An impressive body of epidemiologic data collected over the past decade indicates that the risk of colon cancer is elevated in those with metabolic syndrome. This evidence includes studies that examined the risk of colon cancer or adenoma in relation to determinants of the metabolic syndrome (obesity, abdominal distribution of adiposity, and physical inactivity), clinical consequences of this syndrome (type 2 diabetes and hypertension), plasma or serum components of the definition of metabolic syndrome (hypertriglyceridemia, hyperglycemia, and low HDL cholesterol), and markers of hyperinsulinemia or insulin resistance (insulin and C-peptide), which is the underlying metabolic defect of the metabolic syndrome. The mechanism underlying these associations is unknown but may involve the influence of hyperinsulinemia in enhancing free or bioavailable concentrations of insulin-like growth factor-1. Future studies should also be based on better measurements of insulin resistance, beta-cell depletion, and insulin responses to better assess which aspects of insulin resistance are most closely related to the risk of colon neoplasia.

BACKGROUND

Exercise is generally recommended for people with type 2 diabetes mellitus. However, some studies evaluate an exercise intervention including diet or behaviour modification or both, and the effects of diet and exercise are not differentiated. Some exercise studies involve low participant numbers, lacking power to show significant differences which may appear in larger trials.

OBJECTIVE

To assess the effects of exercise in type 2 diabetes mellitus.

METHODS

Trials were identified through the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and manual searches of bibliographies. Date of last search was March 3, 2005.

METHODS

All randomised controlled trials comparing any type of well-documented aerobic, fitness or progressive resistance training exercise with no exercise in people with type 2 diabetes mellitus.

METHODS

Two authors independently selected trials, assessed trial quality and extracted data. Study authors were contacted for additional information. Any information on adverse effects was collected from the trials.

RESULTS

Fourteen randomised controlled trials comparing exercise against no exercise in type 2 diabetes were identified involving 377 participants. Trials ranged from eight weeks to twelve months duration. Compared with the control, the exercise intervention significantly improved glycaemic control as indicated by a decrease in glycated haemoglobin levels of 0.6% (-0.6 % HbA(1c), 95% confidence interval (CI) -0.9 to -0.3; P < 0.05). This result is both statistically and clinically significant. There was no significant difference between groups in whole body mass, probably due to an increase in fat free mass (muscle) with exercise, as reported in one trial (6.3 kg, 95% CI 0.0 to 12.6). There was a reduction in visceral adipose tissue with exercise (-45.5 cm(2), 95% CI -63.8 to -27.3), and subcutaneous adipose tissue also decreased. No study reported adverse effects in the exercise group or diabetic complications. The exercise intervention significantly increased insulin response (131 AUC, 95% CI 20 to 242) (one trial), and decreased plasma triglycerides (-0.25 mmol/L, 95% CI -0.48 to -0.02). No significant difference was found between groups in quality of life (one trial), plasma cholesterol or blood pressure.

CONCLUSIONS

The meta-analysis shows that exercise significantly improves glycaemic control and reduces visceral adipose tissue and plasma triglycerides, but not plasma cholesterol, in people with type 2 diabetes, even without weight loss.

Liver X receptors (LXRs) and farnesoid X receptor (FXR) are nuclear receptors that function as intracellular sensors for sterols and bile acids, respectively. In response to their ligands, these receptors induce transcriptional responses that maintain a balanced, finely tuned regulation of cholesterol and bile acid metabolism. LXRs also permit the efficient storage of carbohydrate- and fat-derived energy, whereas FXR activation results in an overall decrease in triglyceride levels and modulation of glucose metabolism. The elegant, dual interplay between these two receptor systems suggests that they coevolved to constitute a highly sensitive and efficient system for the maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that the tissue-specific action of these receptors is also crucial for the proper function of the cardiovascular, immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXR represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases.

BACKGROUND

Physical activity is associated with low mortality in men, but little is known about the association in women, different age groups, and everyday activity.

OBJECTIVE

To evaluate the relationship between levels of physical activity during work, leisure time, cycling to work, and sports participation and all-cause mortality.

