Several antibiotics which inhibit protein synthesis on 70S ribosomes, including clindamycin, pirlimycin, 4'-pentyl-N-demethyl clindamycin, four tetracyclines, chloramphenicol, thiamphenicol, and erythromycin, had antimalarial effects against Plasmodium falciparum in culture which were greatly influenced by the duration of drug exposure and by oxygen tension. In 96-h incubations, potency was increased by a factor of up to 10(6) over the first 48-h period and by a factor of up to 10(4) in 15% O2 versus 1% O2. Two aminoglycosides, kanamycin and tobramycin, had no antimalarial activity. Rifampin and nalidixic acid, which inhibit nucleic acid synthesis, were not similar to the 70S inhibitors. The mitochondrial inhibitors Janus Green, rhodamine 123, antimycin A1, and 8-methylamino-8-desmethyl riboflavin had activities which were influenced by the duration of exposure and oxygen tension. Quinoline-containing antimalarial agents, ionophores, and other antimalarial drugs were influenced to a minor extent by the duration of exposure but were not affected by oxygen tension. These data can best be explained by the hypothesis that antimalarial 70S ribosome-specific protein synthesis inhibitors are toxic to the parasites by acting on the mitochondrion.

Increases or decreases of red cell glutathione reductase (GR) have been described in connection with many clinical abnormalities. We find that GR activity as measured in hemolysates represents only a portion of the available GR activity. The addition of small amounts of flavin adenine dinucleotide (FAD), but not of flavin mononucleotide or riboflavin, activates the GR of hemolysates. 1 muM FAD results in a maximal activation within 10 min; gradually increasing activation occurs at much lower, for example, 20 mmuM FAD concentrations. Once FAD has activated GR, dilution or dialysis does not reverse activation of the enzyme. Activation of GR by FAD can be inhibited by adenosine triphosphate (ATP), and to a lesser extent by adenosine diphosphate (ADP) and adenosine monophosphate (AMP), if these adenine nucleotides are added before the addition of FAD, but only to a slight extent if FAD is added before the adenine nucleotides. The addition of FAD to GR does not alter its electrophoretic mobility but produces intensification of the bands. The administration of 5 mg of riboflavin daily produces marked stimulation of red cell GR activity within only 2 days. After cessation of riboflavin administration, the GR activity again begins to fall. The degree of stimulation of GR activity by riboflavin is inversely correlated with the level of dietary riboflavin intake. The base line GR activity of normal individuals is directly correlated with the level of dietary riboflavin intake. The previously unexplained variations of glutathione reductase in health and disease must be reevaluated in light of the state of riboflavin nutrition and metabolism of the subject.

Changes in the biomechanical properties of the human cornea play an important role in the pathogenesis of corneal ectatic diseases. Biomechanical investigation shows significant differences between human ectatic corneas and normal corneas, including decreased stiffness and reduction of collagen crosslinks in the ectatic cornea. Induction of crosslinks is a well-established procedure in polymer chemistry to increase the elastic modulus of materials. Crosslinking (CXL) in connective tissue can occur during aging and as a side effect of diabetes mellitus. CXL has been used medically to increase stability and reduce the biodegradation of collagen-based biomaterials for bioprostheses. CXL of the cornea using riboflavin and UVA light with a wavelength of 370 nm and a dosage of 5.4 J/cm² is a new approach that increases the mechanical and biochemical stability of stromal tissue. This technique combines the principles of CXL (chemical and nonenzymatic) and the biochemical mechanisms of photo-oxidative CXL with riboflavin as a photosensitizer. In this review, the enrichment of riboflavin in the stroma by standard (epi-off) and transepithelial (epi-on) CXL is discussed. The theoretical and experimental measurements of the absorption of UV light explain the stronger CXL effect in the anterior stroma and its importance for the prevention of damage to the endothelial cells. UV devices are described. Changes of the physical properties after CXL, as well as the cellular changes, are discussed. From these basic investigations, treatment parameters for effective and safe CXL are identified.

Riboflavin-based coenzymes, tightly bound to enzymes catalyzing substrate oxidations and reductions, enable an enormous range of chemical transformations in biosynthetic pathways. Flavoenzymes catalyze substrate oxidations involving amine and alcohol oxidations and desaturations to olefins, the latter setting up Diels-Alder cyclizations in lovastatin and solanapyrone biosyntheses. Both C(4a) and N(5) of the flavin coenzymes are sites for covalent adduct formation. For example, the reactivity of dihydroflavins with molecular oxygen leads to flavin-4a-OOH adducts which then carry out a diverse range of oxygen transfers, including Baeyer-Villiger type ring expansions, olefin epoxidations, halogenations via transient HOCl generation, and an oxidative Favorskii rerrangement during enterocin assembly.

