Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

BACKGROUND:

Research indicates that a diet rich in whole grains may reduce the risk of prevalent chronic diseases, including cardiovascular disease, diabetes, and some cancers, and that risk for these diseases varies by ethnicity. The objective of the current study was to identify major dietary sources of grains and describe their contribution to B vitamins in five ethnic groups.

METHODS:

A cross-sectional mail survey was used to collect data from participants in the Multiethnic Cohort Study in Hawaii and Los Angeles County, United States, from 1993 to 1996. Dietary intake data collected using a quantitative food frequency questionnaire was available for 186,916 participants representing five ethnic groups (African American, Latino, Japanese American, Native Hawaiian and Caucasian) aged 45--75 years. The top sources of grain foods were determined, and their contribution to thiamin, riboflavin, niacin, vitamin B6, and folic acid intakes were analyzed.

RESULTS:

The top source of whole grains was whole wheat/rye bread for all ethnic-sex groups, followed by popcorn and cooked cereals, except for Native Hawaiian men and Japanese Americans, for whom brown/wild rice was the second top source; major contributors of refined grains were white rice and white bread, except for Latinos. Refined grain foods contributed more to grain consumption (27.1-55.6%) than whole grain foods (7.4-30.8%) among all ethnic-sex groups, except African American women. Grain foods made an important contribution to the intakes of thiamin (30.2-45.9%), riboflavin (23.1-29.2%), niacin (27.1-35.8%), vitamin B6 (22.9-27.5%), and folic acid (23.3-27.7%).

CONCLUSIONS:

This is the first study to document consumption of different grain sources and their contribution to B vitamins in five ethnic groups in the U.S. Findings can be used to assess unhealthful food choices, to guide dietary recommendations, and to help reduce risk of chronic diseases in these populations.

OBJECTIVES:

To compare the efficacy and safety of innovator infliximab (INX) and CT-P13, an INX biosimilar, in active rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment.

METHODS:

Phase III randomised, double-blind, multicentre, multinational, parallel-group study. Patients with active disease despite MTX (12.5-25 mg/week) were randomised to receive 3 mg/kg of CT-P13 (n=302) or INX (n=304) with MTX and folic acid. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 30. Therapeutic equivalence of clinical response according to ACR20 criteria was concluded if the 95% CI for the treatment difference was within ±15%. Secondary endpoints included ACR response criteria, European League Against Rheumatism (EULAR) response criteria, change in Disease Activity Score 28 (DAS28), Medical Outcomes Study Short-Form Health Survey (SF-36), Simplified Disease Activity Index, Clinical Disease Activity Index, as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and immunogenicity.

RESULTS:

At week 30, ACR20 responses were 60.9% for CT-P13 and 58.6% for INX (95% CI -6% to 10%) in the intention-to-treat population. The proportions in CT-P13 and INX groups achieving good or moderate EULAR responses (C reactive protein (CRP)) at week 30 were 85.8% and 87.1%, respectively. Low disease activity or remission according to DAS28-CRP, ACR-EULAR remission rates, ACR50/ACR70 responses and all other PK and PD endpoints were highly similar at week 30. Incidence of drug-related adverse events (35.2% vs 35.9%) and detection of antidrug antibodies (48.4% vs 48.2%) were highly similar for CT-P13 and INX, respectively.

CONCLUSIONS:

CT-P13 demonstrated equivalent efficacy to INX at week 30, with a comparable PK profile and immunogenicity. CT-P13 was well tolerated, with a safety profile comparable with that of INX. CLINICALTRIALS.GOV IDENTIFIER: NCT01217086.

