Rutin and Hesperidin Revoke the Hepatotoxicity Induced by Paclitaxel in Male Wistar Rats via Their Antioxidant, Anti-Inflammatory, and Antiapoptotic Activities.

Paclitaxel, one of the most effective chemotherapeutic drugs, is used to treat various cancers but it is exceedingly toxic when used long-term and can harm the liver. This study aimed to see if rutin, hesperidin, and their combination could protect male Wistar rats against paclitaxel (Taxol)-induced hepatotoxicity. Adult male Wistar rats were subdivided into 5 groups (each of six rats). The normal group was orally given the equivalent volume of vehicles for 6 weeks. The paclitaxel-administered control group received intraperitoneal injection of paclitaxel at a dose of 2 mg/Kg body weight twice a week for 6 weeks. Treated paclitaxel-administered groups were given paclitaxel similar to the paclitaxel-administered control group together with oral supplementation of rutin, hesperidin, and their combination at a dose of 10 mg/Kg body weight every other day for 6 weeks. The treatment of paclitaxel-administered rats with rutin and hesperidin significantly reduced paclitaxel-induced increases in serum alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transferase activities as well as total bilirubin level and liver lipid peroxidation. However, the levels of serum albumin, liver glutathione content, and the activities of liver superoxide dismutase and glutathione peroxidase increased. Furthermore, paclitaxel-induced harmful hepatic histological changes (central vein and portal area blood vessel congestion, fatty changes, and moderate necrotic changes with focal nuclear pyknosis, focal mononuclear infiltration, and Kupffer cell proliferation) were remarkably enhanced by rutin and hesperidin treatments. Moreover, the elevated hepatic proapoptotic mediator (caspase-3) and pro-inflammatory cytokine (tumor necrosis factor-α) expressions were decreased by the three treatments in paclitaxel-administered rats. The cotreatment with rutin and hesperidin was the most effective in restoring the majority of liver function and histological integrity. Therefore, rutin, hesperidin, and their combination may exert hepatic protective effects in paclitaxel-administered rats by improving antioxidant defenses and inhibiting inflammation and apoptosis.

Rutin and Hesperidin Alleviate Paclitaxel-Induced Nephrocardiotoxicity in Wistar Rats via Suppressing the Oxidative Stress and Enhancing the Antioxidant Defense Mechanisms.

Paclitaxel is a primary chemotherapy agent that displays antitumor activity against a variety of solid tumors. However, the clinical effectiveness of the drug is hampered by its nephrotoxic and cardiotoxic side effects. Thus, this investigation aimed at assessing the protective effects of rutin, hesperidin, and their combination to alleviate nephrotoxicity caused by paclitaxel (Taxol), cardiotoxicity in male Wistar rats, as well as oxidative stress. Rutin (10 mg/kg body weight), hesperidin (10 mg/kg body weight), and their mixture were given orally every other day for six weeks. Rats received intraperitoneal injections of paclitaxel twice weekly, on the second and fifth days of the week, at a dose of 2 mg/kg body weight. In paclitaxel-treated rats, the treatment of rutin and hesperidin decreased the elevated serum levels of creatinine, urea, and uric acid, indicating a recovery of kidney functions. The cardiac dysfunction in paclitaxel-treated rats that got rutin and hesperidin treatment also diminished, as shown by a substantial reduction in elevated CK-MB and LDH activity. Following paclitaxel administration, the severity of the kidney and the heart's histopathological findings and lesion scores were markedly decreased by rutin and hesperidin administration. Moreover, these treatments significantly reduced renal and cardiac lipid peroxidation while markedly increased GSH content and SOD and GPx activities. Thus, paclitaxel likely induces toxicity in the kidney and the heart by producing oxidative stress. The treatments likely countered renal and cardiac dysfunction and histopathological changes by suppressing oxidative stress and augmenting the antioxidant defenses. Rutin and hesperidin combination was most efficacious in rescuing renal and cardiac function as well as histological integrity in paclitaxel-administered rats.

