were detected in low amounts after chemostat fermentation. The catabolites showed lowered antioxidant activity and cell growth inhibition potential. Results suggest that colonic fermentation may alter the biological activity of blueberry polyphenols.

Stimulation of fat oxidation, but no sustained reduction of hepatic lipids by prolonged pharmacological inhibition of acetyl CoA carboxylase.

Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat metabolism and their inhibition has been postulated to be beneficial for the treatment of the metabolic syndrome by decreasing ectopic fat accumulation. In order to validate this approach pharmacologically, we characterized the chronic effect of the small molecule ACC1/2 inhibitor SAR210 in 2 rodent models of fatty liver. Chronic administration of SAR210 increased serum ketone levels in both diet-induced obese mice and female ZDF rats. The inhibitor neither reduced hepatic triglycerides nor influenced body weight in either diet-induced obese mice or female ZDF rats. Thus, chronic pharmacological inhibition of ACC1/2 stimulated fat oxidation, which was, however, not sufficient to reduce hepatic triglycerides.

[The Doxa of the social-gerontological field: successful and productive aging-orthodoxy, heterodoxy or allodoxy?]. / Zur Doxa des sozialgerontologischen Feldes: Erfolgreiches und produktives Altern-Orthodoxie, Heterodoxie oder Allodoxie?

Without any precise or consistent definition, the imagination of successful and productive aging has meanwhile become the basic illusio of the (psycho) gerontological field. The article examines to what extent a utilitarian term like success can be applied to the aging process. It examines further, if the imagination of successful aging is a faulty representation (allodoxy) of aging, which was brought in as a consciously antipodal system of explanation (heterodoxy) nourished by the attempt to set something positive against the negative societal stereotypes of aging, thus, deceiving itself being the prevailing modus of interpretation (orthodoxy) in the socio-gerontological field.

Advocacy in perioperative nursing practice.

Advocacy describes the act of pleading for, supporting, and active espousal. It implies taking action to achieve a goal on behalf of oneself or another. In nursing, the patient's wishes often serve as the impetus for advocacy. Perioperative nurses function as advocates and accept responsibility to safe-guard the rights of surgical patients. This article describes historical aspects of and conceptual problems in nursing advocacy, and it presents case studies that demonstrate advocacy by the perioperative nurse.

Expanded practice: the nurse as bioethics consultant.

The field of bioethics is evolving in health care. Nurses, with their clinical knowledge and expertise, are prime candidates for the role of ethics consultant. Many educational programs are available throughout the country for study in the field of bioethics. Nurses functioning in this role will find it a stimulating and challenging experience.

Ion chemistry of anti-o,o dibenzene.

The ion chemistry of anti-o,o'-dibenzene (1) was examined in the gaseous and the condensed phase. From a series of comparative ion cyclotron resonance (ICR) mass spectrometry experiments which involved the interaction of Cu+ with 1, benzene, or mixtures of both, it was demonstrated that 1 can be brought into the gas phase as an intact molecule under the experimental conditions employed. The molecular ions, formally 1*+ and 1*- , were investigated with a four-sector mass spectrometer in metastable-ion decay, collisional activation, charge reversal, and neutralization-reionization experiments. Surprisingly, the expected retrocyclization to yield two benzene molecules was not dominant for the long-lived molecular ions; however, other fragmentations, such as methyl and hydrogen losses, prevailed. In contrast, matrix ionization of 1 in freon (77 K) by gamma-radiation or in argon (12 K) by X-irradiation leads to quantitative retrocyclization to the cationic dimer of benzene, 2*+. Theoretical modeling of the potential-energy surface for the retrocyclization shows that only a small, if any, activation barrier is to be expected for this process. In another series of experiments, metal complexes of 1 were investigated. 1/Cr+ was formed in the ion source and examined by metastable ion decay and collisional activation experiments, which revealed predominant losses of neutral benzene. Nevertheless, comparison with the bis-ligated [(C6H6)2Cr]+ complex provided evidence for the existence of an intact 1/Cr+ under these experimental conditions. No evidence for the existence of 1/Fe+ was obtained, which suggests that iron mediates the rapid retrocyclization of 1/Fe+ into the bis-ligated benzene complex [(C6H6)2Fe]+.

Ethical perception and resulting action in perioperative nurses.

This study examined whether perioperative nurses (n = 40) were able to perceive and identify selected ethical issues occurring within their practice setting. The nurses described ethical conflicts and identified factors influential to their ethical decision making. The issues reported were organized into five categories: consent/advocacy, impaired provider/potential for unsafe practice, misrepresentation by care provider, disrespect for patient, and provider judgment/competency. The results of this study support that perioperative nurses both perceive and identify specific ethical issues in the surgical environment. Analysis of their reported actions revealed that the most common methods used for ethical conflict resolution were reporting to the immediate supervisor or personally confronting those directly involved.

Pain management: ethical issues for the perianesthesia nurse.

Ethical aspects of pain management in the peri-anesthesia practice setting revolve around issues of competence. Nurses must have knowledge relevant to the current scope of nursing practice, changing issues and concerns, and ethical concepts and principles. Nurses and other health care providers must engage in ongoing discussion and deliberation about ethics and culturally sensitive care. Additionally, to ensure optimal outcomes, the care provided must address those aspects that are age specific. It is important not only to develop competence as related to tasks and skills, but also to develop critical thinking and decision making. All nurses need to be able to articulate a personal philosophy. They need to understand their own values and be able to anticipate the impact that ethical choice will have on their professional practice.

Medical futility: interpretation and ethical ramifications for the perioperative nurse.

When is enough "enough" and who decides? The term futility is replete with ambiguity and controversy. By examining the definition and interpretation of futility, perioperative health care providers may be better able to avoid the ethical hazards inherent to the concept.

Perioperative nurses' involvement on nursing ethics committees.

Ethics issues in health care are evolving constantly; however, perioperative nurses often feel unprepared or unqualified to deal with aspects of ethical decision making. Through involvement as members of a nursing ethics committee, perioperative nurses can obtain the knowledge and skills necessary to assist patients and peers in ethical decision making. Participation on nursing ethics committees improves perioperative nurses' levels of moral reasoning, enhances their ethical decision-making and patient advocacy skills, and increases their professional satisfaction.

The ethics of organ donation.

1. The primary bioethics principles, which are evidenced in the analysis and discussion of organ donation are: autonomy, beneficence, justice, and utility. 2. Organ donation encompasses a variety of ethics-laden issues ranging from invalidation of individual rights to the accepted criteria for donation. However, any of these issues can be categorized as relating to procurement, consent, and allocation. 3. The application of bioethical principles is integral to the decision-making process involved in organ-donation issues. It is the responsibility of nurses, physicians, ethics committees, and organ-procurement organizations, as well as the donors, recipients and their respective relations, to understand and determine which principles support a proposed decision on organ donation or allocation. 4. Human beings must discover and utilize valid principles in order to make effective ethical decisions in difficult or complex situations. By defining and applying the principles of bioethics, individuals can make sense of such painful experiences as those that address organ donation.

Implementation of an event-related sterility plan.

A paradigm shift from a time-related sterility method to an event-related sterility assurance plan is possible if the nurse manager's approach to OR staff members is well researched and properly presented. Following research protocols and providing a methodology and rationale to staff members will enhance the success of the implementation process. A successful paradigm shift to an event-related sterility system has the potential of increasing knowledge, improving practice, empowering staff members, and saving money, time, and effort.