Although folic acid and vitamin B12 supplements are recommended during pemetrexed therapy, the optimal duration for supplementation prior to the first dose of pemetrexed has not been defined. We analyzed adverse events during the first cycle of pemetrexed therapy in 350 patients with advanced non-small-cell lung cancer (NSCLC) who had received pemetrexed monotherapy. Patients were divided into two groups: group A and group B included patients who started vitamin supplements 5-14 days versus within 4 days before the first dose of pemetrexed, respectively. Groups A and B included 294 (84.0%) and 56 (16.0%) patients, respectively. The median number of cycles of pemetrexed was three in both groups. Patients in group A and B showed similar rates of leukopenia (6.1% vs. 5.4%, respectively, P=1.00), neutropenia (5.1% vs. 3.6%, P=1.00), thrombocytopenia (3.1% vs. 7.1%, P=0.14), neutropenic fever (0.7% vs. 0%, P=1.00), fatigue (20.1% vs. 19.6%, P=0.94), and anorexia (15.0% vs. 21.4%, P=0.23) during the first cycle of pemetrexed therapy. There were no significant differences in terms of hospitalization (4.4% vs. 5.4%, P=0.73) or unscheduled visits due to pemetrexed-related adverse events (8.2% vs. 12.5%, P=0.31) between groups A and B, respectively. Multivariate logistic regression analysis demonstrated that an age of ≥65 years (odds ratio, 3.49; 95% CI 1.12-10.86) and poor performance status (odds ratio, 3.96; 95% CI 1.12-14.03) were statistically significant predictive factors for grade 3 or 4 hematologic toxicity. The duration of vitamin supplementation before the first dose of pemetrexed did not affect the development of pemetrexed-related toxicities, suggesting that the initiation of pemetrexed-based chemotherapy does not have to be delayed to accommodate a vitamin supplementation schedule.

The present study reports the design, synthesis and biological evaluation of a novel, intravenously injectable, theranostic prodrug based on multiwalled carbon nanotubes (MWCNTs) concomitantly decorated with a fluorochrome (Alexa-fluor, AF488/647), radionucleide (Technitium-99m), tumor targeting module (folic acid, FA) and anticancer agent (methotrexate, MTX). Specifically, MTX was conjugated to MWCNTs via a serum-stable yet intracellularly hydrolysable ester linkage to ensure minimum drug loss in circulation. Cell uptake studies corroborated the selective internalization of AF-FA-MTX-MWCNTs (1) by folate receptor (FR) positive human lung (A549) and breast (MCF 7) cancer cells through FR mediated endocytosis. Lysosomal trafficking of 1 enabled the conjugate to exert higher anticancer activity as compared to its non-targeted counterpart that was mainly restricted to cytoplasm. Tumor-specific accumulation of 1 in Ehlrich Ascites Tumor (EAT) xenografted mice was almost 19 and 8.6 times higher than free MTX and FA-deprived MWCNTs. Subsequently, the conjugate 1 was shown to arrest tumor growth more effectively in chemically breast tumor induced rats, when compared to either free MTX or nontargeted controls. Interestingly, the anticancer activities of the ester-linked CNT-MTX conjugates (including the one deprived of FA) were significantly higher than their amide-linked counterpart suggesting that cleavability of linkers between drug and multifunctional nanotubes critically influence their therapeutic performance. The results were also supported by in silico docking and ligand similarity analysis. Toxicity studies in mice confirmed that all CNT-MTX conjugates were devoid of any perceivable hepatotoxicity, cardiotoxicity and nephrotoxicity. Overall, the delivery property of MWCNTs, high tumor binding avidity of FA, optical detectability of AF fluorochromes and radio-traceability of 99mTc could be successfully integrated and partitioned on a single CNT-platform to augment the therapeutic efficacy of MTX against FR over-expressing cancer cells while allowing a real-time monitoring of treatment response through multimodal imaging.

This study aims to evaluate the serum levels of hemoglobin, vitamin B12 and folic acid in patients with recurrent minor aphthous stomatitis.Between June 2010 and January 2012, a total of 112 patients including 57 with recurrent aphthous stomatitis (study group; 30 males 27 females; mean age 36.7±13.9 years; range 13 to 74 years) and 45 with chronic tinnitus patients without recurrent aphthous stomatitis (control group; 18 males 27 females; mean age 39.7±15.1 years; range 20 to 80 years) who were admitted to our clinic were included in this study. The serum hemoglobin, vitamin B12 and folic acid levels of the patients were measured and statistically compared.There was no significant difference in serum levels of hemoglobin and folic acid between the groups. Serum levels of vitamin B12 were significantly lower in the study group, compared to the control group (p<0.05). Serum levels of hemoglobin and folic acid were significantly lower in women compared to men in both groups (p<0.05).Vitamin B12 deficiency, but not lower levels of folic acid and hemoglobin, may play a role in the underlying etiology of aphthous stomatitis. Vitamin B12 supplements may be added to the treatment of recurrent aphthous stomatitis.

