Therapeutic Effects of Metformin on Central Nervous System Diseases: A Focus on Protection of Neurovascular Unit.

Metformin is one of the most commonly used oral hypoglycemic drugs in clinical practice, with unique roles in neurodegeneration and vascular lesions. Neurodegeneration and vasculopathy coexist in many diseases and typically affect the neurovascular unit (NVU), a minimal structural and functional unit in the central nervous system. Its components interact with one another and are indispensable for maintaining tissue homeostasis. This review focuses on retinal (diabetic retinopathy, retinitis pigmentosa) and cerebral (ischemic stroke, Alzheimer's disease) diseases to explore the effects of metformin on the NVU. Metformin has a preliminarily confirmed therapeutic effect on the retinal NUV, affecting many of its components, such as photoreceptors (cones and rods), microglia, ganglion, Müller, and vascular endothelial cells. Since it rapidly penetrates the blood-brain barrier (BBB) and accumulates in the brain, metformin also has an extensively studied neuronal protective effect in neuronal diseases. Its mechanism affects various NVU components, including pericytes, astrocytes, microglia, and vascular endothelial cells, mainly serving to protect the BBB. Regulating the inflammatory response in NVU (especially neurons and microglia) may be the main mechanism of metformin in improving central nervous system related diseases. Metformin may be a potential drug for treating diseases associated with NVU deterioration, however, more trials are needed to validate its timing, duration, dose, clinical effects, and side effects.

COMPARISON OF THE EFFICACY AND SAFETY OF RANIBIZUMAB 0.5 MG VERSUS 1.0 MG WITH PARS PLANA VITRECTOMY FOR THE TREATMENT OF PROLIFERATIVE DIABETIC RETINOPATHY: A Randomized Controlled Trial.

PURPOSE: To investigate the effectiveness of two regimens of ranibizumab-assisted pars plana vitrectomy in the treatment of patients with proliferative diabetic retinopathy. METHODS: This is a prospective, 6-month, randomized controlled trial. Eighty patients with 87 eyes requiring pars plana vitrectomy treatment for proliferative diabetic retinopathy were included and randomly divided into a 1.0-mg injection group and a 0.5-mg injection group. The ranibizumab was delivered intraoperatively, at the close of surgery. The vitreous hemorrhage grade, best-corrected visual acuity, central macular thickness, and safety data were assessed to Month 6. RESULTS: The 1.0-mg injection group had a milder grade and a lower reoccurrence rate of early postoperatively vitreous hemorrhage than the 0.5-mg injection group (35.0% and 63.4%, respectively, P = 0.0195). The mean best-corrected visual acuity of two groups was significantly improved from baseline to 6 months after surgery, 1.60 ± 0.72 Logarithm of the Minimum Angle of Resolution (LogMAR) (<20/200) to 0.47 ± 0.49 LogMAR (20/59) for the 1.0-mg injection group and 1.51 ± 0.69 LogMAR (<20/200) to 0.50 ± 0.31 LogMAR (20/63) for the 0.5-mg injection group, but there was no significant difference between the two groups ( P = 0.74). There was no significant difference in the mean decrease in central macular thickness and probability of postoperative adverse events between the two groups. CONCLUSION: Intravitreal injection of 1.0 mg of ranibizumab after pars plana vitrectomy compared with the recommended dose of 0.5 mg significantly reduced the recurrence and severity of early postoperative vitreous hemorrhage in patients with proliferative diabetic retinopathy. It also contributed to the early recovery of visual acuity after surgery and did not increase postoperative adverse events.

A three-step approach to close refractory persistent macular holes: a releasing-closing-tapping approach.

