Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Analysis of the antibiotic prophylaxis prescribed by Spanish oral surgeons

Aim: To identify prophylactic antibiotic prescription practices among Spanish dentists with preferential dedication to Oral Surgery in different types of tooth extraction surgeries. Method: Members of the Spanish Oral Surgery Society were surveyed on antibiotic prophylaxis use in 4 different tooth extraction modalities scaled according to their surgical invasiveness. Results: Sixty-nine of the 105 distributed questionnaires were returned completed. Thirteen percent of the surveyed surgeons would prescribe antibiotics to prevent postoperative wound infection when confronted with conventional tooth extraction lasting less than 5 minutes. In the case of surgery lasting more than 5 minutes, the percentage of participants that would prescribe antibiotics increased to 39%. When a mucoperiosteal flap was elevated or an ostectomy was performed, 87% and 100%, respectively, would prescribe antibiotic prophylaxis. Amoxicillin and its combination with clavulanic acid were the most commonly prescribed antibiotics. All participants would prescribe the antibiotic orally, starting after surgery and with a duration that ranged from 2-8 days. Conclusions: The results obtained suggest that antibiotic prophylaxis for preventing local odontogenic infection is not being correctly implemented in Spain. This can generate new bacterial resistances, facilitate adverse drug reactions and favor opportunistic infections. Better designed studies are needed in order to clarify the role of antibiotics in the prevention of postsurgical wound infection

Up-conversion effect of Er- and Yb-doped ZnO thin films

Visible up-conversion in ZnO:Er and ZnO:Er:Yb thin films deposited by RF magnetron sputtering under different O2-rich atmospheres has been studied. Conventional photoluminescence (325 nm laser source) and up-conversion (980 nm laser source) have been performed in the films before and after an annealing process at 800 °C. The resulting spectra demonstrate that the thermal treatment, either during or post-deposition, activates optically the Er3+ ions, being the latter process much more efficient. Moreover, the atmosphere during deposition was also found to be an important parameter, as the deposition under O2 flow increases the optical activity of Er+3 ions. In addition, the inclusion of Yb3+ ions into the films has shown an enhancement of the visible up-conversion emission at 660 nm by a factor of 4, which could be associated to either a better energy transfer from the 2F5/2 Yb level to the 4I11/2 Er one, or to the prevention of having Er2O3 clustering in the films.

Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content

Polyphenols are a major class of bioactive phytochemicals whose consumption may play a role in the prevention of a number of chronic diseases such as cardiovascular diseases, type II diabetes and cancers. Phenol-Explorer, launched in 2009, is the only freely available web-based database on the content of polyphenols in food and their in vivo metabolism and pharmacokinetics. Here we report the third release of the database (Phenol-Explorer 3.0), which adds data on the effects of food processing on polyphenol contents in foods. Data on >100 foods, covering 161 polyphenols or groups of polyphenols before and after processing, were collected from 129 peer-reviewed publications and entered into new tables linked to the existing relational design. The effect of processing on polyphenol content is expressed in the form of retention factor coefficients, or the proportion of a given polyphenol retained after processing, adjusted for change in water content. The result is the first database on the effects of food processing on polyphenol content and, following the model initially defined for Phenol-Explorer, all data may be traced back to original sources. The new update will allow polyphenol scientists to more accurately estimate polyphenol exposure from dietary surveys. Database URL: http://www.phenol-explorer.eu