Colorectal adenoma (CRA) is the precursor lesion of colorectal cancer (CRC). Several agents have been shown to be effective in the chemoprevention of CRA recurrence, but there has been little research on its primary prevention. Participants aged>50 years with no adenomas were recruited for our study and randomized to receive either 1 mg/d FA supplement or treatment without FA. After 3 years of follow-up, plasma folate and colonoscopy were evaluated. Seven-hundred and ninety-one participants (91.98%) completed the study. CRA occurred in 64 (14.88%) participants in the FA group and 132 (30.70%) in the control group (unadjusted RR,0.49; 95%CI:0.37-0.63; P<0.01); left-sided adenoma (unadjusted RR,0.54; 95%CI:0.38-0.76; P=0.001) and advanced CRA (unadjusted RR,0.36; 95%CI:0.16-0.81; P=0.01) were most common. There was no significance difference in the occurrence of three or more adenomas (unadjusted RR, 0.70; 95%CI: 0.36-1.77; P=0.38) or right-sided adenoma (unadjusted RR,0.55; 95%CI: 0.30-1.00; P=0.07) between the two groups. Participants with low plasma folate may had a high risk of CRA. In conclusion, primary prevention with 1mg/d FA supplementation could reduce the incidence of CRA, especially left-sided and advanced disease in those with no previous adenomas. People with differing baseline plasma folate levels should be given individualized treatment. Those with low plasma folate should be encouraged to take adequate supplements; plasma folate should be elevated to an effective therapeutic level, which may reduce the incidence of CRA.

Folic acid (FA) and doxorubicin (DOX) are coupled separately onto Fe3 O4 @SiO2 and polystyrene surfaces of a unique polystyrene/Fe3 O4 @SiO2 Janus structure. This super-paramagnetic, dual-functionalized Janus nanocomposite enables effective tumor cell targeting and internalization via the folate receptor, and induces significant cancer cell death by controlled, stimulus-induced drug release under acidic conditions in endosomal compartments.

Glycaemic response to dietary carbohydrates might have an impact on cognitive performance. The present study investigated the effects of growing-up milks (GUM) with isomaltulose and extra minerals and vitamins or lower protein content on cognitive parameters in children aged 5-6 years. In a blinded, partly randomised, controlled, cross-over study, four GUM were provided, each taken over 14 d (2 × 200 ml/d): standard (Std) GUM; Std GUM+5 g isomaltulose (Iso-5 GUM); Iso-5 GUM with 26 % less protein (Iso-5 LP GUM); Std GUM with 2·5 g isomaltulose and extra Mg, Zn, Se, D3, B1, B2, B12, folic acid and choline (Iso-2·5 GUM). At test days, when GUM replaced breakfast, repeated (0, 60, 120 and 180 min post-dose) cognitive tasks were performed (picture presentation, simple reaction time, digit vigilance, choice reaction time, spatial and numeric working memory and picture recognition). Task performance of all subjects (n 50) worsened over the morning. Best performance was seen on isomaltulose GUM, most notably at 180 min. Iso-2·5 GUM showed best performance on several parameters of attention and memory, Iso-5 GUM performed best on parameters of memory and Iso-5 LP GUM was positively associated with parameters of attention but less with memory. Std GUM showed only a benefit on one attention and one memory task. Thus, isomaltulose-enriched GUM positively affected parameters of attention and memory at 180 min post-dose when compared with Std GUM. Extra minerals and vitamins seem beneficial, whereas lowering protein content might improve attention in particular.

In spite of intervention efforts, in Uganda, as in other developing countries, high levels of anaemia among pregnant women continue. Anaemia among women of reproductive age (15-49 years) is a matter of national concern. This study was carried out to assess determinants of anaemia in Kiboga district.This was a single cross-sectional, descriptive survey. The anaemia status of the pregnant women was determined by measuring their haemoglobin levels. Possible determinant factors including socio-economic characteristics, knowledge, attitudes, practices and food intake were assessed using a structured questionnaire.Results showed that the prevalence of anaemia among pregnant women in Kiboga district was high enough (63.1%) to be described as a severe public health problem. The uptake and utilisation of the public-health intervention package to combat anaemia in pregnancy was low, with iron/folic acid supplementation at 13.2%, use of intermittent preventive treatment of malaria 45.4%, and use of de-worming medicines 14.5%. Women from households without a functional radio were 2.07 times more likely be anaemic (95%CI, 1.08-3.00) compared with women from households where there was a functional radio. There was little awareness and functional knowledge about anaemia among pregnant women.The high prevalence of anaemia observed in Kiboga district can be attributed to poverty and limited access to nutrition and health education information which lead to low uptake and utilization of the public-health intervention package to combat anaemia in pregnancy.