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Biotinidase deficiency disorder is a rare inherited metabolic disorder with typical neurological manifestations of hypotonia, developmental delay, rashes, seizures, hearing and vision impairment. We present two cases with different and unusual clinical profiles, whose neuroimaging resembled Neuromyelitis Optica Spectrum Disorder. Case 1 was initially treated with immunomodulation with steroids and intravenous immunoglobulins, with partial improvement. However reinvestigation for worsening of symptoms showed more extensive changes on spine magnetic resonance imaging. Raised lactate and alanine levels on repeat cerebrospinal fluid testing resulted in further investigations that revealed a biotinidase deficiency. Case 2 presented mainly with respiratory symptoms: a barium swallow suggested bulbar dysfunction. Neuroimaging of brain and spine was similar to that in case 1 and the child was promptly investigated for and confirmed to have biotinidase deficiency. Both cases responded to biotin supplementation. It is important to be cognisant of atypical neurological presentations of biotinidase deficiency including those that mimic immune mediated neurodemyelination disorders, as biotinidase deficiency is potentially treatable.

Pyridoxine‐dependent epilepsy (PDE) is a potentially treatable vitamin‐responsive epileptic encephalopathy. The most prevalent form of PDE is due to an underlying genetic defect in ALDH7A1 encoding Antiquitin (ATQ), an enzyme with α‐aminoadipic semialdehyde dehydrogenase (AASADH) activity which facilitates cerebral lysine degradation. Devastating outcomes including intellectual disability and significant developmental delays are still observed in 75% to 80% of pyridoxine responsive individuals with good seizure control, potentially attributable to the accumulation of toxic intermediates α‐aminoadipic semialdehyde (AASA) and its cyclic form Δ1‐piperideine‐6‐carboxylate (P6C) in plasma, urine and CSF. Thus, adjunct treatment strategies incorporating lysine restriction and arginine supplementation, separately or in combination with pyridoxine have been attempted to enhance seizure control and improve cognitive function. We describe a 4 year old girl with classical PDE who demonstrated significant improvements in clinical, neurological and developmental outcomes including absence of clinical seizures and cessation of antiepileptic medications since age 3 months, normalisation of EEG, significant improvement in the white matter signal throughout the cerebrum on neuroimaging and significant reduction in urine P6C and pipecolic acid levels post‐ combined therapy with lysine restricted diet in conjunction with pyridoxine and folinic acid. Lysine restriction was well tolerated with impressive compliance and plasma lysine levels remained within the lower reference ranges; mean level 70 μmol/L (ref range 52‐196 μmol/L). This case further emphasizes the benefit of early dietary intervention as an effective adjunct in the management of PDE.

A focus of the semiconductor industry on advanced devices and equipment is expected, but many fabs are also at full capacity with legacy node technology. This results in hundreds of older generation ion implanter tools still being used for semiconductor manufacturing processing. The expectation for better yields and lower cost of ownership is always important no matter the technology node. Fluoride gases, including BF 3 , have a long history of poor ion source life performance due to tungsten transport from halogen cycling inside the arc chamber. This paper will demonstrate the advantages of mixing only hydrogen (H 2 ) with enriched 11Boron Trifluoride to increase source life on an Applied Materials (Varian) E-500 ion implant tool. The use of a single subatmospheric cylinder to provide this benefit, makes converting from pure 11Boron Trifluoride to the Entegris 11Boron Trifluoride mixture simple, easy to maintain, and safe.

In the manufacturing process of advanced node semiconductor devices, germanium tetrafluoride (GeF4) gas is used for pre-amorphization implantation (PAI) of the silicon crystal structure. This germanium implant is required for controlling channeling and reducing Transient Enhanced Diffusion (TED) for better ultra-shallow junction formation. Fluoride gases, including GeF4, have a long history of poor ion source life performance due to tungsten transport from halogen cycling inside the arc chamber of the implant tool. Also, running long periods of GeF4 negatively impacts the arc chamber, which can affect subsequent dopant processes. This paper will demonstrate the advantages of mixing hydrogen (H2) with EnPLUS 72GeF4 gas to increase implanter source life, extend the length of the beam campaign, improve beam performance, and eliminate post beam purge time.

Refsum's Disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes. Patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage. Besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa, additional symptoms include chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, as well as skeletal, cardiac, hepatic, and renal abnormalities. Current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits. Two brothers with Refsum's disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy. We report the effect of the intestinal lipase inhibitor, Orlistat, which led to significant reduction (P-value<0.001on 2-sample unpairedt-test) of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms.