Analysis of the antibiotic prophylaxis prescribed by Spanish oral surgeons

Aim: To identify prophylactic antibiotic prescription practices among Spanish dentists with preferential dedication to Oral Surgery in different types of tooth extraction surgeries. Method: Members of the Spanish Oral Surgery Society were surveyed on antibiotic prophylaxis use in 4 different tooth extraction modalities scaled according to their surgical invasiveness. Results: Sixty-nine of the 105 distributed questionnaires were returned completed. Thirteen percent of the surveyed surgeons would prescribe antibiotics to prevent postoperative wound infection when confronted with conventional tooth extraction lasting less than 5 minutes. In the case of surgery lasting more than 5 minutes, the percentage of participants that would prescribe antibiotics increased to 39%. When a mucoperiosteal flap was elevated or an ostectomy was performed, 87% and 100%, respectively, would prescribe antibiotic prophylaxis. Amoxicillin and its combination with clavulanic acid were the most commonly prescribed antibiotics. All participants would prescribe the antibiotic orally, starting after surgery and with a duration that ranged from 2-8 days. Conclusions: The results obtained suggest that antibiotic prophylaxis for preventing local odontogenic infection is not being correctly implemented in Spain. This can generate new bacterial resistances, facilitate adverse drug reactions and favor opportunistic infections. Better designed studies are needed in order to clarify the role of antibiotics in the prevention of postsurgical wound infection

Use of amitriptyline for the treatment of chronic tension-type headache. Review of the literature

Amitriptyline is a tricyclic antidepressant, considered the treatment of choice for different types of chronic pain, including chronic myofascial pain. Its antinociceptive property is independent of its antidepressant effect. Although its analgesic mechanism is not precisely known, it is believed that the serotonin reuptake inhibition in the central nervous system plays a fundamental role in pain control. Although this medication is widely used in the prevention of chronic tension-type headache, few studies have investigated the efficacy of this treatment and the published results are contradictory. The objective of this article was to review the literature published on the use of amitriptyline in the prophylactic treatment of chronic tension-type headache, considering the level of scientific evidence of the different studies using the SORT criteria. From this review, 5 articles of evidence level 1, and another 5 articles of evidence level 2 were selected. Following analysis of the 10 studies, and in function of their scientific quality, a level A recommendation was made in favor of using amitriptyline in the treatment of chronic tension-type headache.

Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease

Background: Epidemiologic studies have suggested that flavonoid intake plays a critical role in the prevention of coronary heart disease. Because atherosclerosis is considered a low-grade inflammatory disease, some feeding trials have analyzed the effects of cocoa (an important source of flavonoids) on inflammatory biomarkers, but the results have been controversial. Objective: The objective was to evaluate the effects of chronic cocoa consumption on cellular and serum biomarkers related to atherosclerosis in high-risk patients. Design: Forty-two high-risk volunteers (19 men and 23 women; mean 6 SD age: 69.7 6 11.5 y) were included in a randomized crossover feeding trial. All subjects received 40 g cocoa powder with 500 mL skim milk/d (C+M) or only 500 mL skim milk/d (M) for 4 wk. Before and after each intervention period, cellular and serum inflammatory biomarkers related to atherosclerosis were evaluated. Results: Adherence to the dietary protocol was excellent. No significant changes in the expression of adhesion molecules on T lymphocyte surfaces were found between the C+M and M groups. However, in monocytes, the expression of VLA-4, CD40, and CD36 was significantly lower (P = 0.005, 0.028, and 0.001, respectively) after C+M intake than after M intake. In addition, serum concentrations of the soluble endothelium-derived adhesion molecules P-selectin and intercellular adhesion molecule-1 were significantly lower (both P = 0.007) after C+M intake than after M intake. Conclusions: These results suggest that the intake of cocoa polyphenols may modulate inflammatory mediators in patients at high risk of cardiovascular disease. These antiinflammatory effects may contribute to the overall benefits of cocoa consumption against atherosclerosis. This trial was registered in the Current Controlled Trials at London, International Standard Randomized Controlled Trial Number, at controlled-trials.com as ISRCTN75176807.