Absorption of riboflavin is mediated by transporter(s). However, a mammalian riboflavin transporter has yet to be identified. In the present study, the novel human and rat riboflavin transporters hRFT1 and rRFT1 were identified on the basis of our rat kidney mRNA expression database (Horiba N, Masuda S, Takeuchi A, Saito H, Okuda M, Inui K. Kidney Int 66: 29-45, 2004). hRFT1 and rRFT1 cDNAs have an open reading frame encoding 448- and 450-amino acid proteins, respectively, that exhibit 81.1% identity and 96.4% similarity to one another. In addition, an inactive splice variant of hRFT1, hRFT1sv, was also cloned. The hRFT1sv cDNA, which encodes a 167-amino acid protein, retains an intron between exons 2 and 3 of hRFT1. Real-time PCR revealed that the sum of hRFT1 and hRFT1sv mRNAs was expressed strongly in the placenta and small intestine and was detected in all tissues examined. In addition, hRFT1 and hRFT1sv were expressed in human embryonic kidney (HEK)-293 and Caco-2 cells. HEK-293 cells transfected with green fluorescent protein-tagged hRFT1 and rRFT1 exhibited a fluorescent signal in the plasma membrane. Overexpression of hRFT1 and rRFT1, but not hRFT1sv, increased the cellular accumulation of [(3)H]riboflavin. The transfection of small interfering RNA targeting both hRFT1 and hRFT1sv significantly decreased the uptake of [(3)H]riboflavin by HEK-293 and Caco-2 cells. Riboflavin transport is Na(+), potential, and pH independent. Kinetic analyses demonstrated that the Michaelis-Menten constants for the uptake by HEK-293 and Caco-2 cells were 28.1 and 63.7 nM, respectively. We propose that hRFT1 and rRFT1 are novel mammalian riboflavin transporters, which belong to a new mammalian riboflavin transporter family.

Recently, we have developed collagen crosslinking induced by combined riboflavin/UVA treatment, thus increasing the biomechanical rigidity of the cornea to treat progressive keratoconus. The present safety study was performed to evaluate possible cytotoxic effects of combined riboflavin/UVA treatment on the corneal endothelium in vitro. Endothelial cell cultures from porcine corneas were treated with 500 microM riboflavin solution, exposed to various endothelial UVA irradiances (370 nm) ranging from 0.1 to 1.6 mW/cm2 for 30 min and evaluated 24 h later using trypan blue staining and Yopro fluorescence staining. The effect of either treatment alone (UVA irradiation ranging from 0.2 to 6 mW/cm2) was also tested. An abrupt cytotoxic threshold irradiance level was found at 0.35 mW/cm2 after combined treatment with riboflavin plus UVA irradiation and at 4 mW/cm2 with UVA irradiation alone. Riboflavin alone was not toxic. A cytotoxic effect of the combined riboflavin/UVA treatment on corneal endothelial cells is to be expected with a corneal thickness of less than 400 microm. Therefore, pachymetry should be routinely performed before riboflavin/UVA treatment to exclude patients at risk.

Despite recent breakthroughs in identifying mucosal-associated invariant T (MAIT) cell antigens (Ags), the precise requirements for in vivo MAIT cell responses to infection remain unclear. Using major histocompatibility complex-related protein 1 (MR1) tetramers, the MAIT cell response was investigated in a model of bacterial lung infection employing riboflavin gene-competent and -deficient bacteria. MAIT cells were rapidly enriched in the lungs of C57BL/6 mice infected with Salmonella Typhimurium, comprising up to 50% of αβ-T cells after 1 week. MAIT cell accumulation was MR1-dependent, required Ag derived from the microbial riboflavin synthesis pathway, and did not occur in response to synthetic Ag, unless accompanied by a Toll-like receptor agonist or by co-infection with riboflavin pathway-deficient S. Typhimurium. The MAIT cell response was associated with their long-term accumulation in the lungs, draining lymph nodes and spleen. Lung MAIT cells from infected mice displayed an activated/memory phenotype, and most expressed the transcription factor retinoic acid-related orphan receptor γt. T-bet expression increased following infection. The majority produced interleukin-17 while smaller subsets produced interferon-γ or tumor necrosis factor, detected directly ex vivo. Thus the activation and expansion of MAIT cells coupled with their pro-inflammatory cytokine production occurred in response to Ags derived from microbial riboflavin synthesis and was augmented by co-stimulatory signals.