METHODS

Prospective study to assess different types of physical activity associated with risk of mortality during follow-up after the subsequent examination. Mean follow-up from examination was 14.5 years.

METHODS

Copenhagen University Hospital, Copenhagen, Denmark.

METHODS

Participants were 13,375 women and 17,265 men, 20 to 93 years of age, who were randomly selected. Physical activity was assessed by self-report, and health status, including blood pressure, total cholesterol level, triglyceride levels, body mass index, smoking, and educational level, was evaluated.

METHODS

All-cause mortality.

RESULTS

A total of 2,881 women and 5,668 men died. Compared with the sedentary, age- and sex-adjusted mortality rates in leisure time physical activity groups 2 to 4 were 0.68 (95% confidence interval, 0.64-0.71), 0.61 (95% confidence interval, 0.57-0.66), and 0.53 (95% confidence interval, 0.41-0.68), respectively, with no difference between sexes and age groups. Within the moderately and highly active persons, sports participants experienced only half the mortality of nonparticipants. Bicycling to work decreased risk of mortality in approximately 40% after multivariate adjustment, including leisure time physical activity.

CONCLUSIONS

Leisure time physical activity was inversely associated with all-cause mortality in both men and women in all age groups. Benefit was found from moderate leisure time physical activity, with further benefit from sports activity and bicycling as transportation.

To develop a murine model system to test the role of monocyte-derived macrophage in atherosclerosis, the osteopetrotic (op) mutation in the macrophage colony-stimulating factor gene was bred onto the apolipoprotein E (apoE)-deficient background. The doubly mutant (op/apoE-deficient) mice fed a low-fat chow diet had significantly smaller proximal aortic lesions at an earlier stage of progression than their apoE-deficient control littermates. These lesions in the doubly mutant mice were composed of macrophage foam cells. The op/apoE-deficient mice also had decreased body weights, decreased blood monocyte differentials, and increased mean cholesterol levels of approximately 1300 mg/dl. Statistical analysis determined that atherosclerosis lesion area was significantly affected by the op genotype and gender. The confounding variables of body weight, plasma cholesterol, and monocyte differential, which were all affected by op genotype, had no significant additional effect on lesion area once they were adjusted for the effects of op genotype and gender. Unexpectedly, there was a significant inverse correlation between plasma cholesterol and lesion area, implying that each may be the result of a common effect of macrophage colony-stimulating factor levels. The data support the hypothesis that macrophage colony-stimulating factor and its effects on macrophage development and function play a key role in atherogenesis.

OBJECTIVE

Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown.

OBJECTIVE

To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors.

METHODS

A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008.

METHODS

Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized.

METHODS

Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg.

RESULTS

All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group.

CONCLUSIONS

In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events.

BACKGROUND

clinicaltrials.gov Identifier: NCT00641251.

Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans. To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. The transgenes were expressed primarily in the liver and small intestine, mirroring the expression pattern of the endogenous genes. Transgene expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. Fecal neutral sterol excretion was increased three- to sixfold and hepatic cholesterol synthesis increased two- to fourfold in the transgenic mice. No significant changes in the pool size, composition, and fecal excretion of bile acids were observed in the transgenic mice. Transgene expression attenuated the increase in hepatic cholesterol content induced by consumption of a high cholesterol diet. These results demonstrate that increased expression of ABCG5 and ABCG8 selectively drives biliary neutral sterol secretion and reduces intestinal cholesterol absorption, leading to a selective increase in neutral sterol excretion and a compensatory increase in cholesterol synthesis.

The medical hazards of obesity are discussed. Risks include insulin resistance, diabetes mellitus, hypertriglyceridemia, decreased levels of high-density lipoprotein cholesterol, and increased levels of low-density lipoprotein cholesterol. Obesity is also associated with gallbladder disease and some forms of cancer as well as sleep apnea, chronic hypoxia and hypercapnia, and degenerative joint disease. Obesity is an independent risk factor for death from coronary heart disease. A central distribution of body fat enhances the risk for most of these conditions.

