Longitudinal Characterization of the Gut Microbiota in the Diabetic ZDSD Rat Model and Therapeutic Potential of Oligofructose.

The complex development of type 2 diabetes (T2D) creates challenges for studying the progression and treatment of the disease in animal models. A newly developed rat model of diabetes, the Zucker Diabetic Sprague Dawley (ZDSD) rat, closely parallels the progression of T2D in humans. Here, we examine the progression of T2D and associated changes in the gut microbiota in male ZDSD rats and test whether the model can be used to examine the efficacy of potential therapeutics such as prebiotics, specifically oligofructose, that target the gut microbiota. Bodyweight, adiposity, and fed/fasting blood glucose and insulin were recorded over the course of the study. Glucose and insulin tolerance tests were performed, and feces collected at 8, 16, and 24 weeks of age for short-chain fatty acids and microbiota analysis using 16s rRNA gene sequencing. At the end of 24 weeks of age, half of the rats were supplemented with 10% oligofructose and tests were repeated. We observed a transition from healthy/nondiabetic to prediabetic and overtly diabetic states, via worsened insulin and glucose tolerance and significant increases in fed/fasted glucose, followed by a significant decrease in circulating insulin. Acetate and propionate levels were significantly increased in the overt diabetic state compared to healthy and prediabetic. Microbiota analysis demonstrated alterations in the gut microbiota with shifts in alpha and beta diversity as well as alterations in specific bacterial genera in healthy compared to prediabetic and diabetic states. Oligofructose treatment improved glucose tolerance and shifted the cecal microbiota of the ZDSD rats during late-stage diabetes. These findings underscore the translational potential of ZDSD rats as a model of T2D and highlight potential gut bacteria that could impact the development of the disease or serve as a biomarker for T2D. Additionally, oligofructose treatment was able to moderately improve glucose homeostasis.

Osteokeratoprosthesis Using Tibial Bone: Surgical Technique and Outcomes.

PURPOSE: To analyze the anatomical and functional results of keratoprosthesis using tibial bone autograft. METHODS: We reviewed 113 charts of patients who underwent tibial bone osteokeratoprothesis implantation at the Centro de Oftalmologia Barraquer. Kaplan-Meier survival curves with 95% confidence interval were calculated for functional success, defined as best corrected visual acuity (BCVA) ≥0.05 on the decimal scale, and for anatomical success, defined as retention of the keratoprosthesis lamina. Multivariate analysis was used to test the impact of clinical factors on anatomical and functional survival rates. RESULTS: Based on Kaplan-Meier analyses, tibial bone keratoprosthesis 5-year and 10-year anatomical survival rates were 69.5% and 53.5%, respectively. Functional survival rate at 5 years was 33% and at 10 years was 19.2%. Considering primary diagnosis, chemical burn had better anatomical and functional survival rates than autoimmune or infectious diseases. Patient age did not have a significant effect on keratoprosthesis survival rates. About 48.7% of the patients who underwent surgery had complications: keratoprosthesis extrusion, glaucoma, retinal detachment and buccal mucosa necrosis were the most frequent ones. CONCLUSION: Half of the patients with tibial bone KPro had retained the keratoprosthesis after 10 years post-surgery and one-fifth of them had visual acuity of 0.05 or better at the same period. Considering that these patients have no other way to recover their vision either because they have no canine tooth or their buccal or dental conditions are not adequate for OOKP, this modified surgery is their only hope.

Progression of Cutaneous Vitiligo in a Patient with Large Posterior Choroidal Melanoma: A Case Report.

BACKGROUND/AIMS: The aim of our study was to report a case of progression of cutaneous vitiligo after large posterior choroidal melanoma diagnosis. METHODS: The clinical history, fundus findings and histopathological features suggest the diagnosis of cutaneous vitiligous progression after a diagnosis of large posterior choroidal melanoma. RESULTS: A 30-year-old female, with a personal history of cutaneous vitiligo for 12 years, was diagnosed with choroidal melanoma 18 months previously. The cutaneous vitiligo had progressed over her back, body and arms during the preceding 3 years. She refused treatment because she was in her 28th week of pregnancy. When she came to our clinic her visual symptoms had worsened, and the fundus examination showed a melanocytic choroidal mass. After confirming that there was no extraocular extension, she was treated with enucleation. A histopathological study confirmed the choroidal melanoma diagnosis. CONCLUSION: The association between the progression of vitiligo and the diagnosis of uveal melanoma could be considered a good prognostic factor, as has been described in cases of cutaneous melanoma. A longer follow-up of these patients will allow us to confirm this association.

Therapeutic reactivation of mutant p53 protein by quinazoline derivatives.

PURPOSE: The human tumour suppressor protein p53 is mutated in nearly half of human tumours and most mutant proteins have single amino acid changes. Several drugs including the quinazoline derivative 1 (CP-31398) have been reported to restore p53 activity in mutant cells. The side chain of 1 contains a styryl linkage that compromises its stability and we wished to explore the activity of analogues containing more stable side chains. METHODS: Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G(1)-phase cell cycle arrest and by western blotting to determine expression of p21(WAF1). DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out. RESULTS: Screening of analogues for potentiation of radiation-induced G(1)-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53(R248Q) mutation, demonstrated that the (2-benzofuranyl)-quinazoline derivative 5 was among the most active of the analogues. Compound 5 showed similar effects in several other p53 mutant human tumour cell lines but not in a p53 null cell line. 5 also potentiated p21(WAF1) expression induced by radiation. DNA binding affinity was measured and found to correlate with p53 reactivation activity. Plasma concentrations of 5 in mice were sufficient to suggest in vivo activity and a small induced tumour growth delay (7 days) of NZM4 melanoma xenografts was observed. CONCLUSION: Compound 5 restores p53-like function to a human tumour cells lines expressing a variety of mutant p53 proteins, thus providing a basis for the design of further new drugs.