Syntactic development in children with intellectual disabilities - using structured assessment of syntax.

BACKGROUND: Children with intellectual disabilities (IDs) have a severe delay in syntactic development compared with other language abilities. This study investigated conditions of syntactic development in native Japanese-speaking children with ID. METHODS: Children with ID [N = 51; 18 autism spectrum disorders (ASD), 18 Down syndrome (DS) and 15 ID without ASD and DS] were compared with typically developing children (N = 78) with the same mental age (MA). The development of syntax in spoken language was examined by receptive and production tasks. RESULTS: The development of syntax in children with ID was significantly delayed than in typically developing children with the same MA. However, when reaching the MA of 7-9, syntax abilities started to develop remarkably. Moreover, children with ASD had significant difficulties in acquiring passive voice, whereas children with DS showed a significant delay in syntactic development. CONCLUSIONS: The development of syntax in children with ID might be affected by MA and the type of disability. Moreover, it is necessary to exceed an MA of 7-9 years for children with ID to develop syntax abilities.

Comparing pig breeds with genetically low and high backfat thickness: differences in expression of adiponectin, its receptor, and blood metabolites.

Here we characterized gene expressions in subcutaneous adipose tissue and blood metabolites of pigs with genetically low backfat (Landrace) and high backfat (Meishan). As pigs aged from 1 wk-to 3-mo old, mRNA levels of adipose-specific genes increased, although their gene expressions coding for major enzymes involved in lipid metabolism (lipoprotein lipase, fatty acid synthase, and hormone-sensitive lipase) did not differ between lean and fat pigs. Instead, there were significant effects for adiponectin and its receptor AdipoR1 mRNA levels between the two breeds of which respective expressions were lower and higher in Meishan by 3 mo of age. Contrary to changes in gene expressions, the concentrations of blood glucose, triglyceride (TG), and NEFA in both breeds decreased during growth, and 3-mo-old Meishan evidenced lower glucose with higher TG than the Landrace. The homeostasis model assessment insulin resistance (HOMA-IR) index was also calculated from the measurements of fasting glucose and insulin concentration, and Meishan showed a higher value than the Landrace. We next examined these differences in Landrace and Meishan crossbreds, which were phenotypically distinguishable by the backfat thickness as the former lean type and the latter fat type. As with the purebreds, high backfat Meishan crosses showed the characteristics of lower glucose and higher TG in circulating levels and also lower adiponectin transcripts in subcutaneous adipose tissue. Collectively, our results demonstrate that levels of adiponectin and its receptor gene expressions, blood glucose, blood lipids, and HOMA-IR in pigs vary between lean and fat. These observations strongly suggest the possibility that overall metabolic differences rather than adipocyte ability itself contribute to the fatness of genetically high backfat pigs.

Relationship between Sensory Perception and Frailty in a Community-Dwelling Elderly Population.

BACKGROUND: Aging anorexia, defined as loss of appetite and/or reduced food intake, has been postulated as a risk factor for frailty. Impairments of taste and smell perception in elderly people can lead to reduced enjoyment of food and contribute to the anorexia of aging. OBJECTIVE: To evaluate the relationship between frailty and taste and smell perception in elderly people living in urban areas. DESIGN: Data from the baseline evaluation of 768 residents aged ≥ 65 years who enrolled in a comprehensive geriatric health examination survey was analyzed. Fourteen out of 29-items of Appetite, Hunger, Sensory Perception questionnaire (AHSP), frailty, age, sex, BMI, chronic conditions and IADL were evaluated. AHSP was analyzed as the total score of 8 taste items (T) and 6 smell items (S). Frailty was diagnosed using a modified Fried's frailty criteria. RESULTS: The area under the receiver operator curves for detection of frailty demonstrated that T (0.715) had moderate accuracy, but S (0.657) had low accuracy. The cutoffs, sensitivity, specificity and Youden Index (YI) values for each perception were T: Cutoff 26.5 (YI: 0.350, sensitivity: 0.639, specificity: 0.711) and S: Cutoff 18.5 (YI: 0.246, sensitivity: 0.690, specificity: 0.556). Results from multiple logistic regression models, after adjusting for age, sex, IADL and chronic conditions showed that participants under the T cutoff were associated with exhaustion and those below the S cutoff were associated with slow walking speed. The adjusted logistic models for age, sex, IADL and chronic conditions showed significant association between T and frailty (OR 2.81, 95% CI 1.29-6.12), but not between S and frailty (OR 1.73, 95% CI 0.83-3.63). CONCLUSIONS: Taste and smell perception, particularly taste perception, were associated with a greater risk of frailty in community-dwelling elderly people. These results suggest that lower taste and smell perception may be an indicator of frailty in old age.

