3Patherogenic and anti-inflammatory effects in monocyteshnacrophages, and binds thiazolidinedionesnovel antidiabetic agents with insulin-sensitising effects. However, there is no direct evidence to conclusively implicate this receptor in the regulation of mammalian glucose homeostasis. We have screened the PPARy gene in 85 unrelated subjects with severe insulin resistance. Two different heterozygous mutations (P467L, V290M) were identified within the ligand-binding domain in three affected individuals, all of whom exhibited a distinct clinical phenotype of severe early onset type 2 diabetes mellitus and hypertension. In the crystal structure, these mutations destabilise helix 12 which is critical for transactivation by the receptor. Consistent with this, both receptor mutants exhibit impaired ligand binding, coactivator recruitment and transcriptional activity. Moreover, they inhibit the action of coexpressed wild type PPARy in a dominant negative manner, an effect which correlates with their ability to silence basal gene transcription. These data provide compelling genetic evidence for a direct role of PPARy in the control of mammalian glucose homeostasis and blood pressure.To further investigate the mechanism of dominant negative inhibition, an artificial PPARy mutant (L468AE471A) was also generated. Both natural and artificial mutants recruit nuclear corepressors (SMRT and NCoR) in a 2-hybrid assay and exhibit delayed ligand-dependent corepressor release. Our studies indicate that, as in other mutant nuclear receptor contexts (acute promyelocytic leukaemia, resistance to thyroid hormone), such aberrant corepressor interaction is linked to dominant negative activity. To date, no complete, specific chemical PPARy antagonists exist. The artificial dominant negative PPARy mutant was therefore introduced into a recombinant adenovirus and used to specifically inhibit PPARy-mediated differentiation of primary cultured human preadipocytes. We plan to use this biological receptor antagonist to elucidate the mechanisms by which PPARy regulates insulin action and vascular tone. Edinburgh. EH8 9AG Introduction. We have previously reported our finding of significantly elevated levels of IL-8 within the alveolar airspaces of patients at risk of developing ARDS (Lancet 1993; 341: 643-647), and identified the macrophage as a potent source of this chemokine. Subsequent extended studies in multiple trauma patients confirm that raised lung IL-8 levels are strongly associated with ARDS progression (n=56, P=O.OOOl). The mechanism by which IL-8 is rapidly raised in these circumstances is unknown. A correlation between reduced Pa02Fi02 ratio on presentation to casualty and raised IL-8 levels was noted (r4.56, P=O.OOl). We postulated that acute hypoxia may upregulate IL-8 synthesis in human macrophages. Methods. Macrcphages cultured from peripheral blood mononuclear cells were exposed to hypoxia (Pa02-3.5Kpa) or normoxia (Pa02-20Kpa) for up to 2 hrs. Secreted IL-8 protein was measured by ELSA and mRNA expression by northem blotting. ...

No abstract

No abstract

In health, about four fifths of the solids of the plasma consist of plasma proteins. Their approximate percentages are as follows: total protein, from 7 to 8; albumin, from 4 to 5; globulin, from 1.5 to 3.5; fibrinogen, from 0.1 to 0.25; albumin-globulin ratio, 37.The colloidal osmotic pressure of the blood plasma is from 25 to 30 mm. of mercury and is maintained largely by the plasma proteins, as was first revealed by Starling.1 The colloidal osmotic pressure of the blood plasma (the totality of pressure with which the colloid tends to retain water) is not necessarily proportional to the total concentration of plasma protein, because the individual plasma proteins have different colloidal osmotic pressures. The total amount of protein may remain the same, while variations of the relative proportions of the different proteins may change the osmotic pressure. The colloidal osmotic pressure exerted by the smaller molecular complex of albumin is much greater than that exerted by the larger complex of globulin. Fibrinogen, which has a still larger molecular complex, exerts a still smaller pressure.2 Starling 1 pointed out that since the normal capillary wall is imper¬ meable to the plasma proteins, their colloidal osmotic pressure (attraction of the plasma proteins for water) must tend to counteract transudation from the capillaries and aid absorption from the tissue spaces. The hydrostatic (hydraulic) pressure, which is higher in the arteriolar than in the venous end of the capillary, favors transudation, opposes absorp¬ tion and tends to force fluid out into the tissue spaces. Under healthy conditions, an equilibrium between the transudation and absorption obtains. Any factor markedly altering the colloidal osmotic pressure,

Aneurysms of the thoracic aorta in children, though rare, occur frequently enough to warrant attention, because a group of them are a part of the much more common rheumatic fever syndrome. A great diversity of opinion has existed regarding the etiology of the thoracic aneurysm in the young. Some authors have believed that syphilis is practically always the prime factor in children as in adults, but a careful study of the available cases does not confirm this view.The etiologic factors in the production of aortic aneurysms in childhood have been classified by Bronson and Sutherland 1 in the following manner: (1) atheromatous degeneration; (2) trauma (rare); (3) erosion of the aorta from without; (4) congenital malformation (in a few cases), and (5), probably the most important, acute infectious diseases.Up to the present forty-four cases of aneurysm of the thoracic aorta in persons under 18 have been reported. In twenty-one of the cases there was an association with endocarditis (ten instances) or clinical rheumatic fever (eleven). In all of the cases of the former group autopsies confirmed the presence of lesions in the endocardium as well as in the aorta. In the latter group autopsy was performed in only one case, in which in addition to a dissecting aneurysm of the aorta there were mild coarctation and acute pericarditis with hemopericardium ; a year before death the patient had pains and swelling of the joints.-Two cases of this group were seen and reported by one of us (J. K. C.s) ; the patients gave a definite history of rheumatic fever and there were physical findings of rheumatic heart disease. Evidence