Sensory neuropathy as a manifestation of multiple acyl-coenzyme A dehydrogenase deficiency.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder which typically manifests with muscle weakness. However, despite late-onset MADD being treatable, it is often misdiagnosed, due in part to the heterogeneity of presentations. We report a case of late-onset MADD manifesting first as a sensory neuropathy before progressing to myopathic symptoms and acute metabolic decompensation. Early diagnostic workup with acylcarnitine profiling and organic acid analysis was critical in patient outcome; metabolic decompensation and myopathic symptoms were completely reversed with riboflavin supplementation and dietary modification, although sensory neuropathy persisted. Clinical consideration of MADD as part of the differential diagnosis of neuropathy with myopathy is crucial for a timely diagnosis and treatment of MADD.

Oxygen-supplemented and topography-guided epithelium-on corneal crosslinking with pulsed irradiation for progressive keratoconus.

PURPOSE: To investigate the effects of customized topography-guided epithelium-on crosslinking (epi-on CXL) with oxygen supplementation on procedural efficacy and corrected distance visual acuity (CDVA) in patients with progressive keratoconus (KC) at 1 year. SETTING: Private eye clinic, Brisbane, Australia. DESIGN: Retrospective, single-center, nonrandomized case series. METHODS: Topography-guided epi-on CXL using the Mosaic system was performed on patients with progressive KC. Oxygen goggles; transepithelial riboflavin; and pulsed, high UV-A irradiance (1 second on, 1 second off; 30 mW/cm2) were applied to enhance oxygen kinetics and bioavailabilities of riboflavin and UV-A. Guided by baseline topography, a higher UV-A dose (15 J/cm2) was applied to the area of steepest anterior curvature with decreasing fluence (as low as 7.2 J/cm2) toward the outer 9 mm. Postoperative CDVA and maximum keratometry (Kmax) were evaluated. RESULTS: 102 eyes (80 patients) were followed for 11.5 ± 4.8 months. At the latest follow-up, mean CDVA (logMAR), mean K, and Kmax (diopters [D]) improved from 0.18 ± 0.28, 46.2 ± 3.8, and 53.0 ± 5.67 at baseline to 0.07 ± 0.18, 45.8 ± 3.7, and 51.9 ± 5.56, respectively (P < .001). 3 eyes (3%) lost more than 1 CDVA line, and another 3 eyes (3%) had increased Kmax greater than 2 D. 43 eyes were followed for at least 12 months (n = 43): mean CDVA, mean K, and Kmax improved from 0.19 ± 0.33 logMAR, 46.5 ± 3.5 D, and 53.6 ± 5.67 D to 0.07 ± 0.17 logMAR, 46.0 ± 3.5 D, and 52.33 ± 5.49 D, respectively (P ≤ .002). No complications were observed. CONCLUSIONS: Tailoring oxygen-supplemented epi-on CXL with differential UV-A energy distributions, guided by baseline topography, in patients with KC seems to be safe and effective. At 1 year, study reports sustained improved CDVA and corneal stabilization.

Photoactivated chromophore-corneal cross-linking accelerates corneal healing in fungal keratitis: an updated meta-analysis.

AIM: To determine the effectiveness and safety of photoactivated chromophore-corneal cross-linking (PACK-CXL) adjuvant in infectious keratitis by April 5, 2022. METHODS: We searched randomized controlled trials (RCTs) comparing standard antibiotic treatment (SAT) plus PACK-CXL to SAT in infectious keratitis in Embase, MEDLINE with PubMed, Web of Science, and Cochrane Library. We independently screened and extracted data using predesigned tables. Cochrane's risk-of-bias tool was utilized to examine the quality of RCTs. A random-effects model was employed to determine the overall effect size of the meta-analyses. Grading of Recommendations, and Assessment, Development and Evaluations (GRADE) was also performed to examine the quality of evidence. RESULTS: Seven eligible RCTs with 283 patients were acquired. Adjuvant PACK-CXL reduced the time needed to perform corneal healing in fungal keratitis (- 1.33 months; 95% CI, - 1.83 to - 0.42, I2 = 0%, P < 0.05) as compared to SAT alone. The risks of adverse events were not significantly different both in fungal and bacterial keratitis. Due to the substantial heterogeneity among studies, such as population, the type and severity of infectious keratitis, drug regimens of SAT, PACK-CXL protocol, and the judgment of subjective outcomes, the evidence grade was low. CONCLUSION: Adjuvant PACK-CXL accelerates fungal keratitis healing as compared to SAT alone. But more rigorous RCTs are required to determine the clinical effectiveness and safety.

