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At least 217 records · Page 12Linked to original sources
PubMed2003

Defining and classifying periodontitis: need for a paradigm shift?

The past two decades have witnessed a large number of proposals for the classification of periodontitis. These proposals are all founded in an essentialistic disease concept, according to which periodontitis is a link between the causes and the signs and symptoms of periodontitis. Essentialistic definitions are necessarily rather imprecise and thereby subject to multiple interpretations. Consequently, it remains unknown to what extent current knowledge regarding 'different' forms of periodontitis is based on the 'same' type of patients. However, periodontitis is a syndrome, the clinical manifestations of which may come in all sizes. Thereby, periodontitis has no diagnostic truth, just as there is no natural basis for a sharp distinction between health and disease or between 'different' forms of periodontitis. Recognition of these facts and adoption of a nominalistic approach to the definition of periodontitis is needed to provide a rational framework for the development of a classification system that meets the needs of both clinicians and scientists.

Acute Disease↗
PubMed2001

Knockout mice: a paradigm shift in modern immunology.

In the past decade, advances in genetic engineering and mouse knockout technology have transformed our understanding of the immune system. In particular, new perspectives on T-cell development, co-stimulation and activation have emerged from the study of single and multiple gene-knockout animals, as well as from conditional knockout and 'knock-in' mutants. Analysis of these animals has clarified important intracellular signalling pathways and has shed light on the regulatory mechanisms that govern normal immune responses and autoimmunity.

Animals↗
PubMed1996

The hyperfiltration theory: a paradigm shift in nephrology.

Experimental studies incriminate glomerular hypertension in mediating progressive renal damage after any of a variety of initiating injuries. Prevention of glomerular hypertension by dietary protein restriction or antihypertensive therapy lessens progressive glomerular damage in several experimental models of chronic renal disease. Glomerular hypertension and hyperfiltration also occur in humans with diabetes mellitus, solitary or remnant kidneys, and various forms of acquired renal disease. Clinical studies indicate that dietary protein restriction and antihypertensive therapy also slow progression in many of these disorders. Large multicenter trials confirm the beneficial effects of these therapeutic maneuvers on the rate of progression of chronic renal disease.

Humans↗
PubMed2004

From monoamines to genomic targets: a paradigm shift for drug discovery in depression.

Depression, a complex psychiatric disorder that affects approximately 15% of the population, has an enormous social cost. Although the disorder is thought to be the outcome of gene-environmental interactions, the causative genes and environmental factors underlying depression remain to be identified. All the antidepressant drugs now in use--the forerunner of which was discovered serendipitously 50 years ago--modulate monoamine neurotransmission, and take six to eight weeks to exert their effects, but each drug is efficacious in only 60-70% of patients. A conceptually novel antidepressant that acted rapidly and safely in a high proportion of patients would almost certainly become the world's bestselling drug. Yet such a drug is not on the horizon. Here, we cover the different phases of antidepressant drug discovery in the past, present and future, and comment on the challenges and opportunities for antidepressant research.

Animals↗
PubMed2006

Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond.

Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca(2+) influx through the receptor's associated ion channel and consequent free-radical formation.

Animals↗
PubMed2006

Genetics of Parkinson disease: paradigm shifts and future prospects.

Parkinson disease is a complex, multifactorial neurodegenerative disease. Although a heritable basis was originally thought unlikely, recent studies have implicated several genes in its pathogenesis, and molecular findings now allow accurate diagnosis and challenge past criteria for defining Parkinson disease. Most importantly, genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested. Neuroprotective therapies can now be designed to slow or halt disease progression in affected subjects and asymptomatic carriers.

Environment↗
PubMed2003

A paradigm shift in the construction of heterobimetallic complexes: synthesis of group 2 & 4 metal-calix[6]arene complexes.

Deprotonation of calix[6]arenes with barium in methanol followed by the addition of [Ti(OPr(i))(4)] or [Zr(OBu(n))(4)] is effective in the formation of novel dimeric 2:1 barium-titanium(IV)/zirconium(IV) calix[6]arene complexes. In these complexes a central Ti(IV)/Zr(IV) coordinated in the exo-position connects the two calix[6]arenes in the 1,3-alternate conformation, each with an endo-barium sharing common phenolate groups with the titanium/zirconium centre and participating in cation-pi interactions. A homometallic barium calix[6]arene dimer was also prepared wherein the calix[6]arenes are in the 1,3-alternate conformation with each coordinating one endo- and one exo-barium centre. The exo-barium cations connect the two calix[6]arenes through bridging methanol ligands. In this and the heterometallic complexes, cation-pi complexation of the Ba(2+) ion within the 1,3 alternate conformation of calix[6]arene facilitates the formation of the dimeric complexes in methanol. In contrast, the smaller Sr(2+) ion did not form similar complexes in methanol, and the formation of an analogous 2:1 strontium-titanium calixarene complex required the use of the more sterically demanding donor alcohol, isopropanol, the resulting complex being devoid of cation-pi interaction. The results show (i) that a subtle interplay of solvation strength, coordination array type and cavity/cation size influences the accessibility of heterobimetallic complexes based on calix[6]arenes, and (ii) a synergistic endo-exo binding behaviour.

Journal Article↗