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Quantitative bioactivity and toxicity assessment of chemical compounds plays a central role in drug discovery as it saves a substantial amount of resources. To this end, high-performance computing has enabled researchers and practitioners to leverage hundreds, or even thousands, of computed molecular descriptors for the activity prediction of candidate compounds. In this paper, we evaluate the utility of two large groups of chemical descriptors by such predictive modelling, as well as chemical structure discovery, through empirical analysis. We use a suite of commercially available and in-house software to calculate molecular descriptors for two sets of chemical mutagens - a homogeneous set of 95 amines, and a diverse set of 508 chemicals. Using calculated descriptors, we model the mutagenic activity of these compounds using a number of methods from the statistics and machine-learning literature, and use robust principal component analysis to investigate the low-dimensional subspaces that characterize these chemicals. Our results suggest that combining different sets of descriptors is likely to result in a better predictive model - but that depends on the compounds being modelled and the modelling technique being used.

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Studies of reproductive physiology involve rapid sampling protocols that result in time series of hormone concentrations. The signature pattern in these times series is pulses of hormone release. Various statistical models for quantifying the pulsatile release features exist. Currently these models are fitted separately to each individual and the resulting estimates averaged to arrive at post hoc population-level estimates. When the signal-to-noise ratio is small or the time of observation is short (e.g., 6 h), this two-stage estimation approach can fail. This work extends the single-subject modelling framework to a population framework similar to what exists for complex pharamacokinetics data. The goal is to leverage information across subjects to more clearly identify pulse locations and improve estimation of other model parameters. This modelling extension has proven difficult because the pulse number and locations are unknown. Here, we show that simultaneously modelling a group of subjects is computationally feasible in a Bayesian framework using a birth-death Markov chain Monte Carlo estimation algorithm. Via simulation, we show that this population-based approach reduces the false positive and negative pulse detection rates and results in less biased estimates of population-level parameters of frequency, pulse size, and hormone elimination. We then apply the approach to a reproductive study in healthy women where approximately one-third of the 21 subjects in the study did not have appropriate fits using the single-subject fitting approach. Using the population model produced more precise, biologically plausible estimates of all model parameters. Copyright © 2017 John Wiley & Sons, Ltd.

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In this paper, we derive forms of estimators and associated variances for regression calibration with instrumental variables in longitudinal models that include interaction terms between two unobservable predictors and interactions between these predictors and covariates not measured with error; the inclusion of the latter interactions generalize results we previously reported. The methods are applied to air pollution and health data collected on children with asthma. The new methods allow for the examination of how the relationship between health outcome leukotriene E4 (LTE4, a biomarker of inflammation) and two unobservable pollutant exposures and their interaction are modified by the presence or absence of upper respiratory infections. The pollutant variables include secondhand smoke and ambient (outdoor) fine particulate matter. Simulations verify the accuracy of the proposed methods under various conditions.

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Many endocrine systems are regulated by pulsatile hormones - hormones that are secreted intermittently in boluses rather than continuously over time. To study pulsatile secretion, blood is drawn every few minutes for an extended period. The result is a time series of hormone concentrations for each individual. The goal is to estimate pulsatile hormone secretion features such as frequency, location, duration, and amount of pulsatile and non-pulsatile secretion and compare these features between groups. Various statistical approaches to analyzing these data have been proposed, but validation has generally focused on one hormone. Thus, we lack a broad understanding of each method's performance. By using simulated data with features seen in reproductive and stress hormones, we investigated the performance of three recently developed statistical approaches for analyzing pulsatile hormone data and compared them to a frequently used deconvolution approach. We found that methods incorporating a changing baseline modeled both constant and changing baseline shapes well; however, the added model flexibility resulted in a slight increase in bias in other model parameters. When pulses were well defined and baseline constant, Bayesian approaches performed similar to the existing deconvolution method. The increase in computation time of Bayesian approaches offered improved estimation and more accurate quantification of estimation variation in situations where pulse locations were not clearly identifiable. Within the class of deconvolution models for fitting pulsatile hormone data, the Bayesian approach with a changing baseline offered adequate results over the widest range of data.