Low plasma levels of high-density-lipoprotein cholesterol (HDL-C) and high triglyceride (TG) are strongly associated with cardiovascular disease (CVD). Clinical recognition of this high-risk population demands accurate measurement of HDL-C, whereas cost and clinical demand dictate that optimal HDL-C measurement requires fully automated methods that avoid manual precipitation. Commercial techniques use specific reagents to selectively expose and "directly" measure cholesterol in HDL. However, these "direct" methods may experience interference from the cholesterol content of triglyceride-rich-lipoproteins (TRL), leading to analytical overestimation of HDL-C, with subsequent underestimation of low-density-lipoprotein cholesterol (LDL-C) and of CVD risk.The aim of this study was to develop a method to overcome this interference.Serum/Li+-heparin plasma samples from consecutive patients were analyzed for HDL-C by the comparison of three generations of the Roche Diagnostics, HDL-C assay on a Hitachi-917 or Modular-PPE analyzer. HDL-C measurement was performed before and after removal of TRL by ultracentrifugation ("direct" HDL-C and HDL-UC, respectively). We examined the effect of TG on the relationship between HDL-UC and "direct" HDL-C. Analysis of variance multiregression analysis was performed for each generation of the commercial assay.We observed progressive TG interference that increased "direct" HDL-C by 10% to 15% or more in moderately hypertriglyceridemic samples (600 mg/dL). Predictive equations were derived for each generation of the assay to estimate HDL-C in the absence of TRL.This study casts doubt on the specificity of "direct" HDL-C assays in the presence of hypertriglyceridemia. The use of assay-specific correction formulae to adjust for interference from TRL reduces the overestimation of HDL-C that influences CVD risk calculation, treatment, and follow-up of patients.

Two types of end-point measurement are presently available in clinical trials of the effect of treatment of hyperlipidaemia on cardiovascular disease; these are the incidence of clinical events and the arteriographic assessment of progression or regression of atherosclerosis. These approaches are briefly reviewed. In the present trial, 25 hyperlipidaemic men with symptomatic femoral atherosclerosis underwent biplanar femoral arteriography at baseline. They were then randomised into treatment and usual-care groups; treatment was individualized, comprising a lipid-lowering diet with cholestyramine, nicotinic acid or clofibrate as appropriate for the lipoprotein disorder. Mean cholesterol and triglyceride levels were 19% and 37% lower in the treatment group. Arteriography was repeated after a mean period of 19 months. With attention to blinding of observers, changes in arteriograms were quantitated using computerised image analysis and visual methods, and expressed both by patient and by arterial segment. All end-points were in conformity and showed a lower rate of progression of arterial disease in the treatment group, and a higher frequency of segmental regression in treated patients. In this small trial of patients with functionally-significant atherosclerosis, effective treatment of hyperlipidaemia favourably affected the course of the arterial disease.

Ion implantation of germanium in silicon wafers is often troubled by reduced ion source life due to use of germanium tetrafluoride (GeF 4 ) as a source material. The problem is mainly due to tungsten re-deposition, a result of a fluorine-induced halogen cycle initiated within the ion source. The halogen cycle is particularly pronounced in the case of GeF 4 by easy fragmentation of the molecule, as well as low utilization of germanium due to wide isotopic distribution of natural abundance GeF 4 . Through isotopic enrichment of 72GeF 4 , benefits such as enhanced ion implantation beam current, lower gas flow, and longer source life can be achieved versus natural GeF 4 . Additional benefits can be realized when using mixtures of GeF 4 with hydrogen (H 2 ). Data are presented that show the effect of H 2 content on beam current as well as on tungsten transport. Lastly, thermodynamics and stability results are presented for a single cylinder mixture of GeF 4 with H 2 .

The World Health Organization (WHO) has recommended measurement of neonatal thyroid-stimulating hormone (TSH) as a marker of population iodine status. A population is considered iodine sufficient when3% of neonatal blood samples collected 3-4 days after birth have TSH concentrations5 mIU/L. However, changes in technology and clinical practices have opened the WHO criteria to various interpretations.This study aimed to investigate the effects of time of sampling, weight, and sex on neonatal TSH concentrations by analyzing neonatal TSH data, based on the WHO criteria for population iodine sufficiency.We analyzed the Western Australian (WA) Newborn Screening Program records for 198,826 babies born in WA between 2005 and 2011, to determine the relationship between neonatal TSH concentrations and time of sampling, weight, and sex.The proportion of TSH results above the WHO cut-off was higher for samples collected 48-72 h after birth rather than later, for males, for birth weights below 2500 g, and when a cut-off of 5.0 mIU/L was used.Following changes in newborn screening protocols and earlier collection of blood samples, the WHO criteria appear inappropriate. We recommend that WHO revise current guidelines regarding use of neonatal TSH for monitoring population iodine status.

Clinical management of the lipoprotein abnormalities associated with diabetes mellitus requires effective laboratory assessment. Lipoprotein abnormalities vary according to the aetiology of the diabetes, but both type 1 and type 2 diabetes may result in quantitative and/or qualitative changes in lipoproteins. Routine assessment is based on assays that are readily available thanks to high-throughput automated analytical techniques. Preanalytical considerations, such as the need to fast and analytical performance of individual assays, should be considered in the context of the requirements for clinical decision-making. In particular, the risk of macrovascular complications of diabetes can be anticipated by consideration of major cardiovascular risk factors including total cholesterol (TC), fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C), from which additional indicators such as low-density lipoprotein cholesterol (LDL-C) and non-HDL cholesterol (NHDL-C) may be derived.

