Comparación fluorofotométrica de la administración de riboflavina en la cámara anterior mediante aplicación corneal e instilación en el fórnix / A fluorophotometric comparison of anterior chamber riboflavin delivery via corneal application and fornix instillation

Introducción y objetivos Investigamos si la autoadministración de riboflavina por parte de los pacientes podría ser una opción viable para el cross-linking corneal (CXL), teniendo en cuenta los importantes recursos necesarios para la impregnación de la córnea. Analizamos si administrar la riboflavina en el fórnix inferior (lugar de autoadministración) resulta en concentraciones de riboflavina no menores a cuando se aplica directamente en la córnea (zona de aplicación por personal médico). Pacientes y métodos Realizamos un estudio prospectivo para evaluar las concentraciones de riboflavina en seis puntos de tiempo (basal, cinco, 15, 30, 45 y 60 minutos) en 18 voluntarios para cada uno de los dos lugares de aplicación: córnea y fórnix. Las concentraciones de riboflavina (Peschke® TE 0,25%; Peschke Trade GmbH, Huenenberg, Suiza) en la cámara anterior fueron medidas por fluorofotometría (FluorotronTM Master FM-2; OcuMetrics Inc., Mountain View, CA, EE. UU.). Resultados En los dos lugares de aplicación, córnea y fórnix, se observó una autofluorescencia de 16,7 ng/mL (desviación estándar [DE] 5,5) y 14,6 ng/mL (DE 4,6) al inicio de la serie de mediciones (p = 0,221). Después de 30 minutos, las concentraciones de fluorescencia en la cámara anterior habían aumentado a 55,1 ng/mL (DE 25,5) y a 46,1 ng/mL (DE 25,1) (p = 0,293) sin un incremento relevante adicional a los 60 minutos. Conclusiones Este estudio encontró que la aplicación de gotas de riboflavina en el fórnix inferior no fue menor a la aplicación directa en la córnea, según las mediciones fluorométricas de las concentraciones de riboflavina en la cámara anterior. Sugiere que la autoadministración es viable en términos de impregnación corneal de riboflavina (AU)

Introduction and objectives We investigated whether riboflavin self-administration by patients could be a feasible option for corneal cross-linking, given the considerable resources required to impregnate the cornea with riboflavin. We analysed whether administering riboflavin in the inferior fornix (the site of self-administration) results in non-inferior riboflavin concentrations as when applied directly on the cornea (the site of administration by medical personnel). Patients and methods We conducted a prospective study to evaluate riboflavin concentrations at six time-points (baseline, 5, 15, 30, 45 and 60min) in 18 healthy volunteers for each of two application sites: cornea and fornix. Anterior chamber riboflavin (Peschke® TE 0.25%) concentrations were measured by fluorophotometry (Fluorotron™ Master FM-2). Results For the two application sites cornea and fornix, participants did not differ in terms of age and sex. At baseline, the autofluorescence in the anterior chamber was 16.7ng/ml (SD 5.5) and 14.6ng/ml (SD 4.6) (p=0.221). After 30min, anterior chamber fluorescein concentrations had risen to 55.1ng/ml (SD 25.5) and 46.1ng/ml (SD 25.1) (p=0.293) without a further relevant increase by 60min. Conclusions This study found that applying riboflavin drops in the inferior fornix was non-inferior to applying it directly to the cornea, based on fluorophotometric measurements of anterior chamber riboflavin concentrations. This suggests that self-application of riboflavin is feasible in terms of corneal riboflavin impregnation (AU)

Bromhidrosis por trimetilaminuria. Dificultades en su diagnóstico y tratamiento / Bromhidrosis caused by trimethylaminuria. Difficulties in its diagnosis and treatment

La trimetilaminuria es una causa de bromhidrosis, que hay que tener en cuenta en niños prepúberes con un desarrollo normal. Su relación con la ingesta, sobre todo de pescado marino, nos hará sospechar su existencia, que deberemos confirmar mediante el análisis de la excreción urinaria de trimetilamina y el estudio genético. Presentamos cuatro casos de trimetilaminuria donde se analizan y discuten las fórmulas más empleadas para valorar una excreción urinaria aumentada de trimetilamina, su correlación con la gravedad del cuadro y con el rendimiento de las pruebas genéticas. Por último, se describen los tratamientos empleados y se realiza una propuesta de tratamiento, basada en las recomendaciones dietéticas y en el asesoramiento a los padres para un mejor conocimiento y manejo de la enfermedad (AU)