PURPOSE: The aim of this study was to assess the efficacy and safety of a novel releasing-closing-tapping approach in the treatment of persistent macular holes (PMHs) after initial surgery with internal limiting membrane (ILM) peeling. METHODS: We retrospectively analyzed patients with PMHs after initial surgery with ILM peeling who were treated with a novel releasing-closing-tapping approach. After repeated pars plana vitrectomy (PPV), the surgeon effectively released the adhesion between the edges and retinal pigment epithelium (RPE) by gently scraping the retinal neuroepithelium. Then, the hole was converted into a transverse slit, and the edges were gently tapped flat so that they attached to the RPE, and no space was left under the edges. Finally, air tamponade was carried out. The primary outcome measures included MH closure and the change in best-corrected visual acuity (BCVA) from preoperatively to postoperatively. RESULTS: The study included 11 PMH patients with a mean age of 63.82 ± 3.31 years. The mean minimum linear diameter of PMHs was 666.3 ± 208.1 µm, and the mean basal diameter was 1547.2 ± 351.8 µm. MH closure was achieved in 90.9% (10/11) of eyes, with significant improvement of visual acuity from 1.19 ± 0.30 logMAR to 0.65 ± 0.29 logMAR postoperatively. CONCLUSION: The releasing-closing-tapping approach with repeated PPV is a simple, effective, and safe surgical procedure for refractory PMHs after initial surgery with ILM peeling that can significantly improve the visual outcome and achieve a high surgical success rate.

A patient with a Berger's space filled by silicone oil.

BACKGROUND: To report a case in which silicone oil accidentally entered Berger's space (BS) after vitrectomy and to explore the effective treatments and possible etiological mechanisms. CASE PRESENTATION: A 68-year-old male underwent vitrectomy and silicone oil injection for the treatment of retinal detachment (RD) in the right eye. Six months later, we noticed an unexpected lens-like round translucent substance located behind the posterior lens capsule and diagnosed it as BS filled by silicone oil. Subsequently, we conducted vitrectomy and the drainage of the silicone oil in BS in the second surgery. A 3-month follow-up showed significant anatomic recovery and visual recovery. CONCLUSIONS: Our case report presents a patient with silicone oil entering BS after vitrectomy and provides photographs of BS from a relatively unique perspective. Furthermore, we illustrate the surgical treatment procedure and reveal the possible etiology and prevention method of silicon oil entering BS, which will provide good insights for clinical diagnosis and treatment.

Effect of dietary inclusion of tea residue and tea leaves on ruminal fermentation characteristics and methane production.

The aim of this study was to compare the differences of dietary tea leaves (TL) and tea residue (TR) inclusion on rumen fermentation characteristics and to explore whether TR could be an alternative feedstuff of ruminants. For these purposes, seven treatments consisted of two inclusion types (TL vs. TR) and three inclusion levels (g/g of dry matter basis) of 10% (TL10/TR10), 20% (TL20/TR20), and 30% (TL30/TR30) in each inclusion type, plus control group with inclusion of 0% (CON) were designed, with four replicates in each group, to conduct an in vitro ruminal fermentation test. Results showed that the contents of crude protein, neutral detergent fiber, and acid detergent fiber were higher in TR than TL, while TL contained more ether extract and crude ash than TR. Interaction effects between inclusion type and inclusion level were observed in concentrations of isobutyrate and microbial crude protein (MCP), as well as in gas production and digestibility of organic matter. Fermentation characteristics were significantly influenced by TL and TR depending on the inclusion level, except for the concentration of total branched-chain volatile fatty acid. These significant differences of fermentation characteristics due to inclusion level mainly focused on CON and tea inclusion, with higher values in CON than TR or TL groups. The total gas production during the 48-h incubation showed no differences among CON, TL10, and TR10. The inclusion of TR and TL decreased the production of methane. The concentration of MCP in CON, TR10 and TR30 was lower than TR20 and all TL groups. In conclusion, dietary inclusion of TR and TL possessed equivalent effect on rumen fermentation characteristics and methane production, substituting diet with TR or TL for over 10% would inhibit rumen fermentation despite positive effects in TR20 and all TL groups regarding more MCP and less methane production. This study indicates that special attention should be paid to the inclusion level of TR and TL when considering them as alternative feedstuffs of ruminants. Further in vivo study is needed to evaluate the applicability of tea residue as a feedstuff for production of ruminants.

An in vitro cell model to study microglia activation in diabetic retinopathy.

Microglial activation has been studied extensively in diabetic retinopathy. We have previously detected activation and migration of microglia in 8-week-old diabetic rat retinas. It is widely acknowledged that microglia-mediated inflammation contributes to the progression of diabetic retinopathy. However, existing cell models do not explore the role of activated microglia in vitro. In this study, microglia were subject to various conditions mimicking diabetic retinopathy, including high glucose, glyoxal, and hypoxia. Under high glucose or glyoxal treatment, microglia demonstrated only partially functional changes, while under hypoxia, microglia became fully activated showing enlarged cell bodies, enhanced migration and phagocytosis as well as increased production of pro-inflammatory factors such as cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), and inducible nitric oxide synthase (iNOS). The data indicate that hypoxia-treated microglia is an optimal in vitro model for exploration of microglia activation in diabetic retinopathy.

TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination.

PURPOSE: Increased permeability of retinal capillary endothelial cells is a key feature in the progression of diabetic retinopathy (DR). Precisely why and how diabetes causes dysfunction in retinal capillary endothelial cells is not well understood, making it challenging to explore more advanced therapeutics. METHODS: Cell proliferation was assessed by the Cell Counting Kit-8 assay. Ferroptosis was evaluated by measuring lipid reactive oxygen species levels by flow cytometry and determining malondialdehyde, superoxide dismutase, and glutathione peroxidase levels through biochemical assays. Western blot analysis and quantitative PCR were respectively used to check the expression of proteins and RNAs. Co-immunoprecipitation assays were used to confirm the interaction between TRIM46 and GPX4. RESULTS: High glucose (HG, 25 mM glucose) significantly suppressed cell growth, which could be reversed by the ferroptosis inhibitor, ferrostatin-1. HG treatment time-dependently induced ferroptosis in human retinal capillary endothelial cells (HRCECs) and induced TRIM46 expression. Lentiviral-mediated overexpression of TRIM46 decreased cell resistance against HG-induced ferroptosis, whereas knockdown showed the opposite effect. Administration of RSL3, a ferroptosis agonist, was able to reverse the protective effects of TRIM46 silencing. TRIM46 interacted with GPX4, an important enzyme that suppresses ferroptosis, and promoted GPX4 ubiquitination. Furthermore, lentiviral-mediated overexpression ofGPX4 ameliorated the effects of TRIM46 overexpression and conferred protection to cells against HG-induced ferroptosis. CONCLUSION: TRIM46 and GPX4 form a regulatory pathway that controls HG-induced ferroptosis of HRCECs. Inhibiting this pathway or sustaining the expression of GPX4 enables cells to resist damage caused by HG. We provide new mechanistic insight into the pathology of DR and identified TRIM46 and GPX4 as two molecular targets for the development of effective drugs for DR treatment.

Effects of rumen-protected creatine pyruvate on blood biochemical parameters and rumen fluid characteristics in transported beef cattle.

BACKGROUND: The fasting and stress associated with road transportation contributes to a lack of energy and a decline in the immune system of beef cattle. Therefore, it is essential for beef cattle to enhance energy reserves before transportation. Creatine pyruvate (CrPyr) is a new multifunctional nutrient that can provide both pyruvate and creatine, which are two intermediate products of energy metabolism. To investigate the effects of transport and rumen-protected (RP)-CrPyr on the blood biochemical parameters and rumen fluid characteristics of beef cattle, twenty male Simmental crossbred cattle (659 ± 16 kg) aged 18 months were randomly allocated to four groups (n = 5) using a 2 × 2 factorial arrangement with two RP-CrPyr supplemental levels (0 or 140 g/d) and two transport treatments (5 min or 12 h): T_CrPyr140, T_CrPyr0, NT_CrPyr140, and NT_CrPyr0. After feeding for 30 days, three cattle per treatment were slaughtered. RESULTS: Compared with nontransport, transport decreased the total antioxidant capacity, catalase activity, contents of IgA, interferon γ, interleukin-1ß (IL-1ß), and IL-6 in serum, and the amounts of total volatile fatty acids (TVFA), acetate, and butyrate in rumen (P < 0.05); increased the serum lipopolysaccharide (LPS) level, contents of rumen LPS and ammonia nitrogen (P < 0.05). RP-CrPyr supplementation decreased the levels of cortisol and LPS in serum and the butyrate concentration in the rumen of beef cattle compared with those in the unsupplemented groups (P < 0.05). RP-CrPyr and transport interaction had a significant effect on the contents of serum tumour necrosis factor-α, IL-6, LPS, ruminal pH, acetate content, and acetate/propionate (P < 0.05). In terms of ruminal bacterial composition, group T_CrPyr0 increased the Prevotella genus abundance compared with group NT_CrPyr0 (P < 0.05), while group T_CrPyr140 increased Firmicutes phylum abundance and decreased Bacteroidetes phylum and genus Prevotella abundance compared with group T_CrPyr0 (P < 0.05). Moreover, Bacteroidetes was positively correlated with serum LPS. CONCLUSIONS: These results indicated that dietary supplementation with RP-CrPyr might be beneficial to alleviate transport stress by decreasing serum cortisol and LPS levels and promoting the restoration of the rumen natural flora.