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In this study, we determined the in vitro and in vivo efficacy of sodium iodide symporter (NIS) gene transfer and the therapeutic potential of oncolytic virotherapy combined with radioiodine therapy using a conditionally replicating oncolytic adenovirus. For this purpose, we used a replication-selective adenovirus in which the E1a gene is driven by the mouse alpha-fetoprotein (AFP) promoter and the human NIS gene is inserted in the E3 region (Ad5-E1/AFP-E3/NIS). Human hepatocellular carcinoma cells (HuH7) infected with Ad5-E1/AFP-E3/NIS concentrated radioiodine at a level that was sufficiently high for a therapeutic effect in vitro. In vivo experiments demonstrated that 3 days after intratumoral (i.t.) injection of Ad5-E1/AFP-E3/NIS HuH7 xenograft tumors accumulated approximately 25% ID g(-1) (percentage of the injected dose per gram tumor tissue) (123)I as shown by (123)I gamma camera imaging. A single i.t. injection of Ad5-E1/AFP-E3/NIS (virotherapy) resulted in a significant reduction of tumor growth and prolonged survival, as compared with injection of saline. Combination of oncolytic virotherapy with radioiodine treatment (radiovirotherapy) led to an additional reduction of tumor growth that resulted in markedly improved survival as compared with virotherapy alone. In conclusion, local in vivo NIS gene transfer using a replication-selective oncolytic adenovirus is able to induce a significant therapeutic effect, which can be enhanced by additional (131)I application.

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UNLABELLED: Dental panoramic radiographs could be used to screen for osteopenia. We found the fractal dimension to be a good discriminator of osteopenia in both men and women but that the mandibular cortical width (MCW) did not perform as well in men. The fractal dimension may be a valid screening tool. INTRODUCTION: The aim of this study was to assess the diagnostic capability of the fractal dimension and MCW measured from dental panoramic radiographs in identifying men and women with decreased bone mineral density (BMD). METHODS: The MCW and fractal dimension were measured from dental panoramic radiographs as surrogates for BMD. These measures were then compared to the results from dual-energy X-ray absorptiometry (DXA) performed for clinical purposes. A total of 56 subjects with the panoramic radiograph taken within 6 months of the DXA exam were used in the analysis for this study. RESULTS: The area under the curve of the fractal dimension for identifying low BMD (T-score <-1.0) was 0.81 (0.67, 0.95) and 0.78 (0.49, 1.00) for men and women, respectively. For the MCW, the area under the curve was found to be 0.53 (0.34, 0.72) and 0.80 (0.58, 1.00) for men and women, respectively. CONCLUSIONS: In this largely male study population, the fractal dimension was found to be a good discriminator of low BMD in both men and women. The MCW did not perform as well in men.

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Gaze-evoked amaurosis is a quite unique symptom. We present a 37-year-old patient with unilateral gaze-evoked amaurosis caused by an orbital tumor. Possible mechanisms include transient ischemia of the optic nerve and the retina or inhibition of the axonal impulses. While not common as a cause of amaurosis fugax, an orbital mass should be considered in the differential diagnosis of gaze-evoked atypical monocular amaurosis fugax.

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OBJECTIVE: To investigate whether insulin resistance modifies the rate of weight gain associated with a high percent of energy intake from dietary fat. DESIGN: Longitudinal, observational population study. SUBJECTS: A total of 782 nondiabetic Hispanic and non-Hispanic white free-living adult residents of the San Luis Valley in Colorado. MEASUREMENTS: Subjects were seen up to three times over a 14-y period. Weight, height, fasting insulin and glucose, diet by 24 h recall, and self-reported physical activity were collected at each visit. RESULTS: Percentage of energy intake from dietary fat was positively associated with weight gain over time (P=0.0103). High intake of dietary fat was more strongly related to weight gain in women than in men, and in those with lower total energy intake levels. The relationship between weight change and relative macronutrient intake also varied by baseline insulin sensitivity (P=0.0025). Weight gain over time in individuals with relative insulin resistance at baseline, as measured by QUICKI, was the greatest among those who consumed a higher percent of energy from fat. CONCLUSION: Percentage of total intake from dietary fat predicts weight change independent of total energy intake. Nondiabetic, insulin-resistant individuals are particularly susceptible to the weight gain associated with high levels of dietary fat intake. Further investigation into the relationship between insulin resistance, diet, and weight gain is warranted.

