Eyelash trichomegaly: a systematic review of acquired and congenital aetiologies of lengthened lashes.

Long eyelashes have been popularized and many commercially available products exist to achieve eyelash growth as a desired cosmetic effect. Eyelash trichomegaly may be induced by medications, procedures, or be related to medical conditions; however, the exact mechanisms that govern eyelash growth are not well elucidated. This study aims to identify and summarize aetiologies associated with eyelash trichomegaly. We report a systematic review of 148 clinical trials, prospective and retrospective studies, and case reports describing all evidence-based potential aetiologies of eyelash trichomegaly obtained from the Medline/PubMed and Cochrane Library through January 2021. Inclusion criteria were defined as (i) human studies involving congenital and acquired diseases in which eyelash trichomegaly is a characteristic or (ii) assessment of trichomegaly as an adverse or desired effect of a medication or procedure. Exclusion criteria included: animal studies, articles not available in English, outcomes unrelated to eyelash trichomegaly, and secondary review articles. Pharmacologic agents associated with eyelash trichomegaly included prostaglandin analogues (15-keto fluprostenol isopropyl ester, bimatoprost, latanoprost, and travoprost), epidermal growth factor receptor inhibitors (cetuximab, erlotinib, and panitumumab), interferon-alpha, and calcineurin inhibitors (tacrolimus and cyclosporine). Surgical procedures of the eyelid, as well as allergic rhinitis, atopic dermatitis, HIV, ichthyosis vulgaris (IV), uveitis, and vernal keratoconjunctivitis were also associated with increased eyelash growth. Congenital disorders associated with lengthened eyelashes included Cantú syndrome, CHOPS syndrome, Coffin-Siris syndrome, congenital heart disease, Cornelia de Lange syndrome, Costello syndrome, familial trichomegaly, Floating Harbor syndrome, Hermansky-Pudlak syndrome, Kabuki-Makeup syndrome, KBG syndrome, Oliver-McFarlane syndrome, Rubinstein-Taybi syndrome, and Smith-Magenis syndrome. While the most common cause of eyelash trichomegaly is topical bimatoprost use, better understanding of pathways implicated in eyelash trichomegaly may lead to the discovery of additional medications to stimulate eyelash growth and create avenues for future therapeutic interventions.

Rates of retinal nerve fibre layer thickness change in glaucoma patients and control subjects.

PURPOSE: To examine the rates of retinal nerve fibre layer thickness (RNFLT) change in glaucoma patients and healthy, age-similar control subjects with three techniques: scanning laser polarimetry with variable corneal compensation (VCC) and enhanced corneal compensation (ECC), and time-domain optical coherence tomography (OCT). METHODS: Sixty-one patients and thirty-three controls were examined with each technique and with standard automated perimetry (SAP) every 6 months. Rates of global RNFLT change and SAP mean deviation (MD) change were estimated with linear mixed-effects models. RESULTS: The median (interquartile range) baseline age was 64.4 (58.2, 71.0) years for patients and 62.4 (56.3, 70.1) years for controls (P=0.56). There was a median of seven examinations over 3.1 years for patients and six examinations in 3.0 years for controls. Baseline visual field MD and RNFLT for all imaging modalities were significantly lower (P<0.01) in patients compared with controls. Rates of RNFLT change were not significantly different between patients and controls (P≥0.19). Mean rates of VCC-measured RNFLT change were -0.18 and -0.37 µm per year in patients and controls, whereas the respective figures for ECC and OCT were -0.13 and -0.31 µm per year, and 0.04 and 0.61 µm per year. Mean rates of MD change were -0.20 and 0.03 dB per year in patients and controls, respectively (P=0.01). CONCLUSION: Rates of RNFLT change in glaucoma patients were not statistically different from control subjects for any modality. A significantly negative rate of MD change in patients suggests a genuine, continued deterioration in these patients not reflected by RNFLT changes.

Comparison between confocal scanning laser tomography, scanning laser polarimetry and optical coherence tomography on the ability to detect localised retinal nerve fibre layer defects in glaucoma patients.