Hyperrefective foci in diabetic macular edema with subretinal fluid: association with visual outcomes after anti-VEGF treatment.

INTRODUCTION: To describe the hyperreflective foci (HRF) on optical coherence tomography angiography (OCTA) in diabetic macular edema (DME) with subretinal fluid (SRF) and explore the association of HRF in the outer retina with photoreceptor integrity and visual outcomes after anti-vascular endothelial growth factor (anti-VEGF) treatment. METHODS: We retrospectively reviewed 46 eyes (36 patients) with DME treated with anti-VEGF drugs. The following parameters, including best-corrected visual acuity (BCVA), central macular thickness (CMT), the height of subretinal fluid (SRF), the number of HRF in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and the outer retina, as well as the integrity of external limiting membrane (ELM) and ellipsoid zone (EZ), were evaluated and compared between the baseline and after 2 monthly injections of anti-VEGF drugs. The relationship between the HRF in the outer retina and the integrity of ELM and EZ, as well as BCVA was analyzed. RESULTS: BCVA was significantly improved in DME after anti-VEGF treatment, however, for the subgroup of DME patients with SRF, visual acuity remained unchanged after anti-VEGF treatment (p < 0.05 vs. p = 0.375). The number of HRF (p < 0.05), CMT (p ＜ 0.001), and SRF height (p ＜ 0.001) were significantly reduced, accompanied with partial restoration of ELM and EZ integrity after anti-VEGF injection. The HRF in the outer retina was correlated with the final ELM (p = 0.036) and EZ (p = 0.004) status. The final BCVA was significantly better in eyes with intact ELM (p = 0.002) and EZ at final visit (p< 0.001). CONCLUSION: The number of HRF in outer retina was negatively associated with the microstructural restoration of ELM and EZ, as well as the visual outcome in DME patients with SRF after anti-VEGF treatment.

Melatonin maintains inner blood-retinal barrier via inhibition of p38/TXNIP/NF-κB pathway in diabetic retinopathy.

The pathophysiology of diabetic retinopathy (DR) was complex. Under hyperglycemic conditions, the release of proinflammatory cytokines and the adhesion of leukocytes to retinal capillaries contribute to endothelial damage and the subsequent increase in vascular permeability resulting in macular edema. Melatonin, produced in the retina to regulate redox reactions and dopamine metabolism, plays protective roles against inflammation and oxidative stress. Considering its anti-inflammatory and antioxidative properties, melatonin was speculated to exert beneficial effects in DR. In this study, we characterized the protective effects of melatonin on the inner blood-retinal barrier (iBRB), as well as the possible mechanisms in experimental DR. Results showed that in diabetic rat retinas, the leakage of iBRB and the expression of inflammatory factors (VEGF, TNF-α, IL-1ß, ICAM-1, and MMP9) increased dramatically, while the expression of tight junction proteins (ZO-1, occludin, JAM-A, and claudin-5) decreased significantly. The above changes were largely ameliorated by melatonin. The in vivo data were confirmed in vitro. In addition, the protein expressions of p38 MAPK, NF-κB, and TXNIP were upregulated significantly in diabetes and were downregulated following melatonin treatment. Melatonin could maintain the iBRB integrity by upregulating the expression of tight junction proteins via inhibiting p38/TXNIP/NF-κB pathway, thus decreasing the production of inflammatory factors. This study may shed light on the development of melatonin-based DR therapy.

Silencing Nogo-B improves the integrity of blood-retinal barrier in diabetic retinopathy via regulating Src, PI3K/Akt and ERK pathways.