BACKGROUND

Current guidelines for cardiovascular risk detection are controversial with regard to the clinical utility of different lipid measures, non-high-density lipoprotein cholesterol (non-HDL-C), lipid ratios, apolipoproteins, and C-reactive protein (CRP).

OBJECTIVE

To directly compare the clinical utility of total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, apolipoproteins A-I and B(100), high-sensitivity CRP, and the ratios of total cholesterol to HDL-C, LDL-C to HDL-C, apolipoprotein B(100) to apolipoprotein A-I, and apolipoprotein B(100) to HDL-C as predictors of future cardiovascular events in women.

METHODS

Prospective cohort study of 15,632 initially healthy US women aged 45 years or older (interquartile range, 48-59 years) who were enrolled between November 1992 and July 1995. All participants were followed up over a 10-year period for the occurrence of future cardiovascular events.

METHODS

Hazard ratios (HRs) and 95% confidence intervals (CIs) for first-ever major cardiovascular events (N = 464) according to baseline levels of each biomarker.

RESULTS

After adjustment for age, smoking status, blood pressure, diabetes, and body mass index, the HRs for future cardiovascular events for those in the extreme quintiles were 1.62 (95% CI, 1.17-2.25) for LDL-C, 1.75 (95% CI, 1.30-2.38) for apolipoprotein A-I, 2.08 (95% CI, 1.45-2.97) for total cholesterol, 2.32 (95% CI, 1.64-3.33) for HDL-C, 2.50 (95% CI, 1.68-3.72) for apolipoprotein B(100), 2.51 (95% CI, 1.69-3.72) for non-HDL-C, and 2.98 (95% CI, 1.90-4.67) for high-sensitivity CRP (P<.001 for trend across all quintiles). The HRs for the lipid ratios were 3.01 (95% CI, 2.01-4.50) for apolipoprotein B(100) to apolipoprotein A-I, 3.18 (95% CI, 2.12-4.75) for LDL-C to HDL-C, 3.56 (95% CI, 2.31-5.47) for apolipoprotein B(100) to HDL-C, and 3.81 (95% CI, 2.47-5.86) for the total cholesterol to HDL-C (P<.001 for trend across all quintiles). The correlation coefficients between high-sensitivity CRP and the lipid parameters ranged from -0.33 to 0.15, and the clinical cut points for CRP of less than 1, 1 to 3, and higher than 3 mg/L provided prognostic information on risk across increasing levels of each lipid measure and lipid ratio.

CONCLUSIONS

Non-HDL-C and the ratio of total cholesterol to HDL-C were as good as or better than apolipoprotein fractions in the prediction of future cardiovascular events. After adjustment for age, blood pressure, smoking, diabetes, and obesity, high-sensitivity CRP added prognostic information beyond that conveyed by all lipid measures.

Cholesterol balance is maintained by a series of regulatory pathways that control the acquisition of cholesterol from endogenous and exogenous sources and the elimination of cholesterol, facilitated by its conversion to bile acids. Over the past decade, investigators have discovered that a family of membrane-bound transcription factors, sterol regulatory element-binding proteins (SREBPs), mediate the end-product repression of key enzymes of cholesterol biosynthesis. Recently orphan members of another family of transcription factors, the nuclear hormone receptors, have been found to regulate key pathways in bile acid metabolism, thereby controlling cholesterol elimination. The study of these orphan nuclear receptors suggests their potential as targets for new drug therapies.

OBJECTIVE

Prostate cancer eventually recurs during androgen deprivation therapy despite castrate levels of serum androgens. Expression of androgen receptor and androgen receptor-regulated proteins suggests androgen receptor activation in recurrent prostate cancer. Many groups have pursued mechanisms of ligand-independent androgen receptor activation but we found high levels of testicular androgens in recurrent prostate cancer tissue using RIA.

METHODS

Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from 18 men whose cancer recurred locally during androgen deprivation therapy and androgen-stimulated benign prostate specimens from 18 men receiving no hormonal treatments were studied. Tissue levels of testosterone and dihydrotestosterone were measured in each specimen using liquid chromatography/electrospray tandem mass spectrometry. Testosterone and dihydrotestosterone levels were compared with clinical variables and treatment received.