Trimethylaminuria is a cause of bromhidrosis to be considered in pre-pubertal children, with normal development. Its relation with the ingestion, especially of marine fish, will make us suspect its existence that we will have to confirm by means of the analysis of the urinary excretion of trimetilamine and the genetic study. We present four cases of trimethylaminuria where the most used formulas to assess increased urinary excretion of trimethylamine are analysed and discussed, as well as their correlation with the severity of the disease and with the performance of genetic tests. Finally, the used treatments are described, and a treatment proposal is made, based on dietary recommendations and advices to parents for a better understanding and management of the disease (AU)

Corneal riboflavin gradients and UV-absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1 to 0.5.

Avoiding damage of the endothelial cells, especially in thin corneas, remains a challenge in corneal collagen crosslinking (CXL). Knowledge of the riboflavin gradients and the UV absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1% to 0.5% could optimize the treatment. In this study, we present a model to calculate the UV-intensity depending on the corneal thickness. Ten groups of de-epithelialized porcine corneas were divided into 2 subgroups. Five groups received an imbibition of 10 min and the other five groups for 30 min. The applied riboflavin concentrations were 0.1%, 0.2%, 0.3%, 0.4% and 0.5% diluted in a 15% dextran solution for each subgroup. After the imbibition process, two-photon fluorescence microscopy was used to determine fluorescence intensity, which was compared to samples after saturation, yielding the absolute riboflavin concentration gradient of the cornea. The extinction coefficient of riboflavin solutions was measured using a spectrophotometer. Combining the obtained riboflavin concentrations and the extinction coefficients, a depth-dependent UV-intensity profile was calculated for each group. With increasing corneal depth, the riboflavin concentration decreased for all imbibition solutions and application times. The diffusion coefficients of 10 min imbibition time were higher than for 30 min. A higher RF concentration and a longer imbibition time resulted in higher UV-absorption and a lower UV-intensity in the depth of the cornea. Calculated UV-transmission was 6 percentage points lower compared to the measured transmission. By increasing the riboflavin concentration of the imbibition solution, a substantially higher UV-absorption inside the cornea is achieved. This offers a simple treatment option to control the depth of crosslinking e.g. in thin corneas, resulting in a lower risk of endothelial damage.

B Vitamins Supplementation Can Improve Cognitive Functions and May Relate to the Enhancement of Transketolase Activity in A Rat Model of Cognitive Impairment Associated with High-fat Diets.

OBJECTIVE: To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity. METHODS: To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day. RESULTS: Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05). CONCLUSION: Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.

Optic neuropathy linked to ACAD9 pathogenic variants: A potentially riboflavin-responsive disorder?

Mitochondrial complex I (CI) deficiencies (OMIM 252010) are the commonest inherited mitochondrial disorders in children. Acyl-CoA dehydrogenase 9 (ACAD9) is a flavoenzyme involved chiefly in CI assembly and possibly in fatty acid oxidation. Biallelic pathogenic variants result in CI dysfunction, with a phenotype ranging from early onset and sometimes fatal mitochondrial encephalopathy with lactic acidosis to late-onset exercise intolerance. Cardiomyopathy is often associated. We report a patient with childhood-onset optic and peripheral neuropathy without cardiac involvement, related to CI deficiency. Genetic analysis revealed compound heterozygous pathogenic variants in ACAD9, expanding the clinical spectrum associated to ACAD9 mutations. Importantly, riboflavin treatment (15 mg/kg/day) improved long-distance visual acuity and demonstrated significant rescue of CI activity in vitro.

Enhancement in corneal permeability of riboflavin using cyclodextrin derivates complexes as a previous step to transepithelial cross-linking.