We isolated cDNA coding a new human riboflavin transporter (hRFT)3, which exhibits 86.7 and 44.1% amino acid identity with hRFT1 and hRFT2, respectively. It was predicted to have 10 putative membrane-spanning domains. The functional characteristics of hRFT3 were examined and compared with those of its isoforms, hRFT1 and hRFT2. Real-time PCR revealed that hRFT3 mRNA was strongly expressed in the brain and salivary gland. hRFT1 mRNA was strongly expressed in the placenta and small intestine, whereas hRFT2 mRNA was most abundantly expressed in the testis and strongly in the small intestine and prostate. hRFT-mediated uptake of [3H]riboflavin was evaluated using human embryonic kidney 293 cells transiently transfected with the cDNA coding each hRFT. The apparent Michaelis-Menten constants of hRFT1, hRFT2, and hRFT3 for riboflavin were 1.38, 0.98, and 0.33 micromol/L, respectively. The hRFT-mediated [3H]riboflavin uptake was independent of extracellular Na+ and Cl(-). Specific uptake of [3H]riboflavin by hRFT2, but not hRFT1 and hRFT3, decreased as extracellular pH was changed from 5.4 to 8.4. The substrate specificities of the hRFT family were similar. hRFT-mediated uptake of [3H]riboflavin was inhibited by some riboflavin analogs, but not D-ribose, organic ions, or other vitamins. The newly isolated hRFT3 may play an important role in brain riboflavin homeostasis. Its amino acid sequence and functional characteristics are similar to those of hRFT1, but not hRFT2.

UVA light (320-400 nm) has been shown to produce deleterious biological effects in tissue due to the generation of singlet oxygen by substances like flavins or urocanic acid. Riboflavin, flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), beta-nicotinamide adenine dinucleotide (NAD), and beta-nicotinamide adenine dinucleotide phosphate (NADP), urocanic acid, or cholesterol in solution were excited at 355 nm. Singlet oxygen was directly detected by time-resolved measurement of its luminescence at 1270 nm. NAD, NADP, and cholesterol showed no luminescence signal possibly due to the very low absorption coefficient at 355 nm. Singlet oxygen luminescence of urocanic acid was clearly detected but the signal was too weak to quantify a quantum yield. The quantum yield of singlet oxygen was precisely determined for riboflavin (PhiDelta = 0.54 +/- 0.07), FMN (PhiDelta = 0.51 +/- 0.07), and FAD (PhiDelta = 0.07 +/- 0.02). In aerated solution, riboflavin and FMN generate more singlet oxygen than exogenous photosensitizers such as Photofrin, which are applied in photodynamic therapy to kill cancer cells. With decreasing oxygen concentration, the quantum yield of singlet oxygen generation decreased, which must be considered when assessing the role of singlet oxygen at low oxygen concentrations (inside tissue).

The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy.

OBJECTIVE

Italian National Food Consumption Survey, INRAN-SCAI 2005-06, is the third national food consumption survey performed in Italy. This study describes energy and nutrient intakes in Italy.

RESULTS

A national cross-sectional food consumption survey was conducted using consecutive 3-day food records between October 2005 and December 2006. A sample of 3323 males and females aged 0.1-97.7 years living in private households was investigated. Individual food records were converted into energy and nutrient intakes with the use of recently updated national food composition databases. For each subject, intakes of energy and of 27 nutrients were calculated, including six minerals (i.e., iron, calcium, phosphorus, magnesium, potassium and zinc) and 10 vitamins (i.e., thiamine, riboflavin, vitamin C, vitamin B₆, retinol, β-carotene, vitamin A as retinol equivalents (REs), vitamin E, vitamin D and vitamin B₁₂. On average, 36% of calories appeared to derive from fat (11% from saturated fatty acids) and 45% from available carbohydrates (15% from soluble carbohydrates).

CONCLUSIONS

The results of the INRAN-SCAI 2005-06 survey in terms of nutrient intakes provide an important piece of information for nutrition surveillance of the population and may also be used to identify priorities for further research.

