Evaluation of relationship between ruminal pH and the proportion of de novo fatty acids in milk.

The objective of this study was to evaluate the relationship between ruminal pH and milk de novo fatty acid (DNFA) concentrations determined by Fourier-transform infrared spectroscopy. Data were collected from 18 multiparous Holstein cows fitted with a rumen cannula and fed 1 of the experimental diets differing in starch content (22.1 vs. 28.3%) with or without supplementation of a Saccharomyces cerevisiae fermentation product in a previous study. Milk was sampled on d 7 and 21 after calving, and concentrations of milk fat, DNFA (C6 to C14), mixed-origin fatty acids (FA; C16:0 and C16:1), and preformed FA (≥C18) were estimated using Fourier-transform infrared spectrometry. Ruminal pH was recorded in the ventral sac every 30 s continuously for 72 h on d 7 to 9 and 21 to 23 after calving. Daily maximum, nadir, and mean ruminal pH as well as duration and area below pH 5.8 were determined for each period. Milk DNFA (g/100 g of FA) was positively related to nadir (r = 0.428) and mean (r = 0.471) ruminal pH and negatively related to duration (r = -0.511) and area (r = -0.520) below pH 5.8. Milk fat content did not have a relationship with ruminal pH variables in this study. The regression lines for d 7 and 21 were similar, likely because plasma free FA concentrations were not different between d 7 and 21 (513 vs. 534 µEq/L) for the current data set. The coefficients of determination between DNFA and ruminal pH were greater for DNFA in total milk FA (g/100 g of FA) than in milk (g/100 g of milk), suggesting that DNFA in milk fat (g/100 g of FA) is an appropriate measurement variable that relates to ruminal pH even for cows in early lactation.

Effects of butyrate supplementation on blood glucagon-like peptide-2 concentration and gastrointestinal functions of lactating dairy cows fed diets differing in starch content.

The objective of this study was to evaluate effects of butyrate supplementation on plasma concentration of glucagon-like peptide-2 (GLP-2), apparent total-tract digestibility, and responses to a grain challenge of lactating dairy cows fed diets differing in starch content. Eight Holstein cows averaging 58.6 ± 9.96 d in milk (4 primiparous cows fitted with rumen cannula and 4 multiparous intact cows) were blocked by parity and assigned to one of two 4 × 4 Latin squares balanced for carryover effects with a 2 × 2 factorial arrangement of treatments. Treatments were dietary starch content [20.6 vs. 27.5%, respectively, for low starch (LS) and high starch (HS)] and butyrate supplementation (butyrate vs. control) with 21-d periods. Butyrate was provided as Gustor BP70 WS (Norel, S.A., Madrid, Spain), containing 70% sodium butyrate and 30% fatty acid mixture, at 2% of dietary dry matter (providing butyrate at 1.1% of dietary dry matter), and control premix contained 70% wheat bran and 30% fatty acid mixture. Feeds, orts, and fecal samples were collected from d 17 to 19 to determine apparent total-tract nutrient digestibility. Blood and rumen fluid samples were collected on d 19. The baseline of dry matter intake (DMI) was determined as average DMI from d 17 to 19 for each cow, and cows were feed-restricted at 60% of the baseline DMI on d 20, and a grain challenge was conducted by providing steam-flaked corn grain at 0.6% of body weight, on an as-fed basis, in addition to each treatment diet on d 21, and blood and ruminal fluid samples were collected. The interaction of dietary starch content by butyrate supplementation was significant for plasma GLP-2 concentration, being greater for cows fed butyrate with the HS diet than those fed the other 3 diets. Cows fed butyrate increased n-butyrate concentration in the ruminal fluid and tended to increase dry matter and organic matter digestibility compared with the control. During the grain challenge, rumen endotoxin concentration increased over time and was higher for cows fed the HS diets compared with those fed LS diets. However, response variables related to inflammation were not affected by the grain challenge. However, serum haptoglobin, lipopolysaccharide-binding protein, and serum amyloid-A concentrations were greater for cows fed butyrate with the LS diet, but not for those fed the HS diet. These results indicate that butyrate supplementation may increase plasma GLP-2 concentration for cows fed HS diets, and total-tract digestibility regardless of dietary starch content. However, butyrate supplementation did not mitigate inflammation in this study.