Corneal cross-linking has been described as an effective treatment to slow the progression of keratoconus. The standard protocol entails corneal epithelial removal to allow the diffusion of riboflavin into the stroma. Although, de-epithelization can generate risks or complications that transepithelial cross-linking tries to solve or avoid. Different formulations were developed after verifying that hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobuthylether-ß-cyclodextrin (SBEßCD) in a 20% concentration, increased the solubility of practically insoluble in water drugs such as riboflavin from 0.12 mg/mL to 0.35 mg/mL and 0.29 mg/mL respectively. These values were higher when chitosan and arginine were added to the formulation, showing solubility of 0.78 mg/mL when HPßCD concentration was not modified. Ex vivo corneal permeability was measured after having kept in contact bovine corneas with intact epithelium for 5 h with the 0.1 mg/mL riboflavin solution, the formulations developed and a reproduced nanoemulsion from another work. Riboflavin's permeability was increased when cyclodextrins, chitosan, and arginine were part of the formulations, compared to the control drug solution. The best permeability coefficient was reached when riboflavin was combined with 40% (w/v) HPßCD, 0.5% (w/w) arginine, and 0.5% (w/w) chitosan. After having carried out toxicity studies as bovine corneal opacity and permeability (BCOP) and Hens Egg Test - Chorioallantoic Membrane Test (HET-CAM) it was verified that both, the active ingredients and the excipients of the different formulations were not harmful without generating irritation, loss of transparency or corneal permeability alterations. The results show the great potential of the ocular developed solution for their use in transepithelial cross-linking for keratoconus treatment.

Transepithelial versus epithelium-off corneal crosslinking for progressive keratoconus.

BACKGROUND: Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening. Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process. Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze. OBJECTIVES: To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus. SEARCH METHODS: To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We included 13 studies with 723 eyes of 578 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention. Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI -0.11 to 2.09; 5 studies; 177 eyes; I2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14). Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI -0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported. AUTHORS' CONCLUSIONS: Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs.

Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome- a pilot study.

An increasing body of evidence has shown that gut microbiota imbalances are linked to diseases. Currently, the possibility of regulating gut microbiota to reverse these perturbations by developing novel therapeutic and preventive strategies is being extensively investigated. The modulatory effect of vitamins on the gut microbiome and related host health benefits remain largely unclear. We investigated the effects of colon-delivered vitamins A, B2, C, D, and E on the gut microbiota using a human clinical study and batch fermentation experiments, in combination with cell models for the assessment of barrier and immune functions. Vitamins C, B2, and D may modulate the human gut microbiome in terms of metabolic activity and bacterial composition. The most distinct effect was that of vitamin C, which significantly increased microbial alpha diversity and fecal short-chain fatty acids compared to the placebo. The remaining vitamins tested showed similar effects on microbial diversity, composition, and/or metabolic activity in vitro, but in varying degrees. Here, we showed that vitamins may modulate the human gut microbiome. Follow-up studies investigating targeted delivery of vitamins to the colon may help clarify the clinical significance of this novel concept for treating and preventing dysbiotic microbiota-related human diseases. Trial registration: ClinicalTrials.gov, NCT03668964. Registered 13 September 2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03668964.

Effects of riboflavin supplementation on performance, nutrient digestion, rumen microbiota composition and activities of Holstein bulls.

To investigate the influences of dietary riboflavin (RF) addition on nutrient digestion and rumen fermentation, eight rumen cannulated Holstein bulls were randomly allocated into four treatments in a repeated 4 × 4 Latin square design. Daily addition level of RF for each bull in control, low RF, medium RF and high RF was 0, 300, 600 and 900 mg, respectively. Increasing the addition level of RF, DM intake was not affected, average daily gain tended to be increased linearly and feed conversion ratio decreased linearly. Total tract digestibilities of DM, organic matter, crude protein (CP) and neutral-detergent fibre (NDF) increased linearly. Rumen pH decreased quadratically, and total volatile fatty acids (VFA) increased quadratically. Acetate molar percentage and acetate:propionate ratio increased linearly, but propionate molar percentage and ammonia-N content decreased linearly. Rumen effective degradability of DM increased linearly, NDF increased quadratically but CP was unaltered. Activity of cellulase and populations of total bacteria, protozoa, fungi, dominant cellulolytic bacteria, Prevotella ruminicola and Ruminobacter amylophilus increased linearly. Linear increase was observed for urinary total purine derivatives excretion. The data suggested that dietary RF addition was essential for rumen microbial growth, and no further increase in performance and rumen total VFA concentration was observed when increasing RF level from 600 to 900 mg/d in dairy bulls.

