Correlation Between Tacrolimus Levels in Blood Samples Obtained from Central Catheter and Peripheral Venipuncture in Lung Transplant Patients (Ven-Cat Study).

BACKGROUND: Following lung transplantation (LT), receiving immunosuppressive therapy is crucial. Tacrolimus is considered a drug with a narrow therapeutic range and its use requires constant monitoring. This study aimed to evaluate the correlation between tacrolimus levels obtained from central venous catheter and direct venipuncture in adult patients undergoing LT. METHODS: This prospective study included LT patients hospitalized in conventional ward carrying a central catheter through which no intravenous tacrolimus was administered. Trough samples were obtained through direct puncture and from the central catheter. Pearson correlation coefficient was calculated to quantify the mean difference between the 2 measures. RESULTS: A total of 54 sample pairs from 16 LT patients were obtained, mostly male (81.3%) and bilateral transplant recipients (93.8%); the transplant procedure was the primary reason for admission (81.3%). The difference in tacrolimus levels between both samples was 0.3 (0.1-0.6) mcg/L, with the measurement for the samples obtained through venipuncture being mostly higher than that for those obtained from the catheter. A strong correlation was observed between the tacrolimus levels in the samples obtained from the catheter and through venipuncture (Pearson correlation coefficient, 0.991; P < 0.001; R2 = 0.982). CONCLUSIONS: There is an excellent correlation between tacrolimus levels obtained from venipuncture and those obtained from central venous catheter in LT patients undergoing oral tacrolimus therapy.

Pharmacological Elevation of Cellular Dihydrosphingomyelin Provides a Novel Antiviral Strategy against West Nile Virus Infection.

The flavivirus life cycle is strictly dependent on cellular lipid metabolism. Polyphenols like gallic acid and its derivatives are promising lead compounds for new therapeutic agents as they can exert multiple pharmacological activities, including the alteration of lipid metabolism. The evaluation of our collection of polyphenols against West Nile virus (WNV), a representative medically relevant flavivirus, led to the identification of N,N'-(dodecane-1,12-diyl)bis(3,4,5-trihydroxybenzamide) and its 2,3,4-trihydroxybenzamide regioisomer as selective antivirals with low cytotoxicity and high antiviral activity (half-maximal effective concentrations [EC50s] of 2.2 and 0.24 µM, respectively, in Vero cells; EC50s of 2.2 and 1.9 µM, respectively, in SH-SY5Y cells). These polyphenols also inhibited the multiplication of other flaviviruses, namely, Usutu, dengue, and Zika viruses, exhibiting lower antiviral or negligible antiviral activity against other RNA viruses. The mechanism underlying their antiviral activity against WNV involved the alteration of sphingolipid metabolism. These compounds inhibited ceramide desaturase (Des1), promoting the accumulation of dihydrosphingomyelin (dhSM), a minor component of cellular sphingolipids with important roles in membrane properties. The addition of exogenous dhSM or Des1 blockage by using the reference inhibitor GT-11 {N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide} confirmed the involvement of this pathway in WNV infection. These results unveil the potential of novel antiviral strategies based on the modulation of the cellular levels of dhSM and Des1 activity for the control of flavivirus infection.

Glycolytic shift during West Nile virus infection provides new therapeutic opportunities.

BACKGROUND: Viral rewiring of host bioenergetics and immunometabolism may provide novel targets for therapeutic interventions against viral infections. Here, we have explored the effect on bioenergetics during the infection with the mosquito-borne flavivirus West Nile virus (WNV), a medically relevant neurotropic pathogen causing outbreaks of meningitis and encephalitis worldwide. RESULTS: A systematic literature search and meta-analysis pointed to a misbalance of glucose homeostasis in the central nervous system of WNV patients. Real-time bioenergetic analyses confirmed upregulation of aerobic glycolysis and a reduction of mitochondrial oxidative phosphorylation during viral replication in cultured cells. Transcriptomics analyses in neural tissues from experimentally infected mice unveiled a glycolytic shift including the upregulation of hexokinases 2 and 3 (Hk2 and Hk3) and pyruvate dehydrogenase kinase 4 (Pdk4). Treatment of infected mice with the Hk inhibitor, 2-deoxy-D-glucose, or the Pdk4 inhibitor, dichloroacetate, alleviated WNV-induced neuroinflammation. CONCLUSIONS: These results highlight the importance of host energetic metabolism and specifically glycolysis in WNV infection in vivo. This study provides proof of concept for the druggability of the glycolytic pathway for the future development of therapies to combat WNV pathology.

