Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.     

Regional distribution of thiamin pyrophosphokinase in rat brain

The highest specific activity of thiamin pyrophosphokinase was found in the cerebellum, and lower activity in cerebral cortex and midbrain. The regional difference in the enzyme activity was similar to that in thiamin content and the influx rate in rat brain, suggesting that the enzyme is involved in the thiamin transport.     

Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behavior: a non-invasive approach

Summary Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural randomization, 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning.In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.     

The effect of ethanol on the biosynthesis and regulation of opioid peptides

Summary Alcoholism and alcohol abuse are serious health problems. Alcohol is known to influence the activity of a number of biological systems, for example the hormonal and neuronal systems. One of the biological systems whose activity is greatly influenced by alcohol is the endogenous opiate system. Alcohol modifies the function of both opiate receptors and opioid peptides. In fact it has been proposed that many of the effects of ethanol are mediated by its effects on the endogenous opiate system. This review will present results from various laboratories on the effects of acute and chronic ethanol treatments on various species, and on the release, biosynthesis and post-translational processing of the endorphins, enkephalins and dynorphins, the three known families of endogenous opioid peptides. Furthermore, the effect of acute and chronic ethanol consumption on the -endorphin system in man, and the possible implications of the functional activity of the endogenous opiate system for the genetic predisposition to alcoholism will be discussed.     

Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle

Summary The opioid agonists morphine (selective for -receptors) and ethylketocyclazocine (selective for kappa-receptors), at concentrations evoking strong effects in neuronal structures, did not significantly affect the configuration of the intracellularly recorded action potential and the force of contraction in ventricular heart muscle isolated from guinea pigs, rabbits and man. These results suggest that any changes of heart functions in vivo in response to opioid-like drugs are probably not mediated postsynaptically at the myocardial cell membrane but rather presynaptically, influencing the release of noradrenaline and/or acetylcholine from the nerve terminals.     

The pineal and melatonin: Regulators of circadian function in lower vertebrates

Summary The pineal has been identified as a major circadian pacemaker within the circadian system of a number of lower vertebrates although other pacemaking sites have been implicated as well. The rhythmic synthesis and secretion of the pineal hormone, melatonin, is suggested as the mechanism by which the pineal controls circadian oscillators located elsewhere. Both light and temperature cycles can entrain the pineal melatonin rhythm. The pineal, therefore, acts as a photo and thermoendocrine transducer which functions to synchronize internal cycle with cycles in the environment. A model is presented which portrays the pineal as a major component of a multioscillator circadian system and which suggests how these multiple circadian clocks are coupled to each other and to cycles of light and temperature in the external world.     

Methodological foundations of systems methodologies

In social systems science generally, and in management science particularly, recent developments in the variety of types of specific problem-solving methodologies (under the rubric of hard and soft systems approaches) have given an impetus to a line of inquiry, as well as debate on the nature of those methodologies. On the one hand, there has been the view that what we are witnessing is a form of Kuhnian crisis. On the other hand, a complementarist view of developments has been argued and a contingency approach proposed. But one thing has been common among the competing views: a belief that the prospects for further advances in the design and application of those methodologies, and in resolving the current controversies, lie in serious attempts to reconsider and clarify the underlying metatheoretical assumptions and concerns. This paper is an attempt to contribute to such an endeavor. A brief exposition of three methodological foundations (namely, empiricism, hermeneutics, and critique) is made, not only with the purpose of highlighting the nature as well as the limits of their epistemological and ethical claims, but also as a basis for illuminating both the nature of contemporary work on systems inquiry, design, and problem solving and the ongoing debate on what constitutes appropriate criteria for choice of specific methodologies.     

Misuses of biology in the context of the paranormal

Summary Public suspicion of science stems from science's challenging of perceptions and myths about reality, and a public fear of new technology. The result is a susceptibility to pseudoscience. In claiming that creation science is as valid as evolution the creationists misquote scientists and seek to spread their own scientific myths concerning a young age for the earth, an act of creation based on a particular literalist interpretation of the Christian Bible and a single worldwide flood. They use methods of debate and politics, rather than scientific research. A selection of their arguments is examined and the nature of the evidence for evolution is discussed. Problems with the creation science model are noted. In the myth of the hundredth monkey phenomenon, original research is misquoted to denigrate scientific research and support sentimental ideas of paranormal events. The misuse of science is seen as damaging to society because it reduces the effective gathering and application of scientific information. However, pseudoscience provides a valuable guide to gaps in public scientific education.     

Lack of effect of dihydroergotamine on endothelial and smooth muscle cell proliferation and endothelial cell prostanoid production

Summary The most important effect of dihydroergotamine is venoconstriction, but certain metabolic effects and changes in vessel prostanoid activity have also been suggested. In this study endothelial cell production of 6-keto PGF₁ and TxB₂ was quantitated in vitro. No evidence of altered prostanoid production was noted after incubation with dihydroergotamine (exposure ranging from 5×10^–3 to 5×10^–7 g/l). Similarly, no effect of dihydroergotamine on the growth rates of endothelial cells or smooth muscle cells in vitro was documented.