A method to identify pulmonary intersegmental planes with intravenous vitamin B2 injection.

PURPOSE: The present study investigated whether the pulmonary intersegmental planes could be identified with the intravenous injection of vitamin B2 using a fluorescent camera and whether this method can be used instead of the inflation-deflation technique or the intravenous indocyanine green (ICG) method. METHODS: In experiment 1, the vitamin B2 was intravenously injected to visualize the pulmonary intersegmental plane and perform segmentectomy, and the visualized pulmonary intersegmental line was then compared to the inflation-deflation line in six pigs. In experiment 2, using six pigs, the fluorescent area and duration of fluorescence were compared after the intravenous injection of vitamin B2 and ICG in the same animals. RESULTS: In all animals in experiment 1, it was possible to clearly detect yellow-green fluorescence in the lung, in segments other than the one intended for resection, for at least 60 min. Moreover, the line visualized with vitamin B2 fluorescence matched the inflation-deflation line in all animals. In experiment 2, the area of vitamin B2 fluorescence corresponded to the area of ICG fluorescence in each animal. CONCLUSIONS: The visualization of fluorescence after the intravenous injection of vitamin B2 using a fluorescent camera was a simple, safe, and accurate method for detecting intersegmental planes in a pig model. This method can be an alternative to the inflation-deflation technique and the intravenous ICG method.

Exploring trajectories in dietary adequacy of the B vitamins folate, riboflavin, vitamins B6 and B12, with advancing older age: a systematic review.

Maintaining nutritional adequacy contributes to successful ageing. B vitamins involved in one-carbon metabolism regulation (folate, riboflavin, vitamins B6 and B12) are critical nutrients contributing to homocysteine and epigenetic regulation. Although cross-sectional B vitamin intake in ageing populations is characterised, longitudinal changes are infrequently reported. This systematic review explores age-related changes in dietary adequacy of folate, riboflavin, vitamins B6 and B12 in community-dwelling older adults (≥65 years at follow-up). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, databases (MEDLINE, Embase, BIOSIS, CINAHL) were systematically screened, yielding 1579 records; eight studies were included (n 3119 participants, 2­25 years of follow-up). Quality assessment (modified Newcastle­Ottawa quality scale) rated all of moderate­high quality. The estimated average requirement cut-point method estimated the baseline and follow-up population prevalence of dietary inadequacy. Riboflavin (seven studies, n 1953) inadequacy progressively increased with age; the prevalence of inadequacy increased from baseline by up to 22·6 and 9·3 % in males and females, respectively. Dietary folate adequacy (three studies, n 2321) improved in two studies (by up to 22·4 %), but the third showed increasing (8·1 %) inadequacy. Evidence was similarly limited (two studies, respectively) and inconsistent for vitamins B6 (n 559; −9·9 to 47·9 %) and B12 (n 1410; −4·6 to 7·2 %). This review emphasises the scarcity of evidence regarding micronutrient intake changes with age, highlighting the demand for improved reporting of longitudinal changes in nutrient intake that can better direct micronutrient recommendations for older adults. This review was registered with PROSPERO (CRD42018104364).

Retrospective Observational Study on Riboflavin Prophylaxis in Child and Adolescent Migraine.