The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells

AIMS: Mitofusin-2 (Mfn2) expression is dysregulated in vascular proliferative disorders and its overexpression attenuates the proliferation of vascular smooth muscle cells (VSMCs) and neointimal lesion development after balloon angioplasty. We sought to gain insight into the mechanisms that control Mfn2 expression in VSMCs. METHODS AND RESULTS: We cloned and characterized 2 kb of the 5'-flanking region of the human Mfn2 gene. Its TATA-less promoter contains a CpG island. In keeping with this, 5'-rapid amplification of cDNA ends revealed six transcriptional start sites (TSSs), of which TSS2 and TSS5 were the most frequently used. The strong CpG island was found to be non-methylated under conditions characterized by large differences in Mfn2 gene expression. The proximal Mfn2 promoter contains six putative Sp1 motifs. Sp1 binds to the Mfn2 promoter and its overexpression activates the Mfn2 promoter in VSMCs. Chemical inhibition of Sp1 reduced Mfn2 expression, and Sp1 silencing reduced transcriptional activity of the Mfn2 promoter. In keeping with this view, Sp1 and Mfn2 mRNA levels were down-regulated in the aorta early after an atherogenic diet in apolipoprotein E-knockout mice or in VSMCs cultured in the presence of low serum. CONCLUSION: Sp1 is a key factor in maintaining basal Mfn2 transcription in VSMCs. Given the anti-proliferative actions of Mfn2, Sp1-induced Mfn2 transcription may represent a mechanism for prevention of VSMC proliferation and neointimal lesion and development.

The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells

AIMS: Mitofusin-2 (Mfn2) expression is dysregulated in vascular proliferative disorders and its overexpression attenuates the proliferation of vascular smooth muscle cells (VSMCs) and neointimal lesion development after balloon angioplasty. We sought to gain insight into the mechanisms that control Mfn2 expression in VSMCs. METHODS AND RESULTS: We cloned and characterized 2 kb of the 5'-flanking region of the human Mfn2 gene. Its TATA-less promoter contains a CpG island. In keeping with this, 5'-rapid amplification of cDNA ends revealed six transcriptional start sites (TSSs), of which TSS2 and TSS5 were the most frequently used. The strong CpG island was found to be non-methylated under conditions characterized by large differences in Mfn2 gene expression. The proximal Mfn2 promoter contains six putative Sp1 motifs. Sp1 binds to the Mfn2 promoter and its overexpression activates the Mfn2 promoter in VSMCs. Chemical inhibition of Sp1 reduced Mfn2 expression, and Sp1 silencing reduced transcriptional activity of the Mfn2 promoter. In keeping with this view, Sp1 and Mfn2 mRNA levels were down-regulated in the aorta early after an atherogenic diet in apolipoprotein E-knockout mice or in VSMCs cultured in the presence of low serum. CONCLUSION: Sp1 is a key factor in maintaining basal Mfn2 transcription in VSMCs. Given the anti-proliferative actions of Mfn2, Sp1-induced Mfn2 transcription may represent a mechanism for prevention of VSMC proliferation and neointimal lesion and development.

Loss of intestinal epithelial barrier function in Salmonella Enteritidis infection

Intestinal infection with Salmonella enterica serotype Enteritidis, a food-borne infection spread to humans especially through contaminated eggs and egg-products as well as undercooked contaminated fresh meat, is the most common cause of intestinal inflammation in the European Union. Enteritis caused by Salmonella Enteritidis is characterized by fever, diarrhoea and abdominal pain. The disruption of the intestinal epithelial barrier function contributes to diarrhoea and is responsible for the perpetuation of the inflammatory process. In this sense, oxidative stress and the proinflammatory cytokines TNF-α, IFN-γ and IL-1β are described to induce the disorganization of the tight junctions (TJ), the most apical epithelial intercellular junctions and responsible for the paracellular permeability. The interest of this chapter relies not only in the investigation dealing with the mechanisms of TJ regulation but also in the contribution to the development of new tools for the prevention of epithelial barrier disruption in enteritis caused by Salmonella Enteritidis.

Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk. Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models. Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids). Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality.

The Problem of Invasive Species in River Ecosystems

Invasive nonnative species are a major problem in river ecosystems, and have large ecological and economic costs. Few ecosystems can resist invasions. The species that tend to invade most readily are those that humans. Introduce the most, and the ecosystems they invade are those with the most human activity. Most invasions are irreversible, and control is expensive, so efforts should be focused on prevention of future invasions