3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41.

3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41.

Pharmacokinetic profiles of 3-(4-hydroxy-3-methoxyphenyl) propionic acid and its conjugates in Sprague-Dawley rats.

3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) is one of the end-products from gut microbiota from dietary polyphenols, which might contribute to their health benefits. This study aims to investigate the absorption, metabolism, and tissue accumulation of HMPA in Sprague-Dawley (SD) rats. After HMPA (10 mg/kg body weight) was orally administered, intact and conjugated HMPAs in the bloodstream were detected and reached the maximum concentration in 15 min (HMPA, 2.6 ± 0.4 nmol/mL; sulfated HMPA, 3.6 ± 0.9 nmol/mL; glucuronidated HMPA, 0.55 ± 0.09 nmol/mL). HMPA and its conjugates were also detected in the target organs 6 h postadministration, indicating that HMPA undergoes rapid conversion into conjugates, and they broadly distribute to organs with similar profiles (kidneys > liver > thoracic aorta > heart > soleus muscle > lungs). This study demonstrated that orally administered HMPA (10 mg/kg) in SD rats undergoes rapid metabolism and wide tissue distribution with ≥1.2% absorption ratio.

Intraocular penetration of liposomal amphotericin B after intravenous injection in inflamed human eyes.

PURPOSE: To determine the intraocular penetration of amphotericin B (AMPH-B) after an intravenously injection of liposomal amphotericin B (L-AMB) in inflamed human eyes. METHODS: Seven eyes of 5 patients with fungal eye diseases (endophthalmitis in 6 eyes and keratitis in 1 eye) were treated with intravenous injections of 100-250 mg/day of L-AMB. Samples of blood, corneal button, aqueous humor, and vitreous humor were collected and assessed for AMPH-B. RESULTS: The AMPH-B level in the cornea (604.0 µg/g) of the case with fungal keratitis exceeded the minimum inhibitory concentration. However, the levels in the aqueous and vitreous humors of the cases with fungal endophthalmitis were lower, e.g., 0.02 ± 0.01 µg/ml (0.09% of serum level) in the aqueous humor and 0.05 ± 0.08 µg/ml (0.17% of serum level) in the vitreous humor. CONCLUSIONS: The AMPH-B levels administered intravenously were very low in the aqueous and vitreous humors. Our findings indicate that intravenous L-AMB can be considered only for patients with mild endogenous fungal endophthalmitis, e.g., isolated chorioretinitis without vitreous extensions.

Brachybacterium paraconglomeratum Endophthalmitis Postcataract Operation.

PURPOSE: To present our findings in a case of delayed-onset postoperative endophthalmitis caused by Brachybacterium paraconglomeratum, a rare organism. Observations. A 57-year-old man presented with epiphora and photophobia 17 weeks after a routine cataract extraction with phacoemulsification and intraocular lens implantation. Because endophthalmitis was suspected to be caused by a low-grade pathogen or fungus, an anterior chamber tap was performed. However, both multiplex PCR and culturing were negative. The patient was treated with topical cefmenoxime, oral minocycline, and subconjunctival injection of vancomycin and ceftazidime, but the intraocular inflammation increased. Then, the anterior chamber was tapped again, and the second PCR amplification and direct sequencing which targeted Actinomycetes detected Brachybacterium paraconglomeratum, a rare organism. CONCLUSION: This is the first reported case of an ocular disorder caused by B. paraconglomeratum. We recommend that B. paraconglomeratum be considered in cases of delayed-onset postcataract endophthalmitis.B. paraconglomeratum. We recommend that B. paraconglomeratum be considered in cases of delayed-onset postcataract endophthalmitis.

Moraxella species: infectious microbes identified by use of time-of-flight mass spectrometry.