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OBJECTIVE: To determine if total calcium (Ca(2+)) intake and intake of Ca(2+) from dairy sources are related to whole-body fat oxidation. DESIGN: : Cross-sectional study. SUBJECTS: A total of 35 (21 m, 14 f) non-obese, healthy adults (mean+/-s.d., age: 31+/-6 y; weight: 71.2+/-12.3 kg; BMI: 23.7+/-2.9 kg m(-2); body fat: 21.4+/-5.4%). MEASUREMENTS: Daily (24 h) energy expenditure (EE) and macronutrient oxidation using whole-room indirect calorimetry; habitual Ca(2+) intake estimated from analysis of 4-day food records; acute Ca(2+) intake estimated from measured food intake during a 24-h stay in a room calorimeter. RESULTS: Acute Ca(2+) intake (mg. kcal(-1)) was positively correlated with fat oxidation over 24 h (r=0.38, P=0.03), during sleep (r=0.36, P=0.04), and during light physical activity (r=0.32, P=0.07). Acute Ca(2+) intake was inversely correlated with 24-h respiratory quotient (RQ) (r=-0.36, P=0.04) and RQ during sleep (r=-0.31, P=0.07). After adjustment for fat mass, fat-free mass, energy balance, acute fat intake, and habitual fat intake, acute Ca(2+) intake explained approximately 10% of the variance in 24-h fat oxidation. Habitual Ca(2+) intake was not significantly correlated to fat oxidation or RQ. Total Ca(2+) intake and Ca(2+) intake from dairy sources were similarly correlated with fat oxidation. In backwards stepwise models, total Ca(2+) intake was a stronger predictor of 24 h fat oxidation than dairy Ca(2+) intake. CONCLUSION: Higher acute Ca(2+) intake is associated with higher rates of whole-body fat oxidation. These effects were apparent over 24 h, during sleep and, to a lesser extent, during light physical activity. Calcium intake from dairy sources was not a more important predictor of fat oxidation than total Ca(2+) intake.

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The purpose of the present study was to estimate and compare the effects of macronutrient composition (relative portions of macronutrients) and of non-macronutrient components (e.g. water and fibre) on energy density (energy per unit weight) of the diets of human subjects. We used standard macronutrient energy content values to develop a simple conceptual model and equation for energy density in terms of % energy from dietary fat and % non-macronutrients by weight. To study these effects in self-selected diets of free-living subjects, we used four consecutive days of self-weighed and recorded food records for thirty-two male and thirteen female free-living adult subjects. In the range of typical human diets, the effect of % non-macronutrients by weight was several times greater than that of % energy from dietary fat, both in absolute terms and relative to daily variation in subjects' diets. Both effects were large enough to be physiologically important. Non-macronutrients (% by weight) alone explained much more of the variation in self-selected dietary energy density either between subjects (R2 95 %) or day-to-day (R2 95 %) than did % energy from dietary fat (R2 5 % and 6 % respectively). Omitting beverages gave similar results. The smaller effect of macronutrient composition on energy density of diets is mainly because alterations in macronutrient composition affect only the portion of typical dietary intake that is macronutrients (one-quarter to one-third of weight). Mathematical methods are also useful in analysing observational data and for separating effects of macronutrient composition and non-macronutrients in intervention studies. These results illustrate the importance of considering non-macronutrients in the design and analysis of experimental or observational dietary data.

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BACKGROUND: The impact of off-pump median sternotomy coronary artery bypass grafting procedures on risk-adjusted mortality and morbidity was evaluated versus on-pump procedures. METHODS: Using the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Program records from October 1997 through March 1999, nine centers were designated as having experience (with at least 8% coronary artery bypass grafting procedures performed off-pump). Using all other 34 Veterans Affairs cardiac surgery programs, baseline logistic regression models were built to predict risk of 30-day operative mortality and morbidity. These models were then used to predict outcomes for patients at the nine study centers. A final model evaluated the impact of the off-pump approach within these nine centers adjusting for preoperative risk. RESULTS: Patients treated off-pump (n = 680) versus on-pump (n = 1,733) had lower complication rates (8.8% versus 14.0%) and lower mortality (2.7% versus 4.0%). Risk-adjusted morbidity and mortality were also improved for these patients (0.52 and 0.56 multivariable odds ratios for off-pump versus on-pump, respectively, p < 0.05). CONCLUSIONS: An off-pump approach for coronary artery bypass grafting procedures is associated with lower risk-adjusted morbidity and mortality.

