Hereditary non-neuropathic systemic amyloidosis (Ostertag-type) is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade. In some families it is caused by mutations in the apolipoprotein AI gene but in two unrelated English families under our care the amyloid deposits did not contain apoAI, despite a report that this may have been the case in one of them. Lysozyme is a ubiquitous bacteriolytic enzyme present in external secretions and in polymorphs and macrophages, but its physiological role is not always clear. Here we report that in these two families, lysozyme is the amyloid fibril protein. Affected individuals are heterozygous for point mutations in the lysozyme gene that cause substitution of highly conserved residues, namely threonine for isoleucine at position 56 in one family, and histidine for aspartic acid at residue 67 in the other. Amyloid fibrils from one individual were composed of the full-length Thr-56 variant lysozyme molecule. To our knowledge, this is the first report of naturally occurring variants of human lysozyme and of lysozyme-associated disease. As the structures of human and hen egg-white lysozyme are known to atomic resolution and their folding and structure-function relationships have been exhaustively analysed, our observations should provide a powerful model for understanding amyloidogenesis.

Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.

Background-Particulate air pollution has been associated with excess deaths from, and increases in hospital admissions for, cardiovascular disease among older people. A study was undertaken to determine whether this may be a consequence of alterations in the blood, secondary to pulmonary inflammation caused by the action of fine particles on alveolar cells, by repeatedly measuring haematological factors in older people and relating them to measurements of exposure to airborne particles. Methods-One hundred and twelve individuals aged 60+ years in two UK cities provided repeated blood samples over 18 months, 108 providing the maximum of 12 samples. Estimates of individual exposure to particles of less than 10 µm diameter (PM 10 ), derived from a mathematical model based on activity diaries and comparative measurements of PM 10 at multiple sites and during a variety of activities, were made for each three day period prior to blood sampling. The relationships between blood values and estimates of both personal exposure and city centre measurements of PM 10 were investigated by analysis of covariance, adjusting for city, season, temperature, and repeated individual measurements. Results-Estimated personal exposure to PM 10 over the previous three days showed negative correlations with haemoglobin concentration, packed cell volume (PCV), and red blood cell count (p<0.001), and with platelets and factor VII levels (p<0.05). The changes in red cell indices persisted after adjustment for plasma albumin in a sample of 60 of the subjects. City centre PM 10 measurements over three days also showed negative correlations with haemoglobin and red cell count (p<0.001) and with PCV and fibrinogen (p<0.05), the relationship with haemoglobin persisting after adjustment for albumin. C reactive protein levels showed a positive association with city centre measurements of PM 10 (p<0.01). Based on a linear relationship, the estimated change in haemoglobin associated with an alteration in particle concentration of 100 µg/m 3 is estimated to have been 0.44 g/ dl (95% CI 0.62 to 0.26) for personal PM 10 and 0.73 g/dl (95% CI 1.11 to 0.36) for city centre PM 10 measurements. Conclusions-This investigation is the first to estimate personal exposures to PM 10 and to demonstrate associations between haematological indices and air pollution. The changes in haemoglobin adjusted for albumin suggest that inhalation of some component of PM 10 may cause sequestration of red cells in the circulation. We propose that an action of such particles either on lung endothelial cells or on erythrocytes themselves may be responsible for changing red cell adhesiveness. Peripheral sequestration of red cells oVers an explanation for the observed cardiovascular eVects of particulate air pollution.

Abstractinfluence the prevalence of allergic disease in children most critically would be those of the Background -It has been postulated that dietary antioxidants may influence the ex-mother in pregnancy and during lactation and of the child in the first year or two of life. pression of allergic diseases and asthma. To test this hypothesis a case-control study However, since asthma may start at any age an effect may be demonstrable at any time, and was performed, nested in a cross sectional study of a random sample of adults, to we have taken the opportunity to investigate diet in adults, with and without increased broninvestigate the relationship between allergic disease and dietary antioxidants.chial reactivity, derived from a random sample of a rural population. Methods -The study was performed in rural general practices in Grampian, Scotland. A validated dietary questionnaire was used to measure food intake of cases, defined, firstly, Methods    as people with seasonal allergic-type The original cross sectional study population symptoms and, secondly, those with bron-consisted of 2000 individuals, an approximately chial hyperreactivity confirmed by metha-one in 10 random sample of all adults registered choline challenge, and of controls without with the general practitioners of three villages in allergic symptoms or bronchial reactivity. rural Grampian, Scotland.8 All had completed Results -Cases with seasonal symptoms questionnaires on the presence or absence of a did not differ from controls except with range of seasonal symptoms including those respect to the presence of atopy and an classically associated with allergy. Cases were increased risk of symptoms associated first defined as those who had responded poswith the lowest intake of zinc. The lowest itively to questions about recurrent eye, nasal, intakes of vitamin C and manganese were or respiratory symptoms any time between associated with more than fivefold in-April and August 8 and controls were those with creased risks of bronchial reactivity. De-no such seasonal symptoms. The cases selected creasing intakes of magnesium were also from the original population for the present significantly associated with an increased study were all those from one of these villages risk of hyperreactivity.who had recorded seasonal symptoms on Conclusions -This study provides evi-the questionnaire, together with age and sex dence that diet may have a modulatory matched controls without symptoms from the effect on bronchial reactivity, and is con-same village. They were contacted by telephone sistent with the hypothesis that the ob-and those who agreed to participate were sent served reduction in antioxidant intake in a detailed dietary questionnaire through the the British diet over the last 25 years has post with instructions on how to complete it. been a factor in the increase in the pre-Of 78 cases and 68 controls approached, 52 valence of asthma over this period.and 38, respectively, took part. The main (Thorax 1997;52:166-170) reason...