Hydroxamic acids 6a-h, derived from malonyl amino acids, and 25a-d, derived from succinyl amino acids, were synthesized as inhibitors of human bronchiolar smooth muscle endothelin-converting enzyme (HBSM ECE). Several unexpected side reactions were discovered, particularly in the synthesis of hydroxamates derived from succinates. In vitro evaluation against human bronchiolar ECE revealed that in all cases hydroxamates derived from malonate were more potent than hydroxamates derived from succinate. Isopropyl and isobutyl P 1 ' side chains were suitable ; omission of the P 1 ' side chain seriously diminished potency. In the P 2 ' position, several amino acids gave potent malonate-derived hydroxamate inhibitors (6b,d-h, IC 50 = 0.2-6.8 nM), and β-Ala provided an extremely potent inhibitor (6c, IC 50 = 0.01 nM). C-terminus carboxylates are much more potent ECE inhibitors than the corresponding amides. Most of the hydroxamates were also potent inhibitors of thermolysin and neutral endopeptidase (NEP) ; however, the P 2 ' β-Ala derivative 6c uniquely inhibited HBSM ECE much more potently than NEP.

Abstract To explore possible mechanisms whereby the triglyceride-rich lipoproteins IDL and VLDL may promote atherosclerosis, fractional loss of these lipoproteins from the intima–inner media was measured in vivo in genetically hyperlipidemic rabbits of the St Thomas’s Hospital strain and compared with the fractional loss of LDL, HDL, and albumin. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL. In each rabbit, two aliquots of the same macromolecule, one iodinated with 125 I and the other with 131 I, respectively, were injected intravenously on average 24 and 3 hours, respectively, before removal of the aortic intima–inner media. The fractional loss from the intima–inner media of newly entered macromolecules was then calculated. The average fractional losses for VLDL, IDL, LDL, HDL, and albumin in lesioned aortic arches were 0.1%/h (n=4), −0.2%/h (n=3), 1.8%/h (n=4), 11.4%/h (n=3), and 26.3%/h (n=1), respectively; in nonlesioned aortic arches fractional losses for IDL, LDL, HDL, and albumin were 1.7%/h (n=1), 0.6%/h (n=2), 14.6%/h (n=3), and 25.9%/h (n=3). In both lesioned and nonlesioned aortic arches, the logarithms of these fractional loss values were inversely and linearly dependent on the diameter of the macromolecules ( R 2 =.57, P =.001 and R 2 =.84, P

Carbon co-implantation has been widely adopted for better Ultra-Shallow Junction formation in the fabrication of advanced semiconductor devices. Currently, carbon dioxide (CO2) is the primary feed gas for carbon implantation. The primary disadvantage of CO2 is the high oxygen content, which causes significant oxidation of the implant source components resulting in rapid degradation of the source performance. Usually the C+ beam starts to degrade quickly while running continuously with carbon dioxide. Also, some other species’ implants, especially boron, are significantly affected after a short duration of CO2 usage. Carbon monoxide (CO) is described here as an alternative carbon source material to CO2. In our testing, CO has demonstrated significant improvements compared to CO2 for both source life and beam performance. Additionally, this paper describes a subatmospheric delivery option for CO. The cylinder package with reliability information is provided.

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.

Hydroxamic acids 6a-h, derived from malonyl amino acids, and 25a-d, derived from succinyl amino acids, were synthesized as inhibitors of human bronchiolar smooth muscle endothelin-converting enzyme (HBSM ECE). Several unexpected side reactions were discovered, particularly in the synthesis of hydroxamates derived from succinates. In vitro evaluation against human bronchiolar ECE revealed that in all cases hydroxamates derived from malonate were more potent than hydroxamates derived from succinate. Isopropyl and isobutyl P 1 ' side chains were suitable ; omission of the P 1 ' side chain seriously diminished potency. In the P 2 ' position, several amino acids gave potent malonate-derived hydroxamate inhibitors (6b,d-h, IC 50 = 0.2-6.8 nM), and β-Ala provided an extremely potent inhibitor (6c, IC 50 = 0.01 nM). C-terminus carboxylates are much more potent ECE inhibitors than the corresponding amides. Most of the hydroxamates were also potent inhibitors of thermolysin and neutral endopeptidase (NEP) ; however, the P 2 ' β-Ala derivative 6c uniquely inhibited HBSM ECE much more potently than NEP.