Short communication: Effects of butyrate supplementation on the productivity of lactating dairy cows fed diets differing in starch content.

The objective of this study was to evaluate the effects of butyrate supplementation on the dry matter intake (DMI), milk production, and blood metabolites of lactating dairy cows fed diets differing in starch content. Eight Holstein cows after peak lactation (58.6 ± 9.96 d in milk; mean ± SD) were blocked by parity and assigned to 1 of 2 Latin squares (4 × 4) balanced for carryover effects with a 2 × 2 factorial arrangement of treatments. Treatments differed by dietary starch content (20.6 vs. 27.5%) and butyrate supplementation (butyrate vs. control) with 21-d periods. Experimental diets contained 36 and 30% corn silage, 18 and 15% grass silage, and 46 and 55% concentrates, respectively, for low starch and high starch diets, on a dry matter (DM) basis. Butyrate was provided as Gustor BP70 WS (Norel S.A., Madrid, Spain), containing 70% sodium butyrate and 30% fatty acid mixture, at 2% of dietary DM (providing butyrate at 1.1% of dietary DM), and control premix contained 70% wheat bran and 30% fatty acid mixture. Interaction effects between dietary starch content and butyrate supplementation were not observed for primary response variables, and milk yield was not affected by treatment. Butyrate supplementation increased serum ß-hydroxybutyrate concentration compared with control (0.706 vs. 0.930 mM), but did not exceed 1.2 mM, a commonly accepted value for subclinical ketosis, and DMI was not affected. Cows fed butyrate had increased milk fat content (4.58 vs. 4.37%) and milk fat yield (1.51 vs. 1.42 kg/d), tended to have increased 4% fat-corrected milk yield (35.9 vs. 34.3 kg/d) and feed efficiency (1.56 vs. 1.50; 4% fat-corrected milk yield/DMI), and had decreased milk urea nitrogen (MUN) concentration (10.8 vs. 11.7 mg/dL) compared with control. Cows fed high starch diets tended to have increased DMI (23.3 vs. 22.5 kg/d), increased milk protein yield (1.13 vs. 1.05 kg/d), and decreased MUN concentration (10.3 vs. 12.2 mg/dL). Inclusion of butyrate at 1.1% of dietary DM increased milk fat production and decreased MUN concentration without affecting DMI or increasing the risk of subclinical ketosis, regardless of dietary starch content.

Washing of platelets can be fully automated using a closed-system cell processor and BRS-A platelet additive solution.

This study evaluated the in vitro properties of platelets (PLTs) washed with BRS-A additive solution in the Haemonetics ACP215 automated processing system. Two washing modes, 'manually/automatically adding ACD-A to BRS before/during the washing process', represented the control and test groups, respectively. Outcomes were compared over 7 days of storage (n = 7, for both). PLT recovery following washing processing (26-27 min) was 86·2 ± 1·7% and 86·0 ± 2·2% and plasma protein removal was 98·8 ± 0·3% and 99·0 ± 0·2% in the control and test groups, respectively (not significant). Both groups exhibited comparable in vitro properties.

Dietary Protein to Maintain Muscle Mass in Aging: A Case for Per-meal Protein Recommendations.

It is well accepted that daily protein intake is an important dietary consideration to limit and treat age-related declines in muscle mass, strength, and function. Furthermore, we propose that there is a growing appreciation for the need to consider protein intake on a per-meal basis rather than simply focusing on the total daily protein intake. The existence of a saturable dose-response relationship between muscle protein synthesis (MPS) and the quantity of protein consumed in a single meal/bolus provides the rationale for promoting an even/balanced pattern of daily protein intake. We hypothesize that a balanced/even protein intake pattern with the ingestion a quantity of protein shown to optimally stimulate MPS at each meal may be an effective strategy to alleviate sarcopenic muscle loss. In this review we examine the available evidence supporting the influence of dietary protein intake pattern on muscle protein turnover, muscle mass, and muscle function. We present several practical considerations that, it is proposed, should be taken into account when translating a per-meal protein recommendation into dietary advice for older adults.