Crocin Ameliorates Diabetic Nephropathy through Regulating Metabolism, CYP4A11/PPARγ, and TGF-ß/Smad Pathways in Mice.

INTRODUCTION: Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still needs to be further elucidated. METHOD: In the present study, a mouse model of DN was first established to investigate the therapeutic effect of crocin on DN mice. Subsequently, non-targeted metabolomics techniques were used to analyze the mechanisms of action of crocin in the treatment of DN. The effects of crocin on CYP4A11/PPARγ and TGF-ß/Smad pathway were also investigated. RESULT: Results showed that crocin exhibited significant therapeutic and anti-inflammatory, and anti-oxidative effects on DN mice. In addition, the non-targeted metabolomics results indicated that crocin treatment affected several metabolites in kidney. These metabolites were mainly associated with biotin metabolism, riboflavin metabolism, and arachidonic acid metabolism. Furthermore, crocin treatment upregulated the decreased levels of CYP4A11 and phosphorylated PPARγ, and reduced the increased levels of TGF-ß1 and phosphorylated Smad2/3 in the kidneys of DN mice. CONCLUSION: In conclusion, our study validated the considerable therapeutic, anti-inflammatory, and antioxidative impacts of crocin on DN mice. The mechanism of crocin treatment may be related to the regulation of biotin riboflavin and arachidonic acid metabolism, the activation of CYP4A11/PPARγ pathway, and the inhibition of TGF-ß/Smad pathway in the kidney.

A Case Report of Riboflavin Treatment and Cochlear Implants in a 4-Year-Old Girl with Progressive Hearing Loss and Delayed Speech Development: Brown-Vialetto-Van Laere Syndrome.

BACKGROUND Brown-Vialetto-Van Laere (BVVL) syndrome is a rare autosomal recessive disorder caused by mutations in intestinal riboflavin transporter genes, resulting in a motor neuron disorder of childhood, which can be associated with sensorineural deafness. This report describes a 4-year-old Polish girl with progressive hearing loss and delayed speech development diagnosed with Brown-Vialetto-Van Laere syndrome who was treated with riboflavin (vitamin B2) and cochlear implants. CASE REPORT The case report concerns a girl from Poland who, at the age of 2 years 10 months, developed progressive atypical neurological symptoms of unknown etiology: ataxia of the upper and lower limbs, gait abnormalities, generalized muscle weakness, visual and hearing problems, and regression of speech development. A karyotype study (whole-exome sequencing) revealed alterations within SLC52A2, leading to the diagnosis of Brown-Vialetto-Van Laere syndrome and initiation of high-dose riboflavin treatment. As a 4-year-old child, she presented to the Institute of Physiology and Pathology of Hearing - World Hearing Center in Poland with progressive hearing loss and speech regression. Hearing tests revealed bilateral profound sensorineural hearing loss with auditory neuropathy. Surgical treatment was applied in the form of bilateral cochlear implantation. CONCLUSIONS This report shows the importance of genetic testing in infants who present with atypical symptoms or signs. In this case, the diagnosis of Brown-Vialetto-Van Laere syndrome resulted in timely correction of the genetic riboflavin (vitamin B2) deficiency and improved hearing following the use of cochlear implants.

B-vitamins, related vitamers, and metabolites in patients with quiescent inflammatory bowel disease and chronic fatigue treated with high dose oral thiamine.

BACKGROUND: High doses of oral thiamine improve clinical fatigue scores in patients with quiescent inflammatory bowel disease (IBD) and chronic fatigue. In this study we analysed plasma samples obtained in a randomised clinical trial and aimed compare levels of vitamins B1, B2, B3 and B6, and their related vitamers and metabolites in patients with IBD, with or without chronic fatigue and with or without effect of high dose oral thiamine for chronic fatigue. METHODS: Blood samples from patients with fatigue were drawn prior and after thiamine exposure and only once for patients without fatigue. A wide panel of analysis were done at Bevital AS Lab. RESULTS: Concentration of flavin mononucleotide (FMN) was lower in patients with chronic fatigue compared to patients without fatigue (p = 0.02). Patients with chronic fatigue who reported a positive effect on fatigue after 4 weeks of high dose thiamine treatment had a statistically significantly lower level of riboflavin after thiamine treatment (p = 0.01). CONCLUSION: FMN and Riboflavin were associated with chronic fatigue in patients with quiescent IBD. Levels of other B vitamins and metabolites were not significantly different between the investigated groups or related to effect of the thiamine intervention. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov study identifier NCT036347359. Registered 15 August 2018, https://clinicaltrials.gov/study/NCT03634735?cond=Inflammatory%20Bowel%20Diseases&intr=Thiamine&rank=1.