PURPOSE: To report the clinical manifestations, identification, antimicrobial susceptibilities, and treatment outcomes of ocular infections caused by Moraxella species. STUDY DESIGN: Retrospective study. PATIENTS AND METHODS: The medical records of all patients treated at the Departments of Ophthalmology of the Ogaki Municipal Hospital and the Gifu University Graduate School of Medicine for ocular infections caused by Moraxella species between January 2011 and June 2017 were examined. The stored Moraxella species isolated from ocular samples were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), molecular identification, and the biochemical properties. RESULTS: Sixteen eyes of 16 patients were treated for Moraxella ocular infections. The patients' median age was 72 years. A predisposing systemic or ocular condition was identified in 15 of the patients. Nine of the patients developed keratitis; four, conjunctivitis; and three, blebitis. M lacunata (6 eyes), M catarrhalis (6), M nonliquefaciens (3), and M osloensis (1) were identified by MALDI-TOF MS. All isolates were sensitive to levofloxacin, tobramycin, ceftazidime, ceftriaxone, and cefazolin. Twelve patients with keratitis or blebitis were treated with various topical antimicrobial combinations, and systemic antibiotics were used in 10 of the 12 patients. The mean time for the complete closure of the epithelial defects with keratitis was 24 days. The visual outcomes after treatment were favorable except in 1 keratitis patient who underwent enucleation. CONCLUSIONS: The use of duo-therapy with a combination of fluoroquinolone and cefmenoxime should be considered in cases nonresponsive to monotherapy, such as keratitis and bleb-associated infections. MALDI-TOF MS is useful for the identification of Moraxella to the species level.

3-(4-Hydroxy-3-methoxyphenyl)propionic Acid Produced from 4-Hydroxy-3-methoxycinnamic Acid by Gut Microbiota Improves Host Metabolic Condition in Diet-Induced Obese Mice.

4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders.

Orbital T-Cell Lymphoma with Discrete Enlargements of All Extraocular Muscles Bilaterally in Patient with Moon Face Countenance.

Purpose. To report our findings in a case of orbital T-cell lymphoma in which all of the extraocular muscles (EOMs) were bilaterally and discretely enlarged and the patient had a moon face countenance. Case. A 59-year-old woman presented with visual disturbances in her left eye, hyperemia in both eyes, and a moon face countenance. Examinations showed limited upward gaze in the right eye, blepharoptosis, hypertropia, and limited downward and rightward gaze in the left eye. Slit-lamp examination showed only chemosis and hyperemia of both eyes. Magnetic resonance imaging with contrast revealed discrete enlargements of the muscle bellies in all EOMs without abnormalities of the orbital fat in both eyes. Blood examinations excluded thyroid- and IgG4-related ophthalmopathy, and EOM biopsy revealed peripheral T-cell lymphoma. After beginning aggressive chemotherapy, the enlarged EOMs, limited eye motility, and moon face countenance improved. Unfortunately, the patient died of sepsis during the chemotherapy. Conclusions. A lymphoma should be included in the differential diagnosis of eyes with enlarged EOMs. Because lymphomas can lead to death, it is important for clinicians to consider lymphomas in eyes with enlarged EOMs.

Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization.

Purpose: To determine the relationship between the different isoforms of apolipoprotein E (ApoE) and retinal neovascularization. Methods: The concentrations of ApoE and VEGF in vitreous humor samples with either a macular hole (MH), or diabetic macular edema (DME), or proliferative diabetic retinopathy (PDR) with or without intravitreal injection of bevacizumab (IVB) were measured by ELISA. The effects of each isoform of ApoE on human retinal microvascular endothelial cells (HRMECs) in culture or on the retina of oxygen-induced retinopathy (OIR) mice were investigated. Results: The concentrations of ApoE and VEGF were significantly higher in the vitreous humor of patients with PDR and DME than in patients with an MH. There was a significant positive correlation between the concentrations of ApoE and VEGF in vitreous humor of patients. In vitro assays showed that ApoE2 and ApoE3, but not ApoE4, promoted the VEGF-induced cell proliferation and migration. In vivo assays showed that intravitreal injections of ApoE2 and ApoE3 increased the number and area of nodes in the retina of OIR mice. Moreover, ApoE was expressed in the vascular endothelial cell in both normal and OIR retinas, but their expression levels were different at postnatal day (P) 12 and P17. Conclusions: These results demonstrate that ApoE2 and ApoE3, but not ApoE4, have proangiogenic effects, and the increased expression of ApoE in the vitreous humor of patients with PDR and DME indicates that ApoE2 and ApoE3 are involved in the development of retinal neovascularization in eyes.

Seven cases of localized invasive sino-orbital aspergillosis.