BDNF Propeptide: A Novel Modulator of Synaptic Plasticity.

One of the most characterized neurotrophic factors is brain-derived neurotrophic factor (BDNF), which regulates neuronal survival and differentiation, and functions in activity-dependent plasticity processes such as long-term potentiation, long-term depression (LTD), and learning memory. Similar to other growth factors, BDNF protein is produced by transcriptional and translational mechanisms. Nevertheless, a posttranslational mechanism, the proteolytic conversion of precursor BDNF into at least two fragments, bioactive BDNF and the prodomain, has not been well elucidated. Recently, we demonstrated that the BDNF prodomain, which is named the BDNF propeptide, was endogenously secreted from neuronal cells and facilitated a cellular mechanism of LTD, suggesting the manner through which this posttranslational mechanism multiplies the biological actions of BDNF. In this chapter, we focus on the BDNF propeptide, especially in synaptic plasticity, and discuss the role of this molecule in the brain. The findings regarding the BDNF propeptide would provide new insights for understanding the mechanisms of action of the propeptides of growth factors as well as the biological roles of neurotrophins.

Dielectric property measurement of ocular tissues up to 110 GHz using 1 mm coaxial sensor.

Measurement of the dielectric properties of ocular tissues up to 110 GHz was performed by the coaxial probe method. A coaxial sensor was fabricated to allow the measurement of small amounts of biological tissues. Four-standard calibration was applied in the dielectric property measurement to obtain more accurate data than that obtained with conventional three-standard calibration, especially at high frequencies. Novel data of the dielectric properties of several ocular tissues are presented and compared with data from the de facto database.

Serum pro-BDNF/BDNF as a treatment biomarker for response to docosahexaenoic acid in traumatized people vulnerable to developing psychological distress: a randomized controlled trial.

Our open-label pilot study showed that supplementation with docosahexaenoic acid (DHA) increased serum brain-derived neurotrophic factor (BDNF) levels and that there might be an association between changes in serum BDNF levels and reduced psychological distress. Animal research has indicated that a DHA-enriched diet increases BDNF in the brain. In this randomized double-blind controlled trial of severely injured patients vulnerable to posttraumatic stress disorder (PTSD) and depression, we examined whether DHA increases serum BDNF levels and whether changes in BDNF levels are associated with subsequent symptoms of PTSD and depression. Patients received 1470 mg per day of DHA plus 147 mg per day of eicosapentaenoic acid (EPA; n = 53) or placebo (n = 57) for 12 weeks. Serum levels of mature BDNF and precursor pro-BDNF at baseline and 12-week follow-up were measured using enzyme-linked immunosorbent assay kits. At 12 weeks, we used the Clinician-Administered PTSD Scale to assess PTSD symptoms and depressive symptoms by the Montgomery-Åsberg Depression Rating Scale. We found a significant increase in serum BDNF levels during the trial in the DHA and placebo groups with no interaction between time and group. Changes in BDNF levels were not associated with PTSD severity but negatively associated with depression severity (Spearman's ρ = -0.257, P = 0.012). Changes in pro-BDNF were also negatively associated with depression severity (Spearman's ρ = -0.253, P = 0.013). We found no specific effects of DHA on increased serum levels of BDNF and pro-BDNF; however, evidence in this study suggests that increased BDNF and pro-BDNF have a protective effect by minimizing depression severity.

Effects of fat-enriched diet and methionine on insulin sensitivity in lactating cows.