OBJECTIVE

To evaluate changes in corneal curvature, corneal elevation, corneal thickness, lens density, and foveal thickness after corneal collagen crosslinking with riboflavin and ultraviolet-A (UVA) light in eyes with progressive keratoconus.

METHODS

Grewal Eye Institute, Chandigarh, India.

METHODS

Subjective refraction, best corrected visual acuity (BCVA), Scheimpflug imaging, and optical coherence tomography were performed preoperatively and 1 week, 1, 3, and 6 months, and 1 year after crosslinking.

RESULTS

There were no significant differences (P>> 0.05) in mean values between preoperatively and 1 year postoperatively, respectively, in BCVA (0.22 +/- 0.10 and 0.20 +/- 0.10), spherical equivalent (-6.30 +/- 4.50 diopters (D) and -4.90 +/- 3.50 D), or cylinder vector (1.58 x 7( degrees ) +/- 3.8 D and 1.41 x 24( degrees ) +/- 3.5 D). There was no significant difference in mean measurements between preoperatively and 1 year postoperatively, respectively, for central corneal thickness (458.9 +/- 40 microm and 455.2 +/- 48.6 microm), anterior corneal curvature (50.6 +/- 7.4 D and 51.5 +/- 3.6 D), posterior corneal curvature (-7.7 +/- 1.2 D and -7.4 +/- 1.1 D), apex anterior (P = .9), posterior corneal elevation (P = .7), lens density (P = .33), or foveal thickness (175.7 +/- 35.6 microm and 146.4 +/- 8.5 microm; P = .1).

CONCLUSIONS

Stable BCVA, spherical equivalent, anterior and posterior corneal curvatures, and corneal elevation 1 year after crosslinking indicate that keratoconus did not progress. Unchanged lens density and foveal thickness suggest that the lens and macula were not affected after UVA exposure during crosslinking.

Mitochondrial dysfunction, with an estimated incidence of 1 in 10 000 live births, is among the most common genetically determined conditions. Missense mutations in the human NDUFV1 gene, which encodes the 51 kDa active site subunit of the NADH-ubiquinone oxidoreductase or complex I, can lead to severe neurological disorders. Owing to the rare and often sporadic nature of mitochondrial disorders, the mechanisms of pathogenesis of most mutations remain poorly understood. We have generated transgenic strains of Caenorhabditis elegans that express disease-causing mutations in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrate hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration. They are also hypersensitive to exogenous oxidative stress, suggesting that cellular defense mechanisms against reactive oxygen species are already taxed by an endogenous stress. The lactic acidosis induced by the NDUFV1 mutations could be partially corrected with the vitamins riboflavin and thiamine or with sodium dichloroacetate, an activator of the pyruvate dehydrogenase complex, resulting in significant increases in animal fitness. Surprisingly, cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Our results indicate that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.

OBJECTIVE

To evaluate a series of patients with corneal ectasia after LASIK that underwent the Athens Protocol: combined topography-guided photorefractive keratectomy (PRK) to reduce or eliminate induced myopia and astigmatism followed by sequential, same-day ultraviolet A (UVA) corneal collagen cross-linking (CXL).

METHODS

Thirty-two consecutive corneal ectasia cases underwent transepithelial PRK (WaveLight ALLEGRETTO) immediately followed by CXL (3 mW/cm(2)) for 30 minutes using 0.1% topical riboflavin sodium phosphate. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent, keratometry, central ultrasonic pachymetry, corneal tomography (Oculus Pentacam), and endothelial cell counts were analyzed. Mean follow-up was 27 months (range: 6 to 59 months).

RESULTS

Twenty-seven of 32 eyes had an improvement in UDVA and CDVA of 20/45 or better (2.25 logMAR) at last follow-up. Four eyes showed some topographic improvement but no improvement in CDVA. One of the treated eyes required a subsequent penetrating keratoplasty. Corneal haze grade 2 was present in 2 eyes.

CONCLUSIONS

Combined, same-day, topography-guided PRK and CXL appeared to offer tomographic stability, even after long-term follow-up. Only 2 of 32 eyes had corneal ectasia progression after the intervention. Seventeen of 32 eyes appeared to have improvement in UDVA and CDVA with follow-up >1.5 years. This technique may offer an alternative in the management of iatrogenic corneal ectasia.

OBJECTIVE

To collect and evaluate food intake data from a culturally diverse population and compare with national survey data.