This study assessed nonfasting cholesterol and triglyceride in plasma and in lipoproteins as predictors of the extent of aortic atherosclerosis in 2 similar groups of rabbits from the St. Thomas's Hospital strain; the lipoprotein classes studied in the 2 groups were very low (VLDL), intermediate (IDL), low (LDL), and high density lipoprotein (HDL), and Sf greater than 60 lipoprotein, Sf 12-60 lipoprotein, LDL and HDL, respectively. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL, with plasma cholesterol and triglyceride of up to 23 mmol/l and 7 mmol/l, respectively, and with up to 100% of the aortic intima bearing atherosclerosis-like lesions. In group 1 rabbits (n = 25), univariate linear regression showed that cholesterol in plasma, LDL, IDL and in VLDL each were positively associated with the extent of aortic atherosclerosis. In group 2 rabbits (n = 20), cholesterol in plasma, LDL and Sf 12-60, but not in Sf greater than 60 lipoprotein, was consistently positively associated with the extent of aortic atherosclerosis. Neither plasma triglyceride, triglyceride in lipoprotein fractions nor HDL cholesterol was associated consistently with the extent of atherosclerosis. Using step-up multiple linear regression among lipoprotein lipids, IDL and Sf 12-60 lipoprotein cholesterol were the most powerful independent predictors of the extent of aortic atherosclerosis in the 2 groups of rabbits. LDL cholesterol was the only other independent predictor. The results suggest that remnant lipoproteins, whether defined as IDL or Sf 12-60 lipoprotein, play an important causal role in atherosclerosis under conditions where plasma levels of these lipoproteins are elevated.

Human lung endothelin converting enzyme has been isolated in nearly homogeniously pure form. The enzyme is a zinc containing neutral metalloproteinase which is strongly inhibited by phosphoramidon. The enzyme has a subunit mass of about 100 kda and apparent masses of about 232 and 440 kda by gel filtration.

We examined associations between dietary fatty acids and progression of coronary artery disease (CAD) in 50 men receiving a lipid-lowering diet or usual care in the St Thomas' Atherosclerosis Regression Study. Nutrient intake was assessed by dietary history and computerized food tables. Progression of CAD over 39 mo, measured by a decrease in minimum absolute width of coronary segments (MinAWS) on angiography, was highly correlated with intakes of palmitic, stearic (18:0), palmitoleic, and elaidic (t-18:1) acids (P < 0.001); no protective effects were found with polyunsaturates. Total saturates and trans unsaturates explained 20% of variance in CAD progression. After adjustment for plasma cholesterol and other risk factors, change in MinAWS was most closely associated with intakes of 18:0 and t-18:1 fatty acids (P = 0.009). We suggest that progression of CAD in men is strongly related to intakes of both long-chain saturates and trans unsaturates, the effects of 18:0 and t-18:1 possibly being independent of plasma cholesterol concentration.

Serum cholesterol in man rises when cholesterol intake increases, but the extent of the elevation varies between subjects. Part of the variation between subjects is spurious and not reproducible; it is caused by random diet-independent fluctuations of serum lipid levels. Part is due to consistent metabolic differences between subjects. We have earlier found that responsiveness was associated with higher initial total and HDL cholesterol, lower habitual cholesterol consumption, and lower body mass index, and unrelated to gender, age, or apo E phenotype. We have now investigated the metabolic basis of variability by measuring turnover rates of low density lipoprotein (LDL) apolipoprotein B (apo B) on a low-cholesterol diet (140 mg/day) and a high-cholesterol diet (900 mg/day) in 8 volunteers with well-defined differences in the responsiveness of their serum cholesterol to diet. Autologous 125I-LDL was injected on day 23 of each diet period. Its fractional catabolic rate (FCR) was estimated from the ratio of 125I in urine over that in plasma, seven days after injection. FCR (mean +/- SD) increased from 0.24 +/- 0.02 pools/day on the low- to 0.31 +/- 0.20 on the high-cholesterol diet. LDL-apo B concentration rose from 49 +/- 13 to 63 +/- 12 mg/dl, and LDL-apo B production rate, calculated as FCR x concentration/body weight, from 4.8 +/- 1.2 to 8.0 +/- 1.4 mg/kg/day. The individual rise in production rate was significantly correlated with the rise in the serum concentration of LDL-apo B (r = 0.90) or LDL-cholesterol (r = 0.75), and also with the rise in total serum cholesterol measured in these same subjects in similar experiments 3-4 years earlier (r = 0.74). Degradation of LDL by freshly isolated blood mononuclear cells and by mononuclear cells incubated for 72 h in lipoprotein-deficient medium (derepressed cells) was measured on both diets in these and in additional volunteers. The rate of degradation (mean +/- SD) of standard human LDL by fresh cells was 336 +/- 166 ng LDL protein/mg cell protein per 8 h on the low-cholesterol diet, and decreased by 147 +/- 180 ng/mg per 8 h or 44% on the high-cholesterol diet (n = 23, p < 0.01). The catabolic activity of derepressed cells obtained when subjects were on the low-cholesterol diet was negatively related to the LDL cholesterol response (r = -0.57, n = 18, p < 0.05), and to the total cholesterol response in earlier experiments (r = -0.45, n = 18, p < 0.10).(ABSTRACT TRUNCATED AT 400 WORDS)

CURRENT recommendations for lowering the cholesterol level to prevent coronary heart disease have focused largely on primary prevention and have paid less attention to the issue of lowering cholesterol in patients who already have coronary disease.1 2 3 4 5 6 It remains a common conception that in survivors of infarction the extent of myocardial damage is the prime determinant of outcome and serum cholesterol is not a major risk factor.7 The opposing view is that the modifiable risk factors after a myocardial infarction are the same as those before and merit treatment.8 , 9 In current practice, it appears that most patients with coronary disease do . . .