OBJECTIVE: To examine the mechanisms of Nogo-B (RTN4B) in the protection of blood-retinal barrier in experimental diabetic retinopathy. METHODS: The level of Nogo-B in vitreous and plasma samples was detected with ELISA. Diabetes was induced in Sprague-Dawley rats with intraperitoneal injection of streptozotocin. The rats were injected intravitreally with adeno-associated virus (AAV) for knockdown the expression of Nogo-B in retina or/and as AAV negative control. The permeability of blood-retinal barrier was detected with Rhodamine-B-dextran leakage assay. The expressions of Nogo-B, junctional proteins, inflammatory factors and signaling pathways were examined with Western blot and quantitative real-time PCR. RESULTS: Nogo-B expression was significantly upregulated in clinical samples and experimental diabetic rat models. Under normal condition, Nogo-B knockdown resulted in the increased permeability of retinal blood vessels. In diabetic rat retinas, the vascular leakage was increased significantly, which was partially decreased by Nogo-B knockdown through increasing p/t-Src (Tyr529) and p/t-Akt (Ser473), and decreasing p/t-ERK1/2. CONCLUSION: Nogo-B was increased in diabetic retinopathy and silencing Nogo-B is a promising therapy for diabetic retinopathy.

Dihydroartemisinin ameliorates retinal vascular dysfunction in diabetes mellitus via the FASN/Kmal-mTOR/SREBP1 feedback loop.

Microvascular dysfunction is the primary aetiology of visual impairment caused by diabetic retinopathy (DR). Dihydroartemisinin (DHA), the active metabolite of the antimalarials artemisinins, exhibits antiangiogenic properties in numerous diseases. Here, we investigated the function and mechanisms of DHA as a vasculoprotective agent in DR. DHA exerted its protective effect on vascular injuries in diabetic mice and inhibited cell proliferation and tube formation in human retinal microvascular endothelial cells by decreasing the level of fatty acid synthase (FASN), enhancing the malonylation of mechanistic target of rapamycin (mTOR) at lysine 1218 (K1218) and attenuating the activation of mTOR complex 1 (mTORC1). Impressively, a chemosynthetic small interfering RNA against FASN and mutagenesis of K1218 of mTOR showed therapeutic potential in suppressing cell proliferation and tube formation induced by high glucose. Notably, suppression of mTORC1 kinase activity further inhibited FASN by reducing p70S6K phosphorylation to subsequently reduce the expression of sterol regulatory element binding protein 1, which interacted directly with the FASN promoter at nucleotide positions -64 and -55. In conclusion, our study elucidated the promising effects of FASN and malonylation on vascular injuries of DR and indicated the great potential of DHA as a therapeutic approach.

The Role of the AIMP1 Pathway in Diabetic Retinopathy: AIMP1-Targeted Intervention Study in Diabetic Retinopathy.

INTRODUCTION: We characterized the role of aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) in retinal inflammation and apoptosis regulation, both in vivo and in vitro. In addition, we used clinical specimens to show the relationship between AIMP1 and the development of diabetic retinopathy (DR). OBJECTIVE: To elucidate the role of AIMP1 in DR. METHODS: A diabetic AIMP1-specific knockout (KO) C57 mouse model was used. Human retinal microvascular endothelial cells (HRMECs) were incubated with normal glucose, high glucose (HG), and HG + AIMP1-small interfering RNA (siRNA). The expression of AIMP1 and relative inflammatory and apoptotic cytokines in diabetic mice retina and HRMECs were measured using Western blotting and polymerase chain reaction. The apoptosis of HRMECs was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The levels of AIMP1 in the vitreous humor and serum were determined using ELISA. Possible correlations between the intravitreal level of AIMP1 and blood glucose, glycosylated hemoglobin HbA1c, intravitreal levels of IL-1ß, and caspase-3 were determined. RESULTS: The expression of inflammatory and apoptotic proteins was inhibited in the AIMP1 KO mice and HRMECs incubated with AIMP1-siRNA. The apoptosis of HRMECs was decreased in the AIMP1-siRNA group. The intravitreal level of AIMP1 in DR patients was significantly higher than that in nondiabetic patients (p < 0.01). There was a positive correlation between intravitreal AIMP1 and HbA1c and intravitreal IL-1ß and caspase-3 (p < 0.05). CONCLUSIONS: HG induced increased expression of AIMP1 in HRMECs and retinas from diabetic C57 mice, thereby increasing the expression of inflammatory and apoptotic cytokines, which promoted DR progression. A decrease in AIMP1 expression prevented the development of DR by inhibiting the activation of inflammatory and apoptotic signaling. Therefore, AIMP1 is an effective interfering target for the prevention and treatment of DR.

High-density diet improves growth performance and beef yield but affects negatively on serum metabolism and visceral morphology of Holstein steers.