The hyperinsulinemic-euglycemic clamp (EGC) technique was used to investigate the effects of calcium salts of long-chain fatty acids (LCFA-Ca) and rumen-protected Met (RPM) on insulin sensitivity in the peripheral tissues of lactating cows. Six multiparous Holstein cows were used in a 3 × 3 Latin square experiment in each 14-d period. Dietary treatments were 0 (RPM0), 20 (RPM20), and 60 (RPM60) g/d of RPM, supplemented with a diet containing 1.5% of LCFA-Ca equal to 110% of the cows' ME requirement. And as a control for the 3 LCFA-Ca-containing diets, a dietary treatment without LCFA-Ca (Con) was also included. After a 10-d adaptation period, milk samples were collected for 4 d, and EGC experiments were performed on d 14 of each treatment period. Insulin solution was infused through a jugular vein catheter at a rate of 0.1, 0.2, 0.3, and 0.4 milliunits·kg BW-1·min-1 for 30 min and then at a rate of 0.5 milliunits·kg BW-1·min-1 for 60 min. Glucose solution was variably infused to maintain plasma glucose at steady state through the same catheter. Blood samples for measurements were taken using the contralateral catheter. Plasma total cholesterol, cholesterol ester, free cholesterol, and phospholipid concentrations in RPM0 and RPM20 were higher than those in Con, whereas the concentrations in RPM60 were low at the same degree of those in RPM0 (P < 0.05). Plasma Met concentration was greatest in RPM60 (P < 0.05). In the EGC experiment, the glucose infusion rate was greater in RPM60 than in RPM0 and RPM20 and an effective concentration of insulin resulting in 50% maximal glucose infusion rate was lower in RPM60 compared with RPM0 (P < 0.05), indicating that insulin sensitivity was intensified in RPM60. Although the insulin sensitivity evaluated from the EGC data in RPM0, RPM20, and RPM60 was not different from Con, a slight decline was observed in RPM0 and insulin sensitivity in RPM60 was higher than Con. Our results from the EGC experiment demonstrated that the feeding RPM lead to increased insulin sensitivity, which suggests that dietary Met affects lipid metabolism via insulin action in lactating dairy cows fed a LCFA-Ca-containing diet.

Biomarkers for the evaluation of immunological properties during the shikoku walking pilgrimage.

It is important to determine the immunological properties for the maintenance of health. We chose the Shikoku Walking Pilgrimage to assess the proper biomarkers for the evaluation of immunological properties. We examined whether the Shikoku Walking Pilgrimage could have a positive effect on the mental and physical health of walking participants by using several biomarkers proposed by our laboratory. Twelve non-randomized healthy male volunteers including 3 twice attendees walked the Shikoku Walking Pilgrimage distance of 58.9 km over 3 days. Plasma, serum, urine, and saliva were collected from the volunteers during the pilgrimage and at 1 week before and after it. Immunological biomarkers, including lipid metabolism, oxidative stress, immune function, and catecholamines, were measured. Additionally, mood state scores, alertness, autonomic nervous system activity, and body motion levels during sleep were assessed. A significant decrease was observed in the subjective tension-anxiety levels and in the concentrations of serum low-density lipoprotein cholesterol, plasma hydroxyoctadecadienoic acid (HODE), and urine adrenaline during the pilgrimage as compared to the values of these parameters before the participants embarked on the pilgrimage. The serum levels of brain-derived neurotrophic factor (BDNF) were significantly increased 1 week after the pilgrimage relative to those assessed previously. No significant differences in subjective fatigue and the flicker perception threshold were observed. These results suggest that the Shikoku Walking Pilgrimage can exert a positive effect on mental and physical health as particularly shown in the reduction of tensionanxiety and oxidative stress without the accompaniment of fatigue. HODE correlated significantly with typical immunological marker natural killer cell activity and immunoglobulin G. This suggests that there are promising biomarkers such as HODE, NK activity, BDNF, LDL-c, and IgG for assessing the immunological properties.

Impact of intra-arterial chemotherapy including internal carotid artery for advanced paranasal sinus cancers involving the skull base.