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Molecular similarity methods have emerged as powerful tools in analog selection, chemical classification based on toxic modes of action, and property estimation. The basic assumption of structure-activity relationships (SAR) is that similar structures usually have similar properties. Therefore, similarity methods can be used for the selection of analogs and estimation of properties of chemicals from their structural analogs in property spaces. Each similarity method is user defined. Its efficacy depends on the set of descriptors used to define the intermolecular similarity of chemicals as well as on the mathematical function used to quantify similarity. Also, similarity methods can be based on experimental data or computed molecular descriptors. We have carried out a comparative study of similarity spaces derived from experimental data vis-a-vis computed structural parameters for two sets of chemicals: (a) a diverse set of 76 chemicals derived from the TSCA Inventory and (b) the 166 structurally distinct constituents of JP-8 identified by GC/MS. Property spaces for these two sets of chemicals were created using experimental and calculated physicochemical properties. Atom pairs (APs) and topological indices calculated by POLLY v2.3 were used to create theoretical structure spaces. These spaces were used for the KNN-based estimation of properties with K=1--10, 15, 20, 25. The results will be presented with a comparative analysis of the effectiveness of property spaces and structure spaces in analog selection and property estimation.

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BACKGROUND: A better understanding of the environmental factors that contribute to obesity is imperative if any therapeutic effect on the increasing prevalence of overweight and obesity in the United States is to be achieved. OBJECTIVE: This study examined the effect of the interaction of diet composition and physical inactivity on energy and fat balances. DESIGN: Thirty-five normal-weight and obese subjects were randomly assigned to either a 15-d isoenergetic high-carbohydrate (HC) or high-fat (HF) diet according to a crossover design. During the first 14 d, body weight and physical activity were maintained. On day 15, subjects spent 23 h in a whole-room indirect calorimeter and were fed a diet similar to that consumed during the previous 7 d while remaining physically inactive. RESULTS: Energy intakes required to maintain body weight stability during the first 14 d were similar between diets. Normal-weight and obese subjects consuming both diets had a positive energy balance on the sedentary day (day 15), suggesting that subjects were less active in the calorimeter. There was no significant effect of diet composition on total energy balance and total protein-energy balance on day 15; however, carbohydrate balance was more positive with the HC (2497.8 +/- 301.2 kJ) than with the HF (1159 +/- 301.2 kJ) diet (P = 0.0032). Most importantly, fat balance was more positive with the HF (1790.8 +/- 510.4 kJ) than with the HC (-62.8 +/- 510.4 kJ) diet (P = 0.0011). CONCLUSION: Chronic consumption of a high-carbohydrate diet could provide some protection against body fat accumulation in persons with a pattern of physical activity that includes frequent sedentary days.

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BACKGROUND: Risk factors for short-term mortality after coronary artery bypass grafting are well established, but little is known about risk factors for intermediate-term mortality. METHODS: We analyzed the outcomes of 11,815 patients undergoing coronary artery bypass grafting in one of the 43 cardiac surgery programs of the Department of Veteran Affairs. Risk factors for intermediate- and short-term mortality were determined using Cox proportional hazards regression models. Effects of risk factors during these two periods were explicitly compared. RESULTS: We found important differences in mortality risk-factor sets between the intermediate- and short-term periods after coronary artery bypass grafting. The majority of predictors of intermediate-term mortality were noncardiac-related variables, whereas the majority of predictors of short-term mortality were cardiac-related variables. Impaired functional status, chronic obstructive pulmonary disease, and renal dysfunction had greater effects in the intermediate-term period. Previous heart operation, angina class III or IV, previous myocardial infarction, and preoperative use of an intraaortic balloon pump had greater effects in the short-term period. CONCLUSIONS: The risk factors for intermediate-term mortality identified in this study can augment preoperative risk assessment and counseling of patients. Clinicians should be aware of the importance of noncardiac-related variables as predictors of mortality in the intermediate-term period after coronary artery bypass grafting.

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OBJECTIVES: Low-fat high-carbohydrate diets are recommended to prevent weight gain in normal weight subjects and reduce body weight in overweight and obese. However, their efficacy is controversial. We evaluated the efficacy of ad libitum low-fat diets in reducing body weight in non-diabetic individuals from the results of intervention trials. DESIGN: Studies were identified from a computerized search of the Medline database from January 1966 to July 1999 and other sources. Inclusion criteria were: controlled trials lasting more than 2 months comparing ad libitum low-fat diets as the sole intervention with a control group consuming habitual diet or a medium-fat diet ad libitum. MAIN OUTCOME MEASURES: Differences in changes in dietary fat intake, energy intake and body weight. Weighted mean differences for continuous data and 95% confidence intervals (CIs) were calculated. RESULTS: Two authors independently selected the studies meeting the inclusion criteria and extracted data from 16 trials (duration of 2-12 months) with 19 intervention groups, enrolling 1910 individuals. Fourteen were randomized. Weight loss was not the primary aim in 11 studies. Before the interventions the mean proportions of dietary energy from fat in the studies were 37.7% (95% CI, 36.9-38.5) in the low-fat groups, and 37.4% (36.4-38.4) in the control groups. The low-fat intervention produced a mean fat reduction of 10.2% (8.1-12.3). Low-fat intervention groups showed a greater weight loss than control groups (3.2 kg, 95% confidence interval 1.9-4.5 kg; P < 0.0001), and a greater reduction in energy intake (1 138 kJ/day, 95% confidence interval 564-1712 kJ/day, P = 0.002). Having a body weight 10 kg higher than the average pre-treatment body weight was associated with a 2.6 +/- 0.8 kg (P = 0.011) greater difference in weight loss. CONCLUSION: A reduction in dietary fat without intentional restriction of energy intake causes weight loss, which is more substantial in heavier subjects.