A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and Intolerance to Riboflavin Deficiency.

AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have been associated with multiple clinical phenotypes, but the effectiveness of riboflavin treatment remains controversial. Furthermore, few studies explored the reasons underlying this controversy. We reported a 7-year-old boy with ataxia, sensorimotor neuropathy and muscle weakness. Genetic and histopathological analyses were conducted, along with assessments of mitochondrial function and apoptosis level induced by staurosporine. Riboflavin deficiency and supplementation experiments were performed using fibroblasts. A missense c.1019T > C (p. Met340Thr) variant of AIFM1 was detected in the proband, which caused reduced expression of AIFM1 protein and mitochondrial dysfunction as evidenced by downregulation of mitochondrial complex subunits, respiratory deficiency and collapse of ΔΨm. The proportion of apoptotic cells in mutant fibroblasts was lower than controls after induction of apoptosis. Riboflavin deficiency resulted in decreased AIFM1 protein levels, while supplementation with high concentrations of riboflavin partially increased AIFM1 protein levels in variant fibroblasts. In addition, mitochondrial respiratory function of mutant fibroblasts was partly improved after riboflavin supplementation. Our study elucidated the pathogenicity of the AIFM1 c.1019T > C variant and revealed mutant fibroblasts was intolerant to riboflavin deficiency. Riboflavin supplementation is helpful in maintaining the level of AIFM1 protein and mitochondrial respiratory function. Early riboflavin treatment may serve as a valuable attempt for patients with AIFM1 variant.

Benefit of high-dose oral riboflavin therapy in riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised by pontobulbar palsy, sensorineural deafness, sensory ataxia, muscle weakness, optic atrophy and respiratory failure. Riboflavin supplementation is beneficial in short-term reports, but the quantum of benefit in various clinical domains is not well understood. A PubMed search was conducted, which identified 94 genetically confirmed cases of RTD who received riboflavin supplementation and had follow-up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy-six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some patients had deteriorations in individual domains with no reported deaths. The domains that had the highest rates of response to riboflavin supplementation were gross motor function (93.3% improved), bulbar palsy (91.3%) and ataxia (90.0%). Improvements were also seen in limb muscle weakness, audiology, facial nerve palsy and respiratory function. Despite treatment, many patients required assistance to ambulate and had severe or profound hearing loss and some remained gastrostomy or tracheostomy dependent. Riboflavin supplementation is a lifesaving intervention for patients with RTD and results in a profound improvement in several functional domains, with early diagnosis and treatment further improving outcomes. Despite treatment, patients are left with residual disability. There is a need to accurately measure functional outcomes in children with RTD and develop additional disease-modifying therapies.

Clinical and radiographic peri-implant outcomes with riboflavin loaded Poly-L-glycolic acid nanoparticles incorporated in aloe-vera gel treating peri-implantitis in chronic hyperglycemic patients.

AIM: The objective of the current study was to compare the effectiveness of antimicrobial photodynamic therapy (PDT) versus Poly-L-glycolic acid nanoparticles loaded riboflavin incorporated in aloe vera gel (PGA/RF/AV) on periimplant parameters and bacterial counts in chronic hyperglycemic patients having periimplantitis. METHODS: One hundred and two diabetic patients undergoing mechanical debridement (MD) were equally divided into three groups: Group 1: PGA/RF/AV+ MD, Group 2: PDT + MD, and Group 3: MD alone. Periimplant parameters [Bleeding on probing (BoP), probing depth (PD), plaque index (PI), marginal bone level (MBL)] were recorded in all three groups. Periimplant plaque samples were studied to record the levels of Tannerella forsythia (Tf) and Porphyromonas gingivalis (Pg). The recordings were taken at baseline, 3 months and 6 months post treatment. RESULTS: All three groups showed a reduction in severity of periimplantitis measured in terms of PD, PI, MBL and BoP. A statistically significant reduction in PD, PI and MBL was found in patients in Group 2 whereas participants of Group 1 were found to have a significant decrease in BoP. A statistically significant decline in the numbers of both the bacterial species was seen in Group 2 at the three-month follow-up whereas at the six-month follow-up, a statistically significant reduction was observed in treatment Group 2 in the levels of Tf species only. CONCLUSION: Riboflavin-loaded nanocarrier incorporated in aloe vera gel showed greater clinical efficacy than PDT alone in the treatment of periimplantitis in chronic hyperglycemic individuals.

