Search

Presence of teratoma in the orchiectomy and residual retroperitoneal mass size are known predictors of finding teratoma during postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). We sought to determine if the percentage of teratoma in the orchiectomy specimen could better stratify the risk of teratoma in the retroperitoneum.The Indiana University Testis Cancer Database was reviewed to identify patients who underwent PC-RPLND for nonseminomatous germ cell tumors from 2010 to 2018. A logistic regression model was fit to predict the presence of retroperitoneal teratoma using teratoma and yolk sac tumor in the orchiectomy, residual mass size and log transformed values of prechemotherapy alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin. The study cohort was split into 60% training and 40% validation sets using 200 bootstraps. A predictive nomogram was developed for predicting teratoma in the retroperitoneum.A total of 422 men were included. Presence of teratoma in the orchiectomy (OR 1.02, p0.001), residual mass size (OR 1.16, p0.001) and log transformed prechemotherapy AFP (OR 1.12, p=0.002) were predictive factors for having teratoma in the retroperitoneum. The C-statistic using this model demonstrated a predictive ability of 0.77. Training set C-statistic was 0.78 compared to 0.75 for the validation set. A nomogram was developed to aid in clinical utility.The model better predicts patients at higher risk for teratoma in the retroperitoneum following chemotherapy, which can aid in a more informed referral for surgical resection.

OBJECTIVE To compare the effects of (a) tibolone, (b) continuous combined oestrogen plus progestogen and (c) placebo on plasma lipid and lipoprotein markers of cardiovascular risk in healthy postmenopausal women. STUDY DESIGN Randomized, single-centre, placebo-controlled, double-blind study. PATIENTS One hundred and one postmenopausal women were randomized (1:1:1) into one of three groups taking daily 2.5 mg tibolone, continuous oral oestradiol-17β 2 mg plus norethisterone acetate 1 mg daily (E2 /NETA) or placebo. MAIN OUTCOME MEASURES Fasting serum lipid, lipoprotein and apolipoprotein concentrations measured at baseline and after 6, 12 and 24 months of treatment. RESULTS Both tibolone and E2 /NETA lowered plasma total cholesterol concentrations relative to placebo. With tibolone, high-density lipoprotein cholesterol (HDL-C) was reduced (-27% at 24 months, P

Background UK deaths due to chronic liver diseases such as cirrhosis have quadrupled over the last 40 years, making this condition now the third most common cause of premature death. Most patients with advanced cirrhosis (end-stage liver disease [ESLD]) develop ascites. This is often managed with diuretics, but if refractory, then the fluid is drained from the peritoneal cavity every 10–14 days by large volume paracentesis (LVP), a procedure requiring hospital admissions. As the life expectancy of patients with ESLD and refractory ascites (if ineligible for liver transplantation) is on average ≤ 6 months, frequent hospital visits are inappropriate from a palliative perspective. One alternative is long-term abdominal drains (LTADs), used successfully in patients whose ascites is due to malignancy. Although inserted in hospital, these drains allow ascites management outside of a hospital setting. LTADs have not been formally evaluated in patients with refractory ascites due to ESLD. Methods/design Due to uncertainty about appropriate outcome measures and whether patients with ESLD would wish or be able to participate in a study, a feasibility randomised controlled trial (RCT) was designed. Patients were consulted on trial design. We plan to recruit 48 patients with refractory ascites and randomise them (1:1) to either (1) LTAD or (2) current standard of care (LVP) for 12 weeks. Outcomes of interest include acceptability of the LTAD to patients, carers and healthcare professionals as well as recruitment and retention rates. The Integrated Palliative care Outcome Scale, the Short Form Liver Disease Quality of Life questionnaire, the EuroQol 5 dimensions instrument and carer-reported (Zarit Burden Interview) outcomes will also be assessed. Preliminary data on cost-effectiveness will be collected, and patients and healthcare professionals will be interviewed about their experience of the trial with a view to identifying barriers to recruitment. Discussion LTADs could potentially improve end-of-life care in patients with refractory ascites due to ESLD by improving symptom control, reducing hospital visits and enabling some self-management. Our trial is designed to see if such patients can be recruited, as well as to inform the design of a subsequent definitive trial. Trial registration ISRCTN, ISRCTN30697116. Registered on 7 October 2015. Electronic supplementary material The online version of this article (10.1186/s13063-018-2779-0) contains supplementary material, which is available to authorized users.

Since its discovery in 1975 dobutamine has been used off-label for treating hemodynamic insufficiency in newborns and children. We present a structured literature review of pharmacokinetic and pharmacodynamic data for dobutamine in the pediatric population. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria. Where possible, results for the pharmacodynamic and pharmacokinetic effect of dobutamine were reported as pooled data. Forty-six papers met the inclusion criteria. With regard to pharmacodynamic data a number of studies reported significant increases in a number of clinical parameters such as heart rate, blood pressure, cardiac output across a wide range of pediatric populations. With regard to pharmacokinetic data studies reported that the infusion rate was positively correlated to plasma dobutamine concentration. There was great variability with regard to dobutamine clearance between individuals and as to whether it followed first- or zero-order elimination kinetics. While the pharmacodynamic effects of dobutamine appear to reflect the pharmacological profile of the drug, the pharmacokinetic data are difficult to interpret due to inhomogeneity between study populations ages, comorbidities, dobutamine dosages and methodologies. High-quality prospective pharmacokinetic and pharmacodynamic data especially in newborns are urgently required prior to a large randomized study.

Purpose: The aim of this study was to evaluate optical and visual functional performance of the osteo-odonto-keratoprosthesis (OOKP).\ud \ud Methods: Optical design and analysis was performed with customized optical design software. Nine patients with implanted OOKP devices and 9 age-matched control patients were assessed. Contrast sensitivity was assessed and glare effect was measured with a brightness acuity test. All OOKP patients underwent kinetic Goldmann perimetry and wavefront aberrometry and completed the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25).\ud \ud Results: Optical analysis showed that the optical cylinder is near diffraction-limited. A reduction in median visual acuity (VA) with increasing glare settings was observed from 0.04 logMAR (without glare) to 0.20 logMAR (with glare at “high” setting) and significantly reduced statistically when compared with the control group at all levels of glare (P < 0.05). Contrast sensitivity was significantly reduced when compared with age-matched controls at medium and high spatial frequencies (P < 0.05). Median Goldmann perimetry was 65 degrees (interquartile range, 64–74 degrees; V-4e isopters) and 69 degrees excluding 2 glaucomatous subjects. Several vision-related NEI VFQ-25 subscales correlated significantly with VA at various brightness acuity test levels and contrast sensitivity at medium spatial frequencies, including dependency, general vision, near activities and distance activities.\ud \ud Conclusions: The OOKP optical cylinder provides patients with a good level of VA that is significantly reduced by glare. We have shown in vivo that updates to the optical cylinder design have improved the patient's field of view. Reduction of glare and refinement of cylinder alignment methods may further improve visual function and patient satisfaction.

