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A niche in classical architecture is an exedra or an apse that has been reduced in size, retaining the half-dome heading usual for an apse. Nero's Domus Aurea was the first semi-private dwelling that possessed rooms that were given richly varied floor plans, shaped with niches and exedras; sheathed in dazzling polished white marble, such curved surfaces concentrated or dispersed the daylight.The word derives from the Latin nidus or nest, via the French niche. The Italian nicchio for a sea-shell may also be involved, as the traditional decoration for the top of a niche is a scallop shell, as in the illustration, hence also the alternative term of "conch" for a semi-dome, usually reserved for larger exedra.In Gothic architecture, a niche may be set within a tabernacle framing, like a richly-decorated miniature house , such as might serve for a reliquary. The backings for the altars in churches can be embedded with niches for statues. Though a niche in either Classical or Gothic contexts may be empty and merely provide some articulation and variety to a section of wall, the cult origins of the niche suggested that it be filled with a statue. One of the earliest buildings which uses external niches containing statues is the Church of Orsanmichele in Florence, built between 1380-1404. The Uffizi Palace in Florence modified the concept by setting the niche within the wall so it did not protrude. The Uffizi has two dozen or so such niches containing statues of great historical figures. In England the Uffizi style niches were adopted at Montacute House , where there are 9 exterior niches containing statues of the Nine Worthies. In Fra Filippo Lippi's Madonna the trompe-l'oeil niche frames her as with the canopy of estate that was positioned over a personage of importance in the late Middle Ages and Early Modern Europe. At the same time, the Madonna is represented as an iconic sculpture who has "come alive" with miraculous immediacy.Expanding from its primary sense as an architectural recess, a niche can be applied to a rocky hollow, crack, crevice, or foothold. The sense of a niche as a clearly defined narrow space led to its use describing the relational position of an organism's species, its ecological niche. Wikipedia.


Wierzbicki A.S.,Guys and St. Thomas Hospitals | Viljoen A.,Lister Hospital | Hardman T.C.,NICHE | Mikhailidis D.P.,University College London
Current Opinion in Cardiology | Year: 2013

PURPOSE OF REVIEW: Lipid-lowering is an intervention that reduces atherosclerosis and its complications. Statins currently form the standard of care but are not able to reduce low-density lipoprotein cholesterol (LDL-C) adequately in all patients-particularly those with familial hypercholesterolaemia and those with statin intolerance. RECENT FINDINGS: Combination therapy with statins is well established and ezetimibe is often used as an additional LDL-C-lowering agent reducing LDL-C by 20%. However, its clinical efficacy still remains controversial. Newer, more potent methods of LDL-C reduction are in development. Both lomitapide, a microsomal transfer protein inhibitor (MTPI), and mipomersen, an antisense oligonucleotide (ASO), have been shown to improve LDL-C levels by 25-50% in patients with homozygous familial hypercholesterolaemia. In patients with heterozygous familial hypercholesterolaemia or statin intolerance antibody-based inhibitors of preprotein convertase subtilisin/kexin 9 (PCSK9) produce reductions in LDL-C of 30-65%. Cholesterol ester transfer protein inhibitors (CETPIs) reduce LDL-C by 30-40% as well as raising levels of high-density lipoprotein cholesterol (HDL-C) and may also have a role as additional LDL-C-reducing drugs. SUMMARY: Surrogate outcome trials will be required with lomitapide or mipomersen to confirm their effects in homozygous familial hypercholesterolaemia and clinical endpoint trials will be needed for PCSK9 and CETPIs if these are to be used widely. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source


Hardman T.C.,NICHE | Dubrey S.W.,Hillingdon Hospital
Diabetes Therapy | Year: 2011

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80-90 g [300-400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances. © The Author(s) 2011. Source


The contribution of agricultural land use and management practices to soil degradation was compared on land with: more than 20-years of natural grazing (NG), cultivation of horticultural (HC) and field (FC) crops, and undisturbed savanna (US) in South Africa. Tillage with tractors in the FC and HC plots resulted in greater soil compaction compared with NG and US systems. The soil under FC and HC had a greater percentage of micro-aggregates (<0.25mm; 56.2% and 60.4%, respectively) than NG (16.1%) or US (22.7%). The aggregates in FC were the least water stable followed by that of HC, NG and US. Soil water content was significantly higher (p<0.05) in soil from HC (3.46%) than NG (2.13%), US (1.67%) or FC (0.87%). Soil compaction was greater in the profile of the FC, NG and HC than US. Grazing and cultivation significantly reduced soil organic matter and microbial biomass carbon. Both organic and microbial biomass carbon were significantly positively correlated with many soil properties. Overall, the study showed that both animal grazing and cultivation of crops significantly reduced soil physical and biological properties compared with undisturbed land. The results provide evidence that land management practices are an important component of sustainability in this dry savanna ecosystem. © 2013 Elsevier Ltd. Source


Wierzbicki A.S.,St. Thomas Hospital Campus | Hardman T.C.,NICHE | Viljoen A.,Lister Hospital
Expert Opinion on Investigational Drugs | Year: 2012

Introduction: Pre-protein convertase subtilisin kexin (PCSK)-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. Autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events. Areas covered: As PCSK-9 binds to the LDLR, a number of approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man. This article reviews the biochemistry and physiology of PCSK-9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity. Work in animal models has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls. Expert opinion: PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials. © 2012 Informa UK, Ltd. Source


Wierzbicki A.S.,Metabolic Medicine Chemical Pathology | Hardman T.C.,NICHE | Viljoen A.,Metabolic Medicine Chemical Pathology
International Journal of Clinical Practice | Year: 2012

Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. Statins form the basis of care but are not able to treat all aspects of dyslipidaemia. Many novel therapeutic compounds are being developed. These include additional therapeutics for low-density lipoprotein cholesterol, for example, thyroid mimetics (thyroid receptor beta-agonists), antisense oligonucleotides or microsomal transfer protein inhibitors (MTPI); triglycerides, for example, novel peroxosimal proliferator activating receptors agonists, MTPIs, diacylglycerol acyl transferase-1 inhibitors and high-density lipoprotein cholesterol (HDL-C), for example, mimetic peptides; HDL delipidation strategies and cholesterol ester transfer protein inhibitors and modulators of inflammation, for example, phospholipase inhibitors. Gene therapy for specific rare disorders, for example, lipoprotein lipase deficiency using alipogene tiparvovec is also in clinical trials. Lipid-lowering drugs are likely to prove a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis. © 2012 Blackwell Publishing Ltd. Source

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