Corneal Ulcers in Critically Ill Foals in Intensive Care: Case Series of Standard Treatment and Corneal Cross-Linking.

Riboflavin/UV-A corneal cross-linking (CXL) has been applied to treat corneal ulcers in adult horses, but its use in critically ill neonatal foals has not been described. Five cases of hospitalized, critically ill neonatal foals that were in intensive care with corneal ulcers, the ophthalmic treatment, and their outcome up to 1 year are described. A single treatment of CXL phototherapy was performed in three of five foals (five eyes). The application of a riboflavin ophthalmic solution for 20 minutes was followed by the UV-A light irradiation at 30 mW/cm2 for 3 minutes. Topical antibiotic administration was withdrawn after CXL. Two other foals received standard treatment. Descriptions of ocular lesions, fluorescein staining, and photographic documentation were recorded. The visual outcome, corneal transparency, and aesthetics, as well as healing time were evaluated in the follow-up. The frequency of topical medication considerably decreased in cases treated with CXL. Corneal opacity and pain decreased within 3 days following CXL. In the foals treated with CXL, the ulcers healed (fluorescein stain negative) in 24, 28, and 35 days after the onset of clinical signs and 10, 15, and 21, after CXL. No fibrosis or corneal scars were found in the cases treated with CXL. The two standard treatment cases healed after 26 and 36 days respectively. Corneal cross-linking may be an additional or alternative treatment of corneal ulcers in critically ill neonatal foals and may reduce the use of antibiotics.

Transepithelial corneal crosslinking with oxygen enhancement and pulsed light for progressive ectasia: one-year results.

PURPOSE: To evaluate the efficacy and safety of transepithelial accelerated crosslinking (TE-ACXL) using pulsed light and supplemental oxygen. METHODS: Thirty eyes of 30 consecutive patients with progressive keratoconus or post-LASIK ectasia were enrolled in a prospective non-comparative study conducted at the Magrabi Eye Center (Jeddah, Saudi Arabia). All eyes underwent TE-ACXL with supplemental oxygen. Primary outcome measures were the mean change in corrected distance visual acuity (CDVA) (logMAR) and maximum keratometry (max K) from preoperatively to 12 months postoperatively. Secondary outcome measures included change in manifest refractive spherical equivalent (MRSE), refractive cylinder, keratometry, symmetry index (SI), center-surrounding index (CSI) and ectasia index (EI) of the anterior and posterior corneal surfaces, corneal and epithelial thickness at corneal vertex and thinnest location, corneal densitometry, corneal high order aberrations (HOA) and endothelial cell density (ECD). RESULTS: Mean age was 29.6 ± 8.2 years. At 1 year, the follow up rate was 93.3%. CDVA improved statistically significantly at 12 months (p = 0.027). Measures of corneal keratometry or pachymetry did not change significantly (p < 0.05). Postoperatively, a demarcation line was documented in 78.6% eyes at 1 month, and in 12 (42.9%) eyes at 12 months. The mean depth of the demarcation line was 341.9 ± 49.4 µm. Corneal densitometry increased significantly at 1- and 3-months (p < 0.05) and returned to normal levels at 6- and 12-months postoperatively. CONCLUSION: TE-ACXL with oxygen supplement is effective at halting the progression of corneal ectasia for at least 1 year and can be a refractive neutral procedure.

How Modifications of Corneal Cross-Linking Protocols Influence Corneal Resistance to Enzymatic Digestion and Treatment Depth.