SummaryObjective To undertake a comprehensive evaluation of apolipoprotein risk markers for cardiovascular disease (CVD) according to gender, age and menopausal status. Design Cross-sectional analysis of independent associations of gender, age and menopause with serum apolipoproteins. Participants Apparently healthy Caucasian premenopausal (n = 109) and postmenopausal (n = 252) women not taking oral contraceptives or hormone replacement, and Caucasian men (n = 307). Measurements Serum apolipoprotein (apo) B, A-I and A-II concentrations were measured, plus serum total cholesterol, low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), triglycerides, cholesterol in HDL subfractions and the apoB/apoA-I, LDL-C/apoB, HDL-C/apoA-I and HDL-C/apoA-II ratios. Analyses were undertaken with and without standardization for confounding characteristics and in 5-year age ranges. Results Overall, apoB concentrations were highest in men but in women rose with age and menopause to converge, in the age range of 50–55 years, with concentrations in men. The LDL-C/apoB ratio was generally higher in women than in men. ApoA-I concentrations were highest in postmenopausal women and lowest in men (standardized median (IQR) 144 (130, 158) vs 119 (108, 132) g/l, respectively, P < 0·001). ApoA-II concentrations were also highest in postmenopausal women but were lowest in premenopausal women (40·3 (37·5, 44·5) vs 32·9 (30·5, 35·7) g/l, respectively, P < 0·001). Nevertheless, postmenopausal women had HDL-C/apoA-I and HDL-C/apoA-II ratios approaching the lowest ratios, which were seen in men. Conclusions Consistent with adverse effects on CVD risk, male gender, ageing in women and menopause were associated with increased apoB concentrations, and menopause and male gender were associated with a decreased cholesterol content of HDL particles.

Aim: The authors of this review present the current evidence of the physiology, indications and use of adrenaline in neonates, with particular focus on the treatment of hypotension. Method: A structured literature search was performed across selected electronic databases, reference lists and related articles. Abstracts arising from the search were screened for relevance according to predefined inclusion criteria. Full articles for the selected abstracts were obtained and then reviewed. Articles were analysed through a two stage process until agreement was reached between the research team on the studies for inclusion. Results: We identified 187 animal and human studies (published between 1924-2011) using various methodologies but with two main themes: the physiology of endogenous adrenaline in neonates and the therapeutic uses of this hormone in neonatal medicine. The physiological studies measured catecholamine levels in cord blood, neonatal urine and blood, some in response to interventions such as suctioning, skin massage or morphine infusion. Within the therapeutic studies there was only one randomised controlled trial (RCT): a comparison of dopamine versus adrenaline involving 60 infants of < 32 weeks gestational age. Conclusion: Despite the number of studies identified, we found few adequately-controlled studies on the therapeutic use of adrenaline in neonates. Future research should focus on RCTs comparing adrenaline to other commonly used inotropes.

OBJECTIVE To compare two strategies to enhance placento-fetal blood transfusion in preterm neonates before 33 weeks of gestation. METHODS We recruited women at risk for singleton preterm deliveries. All delivered before 33 completed weeks of gestation. In this single-center trial, women were randomized to either standard treatment (clamping the cord for 30 seconds after delivery) or repeated (four times) milking of the cord toward the neonate. Exclusion criteria included inadequate time to obtain consent before delivery, known congenital abnormalities of the fetus, Rhesus sensitization, or fetal hydrops. RESULTS Of 58 neonates included the trial, 31 were randomized to cord clamping and 27 were randomized to repeated milking of the cord. Mean birth weight was 1,263±428 g in the clamping group and 1,235±468 g in the milking group, with mean gestational age of 29.2±2.3 weeks and 29.5±2.7 weeks, respectively. Mean hemoglobin values for each group at 1 hour after birth were 17.3 g/L for clamping and 17.5 g/L for milking (P=.71). There was no significant difference in number of neonates undergoing transfusion (clamping group, 15; milking group, 17; P=.40) or the median number of transfusions within the first 42 days of life (median [range]: clamping group 0 [0-7]; milking group 0 [0-20]; P=.76). CONCLUSION Milking the cord four times achieved a similar amount of placento-fetal blood transfusion compared with delaying clamping the cord for 30 seconds. CLINICAL TRIAL REGISTRATION National Research Register UK, www.nihr.ac.uk/Pages/default.aspx, N0051177741. LEVEL OF EVIDENCE I.

Forced-air warming is a commonly used warming modality, which has been shown to reduce the incidence of inadvertent perioperative hypothermia (36°C). The reusable resistive heating mattresses offer a potentially cheaper alternative, however, and one of the research recommendations from the National Institute for Health and Care Excellence was to evaluate such devices formally. We conducted a randomized single-blinded study comparing perioperative hypothermia in patients receiving resistive heating or forced-air warming.A total of 160 patients undergoing non-emergency surgery were recruited and randomly allocated to receive either forced-air warming (n=78) or resistive heating (n=82) in the perioperative period. Patient core temperatures were monitored after induction of anaesthesia until the end of surgery and in the recovery room. Our primary outcome measures included the final intraoperative temperature and incidence of hypothermia at the end of surgery.There was a significantly higher rate of hypothermia at the end of surgery in the resistive heating group compared with the forced-air warming group (P=0.017). Final intraoperative temperatures were also significantly lower in the resistive heating group (35.9 compared with 36.1°C, P=0.029). Hypothermia at the end of surgery in both warming groups was common (36% forced air warming, 54% resistive heating).Our results suggest that forced-air warming is more effective than resistive heating in preventing postoperative hypothermia.NCT01056991.

Background Many United Kingdom patients with asthma and rhinitis are allergic, but in primary care few diagnostic and management decisions are made with formal allergy assessment. Arguably, knowing a patient's atopic status might be helpful in distinguishing the cause of disease and in selecting appropriate treatments. Objectives Our objective was to estimate the extent to which a formal allergy assessment (a structured allergy history and skin prick tests to 5 common aeroallergens) would improve the precision of allergy diagnosis compared with a patient's self-report or the structured allergy history alone. Methods One hundred twenty-seven patients with asthma, rhinitis, or both were recruited from 4 general practices in Wessex, United Kingdom. Allergy status based on the patient's opinion and on structured allergy history alone was compared with formal allergy assessment. Assessments were validated by an independent allergy specialist reviewing the files. Patients were given written advice specific to their allergies and followed up 3 months later to assess satisfaction, recall, and effect on health and behavior. Results Self-reporting misclassified allergic status in many patients. A structured allergy history alone was little better and resulted in false-positive rates for cat allergy of 32%, grass pollen of 48%, house dust mite of 75%, tree pollen of 54%, and dog of 27% compared with formal allergy assessment. Skin prick testing combined with a structured history was essential to reach a correct causative diagnosis. Three months later, 41% patients had made changes to lifestyle, medications, or both, and 18% reported clinical improvement. Conclusions Skin prick testing improves the accuracy of an assessment of allergic status based on patient opinion or a structured allergy history alone.