BACKGROUND/AIM: To compare the ability of confocal scanning laser tomography (CSLT), scanning laser polarimetry (SLP) and optical coherence tomography (OCT) in recognising localised retinal nerve fibre layer (RNFL) defects. METHODS: 51 eyes from 43 patients with glaucoma were identified by two observers as having RNFL defects visible on optic disc photographs. 51 eyes of 32 normal subjects were used as controls. Three masked observers evaluated CSLT, SLP and OCT images to determine subjectively the presence of localised RNFL defects. RESULTS: Interobserver agreement was highest with OCT, followed by SLP and CSLT (mean kappa: 0.83, 0.69 and 0.64, respectively). RNFL defects were identified in 58.8% of CSLT, 66.7% of SLP and 54.9% of OCT (p = 0.02 between SLP and OCT) by at least two observers. In the controls, 94.1% of CSLT, 84.3% of SLP and 94.1% of OCT scans, respectively, were rated as normal (p = 0.02 between CSLT and SLP, and SLP and OCT). CONCLUSION: Approximately 20-40% of localised RNFL defects identified by colour optic disc photographs are not detected by CSLT, SPL or OCT. SLP showed a higher number of false-positive results than the other techniques, but also had a higher proportion of correctly identified RNFL defects in the glaucoma population.

Central corneal thickness and progression of the visual field and optic disc in glaucoma.

AIMS: To determine whether central corneal thickness (CCT) is a significant predictor of visual field and optic disc progression in open angle glaucoma. METHODS: Data were obtained from a prospective study of glaucoma patients tested with static automated perimetry and confocal scanning laser tomography every 6 months. Progression was determined using a trend based approach called evidence of change (EOC) analysis in which sectoral ordinal scores based on the significance of regression coefficients of visual field pattern deviation and neuroretinal rim area over time are summed. Visual field progression was also determined using the event based glaucoma change probability (GCP) analysis using both total and pattern deviation. RESULTS: The sample contained 101 eyes of 54 patients (mean (SD) age 56.5 (9.8) years) with a mean follow up of 9.2 (0.7) years and 20.7 (2.3) sets of examinations every 6 months. Lower CCT was associated with worse baseline visual fields and lower mean IOP in the follow up. In the longitudinal analysis CCT was not correlated with the EOC scores for visual field or optic disc change. In the GCP analyses, there was a tendency for groups classified as progressing to have lower CCT compared to non-progressing groups. In a multivariate analyses accounting for IOP, the opposite was found, whereby higher CCT was associated with visual field progression. None of the independent factors were predictive of optic disc progression. CONCLUSIONS: In this cohort of patients with established glaucoma, CCT was not a useful index in the risk assessment of visual field and optic disc progression.

Lyophilized Clostridium perfringens 3 alpha- and Clostridium bifermentans 7 alpha-hydroxysteroid dehydrogenases: two new stable enzyme preparations for routine bile acid analysis.

Preparations of 3 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.50) from Clostridium perfringens were successfully lyophilized into a stable powder form. Purification of the enzyme was achieved using triazine dye affinity chromatography. C. perfringens 3 alpha-hydroxysteroid dehydrogenase was purified 24-fold using Reactive Red 120 (Procion Red) -cross-linked agarose (70% yield). Quantitative measurement of bile acids with the purified enzymes, 3 alpha-hydroxysteroid dehydrogenase and 7 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.159) from Clostridium bifermentans (strain F-6), was achieved spectrophotometrically. Standard curves with chenodeoxycholic acid (CDC) and cholic acid were linear within a concentration range of 20-100 microM. Analysis of mixtures of ursodeoxycholic acid and CDC showed the additive nature of the 3 alpha-hydroxysteroid dehydrogenase and showed also that 7 alpha-hydroxyl groups were independently quantified by the 7 alpha-hydroxysteroid dehydrogenase. Bile acids in Folch extracts of human bile samples were measured using purified preparations of Pseudomonas testosteroni 3 alpha-hydroxysteroid dehydrogenase, C. perfringens 3 alpha-hydroxysteroid dehydrogenase, Escherichia coli 7 alpha-hydroxysteroid dehydrogenase and C. bifermentans (strain F-6) 7 alpha-hydroxysteroid dehydrogenase. Statistical comparison validated the use of C. perfringens 3 alpha- and C. bifermentans 7 alpha-hydroxysteroid dehydrogenases for the quantification of bile acids in bile.

Oxidation of primary bile acids by a 7 alpha-hydroxysteroid dehydrogenase elaborating Clostridium bifermentans soil isolate.