Purpose: The purpose of this study was to determine the effects of the Photoactivated Chromophore for Keratitis Corneal Cross-Linking (PACK-CXL) protocol modifications on corneal resistance to enzymatic digestion and treatment depth. Methods: Eight hundred one ex vivo porcine eyes were randomly divided into groups of 12 to 86 corneas, treated with various epi-off PACK-CXL modifications, including acceleration (30 > 2 minutes, 5.4 J/cm2), increased fluence (5.4 > 32.4 J/cm2), deuterium oxide (D2O) supplementation, different carrier types (dextran versus hydroxypropyl methylcellulose [HPMC]), increased riboflavin concentration (0.1 > 0.4%), and riboflavin replenishment during irradiation (yes/no). Control group eyes did not receive PACK-CXL. A pepsin digestion assay was used to determine corneal resistance to enzymatic digestion. A phalloidin fluorescent imaging assay was used to determine the PACK-CXL treatment effect depth. Differences between groups were evaluated using a linear model and a derivative method, respectively. Results: PACK-CXL significantly increased corneal resistance to enzymatic digestion compared to no treatment (P < 0.03). When compared to a 10 minute, 5.4 J/cm2 PACK-CXL protocol, fluences of 16.2 J/cm2 and higher increased corneal resistance to enzymatic digestion by 1.5- to 2-fold (P < 0.001). Other protocol modifications did not significantly change corneal resistance. A 16.2 J/cm2 fluence also increased collagen compaction in the anterior stroma, whereas omitting riboflavin replenishment during irradiation increased PACK-CXL treatment depth. Conclusions: Increasing fluence will likely optimize PACK-CXL treatment effectiveness. Treatment acceleration reduces treatment duration without compromising effectiveness. Translational Relevance: The generated data help to optimize clinical PACK-CXL settings and direct future research efforts.

Normal Outcome With Prenatal Intervention for Riboflavin Transporter Defect.

BACKGROUND: Riboflavin transporter deficiency is a rare but severe neurometabolic disorder. METHODS: We report two siblings with pathogenic variants in SLC52A3 gene, resulting in riboflavin transporter 3 deficiency. RESULTS: The first sibling was diagnosed at age 11 months with severe respiratory compromise and regression of developmental milestones. His symptoms significantly improved with riboflavin supplementation therapy. The younger sibling was diagnosed by antenatal genetic analysis; riboflavin supplementation was initiated in utero and continued from birth. Now at age two years, he remains clinically asymptomatic despite genetic confirmation of riboflavin transporter deficiency. CONCLUSIONS: Antenatal riboflavin supplementation is a safe and effective treatment for the prevention of symptomatic manifestations of riboflavin transporter deficiency.

The Antibacterial Efficacy of High-Fluence PACK Cross-Linking Can Be Accelerated.

Purpose: To determine whether high-fluence photoactivated chromophore for keratitis cross-linking (PACK-CXL) can be accelerated. Methods: Solutions of Staphylococcus aureus and Pseudomonas aeruginosa with 0.1% riboflavin were prepared and exposed to 365 nm ultraviolet (UV)-A irradiation of intensities and fluences from 9 to 30 mW/cm2 and from 5.4 to 15.0 J/cm2, respectively, representing nine different accelerated PACK-CXL protocols. Irradiated solutions and unirradiated controls were diluted, plated, and inoculated on agar plates so that the bacterial killing ratios (BKR) could be calculated. Additionally, strains of Achromobacter xylosoxidans, Staphylococcus epidermidis, and Stenotrophomonas maltophilia were exposed to a single accelerated PACK-CXL protocol (intensity: 30 mW/cm2, total fluence: 15.0 J/cm2). Results: With total fluences of 5.4, 10.0, and 15.0 J/cm2, the range of mean BKR for S. aureus was 45.78% to 50.91%, 84.13% to 88.16%, and 97.50% to 99.90%, respectively; the mean BKR for P. aeruginosa was 69.09% to 70.86%, 75.37% to 77.93%, and 82.27% to 91.44%, respectively. The mean BKR was 41.97% for A. xylosoxidans, 65.38% for S. epidermidis, and 78.04% for S. maltophilia for the accelerated PACK-CXL protocol (30 mW/cm2, 15 J/cm2). Conclusions: The BKR of high-fluence PACK-CXL protocols can be accelerated while maintaining a high, but species-dependent, BKR. The Bunsen to Roscoe law is respected in fluences up to 10 J/cm2 in S. aureus and P. aeruginosa, whereas fluences above 10 J/cm2 show strain dependence. Translational Relevance: The high-fluence PACK-CXL protocols can be accelerated in clinical practice while maintaining high levels of BKR.