Efeito de dentifrícios com alta concentração de flúor na remineralização de substrato dentário com cárie artificial / Effect of toothpaste with high fluoride concentration on remineralization of dental substrate with artificial caries

Introduction: fluoride toothpaste is widely used by the population. Objective: dentifrices with a high concentration of sodium fluoride and the presence of tricalcium phosphate were developed, providing additional protection to patients vulnerable to the development of caries. This study aimed to evaluate the influence of different dentifrices on the surface and internal hardness and enamel wear after artificial caries, pH cycling, and toothbrushing. Material and method: enamel blocks (4x4 mm) were obtained from 20 bovine teeth. The specimens were submitted to artificial caries lesion and then to pH cycling and brushing according to the dentifrice: Colgate Total 12 and Clinpro + Tricalcium Phosphate. Result: after this period, they were submitted to analysis of superficial and internal hardness and profilometry. Scanning Electron Microscopy (SEM) was performed. The data obtained were evaluated by one-way Analysis of Variance (ANOVA) to evaluate the mineral recovery and profilometry, and two-way repeated measures ANOVA to evaluate the superficial and internal hardness. Conclusion: analyzing the surface hardness, after caries induction, there was a significant reduction in hardness that was partially recovered regardless of the dentifrice used. For internal hardness, Clinpro obtained lower values on the control side and up to 90 micrometers on the test side. As for profilometry, Colgate Total 12 showed greater wear when compared to Clinpro. It was concluded that Clinpro promoted lower internal hardness, however, Colgate Total 12 resulted in greater surface wear of tooth enamel.

Introdução: dentifrícios fluoretados são amplamente utilizados pela população. Foram desenvolvidos dentifrícios com alta concentração de fluoreto de sódio e presença de tricálcio fosfato, fornecendo proteção adicional a pacientes vulneráveis ao desenvolvimento da cárie. Objetivo: o objetivo deste estudo foi avaliar a influência de diferentes dentifrícios na dureza superficial, interna e desgaste do esmalte após cárie artificial, ciclagem de pH e escovação. Material e método: blocos de esmalte (4x4 mm) foram obtidos a partir de 20 dentes bovinos. Os espécimes foram submetidos à lesão de cárie artificial e, em seguida, à ciclagem de pH e escovação de acordo com o dentifrício: Colgate Total 12 e Clinpro + Tricálcio Fosfato. Após este período, foram submetidos à análise de dureza superficial e interna e perfilometria. Foi realizada microscopia eletrônica de varredura. Resultado: os dados obtidos foram avaliados por ANOVA um critério para avaliar a recuperação mineral e perfilometria, ANOVA dois critérios medidas repetidas para avaliar a dureza superficial e interna. Conclusão: analisando a dureza superficial, após a indução da cárie houve uma redução significativa na dureza que foi parcialmente recuperada independente do dentifrício utilizado. Para dureza interna, Clinpro obteve valores menores no lado controle e até 90 micrômetros no lado teste. Quanto à perfilometria, o Colgate Total 12 apresentou maior desgaste quando comparado ao Clinpro. Concluiu-se que Clinpro promoveu menor dureza interna, porém, o Colgate Total 12 resultou em maior desgaste superficial do esmalte dentário.

Estimate of the Biological Dose in Hadrontherapy Using GATE.

For the evaluation of the biological effects, Monte Carlo toolkits were used to provide an RBE-weighted dose using databases of survival fraction coefficients predicted through biophysical models. Biophysics models, such as the mMKM and NanOx models, have previously been developed to estimate a biological dose. Using the mMKM model, we calculated the saturation corrected dose mean specific energy z1D* (Gy) and the dose at 10% D10 for human salivary gland (HSG) cells using Monte Carlo Track Structure codes LPCHEM and Geant4-DNA, and compared these with data from the literature for monoenergetic ions. These two models were used to create databases of survival fraction coefficients for several ion types (hydrogen, carbon, helium and oxygen) and for energies ranging from 0.1 to 400 MeV/n. We calculated α values as a function of LET with the mMKM and the NanOx models, and compared these with the literature. In order to estimate the biological dose for SOBPs, these databases were used with a Monte Carlo toolkit. We considered GATE, an open-source software based on the GEANT4 Monte Carlo toolkit. We implemented a tool, the BioDoseActor, in GATE, using the mMKM and NanOx databases of cell survival predictions as input, to estimate, at a voxel scale, biological outcomes when treating a patient. We modeled the HIBMC 320 MeV/u carbon-ion beam line. We then tested the BioDoseActor for the estimation of biological dose, the relative biological effectiveness (RBE) and the cell survival fraction for the irradiation of the HSG cell line. We then tested the implementation for the prediction of cell survival fraction, RBE and biological dose for the HIBMC 320 MeV/u carbon-ion beamline. For the cell survival fraction, we obtained satisfying results. Concerning the prediction of the biological dose, a 10% relative difference between mMKM and NanOx was reported.