The objective of this study was to evaluate the effect of different dietary densities on growth performance, carcass characteristics, meat quality, serum metabolism, ruminal papillae morphology and liver injuries of steers. For this purpose, a total of eighteen Holstein steers were randomly fed one of the three diets: high energy and protein diet (H), standard energy and protein diet (C), and low energy and protein diet (L) for 11 months fattening with three-step finishing strategy. Steers fed with H diet had higher (p < .05) average daily gain, feed efficiency, hot carcass weight, serum aspartate aminotransferase to alanine aminotransferase ratio, and monounsaturated fatty acids along with continuous low ruminal pH value, severer hepatic steatosis and ruminal papillae parakeratosis. Meanwhile, steers fed L diet increased the proportion of C20:0, C22:6n-3, saturated fatty acids and n-3 polyunsaturated fatty acids along with lower n-6 to n-3 ratio in longissimus dorsi muscle as compared to that of steers fed H diet. Dietary densities did not influence (p > .10) proximate nutrients and sensory characteristics of beef. The present study indicates that Holstein steers could achieve better growth and carcass performance under high-density diet, whereas they are under threat of visceral injuries and metabolic disorders. This study gives comprehensive relationship between productivity and animal health and suggests that a proper diet should be adopted for fattening Holstein steers in consideration of both beef quality and quantity and animal health.

7-Ketocholesterol disturbs RPE cells phagocytosis of the outer segment of photoreceptor and induces inflammation through ERK signaling pathway.

7-Ketocholesterol (7KCh), an oxidized form of cholesterol, is present at a high level in drusen and has been believed to play a role in the pathogenesis of age-related macular degeneration (AMD). Therefore, we developed a rat model to study the direct impact of 7KCh on retina. We delivered 7KCh to the rat retina by intravitreal injection using hydroxypropyl-ß-cyclodextrin as a vehicle. We observed that 7KCh mainly deposited in the retinal pigment epithelial (RPE) cells and induced marked photoreceptor apoptosis. Transmission electron microscope examination demonstrated cytoplasmic vacuoles in RPE cells and the microvilli detached from the outer segment after 7KCh treatment. In vitro experiments also revealed that RPE cells could take up 7KCh in culture. Moreover, 7KCh up-regulated IL-1ßmRNA, TNF-αmRNA, IL-6 mRNA, and IL-1ß secretion of RPE. U0126, a MEK1/2 inhibitor, down regulated the expression of these inflammation factors. Our findings may help elucidate the potential role of 7KCh in the pathogenesis of AMD.

Rumen fermentation, intramuscular fat fatty acid profiles and related rumen bacterial populations of Holstein bulls fed diets with different energy levels.

The dietary energy level can affect ruminal microbiota, and further can affect rumen fermentation and fatty acid (FA) synthesis. In this study, we investigated the correlations between rumen bacteria and rumen fermentation parameters and intramuscular fat (IMF) FA profiles of Holstein bulls fed different energy diets via using 16S rRNA high-throughput sequencing and gas chromatography. The results showed that the improved dietary energy increased propionate, isobutyrate and isovalerate concentrations, and decreased acetate concentration and the acetate/propionate ratio. Increased dietary energy improved beef IMF content and had no effects on cooking loss, Warner-Bratzler shear force, water holding capacity, or drip loss. Increase dietary energy also decreased C18:0, C18:1 trans, C22:0, C20:3n-3, C22:6n-3, and saturated fatty acids, and increased C18:1 cis-9, C18:2n-6 trans, and monounsaturated fatty acids. 16S rRNA high-throughput sequencing analysis revealed that dietary energy had no impact on alpha diversity or the relative abundance of most of the major phyla and genera in rumen. In all dietary treatment groups, the dominant microbial phyla were Bacteroidetes (54.91%) and Firmicutes (33.60%), and the major microbial genus was Prevotella_1 (21.75%). Improved dietary energy decreased the abundances of Firmicutes and Tenericutes and increased that of Proteobacteria at the phylum level, while decreasing those of RC9_gut_group, and increased Prevotellaceae_UCG-004, Phocaeicola, Acetitomaculum, Lachnoclostridium_1, Prevotellaceae_UCG-003, and Anaerovibrio at the genus level. Spearman correlation analysis showed high correlations between rumen bacteria and fermentation parameters/IMF FA profiles. Collectively, our data indicated that dietary energy affects the ruminal microbiota, and further affects ruminal fermentation and IMF FA composition.

