In Search of Differential Inhibitors of Aldose Reductase

Aldose reductase, classified within the aldo-keto reductase family as AKR1B1, is an NADPH dependent enzyme that catalyzes the reduction of hydrophilic as well as hydrophobic aldehydes. AKR1B1 is the first enzyme of the so-called polyol pathway that allows the conversion of glucose into sorbitol, which in turn is oxidized to fructose by sorbitol dehydrogenase. The activation of the polyol pathway in hyperglycemic conditions is generally accepted as the event that is responsible for a series of long-term complications of diabetes such as retinopathy, cataract, nephropathy and neuropathy. The role of AKR1B1 in the onset of diabetic complications has made this enzyme the target for the development of molecules capable of inhibiting its activity. Virtually all synthesized compounds have so far failed as drugs for the treatment of diabetic complications. This failure may be partly due to the ability of AKR1B1 to reduce alkenals and alkanals, produced in oxidative stress conditions, thus acting as a detoxifying agent. In recent years we have proposed an alternative approach to the inhibition of AKR1B1, suggesting the possibility of a differential inhibition of the enzyme through molecules able to preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. The rationale and examples of this new generation of aldose reductase differential inhibitors (ARDIs) are presented

Pathways of 4-hydroxy-2-nonenal detoxification in a human astrocytoma cell line

One of the consequences of the increased level of oxidative stress that often characterizes the cancer cell environment is the abnormal generation of lipid peroxidation products, above all 4-hydroxynonenal. The contribution of this aldehyde to the pathogenesis of several diseases is well known. In this study, we characterized the ADF astrocytoma cell line both in terms of its pattern of enzymatic activities devoted to 4-hydroxynonenal removal and its resistance to oxidative stress induced by exposure to hydrogen peroxide. A comparison with lens cell lines, which, due to the ocular function, are normally exposed to oxidative conditions is reported. Our results show that, overall, ADF cells counteract oxidative stress conditions better than normal cells, thus confirming the redox adaptation demonstrated for several cancer cells. In addition, the markedly high level of NADP+-dependent dehydrogenase activity acting on the glutahionyl-hydroxynonanal adduct detected in ADF cells may promote, at the same time, the detoxification and recovery of cell-reducing power in these cells

A Fast, Memory-Efficient Alpha-Tree Algorithm using Flooding and Tree Size Estimation

The alpha-tree represents an image as hierarchical set of alpha-connected components. Computation of alpha-trees suffers from high computational and memory requirements compared with similar component tree algorithms such as max-tree. Here we introduce a novel alpha-tree algorithm using 1) a flooding algorithm for computational efficiency and 2) tree size estimation (TSE) for memory efficiency. In TSE, an exponential decay model was fitted to normalized tree sizes as a function of the normalized root mean squared deviation (NRMSD) of edge-dissimilarity distributions, and the model was used to estimate the optimum memory allocation size for alpha-tree construction. An experiment on 1256 images shows that our algorithm runs 2.27 times faster than Ouzounis and Soille's thanks to the flooding algorithm, and TSE reduced the average memory allocation of the proposed algorithm by 40.4%, eliminating unused allocated memory by 86.0% with a negligible computational cost

The Impact of Venous Thromboembolism on Upper Tract Urothelial Carcinomas Undergoing Open or Minimally Invasive Radical Nephroureterectomy in the USA: Perioperative Outcomes and Health Care Costs from Insurance Claims Data

Background and objective: Venous thromboembolism (VTE) is a significant predictor of worse postoperative morbidity in cancer surgeries. No data have been available for patients with preoperative VTE and upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). Our aim was to assess the impact of a preoperative VTE diagnosis on perioperative outcomes in the RNU context. Methods: Patients aged 18 yr or older with a UTUC diagnosis undergoing RNU were identified in the Merative Marketscan Research deidentified databases between 2007 and 2021. Multivariable logistic regression adjusted by relevant perioperative confounders was used to investigate the association between a diagnosis of VTE prior to RNU and 90-d complication rates, postoperative VTE, rehospitalization, and total costs. A sensitivity analysis on VTE severity (pulmonary embolism [PE] and/or deep venous thrombosis [DVT]) was examined. Key findings and limitations: Within the investigated cohort of 6922 patients, history of any VTE preceding RNU was reported in 568 (8.21%) cases, including DVT (n = 290, 51.06%), PE (n = 169, 29.75%), and superficial VTE (n = 109, 19.19%). The history of VTE before RNU was predictive of higher rates of complications, the most prevalent being respiratory complications (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.43–2.22). Preoperative VTE was found to be associated with an increased risk of VTE following RNU (OR: 14.3, 95% CI: 11.48–17.82), higher rehospitalization rates (OR: 1.26, 95% CI 1.01–1.56) other than home discharge status (OR: 1.44, 95% CI: 1.18–1.77), and higher costs (OR 1.42, 95% CI: 1.20–1.68). Limitations include the retrospective nature and the use of an insurance database that relies on accurate coding and does not include information such as pathologic staging. Conclusions and clinical implications: The presented findings will contribute to the counseling process for patients. These patients may benefit from enhanced pre/postoperative anticoagulation. More research is needed before the following results can be used in the clinical setting. Patient summary: Patients aged 18 yr or older with an upper tract urothelial carcinoma (UTUC) diagnosis undergoing radical nephroureterectomy (RNU) were identified in the Merative Marketscan Research deidentified databases between 2007 and 2021. Multivariable logistic regression adjusted by relevant perioperative confounders was used to investigate the association between a diagnosis of venous thromboembolism (VTE) prior to RNU and 90-d complication rates, postoperative VTE, rehospitalization, and total costs. A sensitivity analysis on VTE severity (pulmonary embolism and/or deep venous thrombosis) was examined. The presented findings will contribute to the counseling of patients with UTUC and preoperative VTE