RESULTS

Testosterone levels were similar in recurrent prostate cancer (3.75 pmol/g tissue) and androgen-stimulated benign prostate (2.75 pmol/g tissue, Wilcoxon two-sided, P=0.30). Dihydrotestosterone levels decreased 91% in recurrent prostate cancer (1.25 pmol/g tissue) compared with androgen-stimulated benign prostate (13.7 pmol/g tissue; Wilcoxon two-sided, P < 0.0001) although dihydrotestosterone levels in most specimens of recurrent prostate cancer were sufficient for androgen receptor activation. Testosterone or dihydrotestosterone levels were not related to metastatic status, antiandrogen treatment, or survival (Wilcoxon rank sum, all P>> 0.2).

CONCLUSIONS

Recurrent prostate cancer may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol. This surprising finding suggests intracrine production of dihydrotestosterone and should be exploited for novel treatment of recurrent prostate cancer.

BACKGROUND

Present cardiovascular disease (CVD) risk prediction algorithms were developed for a < or =10-year follow up period. Clustering of risk factors at younger ages and increasing life expectancy suggest the need for longer-term risk prediction tools.

RESULTS

We prospectively followed 4506 participants (2333 women) of the Framingham Offspring cohort aged 20 to 59 years and free of CVD and cancer at baseline examination in 1971-1974 for the development of "hard" CVD events (coronary death, myocardial infarction, stroke). We used a modified Cox model that allows adjustment for competing risk of noncardiovascular death to construct a prediction algorithm for 30-year risk of hard CVD. Cross-validated survival C statistic and calibration chi2 were used to assess model performance. The 30-year hard CVD event rates adjusted for the competing risk of death were 7.6% for women and 18.3% for men. Standard risk factors (male sex, systolic blood pressure, antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, and diabetes mellitus), measured at baseline, were significantly related to the incidence of hard CVD and remained significant when updated regularly on follow-up. Body mass index was associated positively with 30-year risk of hard CVD only in models that did not update risk factors. Model performance was excellent as indicated by cross-validated discrimination C=0.803 and calibration chi2=4.25 (P=0.894). In contrast, 30-year risk predictions based on different applications of 10-year functions proved inadequate.

CONCLUSIONS

Standard risk factors remain strong predictors of hard CVD over extended follow-up. Thirty-year risk prediction functions offer additional risk burden information that complements that of 10-year functions.

Hepatic lipid synthesis is known to be regulated by food consumption. In rodents fasting decreases the synthesis of cholesterol as well as fatty acids. Refeeding a high carbohydrate/low fat diet enhances fatty acid synthesis by 5- to 20-fold above the fed state, whereas cholesterol synthesis returns only to the prefasted level. Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate genes involved in cholesterol and fatty acid synthesis. Here, we show that fasting markedly reduces the amounts of SREBP-1 and -2 in mouse liver nuclei, with corresponding decreases in the mRNAs for SREBP-activated target genes. Refeeding a high carbohydrate/low fat diet resulted in a 4- to 5-fold increase of nuclear SREBP-1 above nonfasted levels, whereas nuclear SREBP-2 protein returned only to the nonfasted level. The hepatic mRNAs for fatty acid biosynthetic enzymes increased 5- to 10-fold above nonfasted levels, a pattern that paralleled the changes in nuclear SREBP-1. The hepatic mRNAs for enzymes involved in cholesterol synthesis returned to the nonfasted level, closely following the pattern of nuclear SREBP-2 regulation. Transgenic mice that overproduce nuclear SREBP-1c failed to show the normal decrease in hepatic mRNA levels for cholesterol and fatty acid synthetic enzymes upon fasting. We conclude that SREBPs are regulated by food consumption in the mouse liver and that the decline in nuclear SREBP-1c upon fasting may explain in part the decrease in mRNAs encoding enzymes of the fatty acid biosynthetic pathway.