Monte Carlo simulations of nanodosimetry and radiolytic species production for monoenergetic proton and electron beams: Benchmarking of GEANT4-DNA and LPCHEM codes.

PURPOSE: In hadrontherapy, biophysical models can be used to predict the biological effect received by cancerous tissues and organs at risk. The input data of these models generally consist of information on nano/micro dosimetric quantities and, concerning some models, reactive species produced in water radiolysis. In order to fully account for the radiation stochastic effects, these input data have to be provided by Monte Carlo track structure (MCTS) codes allowing to estimate physical, physico-chemical, and chemical effects of radiation at the molecular scale. The objective of this study is to benchmark two MCTS codes, Geant4-DNA and LPCHEM, that are useful codes for estimating the biological effects of ions during radiation therapy treatments. MATERIAL AND METHODS: In this study we considered the simulation of specific energy spectra for monoenergetic proton beams (10 MeV) as well as radiolysis species production for both electron (1 MeV) and proton (10 MeV) beams with Geant4-DNA and LPCHEM codes. Options 2, 4, and 6 of the Geant4-DNA physics lists have been benchmarked against LPCHEM. We compared probability distributions of energy transfer points in cylindrical nanometric targets (10 nm) positioned in a liquid water box. Then, radiochemical species (· OH, e aq - ${\rm{e}}_{{\rm{aq}}}^ - $ , H 3 O + , H 2 O 2 ${{\rm{H}}_3}{{\rm{O}}^ + },{\rm{\;}}{{\rm{H}}_2}{{\rm{O}}_2}$ , H2 , and O H - ) ${\rm{O}}{{\rm{H}}^ - }){\rm{\;}}$ yields simulated between 10-12 and 10-6 s after irradiation are compared. RESULTS: Overall, the specific energy spectra and the chemical yields obtained by the two codes are in good agreement considering the uncertainties on experimental data used to calibrate the parameters of the MCTS codes. For 10 MeV proton beams, ionization and excitation processes are the major contributors to the specific energy deposition (larger than 90%) while attachment, solvation, and vibration processes are minor contributors. LPCHEM simulates tracks with slightly more concentrated energy depositions than Geant4-DNA which translates into slightly faster recombination than Geant4-DNA. Relative deviations (CEV ) with respect to the average of evolution rates of the radical yields between 10-12 and 10-6 s remain below 10%. When comparing execution times between the codes, we showed that LPCHEM is faster than Geant4-DNA by a factor of about four for 1000 primary particles in all simulation stages (physical, physico-chemical, and chemical). In multi-thread mode (four threads), Geant4-DNA computing times are reduced but remain slower than LPCHEM by ∼20% up to ∼50%. CONCLUSIONS: For the first time, the entire physical, physico-chemical, and chemical models of two track structure Monte Carlo codes have been benchmarked along with an extensive analysis on the effects on the water radiolysis simulation. This study opens up new perspectives in using specific energy distributions and radiolytic species yields from monoenergetic ions in biophysical models integrated to Monte Carlo software.

Fungal Keratitis in the Egyptian Delta: Epidemiology, Risk Factors, and Microbiological Diagnosis.