PURPOSE: To describe the clinical manifestations and prognoses in 7 patients with invasive sino-orbital aspergillosis (ISOA). METHODS: This was a retrospective study of consecutive patients who were diagnosed as having ISOA at the Gifu University Hospital and Gifu Municipal Hospital between January 1993 and December 2015. Data were collected on demographics, initial manifestations, examination findings, treatments, clinical course, and outcomes. RESULTS: The median age of the 7 patients with ISOA was 68 years; 5 of them had diabetes. The initial symptoms were reduced blurred vision (57%), unilateral headaches (43%), unilateral abnormal sensations or numbness of the periorbital area (43%), and external ophthalmoplegia (43%). The medical department that the patients first visited was the ophthalmology department in 57% of the cases. The initial CT showed bone destruction in 71% and calcification in 14% of the patients. Six of the 7 cases were misdiagnosed. The definitive diagnosis of ISOA was made by histopathologic examinations of the biopsy specimens, with an average of 2.6 biopsies. All patients received aggressive antifungal treatments after the diagnosis. However, the final visual outcome was no light perception in 86% and death related to the ISOA in 43% of the patients. Patients who were older at the onset had lower survival rates. CONCLUSIONS: The prognosis for patients with ISOA is poor in terms of both vision and life. Ophthalmologists are often the first examiner. ISOA should be considered in the differential diagnosis for patients with a gradually progressive orbital mass, unilateral headaches, numbness of the periorbital area, and a decrease in visual acuity of unknown origin.

Elderly onset vitreous opacities as the initial manifestation in hereditary transthyretin (ATTR Val30Met) carries.

Familial amyloid polyneuropathy (FAP) is a systemic disorder transmitted as an autosomal dominant trait and is characterized by deposits of protein fibrils in various organs leading to physiologic dysfunction. In cases with FAP in Japanese endemic foci, their signs and symptoms often develop before the age of 40 years. We report on two elderly patients (an 80-year-old woman and an 83-year-old man) with progressive vitreous opacities (VOs) as the initial manifestation of hereditary transthyretin (ATTR Val30Met) carries, who had no evidence of systemic involvement or family history of amyloidosis and lived in non-endemic areas. Therapeutic vitrectomy with extensive vitreous removal combined with cataract surgery was performed. Clinicians should consider the possibility of hereditary transthyretin carries in cases presenting with VOs of undetermined etiology to avoid misdiagnosis.

Study of ocular candidiasis during nine-year period.

BACKGROUND: To determine the clinical features, fungal profiles, treatment outcomes, and factors that are significantly associated with the visual outcomes of eyes with endogenous fungal endophthalmitis (EFE). MATERIAL AND METHODS: The medical records of 17 eyes of 9 patients diagnosed with EFE during January 2005 to December 2013 were reviewed. The collected data included patient characteristics, visual acuities (VAs), length between appearance of the first sign of infection and the first ophthalmic examinations, fungal profiles, and treatment regimen. The main outcome measure was the VA. Statistical analyses were done to detect the factors significantly associated with the visual prognosis. RESULTS: The median age at presentation was 67 years. Seven patients had Candida albicans, and 2 had Candida tropicalis. Eight patients received intravenous fosfluconazole, 4 systemic micafungin, 4 oral itraconazole, and 2 intravenous voriconazole. The minimum inhibitory concentrations of fluconazole against Candida albicans isolated from 5 patients ranged from 0.25 to 1.0 µg/mL. A final VA of ≥20/200 was achieved in 69.2% of the eyes. Multiple regression analysis (r(2) = 0.695) detected both initial logMAR (the Logarithm of the minimum angle of resolution) VA (P = 0.0067) and longer length between onset of symptoms and the first ophthalmic examinations (P = 0.0491) as significant worsen factors for final logMAR VA. CONCLUSIONS: Early ophthalmic consultation, better initial visual acuity, and use of effective systemic antifungal treatment might lead to relatively good visual outcomes in EFE.

Inhibitory effects of antimicrobial agents against Fusarium species.