Prediction of complications in radical prostatectomy prostate cancer patients: simulated annealing versus co-morbidity indexes

Background: The Deyo/Charlson co-morbidity index (CCI) and Klabunde co-morbidity index (KCI) co-morbidity indexes represent outdated indexes when the endpoint of complications after radical prostatectomy (RP) is considered. A novel group of co-morbidities derived from International Classification of Diseases-9 diagnostic codes in a contemporary RP database could provide better accuracy. Research Design, Subjects and Measures: We relied on 20,484 patients with clinically localized non-metastatic prostate cancer treated with RP between 2000 and 2009 in the Surveillance, Epidemiology, and End Results-Medicare linked database. We examined 2 endpoints, namely, 90-day medical complication rate and 90-day surgical complication rate after RP. Simulated annealing (SA) was used to develop a novel co-morbidity index. Finally, the newly identified groups of co-morbid conditions were compared with the CO and Klabunde indexes. Results: Our SA identified 10 and 7 individual co-morbid conditions able to predict 90-day medical and surgical complications respectively. This novel model showed improved predictive accuracy over CCI and KCI for the 2 endpoints considered (respectively: 59.4 vs. 58.1 and 58.0% for medical complications, 58,0 vs, 56,8 and 56,7% for surgical complications). Conclusions: The newly defined groupings of co-morbid conditions resulted in better ability to predict the 2 endpoints of interest compared to CCI and KCI. However, the gain was marginal. This implies that better tools should be defined to more accurately predict these outcomes. (C) 2018 S. Karger AG, Basel</p

Development of a new comorbidity assessment tool for specific prediction of perioperative mortality in contemporary patients treated with radical cystectomy

PurposeThe Deyo adaptation of the Charlson comorbidity index (DaCCI), which relies on 17 comorbid condition groupings defined with 200 ICD-9-CM diagnostic codes, lacks specificity in the context of radical cystectomy (RC) for bladder cancer (BCa). We attempted to develop a new comorbidity assessment tool based on individual comorbid conditions and/or BCa manifestations for specific prediction of perioperative mortality after RC.MethodsWe relied on 7076 T1-T4 nonmetastatic BCa patients treated with RC between 2000 and 2009 in the SEER-Medicare linked database. Within the development cohort (n=6076), simulated annealing (SA) was used to identify (1) individual comorbid conditions, (2) individual BCa manifestations, and (3) the combination of both, that satisfy the criteria of maximal accuracy and parsimony for prediction of 90-day mortality after RC, after adjusting for several confounders. The accuracy of the newly identified groups of individual comorbid conditions and/or BCa manifestations and of the original DaCCI was tested in a 1000-patient external validation cohort.ResultsThe combination of six individual comorbid conditions and two individual BCa disease manifestations (type II diabetes without complications, anemia, chronic obstructive pulmonary disease, congestive heart failure, aortocoronary bypass, cardiomegaly, urinary tract infection, and hydronephrosis), and seven individual comorbid conditions (type II diabetes without complications, anemia, chronic obstructive pulmonary disease, congestive heart failure, aortocoronary bypass, osteoarthrosis, and cardiomegaly) respectively showed 71.1 and 70.2% accuracy versus 68.0% for the original DaCCI.ConclusionsThese new approaches are specific to contemporary RC patients and represent simpler methods compared with the original DaCCI, without any compromise in accuracy

Investigation of the Exclusive ^{3}He(e,e'pn)p Reaction

Cross sections for the ^{3}He(e,e'pn)p reaction were measured for the first time at energy transfers of 220 and 270 MeV for several momentum transfers ranging from 300 to 450 MeV/c. Cross sections are presented as a function of the momentum of the recoil proton and the momentum transfer. Continuum Faddeev calculations using the Argonne V18 and Bonn-B nucleon-nucleon potentials overestimate the measured cross sections by a factor 5 at low recoil proton momentum with the discrepancy becoming much smaller at higher recoil momentum.Comment: 5, pages, 3 figure

The Italian National Register of infants with congenital hypothyroidism: twenty years of surveillance and study of congenital hypothyroidism

All the Italian Centres in charge of screening, diagnosis, and follow-up of infants with congenital hypothyroidism participate in the Italian National Registry of affected infants, which performs the nationwide surveillance of the disease. It was established in 1987 as a program of the Health Ministry and is coordinated by the Istituto Superiore di Sanità. The early diagnosis performed by the nationwide newborn screening programme, the prompt treatment and the appropriate clinical management of the patients carried out by the Follow-up Centres, and the surveillance of the disease performed by the National Register of infants with congenital hypothyroidism are the components of an integrated approach to the disease which has been successfully established in our country

On Butterflies and Frankenstein: A Dynamic Theory of Regulation

There are major differences in regulation among various countries. A particular case is the difference between the EU and US in regulating biotechnology.We develop a firmal and dynamic model of government decision-making on regulation. We show that minor differences in consumer preferences can lead to important and persistent regulatory differences, and that temporary shocks to preferences can have long-lasting effects. This hysteresis in regulatory differences is shown to be caused by producer protectionist motives. We argue that this model may contribute to explain the difference between EU and US biotechnology regulation