BACKGROUND: We evaluated the efficacy of riboflavin in pediatric migraineurs. METHODS: A retrospective observational study was performed on 42 patients (aged six to 18 years) with migraine who were evaluated from January to December 2019 at Dell Children's Medical Center in Austin, Texas. Weight-based dosing of riboflavin was recommended for migraine prevention. Descriptive statistics were used to study the population demographics. Nonparametric tests were used for inferential statistics to study the effect of riboflavin on headache frequency, intensity, and duration. RESULTS: Patients treated with riboflavin had a significant reduction in headache days per month (frequency) at the first follow-up visit at 2 to 4 months (T1) (11.07 ± 10.52 days) compared with the baseline T0 (21.90 ± 9.85 days); P < 0.001 in regard to the primary outcome in 42 patients (mean age, 13.38 ± 3.38). Mean headache intensity decreased from 8.85 (±6.41; T0) to 2.30 (±2.51; T1); P < 0.001 on a 0 to 10 scale. The headache duration also reduced significantly from 18.23 ± 17.07 hours (T0) to 10.18 ± 10.49 hours (T1); P = 0.001. There was a positive correlation between riboflavin efficacy and reduced use of acute medications (rs = 0.304; P = 0.05). Riboflavin was useful in reducing the frequency and intensity in two patients with new daily persistent headache. CONCLUSIONS: Patients treated with riboflavin had a reduction in headache frequency, use of acute medications, and days of school missed. Riboflavin prophylaxis also reduced migraine intensity and duration. Riboflavin is recommended as a safe, inexpensive, and effective nutraceutical in the treatment of pediatric migraine.

Inverse Association Between Riboflavin Intake and New-Onset Hypertension: A Nationwide Cohort Study in China.

The prospective relation of dietary riboflavin intake with hypertension remains uncertain. We aimed to investigate the relationship of dietary riboflavin intake with new-onset hypertension and examine possible effect modifiers in general population. A total of 12 245 participants who were free of hypertension at baseline from China Health and Nutrition Survey were included. Dietary intake was measured by 3 consecutive 24-hour dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or diagnosed by physician or under antihypertensive treatment during the follow-up. A total of 4303 (35.1%) subjects developed hypertension during 95 573 person-years of follow-up. Overall, there was a nonlinear, inverse association between total, plant-based, or animal-based riboflavin intake and new-onset hypertension (all P for nonlinearity, <0.001). The risk of new-onset hypertension was increased only in participants with relatively lower riboflavin intake. Accordingly, a significantly lower risk of new-onset hypertension was found in participants in quartiles 2 to 4 of total riboflavin intake (hazard ratio, 0.74 [95% CI, 0.68-0.80]), plant-derived riboflavin intake (hazard ratio, 0.77 [95% CI, 0.71-0.84]), or animal-derived riboflavin intake (hazard ratio, 0.70 [95% CI, 0.65-0.77]), compared with those in quartile 1. In addition, the association between total riboflavin intake and new-onset hypertension was particularly evident in those with lower dietary sodium/potassium intake ratio (P interaction, <0.001). In summary, there was an inverse association between riboflavin intake and new-onset hypertension in general Chinese adults. Our results emphasized the importance of maintaining relatively higher riboflavin intake levels for the prevention of hypertension.

Mitigation potential of selenium nanoparticles and riboflavin against arsenic and elevated temperature stress in Pangasianodon hypophthalmus.

Climate change impact has disturbed the rainfall pattern worsening the problems of water availability in the aquatic ecosystem of India and other parts of the world. Arsenic pollution, mainly through excessive use of groundwater and other anthropogenic activities, is aggravating in many parts of the world, particularly in South Asia. We evaluated the efficacy of selenium nanoparticles (Se-NPs) and riboflavin (RF) to ameliorate the adverse impacts of elevated temperature and arsenic pollution on growth, anti-oxidative status and immuno-modulation in Pangasianodon hypophthalmus. Se-NPs were synthesized using fish gill employing green synthesis method. Four diets i.e., Se-NPs (0 mg kg-1) + RF (0 mg kg-1); Se-NPs (0.5 mg kg-1) + RF (5 mg kg-1); Se-NPs (0.5 mg kg-1) + RF (10 mg kg-1); and Se-NPs (0.5 mg kg-1) + RF (15 mg kg-1) were given in triplicate in a completely randomized block design. The fish were treated in arsenic (1/10th of LC50, 2.68 mg L-1) and high temperature (34 °C). Supplementation of the Se-NPs and RF in the diets significantly (p < 0.01) enhanced growth performance (weight gain, feed efficiency ratio, protein efficiency ratio, and specific growth rate), anti-oxidative status and immunity of the fish. Nitroblue tetrazolium (NBT), total immunoglobulin, myeloperoxidase and globulin enhanced (p < 0.01) with supplementation (Se-NPs + RF) whereas, albumin and albumin globulin (A:G) ratio (p < 0.01) reduced. Stress biomarkers such as lipid peroxidation in the liver, gill and kidney, blood glucose, heat shock protein 70 in gill and liver as well as serum cortisol reduced (p < 0.01) with supplementation of Se-NPs and RF, whereas, acetylcholine esterase and vitamin C level in both brain and muscle significantly enhanced (p < 0.01) in compared to control and stressors group (As + T) fed with control diet. The fish were treated with pathogenic bacteria after 90 days of experimental trial to observe cumulative mortality and relative survival for a week. The arsenic concentration in experimental water and bioaccumulation in fish tissues was also determined, which indicated that supplementation of Se-NPs and RF significantly reduced (p < 0.01) bioaccumulation. The study concluded that a combination of Se-NPs and RF has the potential to mitigate the stresses of high temperature and As pollution in P. hypophthalmus.