In vitro analysis of volume-reduced washed platelet concentrates stored in bicarbonated Ringer's solution containing less than 5% residual plasma.

BACKGROUND AND OBJECTIVES: Volume-reduced washed platelet (PLT) concentrates (PCs) can prevent circulatory overload and allergic reactions in patients undergoing PLT transfusions. For these reasons, they are in demand for paediatric settings and for patients at risk of circulatory overload. Here, we evaluated the quality of volume-reduced washed PCs stored for 5 days in a novel acetate-free PLT additive solution (PAS) containing glucose and bicarbonate (BRS-A) with <5% residual plasma protein. MATERIALS AND METHODS: PCs from two apheresis donations were mixed and divided equally into control and test units. For the test unit (volume-reduced washed PCs), PLTs were washed and stored in 90 ml BRS-A with <5% plasma protein. PLTs in the control unit were stored in 200 ml 100% plasma without any washing manipulations. The in vitro properties of PLTs in both units were compared over a 5-day storage period. RESULTS: The procedure for volume-reduced washed PCs effectively removed >98% plasma protein in 100% plasma PCs and yielded an approximately twofold lower mean volume (91 ml) compared to that observed with the control units. Immediately after washing, the mean PLT concentration of the test units was 20·5 × 10(11) /l, twofold higher than that of the control units. The pH (37°C) levels in the test unit remained above 7·0 for 5 days. Glucose consumption and lactate production rates of the test units on days 1-3 were higher than those of the control units, leading to glucose exhaustion in the test unit by Day 3. Hypotonic shock responses and CD62P and CD42b expression levels in both units were comparable during 5-day storage. CONCLUSION: Considering the pH buffering capacity of BRS-A, a 90-ml volume may be acceptable for maintaining the in vitro quality of washed PLTs for at least 2 days.

Use of T-RFLP and seven restriction enzymes to compare the faecal microbiota of obese and lean Japanese healthy men.

The composition of the intestinal microbiota of 92 healthy Japanese men was measured following consumption of identical meals for 3 days; terminal restriction fragment length polymorphisms were then used to analyse the DNA content of their faeces. The obtained operational taxonomic units (OTUs) were further analysed using seven restriction enzymes: 516f-BslI and -HaeIII, 27f-MspI and -AluI, and 35f-HhaI, -MspI and -AluI. Subjects were classified by their body mass index (BMI) as lean (<18.5) or obese (>25.0). OTUs were then analysed using data mining software. Pearson correlation coefficients on data mining results indicated only a weak relationship between BMI and OTU diversity. Specific OTUs attributed to lean and obese subjects were further examined by data mining with six groups of enzymes and closely related accession numbers for lean and obese subjects were successfully narrowed down. 16S rRNA sequences showed Bacillus spp., Erysipelothrix spp. and Holdemania spp. to be present among 30 bacterial candidates related to the lean group. Fifteen candidates were classified Firmicutes, one was classified as Chloroflexi, and the others were not classified. 45 Microbacteriaceae, 11 uncultured Actinobacterium, and 3 other families were present among the 119 candidate OTUs related to obesity. We conclude that the presence of Firmicutes and Actinobacteria may be related to the BMI of the subject.

228Ra/226Ra ratio and 7Be concentration in the Sea of Japan as indicators for water transport: comparison with migration pattern of Fukushima Dai-ichi NPP-derived 134Cs and 137Cs.

To assess the migration patterns of radiocesium emitted from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), we analyzed (228)Ra/(226)Ra ratios and (7)Be concentrations and compared them with (134)Cs and (137)Cs concentrations in seawater samples collected within the Sea of Japan before and after the FDNPP accident (i.e., during the period 2007-2012) using low-background γ-spectrometry. The (228)Ra/(226)Ra ratios in surface waters exhibited lateral and seasonal variations, reflecting the flow patterns of surface water. This indicates the transport patterns of the FDNPP-derived radiocesium by surface water. Cosmogenic (7)Be (half-life: 53.3 d) exhibited markedly high concentrations (5-10 mBq/L) at depths shallower than 50 m, with concentrations decreasing steeply (0.2-2 mBq/L) at depths of 50-250 m. The distribution of (7)Be concentrations suggests that the downward delivery of the FDNPP-derived radiocesium to below 50 m depth was negligible for a few months prior to its removal from the Sea of Japan.