Ocular Biomarkers of Riboflavin Transporter Deficiency.

BACKGROUND: To describe the clinical presentation with a focus on ocular manifestations and response to riboflavin supplementation of 3 patients with riboflavin transporter deficiency (RTD) caused by mutations in SLC52A2 ( SLC52A2- RTD). METHODS: This is a retrospective review of records of 3 children (aged 18, n = 2 and age = 8, n = 1) with SLC52A2- RTD. Patients underwent comprehensive ophthalmic evaluations including color vision testing, pattern visual-evoked potentials (pVEPs, 1 patient) and spectral domain optical coherence tomography (SD-OCT) imaging. Patients received riboflavin supplements from the time of the molecular diagnosis of RTD. RESULTS: Two unrelated 18-year-old patients with SLC52A2- RTD had a symptomatic onset with sensorineural hearing loss and auditory neuropathy/dys-synchrony since age 3 and 11, respectively. On examination 7 years after symptomatic onset, they showed subnormal visual acuities (20/30 and 20/60, both eyes, respectively), preserved color vision, and a thin but measurable retinal ganglion cell layer (GCL) and nerve fiber (RNFL). The inner and outer nuclear layers were normal. The asymptomatic SLC52A2- positive brother of one of these patients started riboflavin supplementation right after the molecular diagnosis and had normal vision and SD-OCTs 7 years later. Onset of riboflavin supplementation in one of the 2 symptomatic cases resulted in acute improvement of the pattern visual-evoked potential and vision. CONCLUSIONS: Retinal ganglion cells and their axons are uniquely susceptible to RTD compared with other highly energy-dependent retinal neurons, such as photoreceptors, raising the possibility for alternative mechanisms of disease or protection. Riboflavin supplementation results in acute functional improvement of vision and long-term preservation of GCL and RNFL if initiated early.

Theranostic-guided corneal cross-linking: Preclinical evidence on a new treatment paradigm for keratoconus.

Theranostics is an emerging therapeutic paradigm of personalized medicine; the term refers to the simultaneous integration of therapy and diagnostics. In this work, theranostic-guided corneal cross-linking was performed on 10 human sclero-corneal tissues. The samples were soaked with 0.22% riboflavin formulation and underwent 9 minutes UV-A irradiance at 10 mW/cm2 using theranostic device, which provided both a measure of corneal riboflavin concentration and a theranostic score estimating treatment efficacy in real time. A three-element viscoelastic model was developed to fit the deformation response of the cornea to air-puff excitation of dynamic tonometry and to calculate the mean corneal stiffness parameter before and after treatment. Significant correlation was found between the theranostic score and the increase in mean corneal stiffness (R = 0.80; P < .001). Accuracy and precision of the theranostic score in predicting the induced corneal tissue stiffening were both 90%. The riboflavin concentration prior to starting the UV-A photo-therapy phase was the most important variable to allow corneal cross-linking to be effective. Theranostic UV-A light mediated imaging and therapy enables the operator to adopt a precise approach for achieving highly predictable biomechanical strengthening on individual corneas.

A 2-Year Randomized Controlled Trial With Low-Dose B-Vitamin Supplementation Shows Benefits on Bone Mineral Density in Adults With Lower B12 Status.

Folate, vitamins B12, B6, and riboflavin are required for one-carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low-dose B-vitamins for 2 years on bone mineral density (BMD) in a dual-centered, 2-year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B-vitamin supplements or fortified foods >4 times weekly were randomized to receive daily either combined folic acid (200 µg), vitamin B12 (10 µg), vitamin B6 (10 mg), and riboflavin (5 mg), or "active" placebo, whereby both the intervention and placebo groups received vitamin D (10 µg). BMD was assessed before and after intervention using dual-energy X-ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B-vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal-5-phosphate (p < 0.001) and decreases in functional biomarkers of B-vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B-vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from -0.7% to -1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 µmol/L), B-vitamin intervention reduced the 2-year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of -0.003 (-0.008, 0.002) versus -0.015 (-0.021, -0.010) g/cm2 at the total hip and -0.004 (-0.010, 0.001) versus -0.013 (-0.018, -0.007) g/cm2 at the femoral neck. In conclusion, the findings indicate that although low-dose B-vitamin intervention for 2 years had no overall effect on BMD, improving B-vitamin status appears to have specific benefits for bone health in adults with lower B12 status. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Corneal Cross-Linking: Epi-On.