A gram-positive, rod-shaped anaerobe (strain F-6) was isolated from soil. This organism was identified by cellular morphology as well as fermentative and biochemical data as Clostridium bifermentans. Strain F-6 formed 7-ketolithocholic acid from chenodeoxycholic acid and 7-ketodeoxycholic acid from cholic acid in whole cell cultures, but did not transform deoxycholic acid, ursodeoxycholic acid, or ursocholic acid. This reaction is reversible. The structures of 7-ketolithocholic acid and 7-ketodeoxycholic acid were verified by mass spectroscopy and by thin-layer chromatography using Komarowsky's spray reagent. When incubated with the strain F-6 glycine and taurine conjugates of the primary bile acids were partially hydrolyzed and transformed to 7-keto products. Optimal yields of 7-ketolithocholic acid and 7-ketodeoxycholic acid were obtained after 78 h of incubation. Culture pH changed with time and was characterized by an initial drop (1.1 pH units) and a gradual increase back to the starting pH (7.3). Corroborating these observations, an inducible, NADP-dependent, 7 alpha-hydroxysteroid dehydrogenase was demonstrated in cell extracts of strain F-6. A trace of NAD-dependent 7 alpha-hydroxysteroid dehydrogenase was also found. A substantial increase in the specific activity of the NADP-dependent 7 alpha-hydroxysteroid dehydrogenase was observed when either 7-ketolithocholic acid, chenodeoxycholic acid, or deoxycholic acid was included in the growth medium. Optimal induction of the NADP-dependent 7 alpha-hydroxysteroid dehydrogenase was achieved with 0.3-0.4 mM 7-ketolithocholic acid. Production of the enzyme(s) was optimal at 6-8 h of growth and the 7 alpha-hydroxysteroid dehydrogenases had a pH optimum of approximately 11.(ABSTRACT TRUNCATED AT 250 WORDS)

Rutin-induced beta-glucosidase activity in Streptococcus faecium VGH-1 and Streptococcus sp. strain FRP-17 isolated from human feces: formation of the mutagen, quercetin, from rutin.

A fecal isolate, Streptococcus sp. strain FRP-17, and strain VGH-1 of Streptococcus faecium were shown to contain beta-glucosidases which converted rutin (quercetin-3-O-beta-D-glucose-alpha-L-rhamnose) to quercetin and were active against o-nitrophenyl-beta-D-glucose. The activity against rutin could be measured by increased mutagenicity in the Ames assay or visualized on thin-layer chromatography plates. In both organisms, the beta-glucosidase activities were inducible by the addition of rutin to the growth media. Several closely related strains of Streptococcus spp. lacked any beta-glucosidase activity. In cell preparations of the active organisms, activities with rutin and o-nitrophenyl-beta-D-glucose were optimal at pH 6.8 and could be enhanced by increasing the ionic strength of the assay system. At low ionic strengths, both quercetin and a new product (intermediate between the polarities of rutin and quercetin) were formed by the incubation of rutin with cell preparations of either active organism. This product disappeared with increased ionic strength, suggesting that it may be a reaction intermediate, quercetin-3-O-beta-D-glucose. These results suggest that the beta-glucosidase active against rutin and that active against o-nitrophenyl-beta-D-glucose are the same.

Formation of ursodeoxycholic acid from chenodeoxycholic acid by a 7 beta-hydroxysteroid dehydrogenase-elaborating Eubacterium aerofaciens strain cocultured with 7 alpha-hydroxysteroid dehydrogenase-elaborating organisms.

A gram-positive, anaerobic, chain-forming, rod-shaped anaerobe (isolate G20-7) was isolated from normal human feces. This organism was identified by cellular morphology as well as fermentative and biochemical data as Eubacterium aerofaciens. When isolate G20-7 was grown in the presence of Bacteroides fragilis or Escherichia coli (or another 7 alpha-hydroxysteroid dehydrogenase producer) and chenodeoxycholic acid, ursodeoxycholic acid produced. Time course curves revealed that 3 alpha-hydroxy-7-keto-5 beta-cholanoic acid produced by B. fragilis or E. coli or introduced into the medium as a pure substance was reduced by G20-7 specifically to ursodeoxycholic acid. The addition of glycine- and taurine-conjugated primary bile acids (chenodeoxycholic and cholic acids) and other bile acids to binary cultures of B. fragilis and G20-7 revealed that (i) both conjugates were hydrolyzed to give free bile acids, (ii) ursocholic acid (3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acid) was produced when conjugated (or free) cholic acid was the substrate, and (iii) the epimerization reaction was at least partially reversible. Corroborating these observations, an NADP-dependent 7 beta-hydroxysteroid dehydrogenase (reacting specifically with 7 beta-OH-groups) was demonstrated in cell-free preparations of isolate G20-7; production of the enzyme was optimal at between 12 and 18 h of growth. This enzyme, when measured in the oxidative direction, was active with ursodeoxycholic acid, ursocholic acid, and the taurine conjugate of ursodeoxycholic acid (but not with chenodeoxycholic, deoxycholic, or cholic acids) and displayed an optimal pH range of 9.8 to 10.2

Epimerization versus dehydroxylation of the 7 alpha-hydroxyl- group of primary bile acids: competitive studies with Clostridium absonum and 7 alpha-dehydroxylating bacteria (Eubacterium sp.).