To distinguish the effects of menopause, gender and age on serum lipid risk markers for vascular disease, including high-density lipoprotein cholesterol (HDL-C) subfractions 2 and 3 (HDL2-C and HDL3-C).We undertook a cross-sectional database analysis of apparently healthy Caucasian pre- and postmenopausal women and men (n=515, 518 and 800, respectively) not taking drugs affecting lipid metabolism (including contraceptive or post-menopausal steroids). Measurements of serum total cholesterol (TC), low-density lipoprotein (LDL-C), triglycerides (TG), HDL-C, HDL2-C, HDL3-C and non-HDL-C concentrations and the TC/HDL-C concentration ratio were considered.Men had lower TC than postmenopausal women (p0.001) and similar LDL-C. Compared with premenopausal women, postmenopausal women had a more atherogenic lipid profile with lower HDL2-C (median 0.67 vs 0.60 mmol/L, p0.001) but no difference in HDL3-C (0.96 vs 0.96 mmol/L, p=0.8). Compared with either pre or postmenopausal women, men had a more atherogenic profile with lower HDL2-C (0.36 mmol/L) and HDL3-C (0.91 mmol/L, all p0.001). With standardization for confounding variables, including standardization to age of menopause (50 years), differences apparent in the non-standardized comparisons were generally sustained, although HDL3-C levels were lower at menopause, HDL2-C ceased to differ and LDL-C was lower in postmenopausal women than men.Male gender is associated with a more atherogenic profile than female gender, with appreciably lower levels of the HDL2-C subfraction. Among women, menopause is associated with a more atherogenic lipid profile, but has less effect than male gender.

The incentivization of UK primary care through the Quality and Outcomes Framework (QOF) has released an unprecedented supply of data that in theory could aid health equity audit and reduce health inequalities. The current system allows for 'exception reporting' whereby patients can be excluded from calculation of payment for reasons such as failure to attend review. We speculated that such exclusions could be linked to socioeconomic deprivation.We assessed 'exception reporting' rates for 15 diabetes indicators using 2004/05 QOF data for 49 general practitioner (GP) practices in Brighton and Hove and related it to a deprivation ranking for each practice.The standardized diabetes prevalence was 26% higher (P0.001) in the highest compared to the lowest quintile of deprivation. Correlations between 'exception reporting' and deprivation were seen for 10 of the 15 diabetes indicators (r = 0.20-0.41, P0.05). Practices with a more deprived patient population were more likely to report 'exceptions' for QOF indicators, although there was no such relationship with the achievement of QOF targets.Strategies to reduce health inequalities need to take into account that high levels of exception reporting, particularly in practices with deprived populations, may be disguising unmet need in those populations.

Many postmenopausal women are reluctant to take hormone replacement therapy (HRT) and those who do are likely to discontinue within 1 year. Setting aside the beliefs and prejudices of the prescriber, women's own perceptions of risks and benefits may influence their willingness to accept and then persevere with HRT. We conducted a systematic literature review relating women's beliefs about HRT to acceptance and adherence.Using standard guidelines for systematic search procedures, we identified 112 papers (published during 1980-2002) from databases such as Medline, PsycINFO and the NHS and Cochrane libraries.Women hold both positive and negative beliefs about HRT. Their perceptions of benefits are often countered by concerns over potential adverse effects, beliefs that are sometimes at odds with the clinical evidence. The use and discontinuation of HRT are influenced more by short-term symptom relief than by considerations of long-term benefits. Many women who refuse HRT believe that the menopause is a natural event that does not warrant 'chemical' intervention. Doctors and nurses are not used to their full capacity as an education and information resource to counter the possibility of unbalanced stories in the media.Addressing women's preconceptions about HRT should be an important part of the process of prescribing and review. Such an approach will help ensure that a woman's decision to start or continue HRT is informed by an understanding of the known risks and benefits, rather than by myths or mistaken beliefs about the menopause or HRT.

Dietarytransfatty acids are associated with increased risk of CHD. We hypothesized that the changes in plasma lipids associated with a high intake oftransfatty acids would cause adverse effects on procoagulant and fibrinolytic activities. A randomized crossover controlled feeding study was conducted in twenty-nine men. Atrans-rich diet supplying 10 % energy astrans-18:1 was compared with diets in which thetransfatty acids were replaced either with carbohydrate or oleate; each diet was taken for 2 weeks in random order. Fasting fibrinogen and D-dimer concentrations and factor VII coagulant, plasminogen activator inhibitor type 1 and tissue plasminogen activator did not differ between diets. Postprandially, tissue plasminogen activator activity increased and plasminogen activator inhibitor type 1 activity decreased on all diets. Factor VIIc increased postprandially by 15 and 17 % on thetransand oleate diets respectively, compared with an 11 % increase on the carbohydrate diet; the mean difference between oleate and carbohydrate diets was 6 (95 % CI 0·2, 11·9) %. The LDL-cholesterol:HDL-cholesterol and apolipoprotein B: apolipoprotein A-I ratios increased by 13 (95 % CI 5·7, 21·8) and 10 (95 % CI 3·1, 17·2) % respectively on thetransdiet compared with the oleate diet and by 6 (95 % CI 0·1,12·7) and 7 (95 % CI 0, 13·5) % respectively compared with the carbohydrate diet. Plasma HDL2-cholesterol concentration was 18 (95 % CI 0·7, 35·9) % lower on thetransdiet compared with the oleate diet. The results confirm adverse effects oftransfatty acids on HDL-cholesterol concentrations, but suggest thattransfatty acids do not have any specific effects on known haemostatic risk markers for cardiovascular disease in healthy young men in the short-term.

We studied a four-generation family (17 subjects) with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. A 30-year-old Caucasian male with corneal clouding and HDL cholesterol Val), a previously reported mutation (Thr321-->Met) and a common variant (Thr208-->Ser) of the gene. Immunoreactive LCAT concentration (1.2 microg/ml), alpha-LCAT activity (13 nmol/ml per h) and cholesterol esterification rate (CER) (14 nmol/ml per h) in his plasma were, respectively, 14, 8 and 14% of the mean values in healthy subjects. The proband and 13 of his relatives also had familial defective apo B (FDB, Arg3500-->Gln). Six subjects had LCAT Phe382-->Val in combination with FDB. Plasma lipoprotein(a) (Lp(a)) was 24 nmol/l in the proband and 46-211 nmol/l in his father and siblings, consistent with expression of the 16 kringle 4 isoform. The proband had no signs of coronary heart disease (CHD), but his father, a paternal uncle and a female cousin had CHD before age 38 years

Objectives: To investigate in depth the metabolic effects of oestradiol-17 β both alone and in combination with the progestagen dydrogesterone. Methods: Fifteen hysterectomised postmenopausal women were studied before treatment and after 24 weeks taking oestradiol-17 β alone (2 mg per day), then following a further 6 (oestrogen-alone phase) and 12 (oestrogen plus progestagen phase) weeks with inclusion of dydrogesterone (10 mg per day for days 17–28 of each 28 day cycle). Measurements at each visit included fasting serum lipid and lipoprotein concentrations, insulin sensitivity, secretion and elimination by modelling analysis of intravenous glucose tolerance test glucose, insulin and C-peptide concentrations, body fat distribution by dual-energy X-ray absorptiometry (DXA) and arterial function by carotid artery ultrasound. Results: Significant reductions were seen throughout in total and LDL cholesterol. The net reductions in total and LDL cholesterol by the end of the study were 5.8% (P

Background: The adverse effects of inadvertent perioperative hypothermia in the surgical population are well established. The aim of this study was to investigate whether a resistive warming mattress would reduce the incidence of inadvertent perioperative hypothermia in patients undergoing elective caesarean section. Methods: A total of 116 pregnant women booked for elective caesarean section were randomised to either intraoperative warming with a mattress or control. The primary outcome was the incidence of inadvertent perioperative hypothermia, defined as a temperature

