Neurotization of the human cornea – A comprehensive review and an interim report

We present a comprehensive review of existing literature on surgical corneal neurotization (SCN) as a treatment modality for neurotrophic keratopathy (NK) with an interim report of seven cases where SCN was performed using the indirect approach and followed up till 18 months postoperatively to look for improvement in ocular surface, corneal sensations, and nerve regeneration by using in vivo confocal microscopy (IVCM). A literature search was performed for publications with keywords “corneal nerves,” “neurotization,” “esthesiometry,” “corneal anesthesia,” and “neurotrophic keratopathy.” All literature available till December 31, 2020 was reviewed and included to describe NK and its management options, particularly SCN. NK is associated with absent or reduced corneal sensations and is managed using a step-ladder algorithm ranging from medical management for symptomatic relief to surgical corneal neurotization. Both direct and indirect approaches of SCN have a favorable outcome with reduced surgical morbidity in the indirect approach using sural nerve graft. Post neurotization, corneal sensation recovery may take up to 3–6 months, while nerve regeneration on confocal microscopy can take as long as 6 months–1 year.     

Absorption and cleavage of enalapril,a carboxyl ester prodrug,in the rat intestine: in vitro,in situ intestinal perfusion and portal vein cannulation models

In recent years prodrug strategy has been used extensively to improve the pharmacokinetic properties of compounds exhibiting poor bioavailability. Mechanistic understanding of the absorption and the role of intestine and liver in the activation of oral prodrugs is crucial. Enalapril, a carboxyl ester prodrug, is reported to be metabolized by human carboxylesterase‐1 (CES1) but not by carboxylesterase‐2 (CES2) to its active metabolite enalaprilat. Further, it has been reported that the small intestines of both rat and human contain mainly CES2. The objective of this work was to understand whether enalapril remains unchanged as it is absorbed through the intestine into the portal circulation. This was evaluated using different intestinal preparations, an in situ intestinal perfusion experiment and a portal vein cannulated rat model. No turnover of enalapril was seen with commercial rat intestinal S9 and microsomes, but reasonable turnover was observed with freshly prepared rat intestinal and mucosal homogenate and S9. In the intestinal perfusion study, both enalapril and enalaprilat were observed in the mesenteric plasma with the data suggesting 32% hydrolysis of enalapril in the intestine. In the portal vein cannulated rat, about 51% of enalapril absorbed into intestine was converted to enalaprilat. Overall, it was demonstrated that even though enalapril has been shown to be a specific substrate for CES1, it is converted to enalaprilat to a significant extent in the intestine. Such experimental techniques can be applied by other scientific groups who are working on prodrugs to determine the region and extent of activation. Copyright © 2015 John Wiley & Sons, Ltd.     

Simultaneous determination of dacarbazine, its photolytic degradation product, 2-azahypoxanthine, and the metabolite 5-aminoimidazole-4-carboxamide in plasma and urine by high-pressure liquid chromatography.

A high-pressure liquid chromatographic method has been developed that allows for the simultaneous analysis of dacarbazine (DTIC), 5-aminoimidazole-4-carboxamide (AIC), and 2-azahypoxanthine (2-AZA) in plasma or urine. Plasma samples were prepared by ultrafiltration, whereas urine samples were filtered and diluted for analysis. Chromatography was done with a C18 mu Bondapak column along with gradient elution of the drugs. The mobile phase consisted of 100% 0.5 M sodium acetate (pH 7.0) and 25% acetonitrile in 0.05 M sodium acetate (pH 5.5) with detection at 280 nm. Linearity was observed up to 500 micrograms/ml for DTIC and up to 53 micrograms/ml for AIC and 2-AZA. The assay methodology was reproducible, with a lower limit of detection of 5.0, 0.5, and 0.5 micrograms/ml for DTIC, AIC, and 2-AZA, respectively. Interday and intraday coefficients of variation ranged between 4 to 14% and 2 to 16%, respectively. The analytical method was applied to the analysis of plasma and urine samples resulting from the isolation perfusion chemotherapy of an extremity with 57 mg of DTIC per kg in a patient with melanoma.     