No abstract

The results of the study do not suggest a carcinogenic effect of TiO2 dust on the human lung.

The role of low density lipoprotein (LDL) receptors in the pathogenesis of hereditary and acquired forms of hypercholesterolemia has been investigated in vivo by simultaneously determining total and receptor-independent LDL catabolism with "MI-labeled LDL and "'I-labeled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL, determined as the difference between the turnover of 125I and 1311, was found to be virtually absent in two homozygotes with familial hypercholesterolemia and markedly reduced in a hypothyroid patient. Treatment of the latter with L-thyroxine markedly stimulated receptor-mediated catabolism and reduced LDL levels as did cholestyramine administration in a control subject. Reduction of LDL levels by plasma exchange in a control subject and homozygote had no such effect. These results demonstrate the existence of an intrinsic and almost total defect of receptor-mediated LDL catabolism in homozygous familial hypercholesterolemia and demonstrate an analogous but reversible abnormality in hypothyroidism.Hypocatabolism of low density lipoprotein (LDL) characterizes both familial hypercholesterolemia (FH) and hypothyroidism (1, 2). Studies with cultured fibroblasts have revealed an inherited deficiency of LDL receptors in FH, more marked in homozygotes than in heterozygotes, which has been assumed to be the cause of the catabolic defect in vivo (3, 4). Stimulation of high affinity binding and degradation of LDL in normal fibroblasts by triiodothyronine (5) suggests the possibility of an analogous but acquired deficiency of LDL receptors in hypothyroidism. Recently, Shepherd et al. (6) provided in vivo evidence of a decrease in receptor-mediated LDL catabolism in FH heterozygotes, using the technique developed by Mahley et al. (7). This involves the simultaneous administration of 125I-labeled native LDL (l2I-LDL) and '311-labeled LDL (131I-LDL) treated with 1,2-cyclohexanedione (Chd); the latter modification blocks arginine residues and thus inhibits binding of LDL to receptors on fibroblasts and smooth muscle cells (8). Using this approach, we have been able to demonstrate the virtual absence of receptor-mediated LDL catabolism in homozygous FH and the presence of a similar but reversible abnormality in hypothyroidism. Our observations, published previously only as abstracts (9, 10), help validate a novel method ofquantitating receptor-mediated LDL catabolism and illustrate the importance of that pathway in regulating serum cholesterol levels in man.SUBJECTS AND METHODS Two male FH homozygotes (M.M., D.L.), both ages 16 years and with receptor-defective fibroblasts on established criteria (11), whose clinical details are given elsewhere (12), were studied after having discontinued cholesterol-lowering drugs and plasma exchange for 5-6 wk. A 30-year-old woman (E. P.) with overt primary hypothyroidism was studied twice, before and after being rendered euthyroid by a 6-wk treatment with L-thyroxine (0.2 mg/day). Two of the authors, both normolipidemic men, aged 34 and 47, act...

The human plasma apoproteins apoA-I and apoC-I enhanced the activity of partially purified lecithin: cholesterol acyltransferase five to tenfold with chemically defined phosphatidylcholine:cholesterol single bilayer vesicles as substrates. By contrast, apoproteins apoA-II, apoC-II, and apoC-III did not give any enhancement of enzyme activity. The activation by apoA-I and apoC-I differed, depending upon the nature of the hydrocarbon chains of phosphatidylcholine acyl donor. ApoA-I was most effective with a phosphatidylcholine containing an unsaturated fatty acyl chain. ApoC-I activated LCAT to the same extent with both saturated and unsaturated phosphatidylcholine substrates. Two of the four peptides obtained by cyanogen bromide cleavage of apoA-I retained some ability to activate LCAT. The efficacy of each of these peptides was approximately 25% that of the whole protein. Cyanogen bromide fragments of apoC-I were inactive. The apoproteins from HDL, HDL2, and HDL3, at low protein concentrations, were equally effective as activators of LCATand less effective than apoA-I. Higher concentrations of apoHDL, apoHDL2, and apoHDL3 inhibited LCAT activity. ApoC and apoA-II were both found to inhibit the activation of LCAT by apoA-I. The inhibition of LCAT by higher concentrations of apoHDL was not correlated with the aopA-II and apoC content.