Despite being an unprecedented departure from normal physiology, the combined oral contraceptive is not only highly effective, but it also has a remarkably good safety record. Concerns over safety persist, though, particularly with regard to venous thromboembolism (VTE), stroke and myocardial infarction (MI). Epidemiological studies consistently show an increase in risk of VTE, but the results are more contentious with regard to arterial diseases. Despite 40 years of research, the mechanisms behind these adverse effects are not understood. In this review, we integrate information from published studies of the epidemiology and pathology of the occlusive vascular diseases and their risk factors to identify likely explanations for pathogenesis in oral contraceptive users. Oral contraceptives induce both prothrombotic and fibrinolytic changes in haemostatic factors and an imbalance in haemostasis is likely to be important in oral contraceptive-induced VTE. The complexity of the changes involved and the difficulty of ascribing clinical significance has meant that uncertainty persists. A seriously under-researched area concerns vascular changes in oral contraceptive users. Histologically, endothelial and intimal proliferation have been identified in women exposed to high plasma estrogen concentrations and these lesions are associated with thrombotic occlusion. Other structural changes may result in increased vascular permeability, loss of vascular tone and venous stasis. With regard to arterial disease risk, epidemiological information relating to dose effects and joint effects with other risk factors, and studies of pathology and changes in risk factors, suggests that oral contraceptive use per se does not cause arterial disease. It can, nevertheless, synergise very powerfully with subclinical endothelial damage to promote arterial occlusion. Accordingly, the prothrombotic effects of the oral contraceptive estrogen intervene in a cycle of endothelial damage and repair which would otherwise remain clinically silent or would ultimately progress - in, for example, the presence of cigarette smoking or hypertension - to atherosclerosis. Future work in this area should focus on modification of the effects of established risk factors by oral contraceptive use rather than modification of the supposed risk of oral contraceptive use by established risk factors. Attempts to understand vascular occlusion in oral contraceptive users in terms of the general features of VTE or with reference to atherosclerosis may be limiting, and future work needs to acknowledge that such occlusions may have unique features. Unequivocal identification of the mechanisms involved would contribute considerably to the alleviation of fears over vascular disease and to the development of even safer formulations.

Abstract —British Indian Asian men aged P P P P >.05) MI patients compared with respective ethnic control subjects. Fasting glucose and total cholesterol levels did not differ between patients and control subjects. Abdominal obesity, impaired NEFA suppression after oral glucose, and fasting hyperinsulinemia were present in Sikh MI patients and their nondiabetic first-degree relatives compared with Sikh control subjects. PS survivors of premature MI demonstrated impaired insulin-mediated glucose disposal and NEFA suppression compared with ethnic control subjects. BWMI patients showed abnormalities of carbohydrate, but not of NEFA, metabolism compared with white control subjects. Defects of insulin action manifested as abdominal obesity, impaired NEFA suppression, and fasting hyperinsulinemia are present in Sikh MI patients and their asymptomatic, nondiabetic, first-degree relatives. We suggest that these defects may be early metabolic markers that predict risk of premature MI among PSs.

Abstract Modification of dietary fat composition may influence hemostatic variables, which are associated with increased risk of coronary heart disease (CHD). To address this question, we performed a controlled feeding study on 26 healthy male nonsmoking subjects with diets of differing fat composition. For the first 3 weeks, the subjects were given a diet calculated to supply 30% energy as total fat: 8% as monounsaturated, 4% as polyunsaturated, and 16% energy as saturated fatty acids, respectively (saturated diet). This was followed immediately by two diets taken in random order, each of 3-week duration and separated by an 8-week washout period on the subject’s usual diet. Both diets were calculated to supply 30% of energy as fat: 14% monounsaturated, 6% as polyunsaturated, and 8% energy as saturated fatty acids. They both provided 5 g (approximately 1.7% energy) more of polyunsaturated fatty acids than the saturated fat diet; in one diet as long-chain n-3 fatty acids ( n-3 diet) and in the other as linoleic acid ( n-6 diet). Fasting plasma lipids, lipoproteins, and hemostatic factors were measured on the final 3 days of each dietary period. In a subset of 9 subjects the postprandial responses to a test meal were studied on the penultimate day of each period, each meal having the fat composition of its parent diet. On the n-3 diet compared with the n-6 diet, plasma triglyceride, HDL 3 cholesterol, apoprotein AII, and fibrinogen concentrations were lower and HDL 2 cholesterol concentration was higher ( P =.0001, P =.003, P =.0001, P =.004 and P = .001, respectively). On both the n-3 and n-6 diets compared with the saturated diet, fasting plasma total and LDL cholesterol, apoprotein B, β-thromboglobulin concentrations, and platelet counts were lower ( P P P P P P =.02 and P n-3 diet ( P =.004 and P =.01, respectively) compared with the saturated diet. Plasma fibrinogen concentration was significantly greater following the n-6 diet than on the saturated diet ( P =.02). Postprandially, plasma triglyceridemia was greater on the n-6 diet and lowest on the n-3 diet ( P n-3 and n-6 diets (both P n-3 fatty acids decreases fasting plasma triglyceride and apoprotein AII concentrations and increases HDL 2 cholesterol concentrations and results in less postprandial lipemia but leads to an increase in VIIc. An increased intake of linoleic acid may raise plasma fibrinogen concentration. Decreasing the intake of saturated fatty acids reduces plasma LDL cholesterol and apoprotein B without affecting HDL cholesterol concentration independent of the type of polyunsaturated fatty acids in the diet. When advice is given to reduce saturated fat intake, it is important to ensure an appropriate ratio of n-3/n-6 fatty acids in the diet.

Elevated serum lipoprotein(a) [Lp(a)] levels increase the risk of cardiovascular disease if levels of low-density lipoproteins (LDLs) are also high. The biological function of Lp(a) is unknown, but plasma levels may be elevated in inflammatory disease. Endometriosis is a common gynecologic disorder in which endometrial tissue is found outside of the lining of the uterine cavity. There is an immune component to this condition whereby the number of peritoneal macrophages is increased and the level of prostanoids and cytokines in peritoneal fluid is elevated. In the present study, we measured serum lipid, lipoprotein, and apolipoprotein levels in 29 women with endometriosis and in 29 matched healthy controls. Fasting serum triglyceride and apolipoprotein (apo) Al levels were higher in women with endometriosis (+28.1%, P < .001, and +12.3%, P < .01, respectively), but there were no significant differences in LDL or high-density lipoprotein (HDL) cholesterol levels. Serum Lp(a) levels were fivefold higher (P < .01) in the patients (median, 15.0 mg/dL; range, 0.05 to 60.0) than in controls (median, 3.1 mg/dL; range, 0.05 to 57.2). The distribution of apo(a) isoforms was similar in the two groups, but in women with endometriosis the individual apo(a) isoforms tended to be associated with higher serum Lp(a) levels. Endometriosis may represent a relatively common condition in which to investigate the role of Lp(a) in human metabolism.