METHODS

The Foods Of Our Delta Study was a baseline, cross-sectional survey that utilized random-digit dialing methodology to identify the sample. Food intake was obtained from a 24-hour dietary recall administered by computer-assisted telephone interview using the multiple-pass method.

METHODS

One thousand seven hundred fifty-one adults and 485 children in the Lower Mississippi Delta (Delta) of Louisiana, Arkansas, and Mississippi.

METHODS

Comparisons of subsets within the Delta were made using weighted t tests. Comparisons of the Delta with the overall US population from the US Department of Agriculture Continuing Survey of Food Intakes by Individuals and with the Dietary Reference Intakes were made using independent sample z tests of weighted estimates.

RESULTS

Energy intake did not differ between the Delta and the US populations. Intakes of protein were lower, fat higher, and certain micronutrients lower in Delta adults than in US adults. Delta adults had a 20% lower intake of fruits and vegetables than the US adults and generally poorer adherence to recommendations of the Food Guide Pyramid. African American Delta adults generally consumed less-optimal diets than white Delta adults. Delta children had diets similar to children of the Continuing Survey of Food Intakes by Individuals sample population, but lower intakes were noted for vitamins A, C, riboflavin, and B-6, and for calcium and iron.

CONCLUSIONS

Data such as these will help drive intervention development in this rural region and perhaps set the stage for research in similarly impoverished areas.

This study describes the genetic analysis of the riboflavin (vitamin B(2)) biosynthetic (rib) operon in the lactic acid bacterium Lactococcus lactis subsp. cremoris strain NZ9000. Functional analysis of the genes of the L. lactis rib operon was performed by using complementation studies, as well as by deletion analysis. In addition, gene-specific genetic engineering was used to examine which genes of the rib operon need to be overexpressed in order to effect riboflavin overproduction. Transcriptional regulation of the L. lactis riboflavin biosynthetic process was investigated by using Northern hybridization and primer extension, as well as the analysis of roseoflavin-induced riboflavin-overproducing L. lactis isolates. The latter analysis revealed the presence of both nucleotide replacements and deletions in the regulatory region of the rib operon. The results presented here are an important step toward the development of fermented foods containing increased levels of riboflavin, produced in situ, thus negating the need for vitamin fortification.

αβT-cell mediated immunity is traditionally characterised by recognition of peptides or lipids presented by the major histocompatibility complex (MHC) or the CD1 family respectively. Recently the antigenic repertoire of αβT-cells has been expanded with the observation that mucosal-associated invariant T-cells (MAIT cells), an abundant population of innate-like T-cells, can recognise metabolites of vitamin B, when presented by the MHC-related protein, MR1. The semi-invariant MAIT T-cell antigen receptor (TCR) recognises riboflavin and folic acid metabolites bound by MR1 in a conserved docking mode, and thus acts like a pattern recognition receptor. Here we review and discuss the recent observations concerning antigen presentation by MR1, the advent of MR1-Ag tetramers that specifically stain MAIT cells, recognition by the MAIT TCR, and our emerging understanding of MAIT cells in disease.

OBJECTIVE

Ultraviolet (UV) corneal cross-linking is an accepted method for treating corneal ecstatic disorders. The authors evaluated whether a rapid treatment protocol (higher intensity and shorter irradiation time) could achieve the same increase in corneal stiffness as the currently used standard protocol.

METHODS

Stress-strain measurements were performed on porcine corneal strips. The corneas (n = 72) were cut into three strips, each randomly receiving a different treatment: rapid (10 mW/cm(2), 9 minutes), standard (3 mW/cm(2), 30 minutes), or no (control, 0 mW/cm(2)) irradiation. After irradiation, the Young's modulus of each strip was determined. The results of the stress-strain measurements were analyzed statistically.

RESULTS

Statistical analysis showed that, after irradiation, the median value of Young's modulus from both active treatment groups (rapid, 3.83 N/mm(2); standard, 3.88 N/mm(2)) was significantly higher (P < 0.05) than that of the control group (2.91 N/mm(2)). Treatment increased Young's modulus by a factor of 1.3. However, there was no significant difference (P = 0.43) between the rapid and standard groups in the median of Young's modulus.

CONCLUSIONS

Rapid UV cross-linking treatment can be regarded as equivalent to the standard procedure in terms of increase in corneal stiffness. The new rapid protocol shortens the treatment duration by more than two thirds, from 30 to 9 minutes. The safety of the higher intensities must be addressed in further clinical studies.