Feasibility of a closed-system cell processor (ACP215) for automated preparation of washed platelet concentrates.

BACKGROUND AND OBJECTIVES: This study was aimed at evaluating the feasibility of the ACP215 closed-system cell processor for preparing washed platelet concentrates. MATERIAL AND METHODS: Platelet washing was performed with either the ACP215 system or the manual technique with M-sol. Plasma protein removal and platelet recovery were estimated, and the washed platelet concentrates were stored for 5 days. Samples were collected after washing and on days 1, 3 and 5 of storage to determine the effects of the washing methods on the in vitro platelet qualities (platelet count, platelet volume, pH, glucose and lactate concentrations, hypotonic shock response, aggregation response and CD62P expression level). RESULTS: Platelet recovery was 86·9 ± 2·1% and 85·9 ± 1·9% (P = 0·305), and plasma protein removal was 95·8 ± 0·9% and 96·9 ± 0·7% (P = 0·016) after washing with the ACP215 system and manual technique, respectively. No statistically significant differences in the in vitro platelet qualities were observed between the washing methods. CONCLUSION: The ACP215 system is a feasible alternative to manual, labour-intensive, techniques for preparing washed platelet concentrates.

DNA damage in peripheral blood mononuclear cells and neutrophils of dairy cows during the transition period.

This study was designed to investigate the apoptotic process in peripheral blood mononuclear cells (PBMC) and polymorphonuclear neutrophil leukocytes (PMN) in dairy cattle during the transition period. Blood samples were collected from 4 dairy cattle at 3 weeks before the expected parturition (wk -3), parturition (wk 0) and 3 weeks after parturition (wk +3). The DNA damage of PBMC and PMN was evaluated based on the comet assay using visual scoring (arbitrary units). Undamaged DNA remained within the core (score 0) and the broken DNA migrated from the core towards the anode forming the tail of a comet (scores 1-4). Significantly higher scores in PBMC at wk 0 and wk +3 were observed compared with those in PMN although there were no significant changes of scores in either cell type during the experimental period. It is suggested that the apoptotic rate of PBMC is accelerated compared with that of PMC during the transition period.

Long-term lifestyle intervention lowers the incidence of stroke in Japanese patients with type 2 diabetes: a nationwide multicentre randomised controlled trial (the Japan Diabetes Complications Study).

AIMS/HYPOTHESIS: The aim of the study was to clarify whether a therapeutic intervention focused on lifestyle modification affected the incidence of vascular complications in patients with established diabetes. METHODS: A total of 2,033 eligible Japanese men and women aged 40-70 years with type 2 diabetes from 59 institutes were randomised to a conventional treatment group (CON), which continued to receive the usual care, and a lifestyle intervention group (INT), which received education on lifestyle modification regarding dietary habits, physical activities and adherence to treatment by telephone counselling and at each outpatient clinic visit, in addition to the usual care. Randomisation and open-label allocation were done by a central computer system. Primary analysis regarding measurements of control status and occurrence of macro- and microvascular complications was based on 1,304 participants followed for an 8 year period. RESULTS: Although status of control of most classic cardiovascular risk factors, including body weight, glycaemia, serum lipids and BP, did not differ between groups during the study period, the incidence of stroke in the INT group (5.48/1,000 patient-years) was significantly lower than in the CON group (9.52/1,000 patient-years) by Kaplan- Meier analysis (p=0.02 by logrank test) and by multivariate Cox analysis (HR 0.62, 95% CI 0.39-0.98, p=0.04). The incidence of CHD, retinopathy and nephropathy did not differ significantly between groups. Lipoprotein(a) was another significant independent risk factor for stroke. CONCLUSIONS/INTERPRETATION: These findings suggest that lifestyle modification had limited effects on most typical control variables, but did have a significant effect on stroke incidence in patients with established type 2 diabetes. CLINICAL TRIAL REGISTRATION: UMIN-CTR C000000222 FUNDING: The Ministry of Health, Labour and Welfare, Japan

Diversity of molecular forms of plasma brain natriuretic peptide in heart failure--different proBNP-108 to BNP-32 ratios in atrial and ventricular overload.