Efficacy of systemic administration of riboflavin on a rabbit model of corneal alkali burn.

Changes in the barrier mechanisms in the eye should determine the rational route for the administration and dosage of each drug in the treatment of traumatic injuries and other pathologies. The aim of this study was to examine the efficacy of intra-arterial delivery of 14C-riboflavin (as an "indicator") and compare it with intravenous and intramuscular administration in an animal model of chemical eye burn. 14C-riboflavin (14C-I) was administered by intra-arterial (carotid artery), intravenous (femoral vein) and intramuscular (femoral muscle) routes. The total radioactivity was determined over 2 h in the plasma and structures of the rabbit's eyes using a scintillation counter. The results of the study show that intravascular administration of 14C-I gives significantly higher concentrations of total radioactivity in the blood and is accompanied by a significant increase in the permeability of the blood-barrier and barrier in eyes suffering from burns. The highest concentration in the plasma and aqueous humour of the anterior chamber of the eye was observed during the first hour with the intra-arterial route of administration of 14C-I in either burnt and unburnt eyes. The distribution of total radioactivity in the structures of the eye over the 2 h of the experiment showed a higher level of the drug under intra-arterial administered in the uveal regions, namely: the iris, ciliary body, choroid, retina and also the sclera and cornea. This experimental model shows that intra-arterial administration can increase the bioavailability of a drug to the structures of the eye within a short period of time.

Nutritional Optic Neuropathies: State of the Art and Emerging Evidences.

Nutritional optic neuropathy is a cause of bilateral, symmetrical, and progressive visual impairment with loss of central visual acuity and contrast sensitivity, dyschromatopsia, and a central or centrocecal scotoma. The clinical features are not pathognomonic, since hereditary and toxic forms share similar signs and symptoms. It is becoming increasingly common due to the widespread of bariatric surgery and strict vegetarian or vegan diets, so even the scientific interest has recently increased. In particular, recent studies have focused on possible pathogenetic mechanisms, and on novel diagnostic and therapeutic strategies in order to prevent the onset, make a prompt diagnosis and an accurate nutritional supplementation, and to avoid irreversible optic nerve atrophy. Nowadays, there is clear evidence of the role of cobalamin, folic acid, thiamine, and copper, whereas further studies are needed to define the role of niacin, riboflavin, and pyridoxine. This review aims to summarize the etiology, diagnosis, and treatment of nutritional optic neuropathy, and it is addressed not only to ophthalmologists, but to all physicians who could come in contact with a patient with a possible nutritional optic neuropathy, being a fundamental multidisciplinary approach.

Riboflavin Is an Important Determinant of Vitamin B-6 Status in Healthy Adults.