NADPH-cytochrome P450 oxidoreductase (CYPOR) is essential for electron donation to microsomal cytochrome P450-mediated monooxygenation in such diverse physiological processes as drug metabolism (approximately 85-90% of therapeutic drugs), steroid biosynthesis, and bioactive metabolite production (vitamin D and retinoic acid metabolites). Expressed by a single gene, CYPOR's role with these multiple redox partners renders it a model for understanding protein-protein interactions at the structural level. Polymorphisms in human CYPOR have been shown to lead to defects in bone development and steroidogenesis, resulting in sexual dimorphisms, the severity of which differs significantly depending on the degree of CYPOR impairment. The atomic structure of human CYPOR is presented, with structures of two naturally occurring missense mutations, V492E and R457H. The overall structures of these CYPOR variants are similar to wild type. However, in both variants, local disruption of H bonding and salt bridging, involving the FAD pyrophosphate moiety, leads to weaker FAD binding, unstable protein, and loss of catalytic activity, which can be rescued by cofactor addition. The modes of polypeptide unfolding in these two variants differ significantly, as revealed by limited trypsin digestion: V492E is less stable but unfolds locally and gradually, whereas R457H is more stable but unfolds globally. FAD addition to either variant prevents trypsin digestion, supporting the role of the cofactor in conferring stability to CYPOR structure. Thus, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy in utero, if predicted prenatally, or rescued postnatally in less severe cases.

OBJECTIVE

The primary objective of this guideline is to assist the practitioner in choosing an appropriate prophylactic medication for an individual with migraine, based on current evidence in the medical literature and expert consensus. This guideline is focused on patients with episodic migraine (headache on ≤ 14 days a month).

METHODS

Through a comprehensive search strategy, randomized, double blind, controlled trials of drug treatments for migraine prophylaxis and relevant Cochrane reviews were identified. Studies were graded according to criteria developed by the US Preventive Services Task Force. Recommendations were graded according to the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. In addition, a general literature review and expert consensus were used for aspects of prophylactic therapy for which randomized controlled trials are not available.

RESULTS

Prophylactic drug choice should be based on evidence for efficacy, side-effect profile, migraine clinical features, and co-existing disorders. Based on our review, 11 prophylactic drugs received a strong recommendation for use (topiramate, propranolol, nadolol, metoprolol, amitriptyline, gabapentin, candesartan, butterbur, riboflavin, coenzyme Q10, and magnesium citrate) and 6 received a weak recommendation (divalproex sodium, flunarizine, pizotifen, venlafaxine, verapamil, and lisinopril). Quality of evidence for different medications varied from high to low. Prophylactic treatment strategies were developed to assist the practitioner in selecting a prophylactic drug for specific clinical situations. These strategies included: first time strategies for patients who have not had prophylaxis before (a beta-blocker and a tricyclic strategy), low side effect strategies (including both drug and herbal/vitamin/mineral strategies), a strategy for patients with high body mass index, strategies for patients with co-existent hypertension or with co-existent depression and /or anxiety, and additional monotherapy drug strategies for patients who have failed previous prophylactic trials. Further strategies included a refractory migraine strategy and strategies for prophylaxis during pregnancy and lactation.

CONCLUSIONS

There is good evidence from randomized controlled trials for use of a number of different prophylactic medications in patients with migraine. Medication choice for an individual patient requires careful consideration of patient clinical features.

OBJECTIVE

To examine prospectively the association between dietary intake of vitamins C and E, carotene, and riboflavin and cataract extraction in women.

METHODS

Prospective cohort study beginning in 1980 with eight years of follow up.

METHODS

11 states of the United States.

METHODS

Female registered nurses who were 45 to 67 years of age. 50,828 women were included in 1980 and others were added as they became 45 years of age.

METHODS

Incidence of extraction of senile cataracts.

RESULTS

493 cataracts were extracted during 470,302 person years of follow up. Intake of carotene and vitamin A was inversely associated with cataract: in multivariate analyses, women in the highest fifth of total vitamin A intake (excluding supplements) had a 39% lower risk of cataract relative to women in the lowest fifth (relative risk 0.61; 95% confidence interval 0.45 to 0.81). Neither riboflavin nor dietary vitamins E or C were associated with cataract in a multivariate analysis. Among specific food items spinach (rather than carrots, the greatest source of beta carotene) was most consistently associated with a lower relative risk. The risk of cataract was 45% lower among women who used vitamin C supplements for 10 or more years(relative risk 0.55 (0.32 to 0.96)), but no association was noted for multivitamin intake.