BACKGROUND: The most significant problem of intra-arterial chemotherapy for advanced paranasal sinus carcinomas and residual cancers supplied by internal carotid artery (ICA) and involving the skull base is the lack of salvage therapies. OBJECTIVE: The objective of the study was to evaluate the usefulness of intra-arterial chemotherapy including ICA infusion for treating advanced paranasal sinus carcinomas, which have invaded the skull base. METHODS: Forty-six patients with advanced paranasal sinus carcinomas supplied by ICA were treated by intra-arterial chemotherapy using CDDP and sodium thiosulphate (STS) as a neutraliser of CDDP toxicity. After evaluating CT angiography, 150 mg m(-2) of CDDP was superselectively administered weekly to each feeding artery including ICA four times. RESULTS: The 10-year overall survival rate and progression-free survival rate were 70.7 and 60.2%, respectively. Compared with control group without infusing ICA, recurrences at anterior skullbase or anterior ethomoid sinus were significantly diminished. Of 32 patients in which the orbital apex had been invaded, 29 patients were treated with successful preservation of orbital contents. The CT angiography could efficiently determine all feeding arteries supplying the cancers. Consequently, chemotherapy could be administered on schedule, and side effects were minimal and acceptable. CONCLUSIONS: This new method has promising applications in the treatment of advanced paranasal sinus carcinomas involving the skull base.

Ingestion of medium chain fatty acids by lactating dairy cows increases concentrations of plasma ghrelin.

The purpose of this study was to elucidate the effects of medium-chain fatty acids (MCFAs) on plasma ghrelin concentration in lactating dairy cows. Five early-lactating Holstein cows were randomly assigned to 2 dietary treatments in a crossover design with 2-wk periods. Treatments consisted of diets supplemented or not (control) with calcium salts of MCFAs (MCFA-Ca; 1.5% dry matter). Plasma hormone and metabolite concentrations in blood samples taken from the jugular vein were measured on the morning of feeding on day 14 of each period. Dry matter intake, milk protein, and lactose content of cows fed the MCFA-Ca diet were decreased compared with controls, but with no change in milk yield. Plasma ghrelin concentrations were higher in cows fed the MCFA-Ca diet; however, no significant effect was found on glucagon-like peptide-1 concentrations in plasma. Plasma insulin concentrations decreased, but plasma glucagon concentrations remained unchanged in cows fed the MCFA-Ca diet. The concentrations of nonesterified FAs, total cholesterol, and ß-hydroxybutyrate in plasma increased in these cows. In conclusion, dietary MCFAs increase the plasma ghrelin concentrations in lactating dairy cows.

Relationship between pre-radiographic cartilage damage following anterior cruciate ligament injury and biomarkers of cartilage turnover in clinical practice: a cross-sectional observational study.

OBJECTIVE: To determine whether differences in synovial fluid (SF) biomarkers of collagen and proteoglycan turnover are associated with pre-radiographic damage to articular cartilage and menisci following anterior cruciate ligament (ACL) injury and are of clinical value. METHOD: SF samples from ACL injured knees of 108 patients were obtained when damage to cartilages and menisci was evaluated arthroscopically. Concentrations of SF collagenase-generated cleavage neoepitope of type II collagen (C2C) were determined using ELISA and aggrecan-derived disaccharides of chondroitin-4-sulfate (Δdi-C4S), chondroitin-6-sulfate (Δdi-C6S), and keratan sulfate (KS), were measured in SF by High performance liquid chromatography (HPLC). RESULTS: Radiographic examination failed to detect any intra-articular degenerative changes. The number of high-grade cartilage lesions was positively associated with age, duration after injury and the level of C2C, and negatively with the level of KS. There was no association between the number of high-grade cartilage and meniscal lesions. Multivariable logistic regression revealed significant associations of increased C2C (adjusted Odds ratio (OR) of the upper quartile to remainder of 2.49, 95% Confidence interval (CI) = 0.85-7.27) and decreased KS (adjusted OR of the lower quartile to the remainder of 3.32, 95% CI = 1.19-9.24) with the presence of three or more high-grade cartilage lesions, independent of age and duration after injury. The combined impact of increased C2C and decreased KS was 22.8 (95% CI = 1.95-265.9), far exceeding the impact of each independent biomarker. CONCLUSION: Combinations of the C2C and KS as described here may offer greater ability to identify patients with early pre-radiographic high-grade cartilage damage compared to single clinical or biomarker parameters.

Evaluation of chlorinated benz[a]anthracene on hepatic toxicity in rats and mutagenic activity in Salmonella typhimurium.