PURPOSE: The current study evaluates the epidemiological characteristics, risk factors, and microbiological diagnosis of fungal keratitis among patients living in the Egyptian Delta. METHODS: This is a prospective hospital-based study that included patients who were clinically diagnosed and confirmed by culture test to have fungal keratitis. Patients were examined at baseline and risk factors were identified and collected. Patients were followed over 6 months and the outcomes were documented. RESULTS: A total of 171 (67%) of 252 microbial keratitis patients was proved fungal by microbial culture test. Rural residence and agricultural activity were reported in 139 (81.3%) and 85 (49.7%) patients, respectively. Patients presented within 1 week from the start of symptoms were 120 (70.2%). A total of 54 (31.6%) patients reported ocular trauma. Forty patients (23.4%) had prior ocular surgery and 43 (25.1%) patients had a history of previous ocular disorders. Aspergillus species was the most common organism found in 120 (70.17%) patients, followed by Dematiceous fungi that were found in 25 (14.6%) patients. The main outcome was corneal opacity in 132 (77.2%) patients following medical treatment. CONCLUSION: Filamentary fungal predominance in Mansoura is influenced by the rural residence of its population. Therefore, more efforts in spreading awareness about microbial keratitis among villagers are important to reduce blindness caused by corneal opacity in rural areas.

Targeting cardiovascular risk in patients with diabetes: management of dyslipidemia.

PURPOSE OF REVIEW: The management of dyslipidemia in patients with diabetes is a key component of cardiovascular risk reduction. In particular, the atherogenic dyslipidemia of diabetes often requires combination therapy to target aspects of the lipid profile beyond low-density lipoprotein cholesterol. This article will review the characteristics of dyslipidemia in diabetes, and discuss guidelines and strategies for treatment to reduce cardiovascular disease risk. RECENT FINDINGS: A number of clinical outcomes trials supports the use of statins to reduce cardiovascular events in patients with type 2 diabetes mellitus. The disappointing results of clinical trials involving torcetrapib to increase high-density lipoprotein levels may lead to renewed interest and utilization of niacin for the management of atherogenic dyslipidemia. Long-term use of fibrate therapy in patients with atherogenic dyslipidemia has recently been associated with reduction in all-cause, cancer, and cardiovascular mortality rates. Ongoing trials are investigating whether addition of niacin or fibrate to statin therapy is superior to statin therapy alone in preventing cardiovascular events. SUMMARY: Aggressive low-density lipoprotein control continues to be the primary goal of therapy in dyslipidemia management. Given the growing body of evidence showing the cardiovascular benefits of treating other lipid components, however, it is easy to anticipate that full normalization of the lipid profile may become the standard of care for diabetic dyslipidemia.

Prediction of major adverse cardiovascular events by age-normalized carotid intimal medial thickness.

BACKGROUND: Increases in carotid intimal medial thickness (IMT), as measured by noninvasive ultrasonography, have been associated with increased risk of myocardial infarction and stroke, particularly in adults 65 years of age or older. We investigated the value of age-normalized carotid IMT measurements in predicting major adverse cardiovascular events in a population of patients referred for carotid IMT measurement. METHODS: Since 1995, 727 patients had carotid IMT measured at the University of Virginia's Preventive Cardiology practice. We successfully contacted 706 of these patients to determine clinical outcomes; 21 patients were lost to follow-up. The 706 patients were entered into a database, age-specific quartiles of carotid thickness developed, and odds ratios were calculated with logistic regression. RESULTS: Over a mean follow-up period of 4.78 years (range, 2.0-9.3 years), 20 patients had major adverse cardiovascular events: seven patients had myocardial infarctions; seven required revascularization; and six had a stroke or transient ischemic attack. The incidence of events directly correlated with age-normalized measurements of carotid bulb and internal carotid IMT. The highest quartile of carotid bulb IMT demonstrated an odds ratio for all events of 5.8 (95% confidence interval, 1.3-26.6; P = 0.023) when compared to the quartile with the lowest thickness (P = 0.007 for trend). A similar trend for quartiles of internal carotid IMT was also observed (P = 0.03). Common carotid IMT did not significantly predict events. CONCLUSIONS: Age-normalized measurement of carotid bulb and internal carotid IMT may be helpful in determining which individuals would most benefit from aggressive risk-factor modification.