Abstract Familial combined hyperlipidemia (FCHL) is a common cause of premature myocardial infarction, but its metabolic basis is unknown. Insulin resistance has been suggested in some patients by the presence of fasting hyperinsulinemia. We studied insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control subjects by a two-step euglycemic, hyperinsulinemic clamp. During low-dose insulin infusion, steady-state nonesterified fatty acids (NEFAs) were higher in patients than in control subjects (0.36 mmol/L [95% confidence limits, 0.19, 0.53] versus 0.19 mmol/L [0.10, 0.28]; P =.05). The ratio of steady-state to basal NEFAs was increased by 88% in patients compared with control subjects ( P =.005). During high-dose insulin infusion, insulin sensitivity for peripheral glucose disposal was reduced by 60% in FCHL patients compared with control subjects ( P =.03). Hepatic glucose production at baseline and during the clamp was similar in the two groups. In multiple regression analysis, increased upper-body fat in the patient group accounted for the impairment of insulin-mediated glucose disposal but did not influence the defect in insulin-mediated NEFA suppression in the FCHL patients. This defect in fatty acid metabolism may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of this disorder.

Insulin resistance and hyperinsulinaemia may be important in a cluster of coronary heart disease-related metabolic disturbances known as the insulin resistance syndrome. Whether the relationships between insulin and other features of the syndrome are independent of the amount and distribution of body fat is uncertain. We have investigated these relationships in 103 healthy males, using dual-energy X-ray absorptiometry to measure body fat directly. Volunteers underwent an intravenous glucose tolerance test (IVGTT), from which insulin sensitivity, secretion and elimination were determined by mathematical modelling analysis. Independently of adiposity and body fat distribution, serum triglyceride concentration was correlated with fasting C-peptide concentration and second-phase intravenous glucose tolerance test insulin concentration (r = 0.42, P0.001; r = 0.28, P0.05). High density lipoprotein subfraction 2 (HDL2) cholesterol was correlated with fasting C-peptide, first-phase IVGTT insulin concentration, and the hepatic insulin throughout index (r = -0.15 -0.20, -0. 20 respectively, all P0.05). The association of HDL2 cholesterol with the hepatic throughput index was additionally independent of serum triglyceride concentration (r = -0.18, P0.05). Our results suggest that relative hyperinsulinaemia leads to elevated triglyceride concentration, independently of body fat mass and distribution. Furthermore, the independent association of HDL2 cholesterol with hepatic insulin throughput confirms that hepatic insulin processing may may directly influence lipoprotein metabolism.

PURPOSE : We investigated the relationships between the amount and distribution of body fat and fasting serum lipids and lipoproteins to explore whether coronary artery disease (CAD) risk may be mediated through effects on the serum lipid profile. PATIENTS AND METHODS : We determined serum total cholesterol and triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and HDL subfractions 2 and 3 in 103 healthy men, aged 21 to 77 years (mean 48.7). The amount and distribution of fat were determined directly by dual energy X-ray absorptiometry. Adiposity was determined as the ratio between total body fat tissue and total body lean tissue, while fat distribution was taken as the ratio between the mass of fat tissue in the android (central) and gynoid (hip and thigh) regions. RESULTS : Univariate analysis showed both adiposity and fat distribution to be correlated with total serum cholesterol and triglyceride concentrations (adiposity r =.20,.21 ; both P

OBJECTIVE--To determine whether postmenopausal women with cardiological syndrome X (chest pain and abnormal exercise electrocardiogram despite normal coronary angiography) exhibit disturbances in the full range of proposed components of the putative "insulin resistance syndrome". PATIENTS AND METHODS--20 postmenopausal women with syndrome X and 20 healthy controls each underwent measurement of insulin resistance (by minimal model analysis of the intravenous glucose tolerance test), lipid, lipoprotein, and apolipoprotein concentrations, a range of haemostatic variables, serum uric acid concentration, and centrality of body fat distribution (by dual energy x ray absorptiometry). RESULTS--Women with syndrome X had higher fasting triglyceride concentrations than controls (median: 1.60 v 1.02 mmol/l, P < 0.05). Concentrations of high density lipoprotein cholesterol were lower (1.33 v 1.61 mmol/l, P < 0.05) as were those of the high density lipoprotein apolipoproteins AI and AII. Insulin and C peptide responses to the intravenous glucose tolerance test were higher (27.6 v 19.8 microU/ml/min, P < 0.01; 101 v 72 pmol/ml/min, P < 0.05, respectively), and insulin sensitivity was lower (1.89 v 3.09 min/microU/ml, P < 0.05). There were, however, no significant differences between other proposed components of the insulin resistance syndrome (blood pressure, glucose tolerance, proportion of central body fat, serum uric acid concentration, and plasminogen activator inhibitor-1 activity). Antithrombin III activity was higher in women with syndrome X (121 v 113%, P < 0.01). CONCLUSIONS--Women with syndrome X tend to be insulin resistant and have lipid and lipoprotein abnormalities, but do not exhibit all characteristics of the insulin resistance syndrome. Such variation in correlated risk factors is consistent with underlying heterogeneity in the insulin resistance syndrome and cardiological syndrome X.

Insulin resistance is associated with hypertriglyceridemia and elevated free fatty acid (FFA) concentrations in obese and diabetic individuals, but it is unclear to what extent this relationship is independent of obesity and is present in healthy individuals. We studied 92 healthy middle-aged males selected from the top, middle, and lowest quintiles of the insulin sensitivity index (Si) determined in a group of 182 men using the minimal model of glucose disappearance. Plasma FFA, triglyceride, glucose, insulin, and C-peptide concentrations were measured during a 3-hour intravenous glucose tolerance test (IVGTT). The low-Si (most insulin-resistant) group had more central body fat distribution (subscapular/triceps skinfold thickness) and a higher median body mass index (BMI) of 26.8 (range, 21.1 to 41.1) kg.m-2 compared with the middle- and high-Si groups with BMIs of 24.9 (19.1 to 31.5) and 23.7 (18.8 to 33.2) kg.m-2 (P.05). Relatively minor glucose intolerance in the low-Si group was no longer significant when central adiposity was accounted for. Glucose tolerance was maintained by increased insulin secretion, leading to IVGTT insulin responses twofold and fourfold higher in the middle- and low-Si groups, respectively, compared with the high-Si group (P.01). Fasting FFA and triglyceride concentrations were increased in the low-Si group relative to the other groups independent of BMI or central adiposity (P.01). During the IVGTT, FFA decreased to similar minimum concentrations in all three groups. Triglyceride concentrations during the IVGTT increased above their minimum levels, particularly in the low-Si group (P.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of metabolic disturbances has had an important role in the modification of oral contraceptive formulations toward estrogen-progestin combinations with reduced adverse metabolic impact. An increasing number of interrelationships between metabolic risk factors for cardiovascular disease are being recognized, and a metabolic syndrome of disturbances has been identified with insulin resistance as a potential underlying factor. The insulin resistance syndrome includes hyperinsulinemia and impaired glucose tolerance, hypertriglyceridemia, reduced high-density lipoprotein concentrations, and hypertension. Increased concentration of a small, dense, low-density lipoprotein subtype may also be important. Depending on steroid type and dose, combined oral contraceptives may induce all the features of the insulin resistance syndrome. Reduction in estrogen dose and modification of progestin content have resulted in formulations with no adverse effect on high-density lipoprotein and blood pressure, but insulin resistance and hypertriglyceridemia remain. These are caused primarily by the estrogen component. Therefore modification of the estrogen content of oral contraceptives might result in "metabolically transparent" formulations that could conceivably afford a degree of cardiovascular protection. (AM J OBSTET GYNECOL 1994;170:1528–36.)