Time-lapse angiography of the ocular fundus: a new video-angiography.

BACKGROUND: Ocular fundus angiography is an indispensable component of the tests utilized for fundus diseases. Dynamic angiography results can provide additional information; however, many difficulties remain. In this study, we introduce a modified method, time-lapse angiography (TLA), to dynamically present imaging results. METHODS: TLA, combining time-lapse photography and fundus angiography (using Heidelberg retina angiography II, Germany), includes pre-photographing and post- photosynthesis and ultimately produces a video that is approximately 15 s in length. RESULTS: Four typical videos in the article showed the characteristics of TLA, including a short and rapid but continuous and integral presentation, highly valid information, high definition, etc. CONCLUSIONS: TLA is beneficial for the diagnosis of diseases and the assessment of progression and is convenient for peer communication, patient interpretation, and student education. The application of time-lapse photography in ocular fundus angiography is a monumental and innovative attempt.

Inverted internal limiting membrane flap technique for large macular holes: a systematic review and single-arm meta-analysis.

PURPOSE: The aim of this systematic review was to determine the anatomical outcome-macular hole (MH) closure rate-and functional outcome-visual acuity (VA) improvement rate-of the inverted internal limiting membrane (ILM) flap technique for large MH. METHODS: We searched for articles on large MH (> 400 µm) treated with inverted ILM flap technique in databases as of December 1, 2017. And single-arm meta-analysis was performed for the primary outcome of MH closure rate and the secondary outcome of VA improvement rate. In addition, we searched and pooled studies treating large MH with indocyanine green (ICG)-assisted ILM peeling as the reference. R software (version 2.15.2) was used for analysis. RESULTS: This review includes eight studies that used inverted ILM flap technique to treat large MH (> 400 µm). Based on the single-arm meta-analysis performed in R 2.15.2, the pooled MH closure rate and VA improvement rate following inverted ILM flap technique were 95% (95% CI, 88 to 98%) and 75% (95% CI, 62 to 85%), respectively, in fixed-effect models. There was no substantial methodological heterogeneity. In addition, we selected four studies on large MH treated with ICG-assisted ILM peeling as the reference. The fixed-model pooled MH closure rate and VA improvement rate were 87% (95% CI, 79 to 92%) and 57% (95% CI, 46 to 68%), respectively. CONCLUSIONS: Inverted ILM flap technique should be an effective and safe method for treating large MH, with high closure rates and good VA improvement. However, further studies in large randomized controlled trials on minimizing surgical complications and understanding the mechanism of this technique are necessary.

Effect of increased dietary crude protein levels on production performance, nitrogen utilisation, blood metabolites and ruminal fermentation of Holstein bulls.

OBJECTIVE: This study investigated the effect of dietary crude protein (CP) supplementation on nutrient intake, nitrogen (N) utilisation, blood metabolites, ruminal fermentation and growth performance of young Holstein bulls. METHODS: Twenty-one young bulls weighing 277±11.2 kg were equally divided into three groups and were offered diets formulated with low CP (LCP; 10.21% CP and 4.22% rumen degradable protein [RDP]), medium CP (MCP; 12.35% CP and 5.17% RDP) and high CP (HCP; 14.24% CP and 6.03% RDP). Yellow corn silage was used as a unique forage source and was mixed with concentrate. This mixed feed was given ad libitum to the young bulls included in the study. RESULTS: Results showed that CP intake, blood urea nitrogen, N intake, total N excretion and N balance increased linearly with an increase in dietary CP level (p<0.05). However, no significant difference was observed in nutrient digestibility among the bulls receiving the different diets. Ruminal pH (p<0.05) and ammonia nitrogen (NH3-N) concentration (p<0.01) were significantly higher in the bulls receiving the MCP and HCP diets than in those receiving the LCP diet. The bulls receiving the HCP diet showed significantly higher ruminal bacterial protein level, propionate, acetate and total volatile fatty acid (TVFA) concentrations than bulls receiving the LCP diet (p<0.05). Moreover, dietary CP level exerted a significant positive effect on the final body weight, average daily gain and gain-to-feed ratio of the bulls (p<0.05). CONCLUSION: High dietary CP level is optimal for achieving maximum growth and high profitability without exerting a negative effect on the physiology of growing Holstein bulls.