OBJECTIVE: Recent studies have shown that plasma levels of brain natriuretic peptide (BNP)-32 and proBNP-108 are increased in heart failure (HF) and that the BNP-32 assay kit in current clinical use cross-reacts with proBNP-108. We investigated why proBNP is increased without processing in HF was investigated. DESIGN, SETTING AND PATIENTS: Plasma BNP-32 and proBNP-108 in normal individuals (n=10) and in patients with atrial fibrillation (AF) (n=18) and HF (n=132) was measured. BNP-32 and proBNP-108 in ventricular and atrial tissue and in pericardial fluid using a specific fluorescent enzyme immunoassay following Sep-Pak C18 (Waters, Milford, Massachusetts, USA) cartridge extraction and gel filtration was also measured. MAIN OUTCOME MEASURES: Levels of both BNP-32 and proBNP-108 were higher in HF than in control or AF (both p<0.01), and the levels of these peptides significantly correlated (r=0.94, p<0.001). The proBNP-108/total BNP (BNP-32+proBNP-108) ratio was widely distributed and lower in HF (0.33 (0.17)) than in control (0.41 (0.06), p<0.05) and AF (0.45 (0.04), p<0.002). The proBNP-108/total BNP ratio was higher in HF with ventricular than in HF with atrial overload (0.45 (0.10) vs 0.20 (0.11), p<0.001). Consistent with this finding, the major molecular form were proBNP-108 and BNP-32 in ventricular (n=6, 0.67 (0.04)) and atrial (n=7, 0.76 (0.05), p<0.0001) tissues, respectively. ProBNP-108 was also the major molecular form of BNP in pericardial fluid (n=8, 0.82 (0.05)). The proBNP-108/total BNP ratio increased and decreased with HF deterioration and improvement, respectively. CONCLUSION: These results suggest that BNP-32 and proBNP-108 is increased in HF and that the proBNP/total BNP ratio increases in association with pathophysiological conditions such as ventricular overload.

Determination of 240Pu/239Pu isotopic ratios in human tissues collected from areas around the Semipalatinsk Nuclear Test Site by sector-field high resolution ICP-MS.

Information on the 240Pu/239Pu isotope ratios in human tissues for people living around the Semipalatinsk Nuclear Test Site (SNTS) was deduced from 9 sets of soft tissues and bones, and 23 other bone samples obtained by autopsy. Plutonium was radiochemically separated and purified, and plutonium isotopes (239Pu and 240Pu) were determined by sector-field high resolution inductively coupled plasma-mass spectrometry. For most of the tissue samples from the former nine subjects, low 240Pu/239Pu isotope ratios were determined: bone, 0.125 +/- 0.018 (0.113-0.145, n = 4); lungs, 0.063 +/- 0.010 (0.051-0.078, n = 5); and liver, 0.148 +/- 0.026 (0.104-0.189, n = 9). Only 239Pu was detected in the kidney samples; the amount of 240Pu was too small to be measured, probably due to the small size of samples analyzed. The mean 240Pu/239Pu isotope ratio for bone samples from the latter 23 subjects was 0.152 +/- 0.034, ranging from 0.088 to 0.207. A significant difference (a two-tailed Student's t test; 95% significant level, alpha = 0.05) between mean 240Pu/239Pu isotope ratios for the tissue samples and for the global fallout value (0.178 +/- 0.014) indicated that weapons-grade plutonium from the atomic bombs has been incorporated into the human tissues, especially lungs, in the residents living around the SNTS. The present 239,240Pu concentrations in bone, lung, and liver samples were, however, not much different from ranges found for human tissues from other countries that were due solely to global fallout during the 1970's-1980's.

Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestat.

AIMS: The long-term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment. METHODS: Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor-Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity > or = 40 m/s and with glycated haemoglobin (HbA(1c)) < or = 9.0%. Longitudinal data on HbA(1c) and subjective symptoms of the patients for 3 years were analysed (epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. RESULTS: Stratified subgroup analyses revealed significantly better efficacy of epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA(1c) < or = 7.0%). CONCLUSION: Our results suggest that epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.