Target identification of anticancer natural products using a chemical proteomics approach

In recent years, there has been a strong demand worldwide for the identification and development of potential anticancer drugs based on natural products. Natural products have been explored for their diverse biological and therapeutic applications from ancient time. In order to enhance the efficacy and selectivity and to minimize the undesired side effects of anti cancer natural products (ANPs), it is essential to understand their target proteins and their mechanistic pathway. Chemical proteomics is one of the most powerful tools to connect ANP target identification and quantification where labeling and non-labeling based approaches have been used. Herein, we have discussed the various strategies to systemically develop selective ANP based chemical probes to characterise their specific and non-specific target proteins using a chemical proteomic approach in various cancer cell lysates.

Natural products are one of the most effective therapeutic candidates in cancer treatment. In this review, we briefly discuss the target identification of anticancer natural products in different cancer cell lines through a chemical proteomics approach.     

Future Directions in Patellofemoral Imaging and 3D Modeling

Purpose of ReviewPatellofemoral instability involves complex, three-dimensional pathological anatomy. However, current clinical evaluation and diagnosis relies on attempting to capture the pathology through numerous two-dimensional measurements. This current review focuses on recent advancements in patellofemoral imaging and three-dimensional modeling.Recent FindingsSeveral studies have demonstrated the utility of dynamic imaging modalities. Specifically, radiographic patellar tracking correlates with symptomatic instability, and quadriceps activation and weightbearing alter patellar kinematics. Further advancements include the study of three-dimensional models. Automation of commonly utilized measurements such as tibial tubercle–trochlear groove (TT-TG) distance has the potential to resolve issues with inter-rater reliability and fluctuation with knee flexion or tibial rotation. Future directions include development of robust computational models (e.g., finite element analysis) capable of incorporating patient-specific data for surgical planning purposes.SummaryWhile several studies have utilized novel dynamic imaging and modeling techniques to enhance our understanding of patellofemoral joint mechanics, these methods have yet to find a definitive clinical utility. Further investigation is required to develop practical implementation into clinical workflow.     

Studies on gamma-glutamyl transpeptidase of human urine.

A simple and rapid method suitable for clinical laboratories, for the removal of the inhibitors in urine of gamma-glutamyl transpeptidase activity, using an ion-retardation resin, is described. Gel chromatography of urine resulted in appreciable loss of the enzyme activity. Freezing at -5 degrees C and thawing, did not affect the activity of the enzyme. Dimethyl sulfoxide and polyvinyl pyrrolidone up to a creatinine and NaCl at levels found in normal urine did not inhibit the transpeptidase.     

Off-pump coronary artery bypass grafting in patients with significant left ventricular dysfunction

Objective  Off-pump coronary artery bypass grafting (OPCAB) is known to preserve left ventricular function better than conventional coronary artery bypass grafting (CCAB). This study was carried out to investigate the safety, feasibility and efficacy of off-pump coronary artery bypass grafting in patients with significant left ventricular dysfunction. Methods  Three hundred and eighty eight consecutive patients with preoperative left ventricular ejection fraction ≤ 39% who underwent CABG between January 2001 through October 2007 were included in this retrospective study. Two hundred and eleven patients were operated by off-pump technique (group 1) and 178 patients were operated by on-pump technique (CCAB) (group 2). The postoperative outcomes were analyzed. Of these, 204 (52.57%) patients were diabetics, 355 (91.49%) patients had documented prior myocardial infarction, 316 (81.44%) patients were in canadian cardiovascular society(CCS) class III and 47 (12.11%) patients were in CCS class IV. Results  There was no significant difference in the number of grafts per patient between the two groups [group 1 3.02 ± 0.76 vs group 2 3.18 ± 0.72 (P=0.07) and the index of completeness of revascularization was comparable [1.08 ± 0.08) (OPCAB) vs 1.04 ± 0.06 (CCAB) (p=0.52)] The left internal thoracic artery was anastomosed to left anterior descending artery in 98% of patients. Operative mortality was 2.8% (6 deaths) following OPCAB and 3.93% (7 deaths) following CCAB (p=0746). Postoperative usage of IABP support was higher in CCAB group (12 patients vs 4 patients: P<0.03) and usage of moderate or higher doses of inotropic support was also higher in the conventional group (p<0.0006). More worsening of preexisting renal insufficiency was observed in CCAB group (p=0.01) and no significant difference in the incidence of atrial fibrillation was observed between the groups. Conclusions  Off-pump coronary artery bypass grafting is feasible and safe in patients with depressed left ventricular function and the postoperative morbidity was less in OPCAB group compared to on-pump group.     

Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and target-based approach

Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values <10 microM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.