ABSTRACT: When treating corneal ectasias, successful corneal cross-linking (CXL) requires three factors: riboflavin saturation of the corneal stroma, ultraviolet (UV) light, and oxygen. Riboflavin is too large to pass through epithelial tight junctions, so traditionally epithelial debridement is performed before riboflavin is applied making this approach an epithelium-off (epi-off) technique. However, this can result in pain as the epithelium regrows, corneal haze, and an increased infection risk postoperatively, which needs careful management with pharmacotherapy. Epithelium-on (epi-on) CXL should reduce the extent of these issues. Riboflavin can be passed through the epithelium into the stroma either by iontophoresis or with penetration enhancers, however this alone results in suboptimal cross-linking effects, as the epithelium not only absorbs around 20% of incoming UV energy, it also acts as a barrier to oxygen diffusion into the stroma. While it is simple to adjust the UV fluence delivered to the stroma to compensate for the energy lost in the epithelium, compensating for the lack of stromal oxygen is less simple. Several approaches (including oxygen goggles) have been taken to achieve this. However, adding iontophoresis and supplemental oxygen through goggles in the operating theater adds complexities that could be engineered out. Accordingly, the technique has advanced in the laboratory to a point where penetration enhancers, optimized UV irradiation profiles, and atmospheric oxygen can now provide epi-on CXL with the same corneal strengthening efficacy as epi-off CXL, suggesting simple, effective epi-on CXL could soon be in clinical use.

Nutraceuticals and migraine: further strategy for the treatment of specific conditions.

Nutraceuticals might be defined as food or dietary supplements that provide medicinal or health benefits. Current preventive treatment of migraine includes nutraceuticals as well as conventional drugs. These non-pharmacological therapies, such as magnesium, coenzyme Q10, feverfew, riboflavin, and phycocyanins, are particularly useful in certain categories of patients (adolescents, pregnant or breastfeeding women, the elderly with complex drug therapy, the patient with contraindication to the usual pharmacological therapies) when a conventional drug therapy cannot be prescribed or may be not well tolerated. The evidence currently available confirms a modest efficacy but a very good safety and tolerability profile.

Oxygen-supplemented transepithelial-accelerated corneal crosslinking with pulsed irradiation for progressive keratoconus: 1 year outcomes.

PURPOSE: To investigate the effects of combining oxygen supplementation with enhanced UV-A light and increased riboflavin permeability in improving the efficacy of epithelium-on crosslinking (epi-on CXL). SETTING: Private eye clinic in Brisbane, Queensland, Australia. DESIGN: Retrospective single-center nonrandomized uncontrolled longitudinal cohort case series. METHODS: Transepithelial CXL was performed on keratoconic eyes. Applications of an oxygen goggle and pulsed UV-A irradiation (1 second on, 1 second off) were used to enhance oxygen kinetics during epi-on CXL. Additional procedural modifications included the use of benzalkonium chloride and high UV-A irradiance level (30 mW/cm 2 ) to improve the stromal bioavailability of riboflavin and UV-A. The main efficacy outcomes were the changes in mean corrected distance visual acuity (CDVA) and safety over 12 months. Additional refractive and keratometry (K) outcomes were also observed. RESULTS: 53 eyes (38 patients) were included in this study. 12 months postoperatively, mean CDVA improved from a mean of 0.18 ± 0.2 at baseline to 0.07 ± 0.1 logMAR ( P < .0001). No statistically significant change was observed in maximum K (Kmax) and mean K, which were respectively 51.7 ± 5.8 diopters (D) and 46.4 ± 3.85 D at baseline and 51.2 ± 5.7 D ( P = .152) and 46.0 ± 3.84 D ( P = .06) 12 months postoperatively. Only 3 eyes experienced an increase of more than 2 D in Kmax; however, none of these eyes experienced a CDVA loss. There were no reported infections, corneal scarring, or other severe adverse effects. CONCLUSIONS: Performing supplemental oxygen epi-on CXL with accelerated, pulsed UV-A irradiation in conjunction with riboflavin permeability enhancers resulted in improved CDVA ( P < .0001) and stable keratometry up to 12 months postoperatively with a good safety profile.