To illustrate the unitary and mutually inducive nature of clinical and basic research, five related studies of normal and abnormal lipoprotein metabolism in man are reported. 1. Regional lipoprotein metabolism was studied by 39 sets of arteriovenous difference measurements in the splanchnic and peripheral territories to localise and quantify some aspects of the production, conversion and catabolism of very low and low density lipoproteins. 2. By kinetic analyses in 43 patients with genetically defined hyperlipidaemias and in controls the metabolic bases of these disorders were partly characterized; the distinct kinetic mechanisms so defined and a genetic classification of primary hyperlipidaemia were shown to correspond, lending support to the validity of this classification. 3. In a patient with hypertriglyceridaemia due to failure to activate the enzyme lipoprotein lipase, resulting from the rare disorder of absence of apolipoprotein CII, the enzyme was activated acutely by infusion of a source of apo CII; serial changes in the concentration of each lipoprotein class were observed, confirming the protean effects of this enzyme on lipid transport. 4. The mechanisms by which commonly employed therapeutic diets influence hyperlipidaemia were studied by measuring lipoprotein synthesis and fractional catabolism in patients receiving high- and low-fat diets and different ratios of saturated and polyunsaturated fats; the kinetic basis in both instances was a change in synthetic rate of low density lipoprotein. 5. Lastly, studies are presented of the very wide individual differences in the degree of hypercholesterolaemia induced by cholesterol feeding. The efficiency of homeostasis against this challenge correlated with the degree to which the rate of cholesterol synthesis was down-regulated in isolated cells, and with the activity of high-affinity low density lipoprotein receptors on these cells. In subsequent twin studies this receptor activity was shown to be strongly influenced by genetic factors suggesting that this aspect of lipid homeostasis may largely be a familial characteristic.

Since Apoprotein A-I (apo A-I) is partially synthesized in the intestine and is secreted into plasma via chylomicrons, we have tested the effects of the daily distribution of fat intake on the concentration and composition of plasma high density lipoprotein (HDL). Ten normal subjects ingested 136 g fat either as a single load (SL) at 0 h or in 6 divided doses from 0 to 10 h (DL). Serial blood samples were obtained over a 24-h period. Studies were performed 7 days apart using a double crossover design and paired comparisons. HDL apo A-I increased during DL (+11% at 9 h, P < 0.01) but was not significantly altered after SL. The HDL Apo A-II concentration did not change. HDL cholesterol decreased significantly (−4 to −7%) during postprandial lipaemia in both phases of the study. Apo A-I and A-II were detected in lipoproteins of d < 1.006 during alimentary lipaemia but not in fasting plasma. These results indicate that HDL apo A-I increases when fat intake is distributed throughout the day (DL), perhaps due to intestinal production of particles with a higher protein/lipid ratio during DL than after a large bolus of oral lipid (SL). Alimentary lipaemia is associated with acute alterations in HDL components including a transient reduction in HDL cholesterol and an increase in the apo A-I/A-II ratio during DL.

1.(1) When isocaloric diets high in saturated fat or polyunsaturated fat were alternately fed to hyperlipidaemic and normal men, serum triglyceride was 35% lower (P 2.(2) The magnitude of the reduction of both serum triglyceride and cholesterol due to the unsaturated fat was greatest in subjects with highest baseline levels. 3.(3) The reduction of triglyceride levels during the unsaturated fat period was due mainly to a change in the very low density lipoprotein (VLDL) triglyceride. The fall in cholesterol, however, was due to changes both in VLDL and low density lipoprotein (LDL) cholesterol levels. The triglyceride/cholesterol ratio of VLDL was significantly lowered by the unsaturated fat diet, but the ratio of triglyceride to apoproteins A, B and C was not significantly altered. 4.(4) Postprandial serum triglyceride levels were higher during saturated fat feeding than when unsaturated fat was fed. The difference was due to higher fasting levels, the increment due to alimentary lipaemia being similar during the two diets. 5.(5) There was no change in post-heparin lipolytic activity (PHLA) nor in fractional removal rate of triglyceride as measured by the intravenous fat tolerance test (IVFTT); these indices of triglyceride clearance from plasma suggested that the fall of triglyceride concentration induced by polyunsaturated fat could not be accounted for by enhanced uptake from plasma. 6.(6) Albumin-bound [9, 10- 3 H]palmitic acid and [1- 14 C]linoleic acid were simultaneously infused, and their relative rates of incorporation into very low density lipoprotein triglyceride (VLDL-TG) was measured in six normolipidaemic men. The results suggested that the saturated fatty acid was preferentially incorporated, and may imply that dietary polyunsaturated fat decreases the rate of secretion of VLDL-TG into plasma.