In a prospective observational study, the fatty acid content of human umbilical artery and vein wall phospholipids was determined in fetuses classified according to their change in abdominal circumference during the third trimester. Three groups were identified: appropriate for gestational age (AGA; 24 infants) and small for gestational age (SGA; 38 infants) with normal antenatal growth rate, and SGA with fetal growth retardation (22 infants). The venous linoleic acid (18:2 omega 6) content (expressed as a percentage of the total fatty acids identified) was greater in growth retarded SGA fetuses (3.5 (0.6)%) than in SGA fetuses with a normal growth rate (3.1 (0.5)%) and AGA fetuses (3.0 (0.5)%), whereas the venous contents of eicosatrienoic (20:3 omega 6) and docosahexaenoic acid (22:6 omega 3) were lower. In growth retarded SGA fetuses, the venous and arterial 20:3 omega 6 content correlated with the change in abdominal circumference. In SGA fetuses with a normal growth rate, lower contents of arterial 18:2 omega 6 and 22:6 omega 3 were associated with a smaller change in abdominal circumference and birth weight. Different metabolic derangements appear to underly normal and subnormal growth rate in SGA fetuses, suggesting that different strategies of dietary intervention may be required to aid fetal growth and reduce the sequelae of fetal growth retardation.

Our purpose was to investigate the relationship between fetal pancreatic beta-cell function and fetal acidemia and macrosomia in pregnancies complicated by maternal diabetes mellitus.A cross-sectional study at the Harris Birthright Research Centre for Fetal Medicine, London, was performed. In 32 pregnancies complicated by maternal diabetes mellitus cordocentesis was performed at 36 to 39 weeks' gestation for the measurement of umbilical venous blood pH, PO2, PCO2, lactate, and glucose concentration; plasma insulin immunoreactivity; and insulin/glucose ratio. A reference range for plasma insulin and insulin/glucose ratio was constructed by studying fetal blood samples from 80 women who did not have diabetes mellitus.Mean umbilical venous blood pH was significantly lower and plasma insulin immunoreactivity and insulin/glucose ratio were significantly higher than the appropriate normal mean for gestation. There were significant associations between (1) maternal and fetal blood glucose concentrations (r = 0.95, p0.0001), (2) fetal blood glucose and plasma insulin immunoreactivity (r = 0.57, p0.01), (3) fetal plasma insulin immunoreactivity and blood pH (r = -0.39, p0.05), and (4) fetal insulin/glucose ratio and degree of macrosomia (r = 0.76, p0.0001).Fetal pancreatic beta-cell hyperplasia is implicated in the pathogenesis of both fetal acidemia and macrosomia.

Objective: To evaluate the effects of tibolone (Org OD14), a synthetic steroid used for the relief of postmenopausal symptoms, on serum concentrations of lipoprotein(a) (Lp(a)), an independent risk marker for coronary heart disease. Design: Subset of women participating in a non-randomized prospective trial of tibolone therapy. Twenty-seven women requesting relief of menopausal symptoms were treated with tibolone 2.5 mg/day for six months; 27 women who did not request treatment acted as controls. Results: Tibolone induced a substantial fall (p

Sex hormone deficiency is associated with increased coronary heart disease (CHD) risk in women. We measured fasting serum lipids and lipoprotein concentrations in a group of 542 healthy non-obese pre- and postmenopausal women (aged 18-70 years). Ageing was associated with increased concentrations of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein subfraction 3 (HDL3) cholesterol and triglycerides, and decreased concentrations of high density lipoprotein subfraction 2 (HDL2) cholesterol. Body mass index (BMI) was related positively to concentrations of total and LDL cholesterol. Postmenopausal women had significantly higher concentrations of total cholesterol (P < 0.001), triglycerides (P < 0.005), LDL cholesterol (P < 0.001) and high density lipoprotein subfraction 3 (HDL3) cholesterol (P < 0.001), whilst those of HDL and HDL2 cholesterol were significantly lower (P < 0.001). These differences were independent of age, BMI and other potential confounding variables. We conclude that the menopause is associated with potentially adverse changes in lipids and lipoproteins, independent of any effects of ageing. These changes may in part explain the increased incidence of coronary heart disease seen in postmenopausal women.

To comply with the European Working Time Directive (EWTD), from 1 August 2009, junior doctors are required to work no more than 48 hours per week. In accordance with this, East Sussex Hospitals Trust introduced changes to working practice in August 2007. To assess the impact upon patient care and junior doctor welfare a retrospective observational survey comparing data from the year prior to and the year following August 2007 was conducted. No impact on the standard of patient care, as measured by length of stay, death during admission or readmission was found. However, there was a notable increase in episodes of sick leave among junior doctors. Implementation of the EWTD may maintain standards of patient care but may be detrimental to the welfare of doctors in training.

The National Institute for Health and Clinical Excellence guidelines1 for managing childhood urinary tract infection (UTI) suggest restricting subsequent antibiotic prophylaxis to vulnerable groups but giving 3 days prophylaxis to all children undergoing voiding cystourethrography (VCUG). The evidence for this latter recommendation is weak,2 with the only previous study3 being retrospective and without a control group. If antibiotic prophylaxis is unwarranted, then we would certainly not want to use it in these children. After obtaining …

Relationships between serum Lp(a) levels and insulin metabolism were investigated in 147 healthy nonobese men attending an executive health-screening program. Each subject received an IVGTT with measurement of plasma levels of glucose, insulin, and C-peptide. An inverse relationship was seen with the first-phase plasma insulin response when subjects were stratified into quartile ranges of the serum Lp(a) distribution. This relationship was supported by mathematical modeling analyses of these data, which revealed an inverse relationship between serum Lp(a) levels and first-phase pancreatic insulin secretion and plasma Insulin responsiveness to glucose.

Relations between serum lipids, lipoproteins, blood pressure, and insulin metabolism were investigated in 158 healthy men aged 19-77 years and with body mass indexes (BMIs) of 19-41 kg.m-2. Mathematical modeling analysis of glucose, insulin, and C-peptide concentrations during an intravenous glucose tolerance test was used to measure parameters of insulin metabolism. In univariate analysis, both fasting and postglucose insulin concentrations showed significant positive associations with fasting serum triglyceride levels (r = 0.33 and 0.38, respectively) and systolic (r = 0.22 and 0.26) and diastolic (r = 0.21 and 0.24) blood pressure and negative associations with high density lipoprotein subfraction 2 cholesterol (HDL2; r = -0.21 and -0.25). In multivariate analysis, the associations between insulin and HDL2 cholesterol concentrations were found to depend on triglyceride levels. Insulin resistance and basal pancreatic insulin secretion showed significant positive associations with serum triglycerides, which were independent of the effects of age, BMI, and fat distribution. Hepatic insulin throughout was independently associated with HDL2 cholesterol. Associations of insulin-related variables with blood pressure were generally dependent on age and BMI. These results underline the importance of insulin sensitivity and insulin concentrations as determinants of triglyceride metabolism. They also indicate a close relation between hepatic insulin handling and HDL2 concentration that is independent of triglyceride metabolism.