CONCLUSIONS

Dietary carotenoids, although not necessarily beta carotene, and long term vitamin C supplementation may decrease the risk of cataracts severe enough to require extraction.

We have developed an antisense oligonucleotide microarray for the study of gene expression and regulation in Bacillus subtilis by using Affymetrix technology. Quality control tests of the B. subtilis GeneChip were performed to ascertain the quality of the array. These tests included optimization of the labeling and hybridization conditions, determination of the linear dynamic range of gene expression levels, and assessment of differential gene expression patterns of known vitamin biosynthetic genes. In minimal medium, we detected transcripts for approximately 70% of the known open reading frames (ORFs). In addition, we were able to monitor the transcript level of known biosynthetic genes regulated by riboflavin, biotin, or thiamine. Moreover, novel transcripts were also detected within intergenic regions and on the opposite coding strand of known ORFs. Several of these novel transcripts were subsequently correlated to new coding regions.

BACKGROUND

Folic acid is known to reduce risk of neural tube defects (NTDs). Even so, NTDs continue to occur despite individual supplementation or population fortification with folic acid. We investigated other nutrients related to one-carbon metabolism that may affect NTD risk.

METHODS

This prospective study included data from more than 180,000 pregnant women in California from 2003 through 2005. Midpregnancy serum specimens were linked with delivery information regarding the presence of a NTD, another structural malformation, or no malformation in the fetus. We identified 80 NTD-affected pregnancies (cases) and we randomly selected 409 pregnancy controls. Serum specimens were tested for methylmalonic acid, homocysteine, cysteine, methionine, total choline, betaine, cystathionine, vitamin B6, folate, vitamin B12, riboflavin, and creatinine.

RESULTS

We observed elevated NTD risks associated with lower levels of total choline, and reduced risks with higher levels of choline. Specifically, we observed an odds ratio of 2.4 (95% confidence interval = 1.3-4.7) associated with the lowest decile and an odds ratio of 0.14 (0.02-1.0) associated with the highest decile, both relative to the 25th-74th percentiles of the control distribution. These data did not show meaningful differences between cases and controls for any other analytes.

CONCLUSIONS

This is the first study to investigate total choline in NTD-affected pregnancies. Our findings for choline, for which low levels were a risk factor and higher levels were a protective factor for NTDs, may offer a useful clue toward understanding the complex etiologies of NTDs in an era of folic acid fortification of the food supply.

OBJECTIVE

To compare the outcomes of accelerated corneal collagen crosslinking (CXL) and conventional corneal CXL.

METHODS

Private practice, Tokyo, Japan.

METHODS

Comparative study.

METHODS

Eyes with keratoconus had accelerated CXL (KXL system; 15 minutes riboflavin [Vibex Rapid] presoak; 3 minutes 30 mW/cm(2) ultraviolet-A [UVA] light) or conventional CXL (CCL-365 Vario system; 30 minutes riboflavin [Vibex] presoak; 30 minutes 3 mW/cm(2) UVA light). The postoperative changes in visual acuity, keratometry readings, morphologic changes in the cornea, demarcation line existence, and corneal biomechanical responses with accelerated CXL and conventional CXL were compared. The follow-up was 1 year.

RESULTS

The study enrolled 48 eyes of 39 patients; 30 eyes had accelerated CXL, and 18 eyes had conventional CXL. There were no statistically significant differences in postoperative changes in uncorrected or corrected distance visual acuity or in the manifest refraction spherical equivalent between the 2 procedures. There were also no statistically significant differences in the postoperative changes in the keratometric readings from the Pentacam Scheimpflug device or the corneal biomechanical responses from a dynamic bidirectional applanation device (Ocular Response Analyzer) or a dynamic Scheimpflug analyzer (Corvis ST) between the procedures. Similar morphologic changes and a pronounced demarcation line were apparent in eyes in both groups postoperatively.

CONCLUSIONS

Accelerated CXL and conventional CXL were both safe and effective. Accelerated CXL, being a fast procedure, appears to be more beneficial for patients and surgeons.

BACKGROUND

No author has a financial or proprietary interest in any material or method mentioned.