BACKGROUND: Riboflavin is required to generate the active form of vitamin B-6 (pyridoxal 5'-phosphate; PLP) in tissues, but the relevance of this metabolic interaction for nutritional status of vitamin B-6 is unclear because riboflavin biomarkers are rarely measured in human studies. OBJECTIVES: The purpose of this study was to identify the determinants of biomarkers of vitamin B-6 and riboflavin status and to examine the relationship between these nutrients in healthy adults. METHODS: Multiple linear regression was performed on observational data in 407 healthy adults aged 18-92 y who did not use B-vitamin supplements. Vitamin B-6 status was assessed by plasma PLP concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) was used as a functional indicator of riboflavin status. RESULTS: Dietary intakes of vitamin B-6 and riboflavin were below the average requirements in 10% and 29% of participants, respectively. Suboptimal status of vitamin B-6 (PLP ≤30.0 nmol/L) was more prevalent in adults aged ≥60 y than in younger participants (i.e., 14% compared with 5%), whereas a high proportion (i.e., overall 37%) of both age groups had deficient riboflavin status (EGRac ≥1.40). In multiple regression analysis, EGRac (P = 0.019) was a significant determinant of plasma PLP, along with dietary vitamin B-6 intake (P = 0.003), age (P < 0.001), BMI (kg/m2) (P = 0.031), and methylenetetrahydrofolate reductase gene (MTHFR) genotype (P < 0.001). Significant determinants of EGRac were dietary riboflavin intake (P < 0.001), age (P < 0.001) and MTHFR genotype (P = 0.020). Plasma PLP showed a stepwise decrease across riboflavin status categories from optimal (EGRac ≤1.26) to low (EGRac 1.27-1.39) to deficient status (P = 0.001), independent of dietary vitamin B-6 intake. CONCLUSIONS: The findings are consistent with the known metabolic dependency of vitamin B-6 on riboflavin status and indicate that riboflavin may be the limiting nutrient, particularly in older people, for maintaining adequate vitamin B-6 status.

Can broad-spectrum multinutrients treat symptoms of antenatal depression and anxiety and improve infant development? Study protocol of a double blind, randomized, controlled trial (the 'NUTRIMUM' trial).

BACKGROUND: Untreated antenatal depression and anxiety can be associated with short and long term health impacts on the pregnant woman, her infant and the rest of the family. Alternative interventions to those currently available are needed. This clinical trial aims to investigate the efficacy and safety of a broad-spectrum multinutrient formula as a treatment for symptoms of depression and anxiety in pregnant women and to determine the impact supplementation has on the general health and development of the infant. METHODS: This randomised, controlled trial will be conducted in Canterbury, New Zealand between April 2017 and June 2022. One hundred and twenty women aged over 16 years, between 12 and 24 weeks gestation and who score ≥ 13 on the Edinburgh Postnatal Depression Scale (EPDS) will be randomly assigned to take the intervention (n = 60) or an active control formula containing iodine and riboflavin (n = 60) for 12 weeks. After 12 weeks, participants can enter an open-label phase until the birth of their infant and naturalistically followed for the first 12 months postpartum. Infants will be followed until 12 months of age. Randomisation will be computer-generated, with allocation concealment by opaque sequentially numbered envelopes. Participants and the research team including data analysts will be blinded to group assignment. The EPDS and the Clinical Global Impressions Scale of Improvement (CGI-I) will be the maternal primary outcome measures of this study and will assess the incidence of depression and anxiety and the improvement of symptomatology respectively. Generalized linear mixed effects regression models will analyse statistical differences between the multinutrient and active control group on an intent-to-treat basis. A minimum of a three-point difference in EPDS scores between the groups will identify clinical significance. Pregnancy outcomes, adverse events and side effects will also be monitored and reported. DISCUSSION: Should the multinutrient formula be shown to be beneficial for both the mother and the infant, then an alternative treatment option that may also improve the biopsychosocial development of their infants can be provided for pregnant women experiencing symptoms of depression and anxiety. TRIAL REGISTRATION: Trial ID: ACTRN12617000354381 ; prospectively registered at Australian New Zealand Clinical Trials Registry on 08/03/2017.

Micronutrient supplementation of lactating Guatemalan women acutely increases infants' intake of riboflavin, thiamin, pyridoxal, and cobalamin, but not niacin, in a randomized crossover trial.