Newer lower dose formulations are associated with an improved cardiovascular disease risk marker profile, which supports their use for longer periods and among older women. Epidemiologic studies of the newer formulations are limited. Without clinical information, an evaluation of the effects of more recent formulations on metabolic risk markers for cardiovascular disease is useful. In a large cross-sectional study, a reduction in the progestin dose and use of alternative progestins substantially reduced the proportion of oral contraceptive users with values associated with an increased risk of cardiovascular disease. No progression in metabolic changes was found by analyzing the effect of the duration of oral contraceptive use. The user's age interacted positively with the oral contraceptive--induced increase in serum triglyceride levels, but there was no interaction of age with the oral contraceptive's effect on oral glucose tolerance, glucose and insulin responses, low-density lipoprotein cholesterol, or high-density lipoprotein subfraction 2 cholesterol levels.New lower dose oral contraceptive (OC) formulations which include those with the progestins desogestrel, norgestimate, and gestodene appear to reduce the risk of cardiovascular (CV) disease. This may lead to longer OC use and OC use in 35 year old women. Yet there have not been many clinical studies of the new formulations. Further research has not yet confirmed an effect of duration of older medium and high dose OC use or the effect of their past use. Researchers at the Wynn Institute for Metabolic Research in London, England believe that, regarding issues of currently used formulations, scientists should consider the results of studies of the older medium and high dose formulations since they have the only reliable data on long term OC safety. In fact, they examine the metabolic markers for CV disease (carbohydrate and lipid metabolic effects). Wynn researchers did not observe a progression in metabolic risk markers for CV disease in women who used OCs continuously for 2 years. Further no potentially adverse interaction existed between user's age and duration of OC use. In fact, user's age caused serum triglyceride levels to rise. Moreover user's age did not adversely affect oral glucose tolerance, glucose and insulin responses, low density lipoprotein subfraction 2 cholesterol levels. In addition, previous OC use left no apparent metabolic effects in former users. Results of studies done at the Wynn Institute suggest that 35 year old women may indeed be able to take current OC formulations as long as they regularly visit a health professional and have their serum lipid levels measured routinely.

Serum levels of lipids, lipoproteins and apolipoproteins were measured in 26 premenopausal women with endometriosis both before and after six months therapy with the anabolic steroid danazol (600 mg/day) and in 15 untreated women who acted as controls. No changes were seen in the control group over six months. In women treated with danazol, mean levels of low density lipoprotein (LDL) cholesterol increased by 36% while those of high density lipoprotein (HDL) cholesterol decreased by 46%, changes characteristic of androgenic steroids. In contrast to this potentially detrimental lipoprotein profile, lipoprotein(a) [Lp(a)] levels were reduced by 78.6% +/- 24.0% (mean +/- S.D.) in women taking danazol. These dramatic changes in Lp(a) levels correlated with baseline Lp(a) levels but not with changes in LDL or HDL. Anabolic steroids such as danazol appear to be powerful modulators of serum Lp(a) concentrations. This could be due to direct effects on Lp(a) metabolism, or secondary to the effects of these steroids on insulin metabolism or on the coagulation and fibrinolysis system.

The protection afforded by postmenopausal oestrogen replacement against cardiovascular disease is not fully explained by changes in plasma lipoproteins. To investigate the effect of oestrogen on arterial tone, Doppler ultrasound was used to assess blood flow characteristics in the internal carotid arteries of 12 postmenopausal women. Patients were studied pretreatment and at weeks 4, 6, 9, and 22 of therapy with transdermal oestradiol 50 micrograms/day. The pulsatility index (PI), which is thought to represent impedance to blood flow distal to the point of sampling, was measured from the flow velocity waveform. 11 of the 12 patients were within 5 years of menopause; 1 was 8 years postmenopausal but had experienced bleeding 4 years after menopause. In the 11 women there was a highly significant correlation (r = 0.77) between time since menopause and baseline PI. A similar correlation (r = 0.74) was observed when the episode of postmenopausal bleeding was redefined as time of menopause in the twelfth patient. For all 12 patients, there was a significant negative correlation (r = -0.70) between change in PI during transdermal oestradiol therapy and mean of baseline plus week 22 PI value. For all correlations between changes in PI and time since menopause, the longer the time the greater the fall in PI. These results, and previous observations of a reduction in uterine artery PI with oestradiol treatment, suggest that oestrogen has a generalised effect on the arterial system.

Fifteen premenopausal women were studied before and 6 weeks after receiving subcutaneous implants of 100 mg estradiol. Serum estradiol levels doubled; increases were also seen in fasting serum total cholesterol and in high-density lipoprotein cholesterol (HDL). This increase was confined to the HDL2 subfraction, and was not reflected in the HDL apolipoproteins. Low density lipoprotein (LDL) cholesterol levels were unchanged, as were those of apolipoprotein B, the major protein component of LDL. Carbohydrate metabolism was assessed in a subgroup of 12 women. Estrogen implantation reduced fasting plasma glucose levels but did not alter the plasma glucose response to an oral glucose tolerance test. Plasma insulin levels were unchanged both in the fasted state and during the glucose tolerance test. Our findings indicate that parenteral administration of estradiol can alter lipid and carbohydrate metabolism in premenopausal women.

SummaryThe pro- and antiatherogenic roles of apolipoproteins B andA-I, respectively, are well-established although the importance of apolipoprotein A-II remains unclear. There is extensive evidence for the involvement of plasma lipoproteins in haemostatic function. However, in-vivo studies of relationships between haemostatic variables and apolipoprotein concentrations are very limited. Plasma fibrinogen, factors VIIc and Xc (FVIIc and FXc, respectively), apolipoproteins (apo) A-I, A-II and B, triglycerides, total, low-density and high-density lipoprotein (HDL) cholesterol, and cholesterol in HDL subfractions 2 and 3 were measured in 186 apparently healthy Caucasian men (aged 26–78 years; body mass index 19.9–37.8 kg/m2).Associations between haemostatic, apolipoprotein,lipid and lipoprotein variables were explored in uni- and multivariable analyses. Fibrinogen did not correlate with any of the lipid-related variables. FVIIc and FXc were significant positive univariate correlates of total cholesterol (correlation coefficients 0.26,p

Disturbances in the thrombotic and fibrinolytic systems are a feature of insulin resistance, obesity, and the metabolic syndrome. However, there are few studies in which these relationships have been explored in mainly asymptomatic individuals using sophisticated measures of insulin sensitivity and regional adiposity. Variables of the hemostatic system were measured in 106 men (aged 32–68 yr; body mass index, 20–34 kg/m2). Insulin sensitivity was measured by minimal model analysis and regional adiposity by dual energy x-ray absorptiometry. Clustering of intercorrelated variables was assessed by the statistical technique of factor analysis. Plasma levels of procoagulant factors VII and X, anticoagulant proteins C and S, and plasminogen activator inhibitor-1 correlated positively with total and percent central body fat (r = 0.25–0.38; P < 0.05) and negatively with insulin sensitivity (except protein S; r = −0.24 to −0.35; P < 0.05). On factor analysis, procoagulant factors VII and X, proteins C and S, and plasminogen activator inhibitor-1 were components of the cluster of variables that explained the greatest proportion of the variance in the data (39.2%). Other variables included in this cluster were those typical of the metabolic syndrome and also serum γ-glutamyl transferase activity. These results suggest that factors VII and X and proteins C and S are features of the intercorrelated disturbances of the metabolic syndrome. Associations with adiposity and liver enzyme activity suggest the involvement of hepatic fat deposition.