We investigated the inhibitory effects of antibacterial, biocidal, and antifungal agents against Fusarium spp. Seven Fusarium spp: four F. falciforme (Fusarium solani species complex), one Fusarium spp, one Fusarium spp. (Fusarium incarnatum-equiseti species complex), and one F. napiforme (Gibberella fujikuroi species complex), isolated from eyes with fungal keratitis were used in this study. Their susceptibility to antibacterial agents: flomoxef, imipenem, gatifloxacin, levofloxacin, moxifloxacin, gentamicin, tobramycin, and Tobracin® (contained 3,000 µg/ml of tobramycin and 25 µg/ml of benzalkonium chloride (BAK), a biocidal agent: BAK, and antifungal agents: amphotericin B, pimaricin (natamycin), fluconazole, itraconazole, miconazole, voriconazole, and micafungin, was determined by broth microdilution tests. The half-maximal inhibitory concentration (IC50), 100% inhibitory concentration (IC100), and minimum inhibitory concentration (MIC) against the Fusarium isolates were determined. BAK had the highest activity against the Fusarium spp. except for the antifungal agents. Three fluoroquinolones and two aminoglycosides had inhibitory effects against the Fusarium spp. at relatively high concentrations. Tobracin® had a higher inhibitory effect against Fusarium spp. than tobramycin alone. Amphotericin B had the highest inhibitory effect against the Fusarium spp, although it had different degrees of activity against each isolate. Our findings showed that fluoroquinolones, aminoglycosides, and BAK had some degree of inhibitory effect against the seven Fusarium isolates, although these agents had considerably lower effect than amphotericin B. However, the inhibitory effects of amphotericin B against the Fusarium spp. varied for the different isolates. Further studies for more effective medications against Fusarium, such as different combinations of antibacterial, biocidal, and antifungal agents are needed.

An eleven-year retrospective study of endogenous bacterial endophthalmitis.

Purpose. To determine the clinical features, microbial profiles, treatment outcomes, and prognostic factors for endogenous bacterial endophthalmitis (EBE). Methods. The medical records of 27 eyes of 21 patients diagnosed with EBE for 11 years were reviewed. Collected data included age, site of infection, visual acuities (VAs), microbial profiles, and treatment regimen. Results. The mean age was 68.5 years. Gram-positive organisms accounted for 76.2%, while gram-negative ones accounted for 19.0%. Staphylococcus aureus was the most common causative organism (52.3%) of which 72.7% was methicillin-resistant S. aureus. A final VA of ≥20/40 was achieved in 44% and 20/200 or better was in 64%. Eyes with initial VA of ≥20/200 (P = 0.003) and focal involvements (P = 0.011) had significantly better final VA. Initial VA (P = 0.001) and the interval between onset of ocular symptoms and intravitreal antibiotic injection (P = 0.097) were associated with final VA in eyes receiving intravitreal antibiotics. Conclusions. EBE is generally associated with poor visual outcome; however the prognosis may depend on initial VA, extent of ocular involvement, and an interval between onset of ocular symptoms and intravitreal antibiotic injection. Early diagnosis and early intravitreal injection supplement to systemic antibiotics might lead to a relatively good visual outcome.

Case of keratitis caused by Streptomyces thermocarboxydus.

We describe a case of keratitis caused by Streptomyces thermocarboxydus and report the usefulness of molecular analysis in identifying the exact species of Streptomyces. A 50-year-old man was diagnosed with keratitis caused by Streptomyces sp. which was identified as S. thermocarboxydus by sequencing the 16S rDNA. He had no history of trauma or systemic diseases. He was initially treated with topical beta-lactams and fluoroquinolones, and systemic beta-lactams but the keratitis did not improve. His vision improved significantly after topical erythromycin (5 mg/ml) and oral minocycline (200 mg/day) therapy. Our findings demonstrate that molecular analysis can be used to identify the exact Streptomyces species causing the keratitis. This then allowed us to determine the susceptibility of this species to different antibacterial drugs which were used to treat our patient successfully.

Late-onset bleb-related endophthalmitis caused by Streptococcus pseudopneumoniae.

We report our findings in a 63-year-old male who developed late-onset bleb-related endophthalmitis. The patient had undergone glaucoma surgery 46 years earlier, and had a thin-walled cystic bleb prior to the endophthalmitis in his right eye. He underwent immediate vitrectomy with intravitreal injections of ceftazidime and vancomycin. After surgery, he was given topical 0.5 % moxifloxacin and 1 % vancomycin, intravenous doripenem, and oral minocycline. Culture of the vitreous specimen identified Streptococcus pseudopneumoniae by 16S rRNA sequence analysis, by optochin susceptibility test, and by bile solubility test. Our findings indicate that S. pseudopneumoniae can be isolated from a late-onset bleb-related endophthalmitis and that molecular analysis and phenotypic testing can be accurate methods to identify S. pseudopneumoniae.

Intraocular penetration of intravenous micafungin in inflamed human eyes.