Primary bile acids, chenodeoxycholic (3 alpha,7 alpha-dihydroxy-5 beta-cholan-24-oic) and cholic (3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholan-24-oic) were included in cultures of (a) Clostridium absonum alone (b) a mixture of C. absonum and a 7-dehydroxylating organism, Eubacterium sp. (c) a mixture of C. absonum and fecal bacteria, and (d) fecal bacteria alone. C. absonum, when added to Eubacterium sp. cultures totally prevented lithocholic acid formation when the substrate was chenodeoxycholic acid and halved deoxycholic acid formation when the substrate was cholic acid. As expected, formation of 7 beta-hydroxy- and 7-keto-bile acids took precedence over formation of 7 alpha-dehydroxylated bile acids. However, the addition of C. absonum to mixed fecal cultures containing chenodeoxycholic acid did not alter production of lithocholic (3 alpha-hydroxy-5 beta-cholan-24-oic) acid; instead it enhanced formation of ursodeoxycholic acid (3 alpha,7 beta-dihydroxy-5 beta-cholan-24-oic acid) at the expense of 7-keto-lithocholic acid (3 alpha-hydroxyl-7-oxo-5 beta-cholan-24-oic acid). Similarly, the addition of C. absonum to mixed fecal cultures containing cholic acid promoted production of ursocholic acid (3 alpha,7 beta,12 alpha-trihydroxy-5 beta-cholan-24-oic acid) which did not take place when C. absonum was not added. Surprisingly, deoxycholic acid formation was somewhat enhanced when C. absonum was added to fecal cultures. These studies suggest that successful introduction of "foreign" 7 alpha-epimerizing organisms into animal or human intestines may influence bile acid metabolism in vivo.

Nitrite-induced volatile mutagens from normal human feces.

Volatile mutagens (putative carcinogens) were produced from normal human and animal feces upon incubation with sodium nitrite in saline at 37 C for 48 hours. The mutagens were detected by using Ames' Salmonella typhimurium tester strain TA1535 without microsomes, on plates inverted over samples in sealed containers. Mutagenicity was maximal at 0.2 to 0.6 M NaNO2 and at pH 6.2 to 6.8. Reversions per plate varied from approximately 30 to 450 (1.5 to 25 x background) within the normal human population. Sodium ascorbate and alpha-Tocopherol (at one-half [NaNO2]) each reduced the mutagenicity by approximately 30%. Two standard N-nitroso-compounds were mutagenic in the system. We propose that the mutagenicity in our system is probably caused by the formation of volatile N-nitroso-compounds and that addition of nitrite to human feces in vitro enhances a process that occurs in vivo.

Formation of urso- and ursodeoxy-cholic acids from primary bile acids by Clostridium absonum.

Eight strains of Clostridium absonum were shown to form ursocholic acid (UC) from cholic acid (C) and ursodeoxycholic acid (UDC) from chenodeoxycholic acid (CDC) but did not transform deoxycholic acid (DC) in whole cell cultures. The structures of UC and UDC were verified by mass spectroscopy, and by thin-layer chromatography using Komarowsky's spray reagent. The organism transformed C and CDC at concentrations below 1.5. 10(-3) M and 5.0. 10(-4) M, respectively; higher concentrations were inhibitory. Optimal yields of the final products were realized at about 15-22 hr and 9-15 hr of incubation, respectively, and were in the range of 60-70%. Additionally, the 7 keto-derivatives, 7 keto-deoxycholic acid (7K-DC) or 7 keto-lithocholic acid (7K-LC) were also formed from C and CDC. With longer periods of incubation, increasing yields of 7K-DC and 7K-LC and decreasing yields of UC and UDC were observed. These time course studies suggest that 7K-DC and 7K-LC are intermediates in the formation of UC and UDC from the primary bile acids. We propose the occurrence of C right harpoon over left harpoon 7K-DC right harpoon over left harpoon UC and CDC right harpoon over left harpoon 7K-LC right harpoon over left harpoon UDC with increasing dominance of back reaction of the second step on aging of the culture. When the initial pH value of the medium was manipulated within the range of 5.8-9.0, increasing yields of UDC from CDC were obtained at higher pH values (maximum yield at pH 9.0 was 83%), with total inhibition of growth and transformation at pH 5.8. In contrast, UC was produced from C at all pH values studied, with marginal differences in yields (maximum yield at pH 8.0 was 50%). In all cases, formation of UC from C was much slower than that of UDC from CDC. In contrast, C. paraperfringens transformed none of the above bile acids. We propose that C. absonum, or a biochemically similar species, may be present in the human gut and give rise to UDC (and UC) in vivo.-Macdonald, I. A., D. M. Hutchison, and T. P. Forrest. Formation of urso- and ursodeoxycholic acids from primary acids by Clostridium absonum.