At extreme altitude (>5,000 – 5,500 m), sustained hypoxia threatens human function and survival, and is associated with marked involuntary weight loss (cachexia). This seems to be a coordinated response: appetite and protein synthesis are suppressed, and muscle catabolism promoted. We hypothesise that, rather than simply being pathophysiological dysregulation, this cachexia is protective. Ketone bodies, synthesised during relative starvation, protect tissues such as the brain from reduced oxygen availability by mechanisms including the reduced generation of reactive oxygen species, improved mitochondrial (...) efficiency and activation of the ATP‐sensitive potassium (KATP) channel. Amino acids released from skeletal muscle also protect cells from hypoxia, and may interact synergistically with ketones to offer added protection. We thus propose that weight loss in hypoxia is an adaptive response: the amino acids and ketone bodies made available act not only as metabolic substrates, but as metabolic modulators, protecting cells from the hypoxic challenge.Also watch the Video Abstract. (shrink)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather than (...) T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. (shrink)

In the text book treatise on certitude, there usually appears a line in definition of "certitude mere subjectiva," which is, for practical purposes, one of the most important in the book. As an example of what thought and imagination can do to enlarge upon and embelish the outline of class instruction and to ground philosophy deeper in the mind, Mr. Harkins presents this paper, an admirable development of the few short words of the definition which we are so prone to (...) introduce to the memory and then dismiss for good. (shrink)

Research on children's theory of mind often restricts conceptually meaningful talk about knowledge to instances where know references a corresponding mental state. This article offers a reappraisal of that view. From a social-pragmatic perspective, even nonreferential talk is meaningful when appropriately embedded in social routines. A synthesis of corpus data suggests children's early talk about knowledge routinely occurs in question–answer contexts. It is argued that the influence of interrogative contexts is evident in children's over-attributions of knowledge when someone is only (...) guessing. This influence is taken as evidence for the role of linguistic practices in shaping the concept of knowledge. (shrink)

This response to the articles by Breck, Amundsen, and Bresnahan is argued from a traditional Orthodox point of view, which accepts the historical Tradition of the Church and recognizes the relevance of this Tradition in the modern world. Traditional Orthodox ethics is grounded in a radical perception of the Resurrection of Christ. Many Western and Eastern commentators on Orthodox religion and spirituality have noted the centrality of the Resurrection to all facets of our Tradition. Thus the discussion of euthanasia should (...) be seen in the light of the Resurrection of Christ. (shrink)

This entirely new work guides the reader through the most basic systems of modal propositional logic up to systems of modal predicate with identity, dealing with both technical developments and discussing philosophical applications.

Normal propositional modal systems This first chapter has two main aims. One is to give a general account of the propositional modal systems that we shall ...

This essay was written for the 1984 General Motors Intercollegiate Business Understanding Program. It consists of three sections, each responding to a separate issue posed by General Motors. The opinions expressed are not those of the General Motors management.The first section attempts to document, through the use of Harvard Business Review articles, a shift in the notion of managerial responsibility from a narrowly focused role responsibility to a more widely focused moral responsibility.