Chlorinated benz[a]anthracenes (Cl-BaA) are halogenated aromatic compounds (typified by dioxins) found in the environment at relatively high concentrations. Fischer 344 rats were intragastrically administered 0, 1, or 10 mg of Cl-BaA or its parent compound benz[a]anthracene (BaA) per kg of body weight for 14 consecutive days. Both chemicals at 10 mg/kg/day inhibited the gain in body weight, and consequent increase in relative liver weight. Hepatic gene expression of cytochrome P450 (CYP) 1A1, 1A2, and 1B1 was significantly stimulated by administration of BaA (10 mg/kg/day) compared with the control. After administration of Cl-BaA, only the CYP1A2 gene was significantly induced, even at the lower dosage; CYP1A1 and 1B1 mRNA levels remained unchanged in Cl-BaA-treated rats compared with controls. To elucidate the role of such Cl-BaA exposure and induced CYPs at toxicity onset, we investigated the mutagenicity of BaA and Cl-BaA using Salmonella typhimurium TA98 and TA100. BaA and Cl-BaA at 10 µg/plate produced positive results in both strains in the presence of rat S-9. Incubation of Cl-BaA with recombinant rat CYP1A2 produced a significantly higher number of revertant colonies in TA98 and TA100 than in controls, but no such change was observed for BaA. In conclusion, BaA changes its own physiological and toxicological actions by its chlorination; (1) daily exposure to Cl-BaA selectively induces hepatic CYP1A2 in rats and (2) Cl-BaA induces frameshift mutations in the presence of CYP1A2, although BaA does not exert mutagenicity. This indicates that CYP1A2 may metabolize Cl-BaA to active forms.

Effects of glucose and volatile fatty acids on blood ghrelin concentrations in calves before and after weaning.

The effects of feeding and intravenous injections of glucose and VFA on blood ghrelin concentrations were investigated in calves before and after weaning. Eight Holstein bull calves were fed whole milk, allowed free access to solid feeds, and weaned at 7 wk. Measurements were carried out at 2, 4, 6, 9, 11, and 13 wk, at which time jugular blood samples were taken from 4 calves through a catheter from 10 min before to 120 min after their morning feed at 10 min intervals (Exp. 1). An additional 4 calves of the same age were intravenously injected with glucose (1.0 mmol·kg BW(-1)) and a solution of VFA (2.4 mmol·kg BW(-1), acetate:propionate:butyrate in a 6:3:1 ratio) using a catheter, and jugular blood samples were taken temporally relative to the injection time (Exp. 2). In Exp. 1, blood ghrelin concentrations decreased (P < 0.05) after feeding at all ages. However, preprandial ghrelin concentrations were less (P = 0.025) and the degree of postprandial depression of ghrelin tended to be greater during the postweaning period (P = 0.084) than during the preweaning period. Blood glucose concentrations increased after feeding during the preweaning period (P < 0.05), whereas blood acetate concentrations increased during the postweaning period (P < 0.05). In Exp. 2, injection of VFA induced a greater decrease in blood ghrelin concentrations than glucose injection throughout the entire period (P < 0.05). These results indicate that weaning reduces the basal concentration of blood ghrelin because the circulating VFA derived from ruminal fermentation may more strongly depress blood ghrelin concentrations than glucose.

Pharmacokinetics of mizoribine in adult living donor liver transplantation.

We investigated the pharmacokinetics of mizoribine in the acute phase after adult living donor liver transplantation (LDLT). Between February 2004 and October 2009, 16 recipients received immunosuppressive therapy that included mizoribine (100 to 200 mg/d) after undergoing LDLT. We determined the serum levels of mizoribine before (C0) and 3 (C3), 4 (C4), and 10 (C10) hours after administration on postoperative days 3, 7, and 21. We assessed area under the concentration time curve (AUC) (hour · µg/mL), normalized serum concentration (NSC) at C0 [concentration (µg/mL)/dose (mg/kg body weight)], and estimated glomerular filtration rate (eGFR). The mizoribine concentration showed increases at C3 and C4 followed by a decrease at C10 on all days. AUC was 4.3, 5.9, and 8.3 in the 200-mg/d dose group on days 3, 7, and 21, respectively. NSC at C0 increased for 3 weeks after LDLT. There was a significant correlation between the NSC at C0 and eGFR on day 21, but not on days 3 and 7. There were no correlations between the NSC at C0 and either aspartate aminotransferase, total bilirubin, albumin, trough cyclosporine, or trough tacrolimus on any day. The pharmacokinetics of mizoribine in the acute phase after LDLT seems to be affected by postoperative day and renal function.

KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer.

BACKGROUND: KRAS mutations are predictive markers for the efficacy of anti-EGFR antibody therapies in patients with metastatic colorectal cancer. Although the mutational status of KRAS is reportedly highly concordant between primary and metastatic lesions, it is not yet clear whether genotoxic chemotherapies might induce additional mutations. METHODS: A total of 63 lesions (23 baseline primary, 18 metastatic and 24 post-treatment metastatic) from 21 patients who were treated with FOLFOX as adjuvant therapy for stage III/IV colorectal cancer following curative resection were examined. The DNA samples were obtained from formalin-fixed paraffin-embedded specimens, and KRAS, NRAS, BRAF and PIK3CA mutations were evaluated. RESULTS: The numbers of primary lesions with wild-type and mutant KRAS codons 12 and 13 were 8 and 13, respectively. The mutational status of KRAS remained concordant between the primary tumours and the post-FOLFOX metastatic lesions, irrespective of patient background, treatment duration and disease-free survival. Furthermore, the mutational statuses of the other genes evaluated were also concordant between the primary and metastatic lesions. CONCLUSION: Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumours and post-FOLFOX tumour metastases might serve as valid sources of DNA for known genomic biomarker testing.

Proton magnetic resonance spectroscopy of the thalamus in patients with osteoarthritis of the hip.

OBJECTIVES: The purpose of this study was to assess N-acetyl aspartate changes in the thalamus in patients with osteoarthritis of the hip using proton magnetic resonance spectroscopy. METHODS: Nine patients with osteoarthritis of the hip (symptomatic group, nine women; mean age 61.4 years (48 to 78)) and nine healthy volunteers (control group, six men, three women; mean age 30.0 years (26 to 38)) underwent proton magnetic resonance spectroscopy to assess the changes of N-acetyl aspartate in the thalamus. RESULTS: The ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus contralateral to the symptomatic hip in patients with osteoarthritis of the hip was significantly lower than the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus in the control group (1.611 (range; 1.194-1.882) vs 1.355 (range; 1.043-1.502), p < 0.001). And, a strong negative correlation was detected between the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus contralateral to the symptomatic hip in patients with osteoarthritis of the hip and pain duration (r = -0.83, p = 0.018). CONCLUSIONS: We evaluated the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus of patients with osteoarthritis of the hip by using proton magnetic resonance spectroscopy. We concluded that the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus contralateral to the symptomatic hip in patients with osteoarthritis of the hip were significantly lower than those in the thalamus of the control group, and that pain duration was strongly related to the decrease of the ratio of N-acetyl aspartate to creatine plus phosphocreatine.

Effects of up-titration of candesartan versus candesartan plus amlodipine on kidney function in type 2 diabetic patients with albuminuria.

In the present study, we tested the hypothesis that up-titrating the dose of an angiotensin receptor blocker (ARB) is superior to combined treatment with an ARB and a calcium channel blocker for the same degree of blood pressure (BP) reduction, with respect to urinary albumin excretion in diabetic patients treated with a standard dose of the ARB. Hypertensive patients with type 2 diabetes mellitus and albuminuria (≥30 mg g(-1) creatinine) were enroled in the study, and were either started on or switched to candesartan (8 mg per day) monotherapy. After a 12-week run-in period, baseline evaluations were performed and patients with BP ≥130/80 mm Hg were randomly assigned to receive either candesartan (12 mg per day) or candesartan (8 mg per day) plus amlodipine (2.5 mg per day) for a further 12 weeks. The primary end-point was a reduction in urinary albumin levels. Although there was no significant difference in the BP reduction between the two groups, the reduction in urinary albumin was greater in the up-titrated than the combination therapy group (-40±14% vs -9±38%, respectively; P<0.0001). Thus, up-titration of candesartan more effectively reduces urinary albumin excretion than combined candesartan plus amlodipine in hypertensive patients with diabetes for the same degree of BP reduction.