Detergent-insoluble membrane fragments that are rich in sphingolipid and cholesterol can be isolated from both cell lysates and model membranes. We have proposed that these arise from membranes that are in the liquid-ordered phase both in vivo and in vitro [Schroeder et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 12130-12134]. In order to detect formation of the liquid-ordered phase while avoiding possible detergent artifacts, we have now used fluorescence quenching to examine the phase behavior of mixtures of phosphatidylcholines, sphingolipids, and cholesterol. Phase separation was found in binary mixtures of either dipalmitoylphosphatidylcholine (DPPC) or sphingomyelin (SM) and a nitroxide-labeled phosphatidylcholine (12SLPC). A DPPC- or SM-enriched solidlike gel phase coexisted with a 12SLPC-enriched liquid-disordered fluid phase at 23 degrees C. As expected, phase separation was not seen at low concentrations of DPPC or SM. Instead, only a uniform fluid phase was present. Including 33 mol % cholesterol in model membranes greatly promoted phase separation. Phase separation was seen at higher temperatures and/or at lower concentrations of DPPC or SM in the presence of cholesterol than in its absence. Mixtures of DPPC or SM and cholesterol are known to form the liquid-ordered phase. Therefore, the fact that phase separation was observed in the cholesterol-containing membranes shows that liquid-ordered and liquid-disordered phase domains coexist. At 37 degrees C, the SM-enriched liquid-ordered phase was first seen at a SM/PC ratio of close to 0.25, when SM made up 17% of the total lipid including cholesterol. (This is similar to or less than the SM concentration of the plasma membranes of mammalian cells.) Furthermore, the detergent insolubility of cholesterol-containing model membranes correlated well with the amount of liquid-ordered phase as detected by fluorescence quenching. Thus, the detergent-insoluble membranes isolated from cells are likely to exist in the liquid-ordered phase prior to detergent extraction. The promotion of liquid-ordered phase formation may be an important function of cholesterol and sphingolipids in cells and may be a major distinction between the cholesterol- and sphingolipid-rich plasma membrane and most other cellular membranes.

This report of an expert panel of the National Cholesterol Education Program provides new guidelines for the treatment of high blood cholesterol in adults 20 years of age and over. Total cholesterol levels are classified as follows: less than 200 mg/dL--"desirable blood cholesterol"; 200 to 239 mg/dL--borderline-high blood cholesterol; greater than or equal to 240 mg/dL--high blood cholesterol. The guidelines detail which patients should go on to have lipoprotein analysis, and which should receive cholesterol-lowering treatment on the basis of their low density lipoprotein (LDL)-cholesterol levels and status with respect to other coronary heart disease risk factors. Dietary therapy is the primary cholesterol-lowering treatment. The report specifies the LDL-cholesterol levels at which dietary therapy should be started and the goals of therapy, and provides detailed guidance on the nature of the recommended dietary changes. If, after six months of intensive dietary therapy, LDL-cholesterol exceeds specified levels, drug treatment should be considered.

OBJECTIVE

To assess the outcomes of health behavior interventions, focusing on the elementary school environment, classroom curricula, and home programs, for the primary prevention of cardiovascular disease.

METHODS

A randomized, controlled field trial at four sites with 56 intervention and 40 control elementary schools. Outcomes were assessed using prerandomization measures (fall 1991) and follow-up measures (spring 1994).

METHODS

A total of 5106 initially third-grade students from ethnically diverse backgrounds in public schools located in California, Louisiana, Minnesota, and Texas.

METHODS

Twenty-eight schools participated in a third-grade through fifth-grade intervention including school food service modifications, enhanced physical education (PE), and classroom health curricula. Twenty-eight additional schools received these components plus family education.

METHODS

At the school level, two primary end points were changes in the fat content of food service lunch offerings and the amount of moderate-to-vigorous physical activity in the PE programs. At the level of the individual student, serum cholesterol change was the primary end point and was used for power calculations for the study. Individual level secondary end points included psychological factors, recall measures of eating and physical activity patterns, and other physiologic measures.