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PURPOSE: To analyze the dynamics of N- and B-cadherin cell adhesion molecule expression and cytoskeletal interaction during embryonic chick lens development. METHODS: Localization of N- and B-cadherin, F-actin, and connexin 56 were determined by immunohistochemistry of developing lenses or immunocytochemistry of differentiating primary lens cultures. Biochemical analysis of cytoskeletal linkage of N- or B-cadherin was assessed by differential detergent extraction, electrophoresis, and immunoblotting. RESULTS: The results indicate that although both cadherins are expressed throughout lens development, N-cadherin expression detected was similar in both lens epithelial and fiber cells, whereas B-cadherin was preferentially localized to the lens fiber cells. During differentiation, both cadherins become increasingly associated with the lens cytoskeleton, as indicated biochemically by a transition from largely Triton X-100-soluble to Triton X-100-insoluble pools and immunocytologically by cadherin localization to cell-cell borders and colocalization with the actin cytoskeleton. Although a significant fraction of N-cadherin remains Triton X-100-soluble as the lens cells differentiate, B-cadherin becomes resistant to extraction by both Triton X-100 as well as RIPA buffers. As detected immunocytochemically in lens cell cultures, the temporal localization of N-cadherin to cell-cell interfaces precedes that of B-cadherin. Furthermore, temporal localization of B-cadherin, as opposed to N-cadherin, to cell-cell borders more closely parallels that of connexin 56 in vitro as well as in vivo. CONCLUSIONS; These results suggest that while both N- and B-cadherin are expressed during lens cell differentiation, both their patterns of expression as well as their cytoskeletal association differ between epithelial and fiber cells.

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Hierarchical quantitative structure-activity relationships (H-QSAR) have been developed as a new approach in constructing models for estimating physicochemical, biomedicinal, and toxicological properties of interest. This approach uses increasingly more complex molecular descriptors in a graduated approach to model building. In this study, statistical and neural network methods have been applied to the development of H-QSAR models for estimating the acute aquatic toxicity (LC50) of 69 benzene derivatives to Pimephales promelas (fathead minnow). Topostructural, topochemical, geometrical, and quantum chemical indices were used as the four levels of the hierarchical method. It is clear from both the statistical and neural network models that topostructural indices alone cannot adequately model this set of congeneric chemicals. Not surprisingly, topochemical indices greatly increase the predictive power of both statistical and neural network models. Quantum chemical indices also add significantly to the modeling of this set of acute aquatic toxicity data.

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The role of high-fat diets in weight gain and obesity has been questioned because of inconsistent reports in the literature concerning the efficacy of ad libitum low-fat diets to reduce body weight. We conducted a meta-analysis of weight loss occurring on ad libitum low-fat diets in intervention trials, and analysed the relationship between initial body weight and weight loss. We selected controlled trials lasting more than 2 months comparing ad libitum low-fat diets with a control group consuming their habitual diet or a medium-fat diet ad libitum published from 1966 to 1998. Data were included from 16 trials with a duration of 2-12 months, involving 1728 individuals. No trials on obese subjects fulfilled the inclusion criteria. The weighted difference in weight loss between intervention and control groups was 2.55 kg (95% CI, 1.5-3.5; P < 0.0001). Weight loss was positively and independently related to pre-treatment body weight (r = 0.52, P < 0.05) and to reduction in the percentage of energy as fat (0.37 kg/%, P < 0.005) in unweighted analysis. Extrapolated to a BMI of about 30 kg/m2 and assuming a 10% reduction in dietary fat, the predicted weight loss would be 4.4 kg (95% CI, 2.0 to -6.8 kg). Because weight loss was not the primary aim in 12 of the 16 studies, it is unlikely that voluntary energy restriction contributed to the weight loss. Although there is no evidence that a high intake of simple sugars contributes to passive overconsumption, carbohydrate foods with a low glycaemic index may be more satiating and exert more beneficial effects on insulin resistance and cardiovascular risk factors. Moreover, an increase in protein content up to 25% of total energy may also contribute to reducing total energy intake. In conclusion, a low-fat diet, high in protein and fibre-rich carbohydrates, mainly from different vegetables, fruits and whole grains, is highly satiating for fewer calories than fatty foods. This diet composition provides good sources of vitamins, minerals, trace elements and fibre, and may have the most beneficial effect on blood lipids and blood-pressure levels. A reduction in dietary fat without restriction of total energy intake prevents weight gain in subjects of normal weight and produces a weight loss in overweight subjects, which is highly relevant for public health.