A series of 57 hyperlipidaemic patients have been investigated clinically and by measurement of cholesterol and triglyceride levels and inspection of stored serum. Two had secondary (alcoholic) hyperlipidaemia. Those with primary disorders were allocated to three groups believed to require different optimal therapy. At one year 51 of these 55 patients had lipid levels within a predetermined normal range and two others showed improvement. Despite the large number of primary hyperlipidaemic states our results suggest that in most patients successful treatment can be given according to simple classification into three therapeutic categories.

By the method of steady-state gel filtration, cholic and taurocholic acids have been shown to be strongly bound by plasma albumin. Cholic acid is more avidly bound than its taurine conjugate. There is probably one primary binding site per albumin molecule, and approximately 7 secondary sites of weaker affinity. Plasma has a very high binding capacity for bile acids and the binding shows rapid equilibration. In the stagnant loop syndrome, protein binding of unconjugated, bile acids may be a factor contributing to their high concentration in plasma.

It is not a new concept that nutrition is one of the causal factors for coronary heart disease (CHD), nor that diet plays a role in its prevention. That this is so follows from extensive epidemiological data, from animal studies in which atherosclerosis can be induced, and can be caused to regress, by dietary manipulation of plasma cholesterol levels, from controlled clinical trials of plasma lipid lowering diets and drugs and from growing understanding of mechanisms underlying the interactions between diet, plasma lipid transport, atherogenesis and arterial thrombosis.4.9 This paper is concerned with how, rather than whether, nutritional patterns should be modd in some, reduction of dietary cholesterol is specifically advocaw and increasingly in recent reports an increase in complex carbohydrate sources containing soluble fibre is advised. Recommendations to increase intake of polyunsaturated fat are usually made, though the extent of change varies considerably and the type of fatty acid is seldom specified. In small metabolic trials, fat-modified diets reduce plasma cholesterol by M-15%, though most larger field studies are associated with a smaIIer change. In evaluating the extent and nature of dietary modification necessary to reduce CHD incidence materially, it is important to recognize that a dose-response relationship exists between the fall in plasma cholesterol and the fall in CHD incidence. This is borne out by comparisons of different trials and is evident from the LRC trial of cholestyramine in which varying compliance with the drug led to differing cholesterol levels and to parallel changes in incidence. It follows that a substantial change in diet, with concordant major change in the distribution of plasma cholesterol levels, will reduce the rate of CHD in the population more effectively than a more modest intervention. The feasibility of achieving a considerable lowering of mean plasma cholesterol is enhanced by the demonstration. that the effects on cholesterol level of certain changes in nutrient intake are additive. A pronounced effect on cholesterol level, and particularly on that of low density lipoprotein (LDL) cholesterol, has been shown when the diet provides 9% energy each from saturated fatty acids and polyunsaturated (chiefly linoleic) acids, supplemented with fruit and vegetable sources of fibre, and restricted in dietary cholesterol. In an institutional study, this diet reduced plasma cholesterol by 29%, LDL cholesterol by 34.5%.S These considerations should be taken into account in designing an optimal diet for high CHD-risk populations. As a rational basis for selecting a recommended nutrient intake, it is suggested that the goal should be to achieve an optimal distribution of plasma cholesterol concentrations. . The target in designing a diet that is to be recommended for population use is to achieve such a distribution, so that a large majority of the population maintains levels associated with low CHD risk. Selection of optimal distributions .has been the subject of multidisciplinary discussion;’ in adults, a population mean of 4.7 mmol/l (180 mg/dl) was proposed. A WHO Expert Committee has referred to a mean of 5.2 mmol/l (200 mg/dl) or less.” These levels were selected on the basis of cross-cultural and prospective epidemiological studies, clinical findings, observations on lipid levels in human neonates, studies of lipoprotein transfer from plasma into the arterial wall and knowledge of LDL interaction with the high-affinity ceil surface receptor for this lipoprotein.

In a survey of identifiable causes of hypertriglyceridaemia, alcoholic excess seemed to be remarkably common. Accordingly, the mechanism and clinical features of alcoholic lipaemia have been studied in thirteen patients. Alcohol did not decrease peripheral uptake of triglyceride from plasma, as assessed by the intravenous fat-tolerance test. It is suggested that alcohol increases hepatic secretion of lipoprotein, inducing hyperlipidaemia in individuals predisposed by having a relatively low ability to clear triglyceride from plasma.

The roles of lipoprotein lipase (LPL) and hepatic lipase in very low density lipoprotein (VLDL) and VLDL remnant metabolism were investigated by (1) in vivo studies where the kinetics of VLDL-apo B removal were measured in patients with non-functioning lipoprotein lipase systems, and (2) in vitro studies where the relative capacities of hepatic lipase and LPL to hydrolyse the triglyceride (TG) of different lipoprotein substrates was measured. The results indicated that VLDL-apo B removal was not impaired in patients with non-functional LPL, nor ws there any apparent abnormality in the conversion of VLDL-apo B to intermediate- (IDL) and low (LDL) density lipoprotein-apo B. Post-heparin plasma hepatic lipase activity against VLDL was normal in these subjects. Purified normal hepatic lipase had a similar Km for VLDL-TG hydrolysis (1.57 mmol/l) to that of LPL (1.49 mmol/l). However, at equal lipoprotein TG concentration, hepatic lipase had increasing activity with lipoproteins of decreasing particle size, in the order chylomicrons much less than VLDL of Sf 100-400 less than VLDL of Sf 60-100 less than VLDL of Sf 20-60 less than IDL. The mean contribution of hepatic lipase to VLDL-TG hydrolysis by post-heparin plasma was 35% in normal controls, but the contribution to IDL-TG hydrolysis was significantly higher (mean - 58%). It is concluded that hepatic lipase plays a significant role in VLDL and, especially, IDL metabolism, at least in patients with non-functioning lipoprotein lipase.