BACKGROUND: Maternal supplementation during lactation could increase milk B-vitamin concentrations, but little is known about the kinetics of milk vitamin responses. OBJECTIVES: We compared acute effects of maternal lipid-based nutrient supplement (LNS) consumption (n = 22 nutrients, 175%-212% of the RDA intake for the nutrients examined), as a single dose or at spaced intervals during 8 h, on milk concentrations and infant intake from milk of B-vitamins. METHODS: This randomized crossover trial in Quetzaltenango, Guatemala included 26 mother-infant dyads 4-6 mo postpartum who were randomly assigned to receive 3 treatments in a random order: bolus 30-g dose of LNS (Bolus); 3 × 10-g doses of LNS (Divided); and no LNS (Control), with control meals. Mothers attended three 8-h visits during which infant milk consumption was measured and milk samples were collected at every feed. Infant intake was assessed as $\mathop \sum \nolimits_{i\ = \ 1}^n ( {{\rm{milk\ volum}}{{\rm{e}}_{{\rm{feed\ }}n}} \times \ {\rm{nutrient\ concentratio}}{{\rm{n}}_{{\rm{feed}}\ n}}} )$ over 8 h. RESULTS: Maternal supplementation with the Bolus or Divided dose increased least-squares mean (95% CI) milk and infant intakes of riboflavin [milk: Bolus: 154.4 (138.2, 172.5) µg · min-1 · mL-1; Control: 84.5 (75.8, 94.3) µg · min-1 · mL-1; infant: Bolus: 64.5 (56.1, 74.3) µg; Control: 34.5 (30.0, 39.6) µg], thiamin [milk: Bolus: 10.9 (10.1, 11.7) µg · min-1 · mL-1; Control: 7.7 (7.2, 8.3) µg · min-1 · mL-1; infant: Bolus: 5.1 (4.4, 6.0) µg; Control: 3.4 (2.9, 4.0) µg], and pyridoxal [milk: Bolus: 90.5 (82.8, 98.9) µg · min-1 · mL-1; Control: 60.8 (55.8, 66.3) µg · min-1 · mL-1; infant: Bolus: 39.4 (33.5, 46.4) µg; Control: 25.0 (21.4, 29.2) µg] (all P < 0.001). Only the Bolus dose increased cobalamin in milk [Bolus: 0.054 (0.047, 0.061) µg · min-1 · mL-1; Control: 0.041 (0.035, 0.048) µg · min-1 · mL-1, P = 0.039] and infant cobalamin intake [Bolus: 0.023 (0.020, 0.027) µg; Control: 0.015 (0.013, 0.018) µg, P = 0.001] compared with Control. Niacin was unaffected. CONCLUSIONS: Maternal supplementation with LNS as a Bolus or Divided dose was similarly effective at increasing milk riboflavin, thiamin, and pyridoxal and infant intakes, whereas only the Bolus dose increased cobalamin. Niacin was unaffected in 8 h. This trial was registered at clinicaltrials.gov as NCT02464111.

Optimizing corneal riboflavin administration in ex vivo horse, dog, rabbit, and pig samples for use in corneal collagen cross-linking.

PURPOSE: Determine optimal iontophoresis times for riboflavin delivery to the corneal stroma across different species and compare these to corneal injection. METHODS: Ex vivo horse, dog, rabbit, and pig globes were treated with riboflavin administered with either iontophoresis for 2.5-20 minutes with or without corneal epithelium; or with purpose-designed precise corneal injection (PCI) application with intact epithelium. Immediately following riboflavin administration, samples were harvested, frozen, and sectioned. Riboflavin penetration was imaged using fluorescence microscopy. RESULTS: Horse samples processed with iontophoresis without epithelium for 2.5, 5, and 7.5 minutes, and processed with intact epithelium for 20 minutes, had mean percent stromal penetration (%SPmean ) of 63.4%, 93.8%, 100.0%, and 0.0% (respectively). Dog samples processed with iontophoresis without epithelium for 2.5 and 5 minutes, had %SPmean of 60.7% and 82.1% (respectively). Pig samples processed with iontophoresis for 5 minutes without and with epithelium had %SPmean of 63.3% and 35.1% (respectively). Rabbit samples processed with iontophoresis without epithelium for 2.5 and 5 minutes, had %SPmean of 81.8% and 100.0% (respectively). For all injected volumes, riboflavin was observed spanning throughout the corneal stroma, and lamellar separation was noted surrounding all sites of injection. CONCLUSIONS: Both iontophoresis and injection via PCI needles provide efficient and effective means of riboflavin administration in ex vivo horse, dog, rabbit, and pig corneas. Epithelial debridement is required for stromal delivery of riboflavin using iontophoresis in horses. Following epithelial removal, riboflavin penetrated through the horse corneal stroma faster than all other species tested.