Summary objective Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes. design Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol-17 beta with 5 or 10 mg/day dydrogesterone for days 17–28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol-17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9). measurements Patients underwent measurement of glucose, insulin and C-peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured. results In both groups there were significant reductions in fasting glucose, insulin and C-peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P

Androgens and other drugs that reduce plasma concentrations of high density lipoprotein (HDL) cholesterol are often considered to be pro-atherogenic. Tibolone lowers HDL-cholesterol by 20% but the clinical significance of this effect is unknown.In a randomized, double-blind study, 34 women received 2.5 mg tibolone daily and 34 women received placebo. Serum concentrations of lipids, lipoprotein subclasses and apolipoproteins, together with plasma activities of lipid transfer proteins and lipolytic enzymes and the capacity of plasma to induce cholesterol efflux from cultured cells, were measured.Compared to placebo, tibolone reduced serum concentrations of HDL-cholesterol (-14%), HDL phosphatidylcholine (-14%), apolipoprotein (apo)A-I (-12%), HDL subclasses lipoprotein (Lp)A-I (-20%), HDL-apoE (-16%), pre beta-LpA-I (-10%) and alpha-LpA-I (-12%) and increased hepatic lipase activity (+25%) and HDL sphingomyelin : phosphatidylcholine ratio (10.5%), but did not alter serum concentrations of HDL sphingomyelin, apoA-IV and LpA-I/A-II, lipoprotein lipase, the plasma activities of lecithin : cholesterol acyl transferase, cholesteryl ester transfer protein, phospholipid transfer protein or the plasma capacity to release cholesterol from cultured fibroblasts or Fu5AH hepatocytes.Tibolone lowers HDL-cholesterol in part by increasing hepatic lipase activity. Conservation of sphingomyelin and apoA-II in HDL, as well as cholesteryl ester transfer protein activity, preserves the capacity of plasma to release cholesterol, despite the lower concentrations of HDL-cholesterol. This may have important implications for the use of steroid effects on HDL concentrations as surrogates for atherosclerosis.

The effects of an oestrogen/progestagen transdermal therapeutic system (TTS) were evaluated in sixteen oestrogen-deficient women. The patients applied conventional oestradiol-TTS for 14 days, then two combined norethisterone acetate/oestradiol patches for a further 14 days. The treatment was repeated for five cycles. Ten patients then underwent metabolic studies. One patient had amenorrhoea, but the rest experienced regular withdrawal bleeding which was seldom heavy. Fourteen endometrial biopsy samples were taken during the fifth treatment cycle; none showed proliferative or hyperplastic features. The effects of transdermal norethisterone acetate on symptoms, lipid metabolism, and psychological status were determined by comparing features in the oestrogen-only phase and in the combined phase; the effects were very mild. These preliminary findings show that transdermal progestagen can be successfully administered in hormone replacement therapy to prevent endometrial proliferation while minimising the adverse effects that may be seen with oral administration.

Abstract The propensity of atherosclerotic plaques to disrupt may be influenced by their lipid content and the distribution of these lipids within the plaque. To investigate this, we analyzed the morphological and lipid profiles of 668 human aortic plaques from 30 males who had died of ischemic heart disease. Plaques were classified as disrupted or as intact types A or B, the latter distinction being based on the absence or presence, respectively, of disrupted plaques within the same aorta. Disrupted plaques have a greater content of lipid ( P P P P P P

AIM—To compare measures of carbohydrate and lipid metabolism in umbilical venous blood after birth at term in pregnancies with normal and retarded fetal growth during the third trimester. METHODS—Three groups of pregnancies reaching term, in which fetal growth had been prospectively monitored by repeated ultrasound measurements during the third trimester, were studied. Sequential fetal abdominal circumference measurements remained above the 10th centile in 42 (normal size, normal growth group), below the 10th centile but did not depart further than 1.5 SD (small, normal growth group), or below the 10th centile and subsequently fell away by more than 1.5 SD before delivery (small, growth retarded group). Birthweight, neonatal morphometric measures (ponderal index, mid arm:head circumference ratio, subscapular and triceps skinfold thickness), umbilical venous blood concentrations of glucose, insulin, pro-insulin, des 31,32 proinsulin, total cholesterol, free cholesterol, cholesterol ester, triglycerides, lipoprotein (a), apolipoprotein A-1 and apolipoprotein B were measured. RESULTS—The median birthweight of the three groups was significantly different (3570, 2569, and 2277 g, respectively). Median values of ponderal index and mid arm:head circumference ratio were significantly lower in the small, growth retarded group and did not differ between the small and normal size groups with normal growth. Both groups with small fetuses had significantly lower mean glucose and cholesterol ester concentrations, and higher mean free cholesterol:cholesterol ester ratios, compared with the normal size, normal growth group. The group showing fetal growth retardation had mean total cholesterol and mean cholesterol ester concentrations that were significantly lower than those of both the other two groups. Mean des 31,32 proinsulin concentrations were low in both groups of small fetuses, but only significantly so in the group without fetal growth retardation. Mean insulin, proinsulin, free cholesterol, triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B concentrations and the ratio of A-1:B were similar in all three groups. CONCLUSION—The similarity in the umbilical venous blood carbohydrate and lipid profile at term between pregnancies with documented third trimester fetal growth retardation and those with "genetically" small babies argues against a major role for intrauterine nutritional deprivation as a cause for the association between birthweight and subsequent adult disease. Keywords: carbohydrate and lipid metabolism; fetal growth retardation; umbilical venous blood; ultrasonography.

Plasma lipid and lipoprotein assays have become an integral part of national strategies to detect and treat cardiovascular disease.' High plasma concentrations of total and low density lipoproteins (LDL) increase risk, whereas those of high density lipoproteins (HDL) protect. The atherogenic potential of triglycerides is controversial, but this lipid is often used to estimate LDL cholesterol concentrations. The accuracy and precision of these assays are critical as clinical decisions are often made using nationally-defined cut-offs which do not allow for methodological error. In the case of total cholesterol these cut-offs have been lowered so that they now lie well within the normal distribution in the general population and thus their usefulness will be compromised by analytical inaccuracy. For example, a positive bias of 5OJo in a total cholesterol assay would cause misclassification of approximately 40% of patients with high or borderline-high values.? Acknowledgement of widespread inaccuracy in the measurement of total cholesterol led to the UK National Initiative on Cholesterol Accuracy, Methods and Standardization (NICAMS),3 which makes available human sera of known total cholesterol content. The accuracy of triglyceride and HDL cholesterol assays has not been systematically investigated in the UK. We have attempted to estimate the extent of analytical biases for these analytes using data derived from a large UK multicentre study of a lipid-lowering drug."