RESULTS

In intervention school lunches, the percentage of energy intake from fat fell significantly more (from 38.7% to 31.9%) than in control lunches (from 38.9% to 36.2%)(P<.001). The intensity of physical activity in PE classes during the Child and Adolescent Trial for Cardiovascular Health (CATCH) intervention increased significantly in the intervention schools compared with the control schools (P<.02). Self-reported daily energy intake from fat among students in the intervention schools was significantly reduced (from 32.7% to 30.3%) compared with that among students in the control schools (from 32.6% to 32.2%)(P<.001). Intervention students reported significantly more daily vigorous activity than controls (58.6 minutes vs 46.5 minutes; P<.003). Blood pressure, body size, and cholesterol measures did not differ significantly between treatment groups. No evidence of deleterious effects of this intervention on growth or development was observed.

CONCLUSIONS

The CATCH intervention was able to modify the fat content of school lunches, increase moderate-to-vigorous physical activity in PE, and improve eating and physical activity behaviors in children during 3 school years.

Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.

OBJECTIVE

The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on coronary artery calcification (CAC) scoring in comparison with traditional risk factors.

BACKGROUND

CAC as a sign of subclinical coronary atherosclerosis can noninvasively be detected by CT and has been suggested to predict coronary events.

METHODS

In 4,129 subjects from the HNR (Heinz Nixdorf Recall) study (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline, traditional risk factors and CAC scores were measured. Their risk was categorized into low, intermediate, and high according to the Framingham Risk Score (FRS) and National Cholesterol Education Panel Adult Treatment Panel (ATP) III guidelines, and the reclassification rate based on CAC results was calculated.

RESULTS

After 5 years of follow-up, 93 coronary deaths and nonfatal myocardial infarctions occurred (cumulative risk 2.3%; 95% confidence interval: 1.8% to 2.8%). Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects with CAC <100 to the low-risk category and with CAC ≥400 to the high-risk category yielded an NRI of 21.7% (p = 0.0002) and 30.6% (p < 0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p < 0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p < 0.003) and from 0.653 to 0.755 (p = 0.0001), respectively.

CONCLUSIONS

CAC scoring results in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis. Our study supports its application, especially in carefully selected individuals with intermediate risk.

The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40years to review the history of their development and their impact on clinical medicine. This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field. The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and is a paradigm of a successful journey from 'bench to bedside'. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural 'water softener' in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase. The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans. As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated. It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP-dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (γδ) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved 'block-buster' status with annual sales in excess of a billion dollars. As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New 'designer' BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over.

BACKGROUND

Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance.

METHODS

We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.

RESULTS

Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).

CONCLUSIONS

As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design improved second-generation compounds. Here, we describe the use of a genome-wide pool of tagged heterozygotes to assess the cellular effects of 78 compounds in Saccharomyces cerevisiae. Specifically, lanosterol synthase in the sterol biosynthetic pathway was identified as a target of the antianginal drug molsidomine, which may explain its cholesterol-lowering effects. Further, the rRNA processing exosome was identified as a potential target of the cell growth inhibitor 5-fluorouracil. This genome-wide screen validated previously characterized targets or helped identify potentially new modes of action for over half of the compounds tested, providing proof of this principle for analyzing the modes of action of clinically relevant compounds.

Cholesterol/sphingolipid microdomains (lipid rafts) in the membrane are involved in protein trafficking, formation of signaling complexes, and regulation of actin cytoskeleton. Here, we show that lipid rafts exist abundantly in dendrites of cultured hippocampal neurons, in which they are associated with several postsynaptic proteins including surface AMPA receptors. Depletion of cholesterol/sphingolipid leads to instability of surface AMPA receptors and gradual loss of synapses (both inhibitory and excitatory) and dendritic spines. The remaining synapses and spines in raft-depleted neurons become greatly enlarged. The importance of lipid rafts for normal synapse density and morphology could explain why cholesterol promotes synapse maturation in retinal ganglion cells (Mauch et al., 2001) and offers a potential link between disordered cholesterol metabolism and the synapse loss seen in neurodegenerative disease.

Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8(-/-)). The G5G8(-/-) mice had a 2- to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an approximately 30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8(-/-) mice when compared with wild-type animals (mean = 0.4 vs. 5.5 micromol ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8(-/-) mice and increased 2.4- and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.