Eight eyes of 7 patients with fungal disease received intravenous injections of 150 to 300 mg micafungin, and samples of blood, cornea, retina-choroid, aqueous humor, and vitreous humor were collected. The micafungin levels in all collected samples exceeded the MICs; however, the levels in the vitreous and aqueous humors were lower. Our findings suggest that intravenous micafungin should be given in combination with intravitreal antifungal agents after vitrectomy in severe cases of intraocular fungal diseases.

Intraocular penetration of itraconazole in patient with fungal endophthalmitis.

The purpose of this study was to determine the penetration of itraconazole, a type of azole antifungal agent, into the aqueous humor and vitreous after repeated oral administrations. Fungal endophthalmitis developed bilaterally in a 21-year-old man who had a history of intravenous hyperalimentation following abdominal surgery. Itraconazole capsules (200 mg/day) were taken orally for 12 consecutive days. Vitrectomy was performed on the left eye 30 h after the last oral itraconazole. Samples of blood, aqueous, and vitreous were collected during the vitrectomy. The concentration of itraconazole was determined by high performance liquid chromatography. The concentration of itraconazole was 0.492 µg/mL in the plasma, 0.020 µg/mL in the vitreous, and none in the aqueous of the left eye. Although no fungal organisms were isolated from the plasma and vitreous samples from both eyes, fungal DNA was detected in the vitreous from the left eye. Our findings indicate that oral itraconazole has limited penetration in eyes with fungal endophthalmitis.

[Clinical manifestations, treatment and outcome of ocular infections caused by Paecilomyces species].

PURPOSE: To report the predisposing factors, patient background, treatment and outcomes of ocular infections caused by Paecilomyces spp. in Japan. METHODS: We reviewed the medical records and the published literature in Japan on ocular infections caused by microbiologically-proven Paecilomyces spp. Nineteen eyes of 18 patients; 4 eyes of 4 of our patients and 15 eyes of 14 published Japanese patients were studied. RESULTS: Ten men and 8 women (9 OD, 8 OS, 1 OU) were diagnosed with ocular infections caused by Paecilomyces spp. The mean age was 69 years (range 33 to 90 years). The initial diagnosis of ocular infection caused by Paecilomyces spp. was keratitis in 14 eyes and endophthalmitis in 5 eyes. The final diagnosis was keratitis in 2 eyes, keratitis with involvement of the anterior segment of the eye, i.e., hypopyon or corneal rupture, in 12 eyes, and endophthalmitis in 5 eyes. The predisposing factors had a history of ocular surgery, corneal trauma and soft contact lens use. Other factors were diabetes and old age. The infections developed more often in the fall and winter. The identified Paecilomyces spp. had a high sensitivity to micafungin and voriconazole, but low sensitivity to amphotericin B, flucytosine and fluconazole. The prognosis of Paecilomyces spp. ocular infections was very poor, viz., final vision was counting fingers or worse in 60%, ocular perforation in 42%, and eye enucleation in 11%. The percentage of eyes with a final visual acuity worse than counting fingers was 0% in those with keratitis, 50% in those with involvement of the anterior segment, and 100% in those with endophtalmitis (p = 0.0446). Among the antifungal agents, the percentage of cases with final vision of counting fingers or worse was 90% with fluconazole, 80% with itraconazole, 100% with miconazole, and 71% with voriconazole. CONCLUSION: The results show that if the Paecilomyces spp. infection spreads intraocularly, it is difficult to mitigate the clinical damage even with antifungal agents with high sensitivity.

Gemella species-associated late-onset endophthalmitis after trabeculectomy with adjunctive mitomycin C.

PURPOSE: To report 2 cases of delayed-onset, bleb-related endophthalmitis induced by Gemella species. METHODS: Interventional case report. RESULTS: Two patients developed bleb-related ocular infection attributable to Gemella haemolysans and Gemella morbillorum after trabeculectomy with adjunctive mitomycin C. Both patients had thin-walled cystic filtering blebs before ocular infection. One patient underwent urgent vitrectomy with intravitreal injection of ceftazidime and vancomycin. The other received an intraocular injection of vancomycin and ceftazidime. After surgical intervention, 2 cases were administered topical levofloxacin and sulfobenzylpenicillin, and intravenous cefpirome. The DNA from the microorganism was sequenced and identified as G. haemolysans and G. morbillorum. CONCLUSIONS: Gemella species should be added to the long list of organisms that may rarely cause bleb-associated endophthalmitis.