Ultrasonographic characteristics of abdominal and thoracic abscesses in cattle and buffaloes.

Six cows and five buffaloes with abdominal and thoracic abscesses were examined clinically and ultrasonographically. There was a wide range of clinical signs and at least 50% of the animals exhibited dull demeanour, anorexia, abdominal pain, recurrent tympany and/or weight loss. Three cases of abdominal abscesses were imaged in the left ventral abdomen between the rumen and abdominal wall, two cases were imaged at the xiphoid cartilage near the reticular wall and one case was imaged on the right ventral abdomen between the jejunum and right abdominal wall. Four cases of thoracic abscesses were imaged in the third intercostal space on the left side; however, one case of abscess was imaged in the fourth intercostal space, also on the left side. The content of the abscess was echogenic in eight animals and anechoic in three. In three animals, the content of the abscess was partitioned by echogenic septae. In two cows, the echogenic content of the abscess was surrounded by a narrow rim of anechoic fluid. The diameters of the abscesses were 5-10 cm in three cows, 11-15 cm in seven cows and >15 cm in one cow. In every case, the diagnosis was confirmed by centesis and aspiration of the abscess, which yielded purulent material. There were biochemical data of hypoalbuminaemia and hyperglobulinaemia and 90% of tested animals had neutrophilia. Five cows were examined at slaughter, where the ultrasonographic diagnosis was confirmed.

A non-acromegalic case of multiple endocrine neoplasia type 1 accompanied by a growth hormone-releasing hormone-producing pancreatic tumor.

Cases of acromegaly due to GHRHproducing pancreatic endocrine tumors have been reported. Here we present a case of a 31-yr-old nonacromegalic man with hyperparathyroidism and elevated serum IGF-I with normal serum GH levels. Serum GH was not suppressed below 1 ng/ml by the glucose tolerance test and increased in response to TR H and GHRH administration. Magnetic resonance imaging (MRI) revealed pituitary hyperplasia and an abdominal computed tomography (CT ) scan showed a tumor in the pancreatic tail. Plasma concentration of GHRH was elevated. Based on these clinical data, multiple endocrine neoplasia (MEN) type 1 was suspected. Three enlarged parathyroid glands were removed and a distal pancreatectomy was performed. Pathological examination of the parathyroid glands and pancreatic tumor showed nodular hyperplasia and a well-differentiated endocrine tumor, respectively, both compatible with MEN features. Immunohistochemistry revealed positive immunoreactivity for GHRH, SS , insulin, glucagon, chromogranin A, and pancreatic polypeptide in the pancreatic tumor. After pancreatic surgery, elevated levels of GHRH and IGF-I were normalized and pituitary hyperplasia definitely decreased in size. In cases of pituitary hyperplasia with elevated IGF-I, ectopic GHRH syndrome must be considered even if physical features of acromegaly are absent. It is also important to measure plasma GHRH concentrations in order to give a diagnosis.

A trilogy of primary prevention statin trials. Panel discussion.

Presented is a report of a panel discussion held as part of the ISA 2006 Sankyo Forum titled "A Trilogy of Primary Prevention Statin Trials--The Impact of These Landmark Studies on Clinical Practice," Rome, Italy, June 2006. The themes of the panel discussion were the design features of three trials, WOSCOPS, AFCAPS/TexCAPS, and Japan's MEGA Study; comparison of their primary endpoints; and the implications of their results. Among the topics discussed by the panel of experts from Japan, USA, and UK were observations on the benefits associated with pravastatin at low dose as demonstrated in the MEGA Study as well as that study's implications for women, who represented the majority of subjects. Several suggestions were put forth to explain how the low dose used in MEGA elicited similar LDL-C reductions to those observed in WOSCOPS and AFCAPS/TexCAPS at higher doses including the body size hypothesis, genetic variation, and statin-diet interaction. It was felt that in Japan, the current guidelines are adequate; there seemed no merit in radically reducing LDL-C levels since in the Japanese population the risk is generally low. Japanese physicians tend to use small doses of statin and believe that these are effective in lowering cholesterol sufficiently with few side effects and encourage good compliance.