Rho-Mancing to Sensitize Calcium Signaling for Contraction in the Vasculature: Role of Rho Kinase.

Vascular smooth muscle contraction is an important physiological process contributing to cardiovascular homeostasis. The principal determinant of smooth muscle contraction is the intracellular free Ca2+ concentration, and phosphorylation of myosin light chain (MLC) by activated myosin light chain kinase (MLCK) in response to increased Ca2+ is the main pathway by which vasoconstrictor stimuli induce crossbridge cycling of myosin and actin filaments. A secondary pathway for vascular smooth muscle contraction that is not directly dependent on Ca2+ concentration, but rather mediating Ca2+ sensitization, is the RhoA/Rho kinase pathway. In response to contractile stimuli, the small GTPase RhoA activates its downstream effector Rho kinase which, in turn, promotes contraction via myosin light chain phosphatase (MLCP) inhibition. RhoA/Rho kinase-mediated MLCP inhibition occurs mainly by phosphorylation and inhibition of MYPT1, the regulatory subunit of MLCP, or by CPI-17-mediated inhibition of the catalytic subunit of MLCP. In this review, we describe the molecular mechanisms underlying the pivotal role exerted by Rho kinase on vascular smooth muscle contraction and discuss the main regulatory pathways for its activity.

Mitochondrial-derived N-formyl peptides: novel links between trauma, vascular collapse and sepsis.

Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPs) that activate the innate immune system. Mitochondrial DAMPs express at least two molecular signatures, N-formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries. Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses.

The existence of a local 5-hydroxytryptaminergic system in peripheral arteries.

BACKGROUND AND PURPOSE: 5-HT is a vasoconstrictor exhibiting enhanced effects in systemic arteries from subjects with cardiovascular disease. The effect of endogenous 5-HT on arteries is controversial, because the concentration of free circulating 5-HT is low and a 5-hydroxytryptaminergic system has not been identified in peripheral arteries. We hypothesized that a local 5-hydroxytryptaminergic system (including 5-HT synthesis, metabolism, uptake and release) with physiological function exists in peripheral arteries. EXPERIMENTAL APPROACH: The presence of key components of a 5-hydroxytryptaminergic system in rat aorta and superior mesenteric artery was examined using western blot analyses, immunohistochemistry and immunocytochemistry. The function of the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), and 5-HT transporter was tested by measuring enzyme activity and 5-HT uptake, respectively. Isometric contraction of arterial strips was used to demonstrate the function of released endogenous 5-HT in arterial tissues. KEY RESULTS: mRNA for TPH-1 was present in arteries, with low levels of TPH protein and TPH activity. Expression and function of MAO A (5-HT metabolizing enzyme) was supported by immunohistochemistry, western analyses and the elevation of concentrations of 5-hydroxyindoleacetic acid (5-HT metabolite) after exposure to exogenous 5-HT. The 5-HT transporter was localized to the plasma membrane of freshly isolated aortic smooth muscle cells. Peripheral arteries actively took up 5-HT in a time-dependent and 5-HT transporter-dependent manner. The 5-HT transporter substrate, (+)-fenfluramine, released endogenous 5-HT from peripheral arteries, which potentiated noradrenaline-induced arterial contraction. CONCLUSIONS AND IMPLICATIONS: This study revealed the existence of a local 5-hydroxytryptaminergic system in peripheral arteries.

"Idiots, infants, and the insane": mental illness and legal incompetence.

Prior to the second world war, most persons confined in insane asylums were regarded as legally incompetent and had guardians appointed for them. Today, most persons confined in mental hospitals (or treated involuntarily, committed to outpatient treatment) are, in law, competent; nevertheless, in fact, they are treated as if they were incompetent. Should the goal of mental health policy be providing better psychiatric services to more and more people, or the reduction and ultimate elimination of the number of persons in the population treated as mentally ill?

Mental illness: psychiatry's phlogiston.

In physics, we use the same laws to explain why airplanes fly, and why they crash. In psychiatry, we use one set of laws to explain sane behaviour, which we attribute to reasons (choices), and another set of laws to explain insane behaviour, which we attribute to causes (diseases). God, man's idea of moral perfection, judges human deeds without distinguishing between sane persons responsible for their behaviour and insane persons deserving to be excused for their evil deeds. It is hubris to pretend that the insanity defence is compassionate, just, or scientific. Mental illness is to psychiatry as phlogiston was to chemistry. Establishing chemistry as a science of the nature of matter required the recognition of the non-existence of phlogiston. Establishing psychiatry as a science of the nature of human behaviour requires the recognition of the non-existence of mental illness.

What Counts as Disease?. Rationales and Rationalizations for Treatment.

Disease is a fact of nature. Diagnosis is an artefact constructed by human beings. The core concept of disease is a bodily abnormality. Literally, the term 'disease' denotes a demonstrable lesion of cells, tissues, or organs; metaphorically, it may be used to denote any kind of malfunctioning, of individuals, groups, economies. Classic nosology was descriptive, based on somatic pathology. The diagnostician sought to anticipate and approximate the pathologist's findings at autopsy, that is, identify the patients's bodily lesion/disease and its material cause (etiology). For example, the term 'pneumococcal pneumonia' identifies the organ affected, the lungs, and the cause of the illness, infection with the pneumococcus. Contemporary nosology is strategic, based on economic, legal, social, and other interests (unrelated to disease as somatic pathology). The diagnostician seeks to secure reimbursement for medical services, legitimize treatment, justify defining undesirable behavior as disease, and so forth. For example, diagnosis-related groups provide bureaucratic rationale for reimbursing medical services by third-party payers; psychiatric diagnoses provide legal-scientific rationale for treating mental diseases as if they were brain diseases; and so forth. Formerly, diagnoses encoded the objectively verifiable condition of the patient's body (diseases). Today, diagnoses rationalize the health-care policy of the body politic (methods of controlling costs and compensating physicians). We are witnessing the transformation of nosology from the medical-scientific classification of disease as somatic pathology, into the medicalized justification of social policy as 'health care' or 'treatment'.

Routine neonatal circumcision: symbol of the birth of the therapeutic state.

The religious justification for male circumcision proffered by Jewish and Islamic parents is frequently overlooked in current secular (medical/hygienic) discussions that (1) challenge the moral justification of this ancient practice, and (2) question the decisions of today's parents who are committed, on the basis of their religious beliefs, to continue this practice. This paper reviews critically these conflicting values and arguments and calls for compromise in the face of potential state intervention to coerce parents to abandon this practice.

Psychiatric diagnosis, psychiatric power and psychiatric abuse.

Psychiatric abuse, such as we usually associate with practices in the former Soviet Union, is related not to the misuse of psychiatric diagnoses, but to the political power intrinsic to the social role of the psychiatrist in totalitarian and democratic societies alike. Some reflections are offered on the modern, therapeutic state's proclivity to treat adults as patients rather than citizens, disjoin rights from responsibilities, and thus corrupt the language of political-philosophical discourse.

Crazy talk: thought disorder or psychiatric arrogance?

The crazy talk exhibited by some mental patients is re-examined. Our inability to understand the other is not a valid reason for concluding that he is insane, much less than he has a brain disease. The seemingly senseless speech of persons called 'psychotic' resembles glossolalia or the religious phenomenon of 'gift of tongues' rather than a speech disturbance, such as aphasia, indicative of brain disease.