Publisher Summary This chapter presents a report of clinical–pathological section examined in the workshop. Present information from the clinicopathological studies outlined is clearly consistent with the epidemiological finding that atherosclerosis shows independent and opposing relationships with the plasma low-density lipoproteins (LDL)- and high-density lipoproteins (HDL)-cholesterol concentrations and that knowledge of both permits more accurate prediction of coronary risk than does the plasma total cholesterol level. The limited information at present available from clinicopathological studies suggests that the relationship of coronary artery stenosis and tissue cholesterol content to the HDL cholesterol level is continuous over a wide range of concentrations (25–100 mg/dl), without any clear threshold of concentration below which cholesterol deposition becomes particularly marked. The chapter discusses health statistics in populations with low lipid levels, cellular lipid requirements, kinetics of human intimal lipoprotein transport, regression of atheroma in man, lipoproteins and the familial aggregation of coronary heart disease, hypertriglyceridemia, lipoprotein and lipid responses to unifactorial and multifactorial dietary change, genetic variations of plasma lipids, physical activity and plasma lipoproteins, and plasma lipids and lipoproteins in a low-risk community in Naples, Italy.

Summary The treatment of primary hyperlipidaemic states is reviewed. While several metabolically distinct forms of hyperlipidaemia exist, it is possible to classify patients into three groups for the purpose of therapy. Group 1 is defined as hypercholesterolaemia (due to raised levels of β-lipoprotein). In Group 2 the level of endogenous triglyceride is increased, with or without hypercholesterolaemia. In the rare Group 3, there is exogenous hypertriglyceridaemia. A satisfactory response can be attained in at least 90% of cases, using dietary and drug treatment.

Low mean concentrations of high-density lipoprotein (HDL) cholesterol have long been recognized as a characteristic of patients with coronary heart disease, and the measurement of this fraction is a relatively strong discriminator between patients with coronary heart disease and those without. When subjects are ranked by the severity of coronary atherosclerosis determined angiographically, levels of HDL cholesterol, particularly of its HDL2 subclass, are consistently lower in subjects with extensive disease than in those with minimal atheroma. HDL cholesterol is derived from a number of sources, mobilization from peripheral tissues being but one. Generally, longitudinal studies have confirmed that a low HDL cholesterol level is potently and independently predictive of a high risk of coronary heart disease, one exception being a study of subjects with hypercholesterolemia. Despite the strength of these epidemiologic associations, there is no evidence from experimental studies or clinical trials to establish that low HDL levels are causally important in atherogenesis.

In the past decade there have been rapid advances in characterizing the plasma lipoproteins; their lipid and apoprotein content have been well defined, and their structure, including the nature of lipid-protein interactions have in part been identified. The metabolic relationships between the lipoproteins, their physiological roles and the regulation of their synthesis and degradation are the subjects of vigorous research. Some of this work suggests that the conventional, operational definitions of lipoproteins (very-low density, low density and high-density classes, VLDL, LDL and HDL, and chylomicrons) are no longer adequate to the components of this dynamically interrelated system. These names will however be retained in this review.

During the last decade, research on the protein moieties of the plasma lipoproteins has provided a major new dimension to research on the origin of these macromolecules. It is now clear that the triglyceride-rich lipopro- teins are synthesized in near final form in the intestinal mucosa and liver, but the mechanisms of formation of the cholesterol-rich low density lipo- proteins (LDL) and high density lipoproteins (HDL) remain uncertain. Several of the approaches to the origin of lipoproteins and the regulation of lipoprotein biosynthesis were exemplified by the five speakers at this Workshop.

Biochemical risk factors have a potent impact on the overall risk in the development of coronary heart disease (CHD). This impact is greater in men and in women after the menopause. The prevalence of familial hypercholesterolaemia (Familial Type IIa) in the U.K. is approximately 2.5/1000, and 50% of affected males develop overt CHD by the age of 50. The prevalence of Type III hyperlipoproteinaemia is lower. More minor elevations of the plasma cholesterol in association with smoking and/or hypertension, however, may confer a similar overall risk of CHD. Usually minor adverse biochemical effects may be produced by treatment with antihypertensive agents. It is suggested that measurement of fasting cholesterol, including the HDL fraction, together with triglyceride and glucose in new applicants for medical certificates to fly, will identify a small subset at high risk for the development of CHD. Repeat studies at intervals would then be needed. The presence of abnormalities in the plasma lipids associated with excessive smoking and/or minor hypertension make a reasonable case for denying a single-crew certification.