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Members of the cadherin family of cell adhesion molecules participate in calcium-dependent cell-cell adhesions that are necessary for the cell sorting events that regulate early developmental processes. Although individual cadherin molecules have been shown to participate in tissue histogenesis, the regulation of function of these receptors in cell differentiation has been more difficult to identify. We have determined that N-cadherin linkage to the cytoskeleton is correlated with lens cell differentiation in vivo. Through the use of a chick embryo lens culture system that mimics differentiation in vivo, we have determined that N-cadherin linkage to the cytoskeleton is altered and lens differentiation is blocked by function-blocking antibodies to N-cadherin. In the presence of the N-cadherin function-blocking antibody, NCD-2, both N-cadherin and filamentous actin are prevented from organizing at the cortical membranes. This correlates with an inhibition of lens morphogenesis and differentiation. These results are paralleled by changes in the expression of the molecular components of the cadherin-catenin complex and their linkage to the actin cytoskeleton. In the presence of NCD-2, expression of N-cadherin, alpha-catenin, and beta-catenin is inhibited and their association with the cytoskeleton blocked. Overall cadherin expression, however, remains unchanged as demonstrated by studies with a pan-cadherin antibody. This is accompanied by an increase in expression of the cadherin cytoskeletal protein plakoglobin. Although the cells have tried to compensate for the loss of N-cadherin by up-regulation of another cadherin(s) and plakoglobin, this is unable to compensate for N-cadherin function. The data strongly suggest that N-cadherin and its associated cytoskeleton play an important role in the differentiation process that leads to the formation of the crystalline lens.

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INTRODUCTION: Certain fermented dairy milk products may have beneficial effects on plasma cholesterol levels. However, a number of studies have produced conflicting results as to whether dietary supplementation by a probiotic dairy product containing the bacteria culture Causido(R) reduces plasma cholesterol. OBJECTIVE: To conduct a meta-analysis of intervention studies to evaluate the effect of the Causido(R) culture on plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol. THE PROBIOTIC MILK PRODUCT: The yoghurt product Gaio(R) is fermented with Causido(R), composed of one strain of Enterococcus faecium (human species) with the proposed cholesterol-lowering effect, and two strains of Streptococcus thermophilus. STUDY INCLUSION AND DATA EXTRACTION: Six studies were identified from a literature search and from the yoghurt producer. All studies met the inclusion criteria. Summary data for plasma concentrations of total cholesterol and LDL-cholesterol were extracted from the original publications or by personal request to the authors. Data from 4-8 weeks of treatment duration was used. STATISTICAL ANALYSIS: We performed a traditional meta-analysis where mean differences between intervention and control of the pre-post changes in total cholesterol and LDL-cholesterol were calculated, as well as 95% confidence intervals (CIs). RESULTS: In the six studies included in the meta-analysis, the Gaio(R) interventions produced changes in total cholesterol above those of the control groups ranging from -0.02 to -1.02 mmol/l and in LDL-cholesterol ranging from -0.02 to -1.15 mmol/l. After inclusion of an open-label study, the meta-analysis of the double-blind studies showed that Gaio(R) as compared to the control group changed total cholesterol by -0.22 mmol/l (95% CI: -0.35 to -0.08, P<0.01) and LDL-cholesterol by -0.20 mmol/l (95% CI: -0.33 to -0.06, P<0.005). The outcome was essentially the same if all studies were included. CONCLUSIONS: The present meta-analysis of controlled short-term intervention studies shows that the fermented yoghurt product produced a 4% decrease in total cholesterol and a 5% decrease in LDL-cholesterol when the open-label study is excluded. To demonstrate sustained effects on blood lipids, long-term studies are required. SPONSORSHIP: MD Foods A/S, Denmark.

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