Arterial specimens were obtained from 12 patients during arterial repair surgery and 3 patients during nephrectomy following a bolus injection of autologous radio-iodinated very low density lipoprotein (VLDL) up to 30 h before surgery. Radioactivity in apoprotein B (apo B) was determined in lipoprotein fractions isolated from saline extracts of washed intima in the density ranges less than 1.006 g/ml, 1.006-1.019 g/ml and 1.019-1.063 g/ml [intimal VLDL, intermediate-(IDL) and low density lipoprotein (LDL), respectively]. Specific radioactivity of apo B was measured in corresponding plasma protein fractions. In atheromatous intima, minimum influx rates of VLDL-apo B [12.1 +/- 4.3 (SEM) ng . cm-1 . h-1] and IDL-apo B (13.6 +/- 5.1) over 24 h were significantly higher than fluxes of VLDL-apo B (1.2 +/- 0.34) and IDL-apo B (1.4 +/- 1.1) into normal intima (P less than 0.05). Minimum influx rate of LDL-apo B was also significantly higher in atheromatous intima (196 +/- 39) compared with normal intima (25.8 +/- 13.5, P less than 0.01) and was 16-18 fold higher than corresponding VLDL- and IDL-apo B fluxes in both types of intima. Collagenase digestion of intimal samples after saline extraction yielded further significant mass of VLDL but this fraction had little radioactivity compared with saline extractable VLDL.

The peripheral production of high density lipoprotein (HDL) cholesterol and of the subclasses HDL2 and HDL3 was assessed by measurement of the arteriovenous fluxes across the human forearm, at rest and after 20 min isometric exercise in the forearm. Eight subjects were studied twice--fasting and after a high-fat meal--and one other subject was studied only after fat loading. In the fasted state the net fluxes of HDL2 and HDL3 cholesterol were slightly negative in the resting forearm, but they became positive during exercise, indicating greater production during short-term muscular activity. The effect of exercise, particularly that on HDL3 cholesterol, was greatly increased by a high-fat meal; the difference in HDL3 cholesterol arteriovenous flux between rest and exercise was significant (-0.06 [SEM 0.05] vs 0.51 [0.17] mumol/100 ml forearm/min). By contrast, there was no peripheral production of HDL2 or HDL3 cholesterol during exercise in two patients with lipoprotein lipase deficiency. These findings suggest that formation of HDL3 during lipolysis by lipoprotein lipase in the muscle capillary bed is influenced by the supply of chylomicrons and other lipoprotein substrates for this enzyme. Muscle blood flow may therefore be an important determinant of HDL production by this mechanism. The effect of exercise in raising HDL cholesterol, and the inverse relation between exercise and coronary heart disease, may be partly the result of this process.

SUMMARY A patient with partial lipodystrophy is described in whom hypertriglyceridaemia was accompanied by marked hyperinsulinaemia. The hyperlipidaemia was due to increased plasma levels of very low density lipoprotein (VLDL). Kinetic studies, performed after injection of autologous radioiodinated VLDL, indicated that the raised VLDL levels were associated with over-production of this lipoprotein. Administration of diazoxide led to a substantial fall in serum insulin levels, accompanied by reduction in VLDL production and in serum triglyceride concentration. The possible role of insulin in inducing hyperlipidaemia by causing over-production of VLDL is discussed.

INVESTIGATORS in several laboratories, including our own1, have shown that certain unsaturated fats are able to lower the serum cholesterol-level of human subjects. It is possible that this effect is achieved by an increase in the excretion of the end-products of cholesterol metabolism; hence we have commenced a study of the quantitative changes in these end-products during the administration of different dietary fats. Following the demonstration that ingested cholesterol 4-14C is excreted mainly as cholic acid both in rats2 and in a human bile fistula patient3, particular attention was paid to the bile-acid content of the faeces (estimated by the method of Lewis4). In addition, the Liebermann–Burchard reacting neutral sterols of the faeces were measured by the method of Abell et al. 5 and total faecal lipid according to van de Kamer et al. 6. The serum cholesterol was also measured by the method of Abell et al. 5.

Free fatty acid and triglyceride metabolism was studied in diet-responsive and insulin-dependent diabetics and in non-diabetic obese patients before and during treatment. Free fatty acid turnover was elevated in diabetics and in most obese patients, and was decreased by diabetic control; it showed no significant change in the obese patients during caloric restriction. Plasma triglyceride levels exceeded 160 mg/100 ml in 20 of the 34 diabetics, and gross lipaemia occurred both in insulin-requiring and diet-responsive patients. The fractional turnover of injected triglyceride was low in 20 of 33 measurements on untreated diabetics, and was negatively correlated with endogenous triglyceride levels. The fractional turnover increased significantly during diabetic control. These findings are compatible with the view that diabetic hypertrigly ceridaemia may be due in part to impaired removal of triglyceride from plasma.