Direct reductive amination of functionalized aldehydes with aniline derivatives of purines and 7-deazapurines.

Reductive amination plays a key role in the medicinal chemistry toolbox since it allows the mono alkylation of an amine or aniline. In this work, reductive amination of functionalized aldehydes with aniline derivatives of adenine and closely related 7-deazapurines has been successfully performed using H-cube technology so that imine formation and its reduction are performed "in situ". The set-up procedure surmounts some of the drawbacks of "in batch" protocols by avoiding the handling of reductant reagents, long reaction times and tedious work-ups. The here described procedure allows a high conversion into the reductive amination products together with an easy work-up by just evaporation. More interestingly, this set-up does not require the presence of acids so that acid-sensitive protecting groups can be present both at the aldehyde and at the heterocycle.

Salicylanilides and Their Anticancer Properties.

Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human and veterinary medicine as anthelmintics, have recently emerged as candidates for drug repurposing in oncology. The most prominent example of salicylanilide anthelmintic, that is intensively studied for its potential anticancer properties, is niclosamide. Nevertheless, recent studies have discovered extensive anticancer potential in a number of other salicylanilides. This potential of their anticancer action is mediated most likely by diverse mechanisms of action such as uncoupling of oxidative phosphorylation, inhibition of protein tyrosine kinase epidermal growth factor receptor, modulation of different signaling pathways as Wnt/ß-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways or induction of B-Raf V600E inhibition. Here we provide a comprehensive overview of the current knowledge about the proposed mechanisms of action of anticancer activity of salicylanilides based on preclinical in vitro and in vivo studies, or structural requirements for such an activity.

Allosteric Inhibition of Neutral Sphingomyelinase 2 (nSMase2) by DPTIP: From Antiflaviviral Activity to Deciphering Its Binding Site through In Silico Studies and Experimental Validation.

Flavivirus comprises globally emerging and re-emerging pathogens such as Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), among others. Although some vaccines are available, there is an unmet medical need as no effective antiviral treatment has been approved for flaviviral infections. The development of host-directed antivirals (HDAs) targeting host factors that are essential for viral replication cycle offers the opportunity for the development of broad-spectrum antivirals. In the case of flaviviruses, recent studies have revealed that neutral sphingomyelinase 2, (nSMase2), involved in lipid metabolism, plays a key role in WNV and ZIKV infection. As a proof of concept, we have determined the antiviral activity of the non-competitive nSMase2 inhibitor DPTIP against WNV and ZIKV virus. DPTIP showed potent antiviral activity with EC50 values of 0.26 µM and 1.56 µM for WNV and ZIKV, respectively. In order to unravel the allosteric binding site of DPTIP in nSMase2 and the details of the interaction, computational studies have been carried out. These studies have revealed that DPTIP could block the DK switch in nSMase2. Moreover, the analysis of the residues contributing to the binding identified His463 as a crucial residue. Interestingly, the inhibitory activity of DPTIP on the H463A mutant protein supported our hypothesis. Thus, an allosteric cavity in nSMase2 has been identified that can be exploited for the development of new inhibitors with anti-flaviviral activity.

Structural Insights into the Mechanisms of Action of Functionally Distinct Classes of Chikungunya Virus Nonstructural Protein 1 Inhibitors.

Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) harbors the methyltransferase (MTase) and guanylyltransferase (GTase) activities needed for viral RNA capping and represents a promising antiviral drug target. We compared the antiviral efficacies of nsP1 inhibitors belonging to the MADTP, CHVB, and FHNA series (6'-fluoro-homoneplanocin A [FHNA], its 3'-keto form, and 6'-ß-fluoro-homoaristeromycin). Cell-based phenotypic cross-resistance assays revealed that the CHVB and MADTP series had similar modes of action that differed from that of the FHNA series. In biochemical assays with purified Semliki Forest virus and CHIKV nsP1, CHVB compounds strongly inhibited MTase and GTase activities, while MADTP-372 had a moderate inhibitory effect. FHNA did not directly inhibit the enzymatic activity of CHIKV nsP1. The first-of-their-kind molecular-docking studies with the cryo-electron microscopy (cryo-EM) structure of CHIKV nsP1, which is assembled into a dodecameric ring, revealed that the MADTP and CHVB series bind at the S-adenosylmethionine (SAM)-binding site in the capping domain, where they would function as competitive or noncompetitive inhibitors. The FHNA series was predicted to bind at the secondary binding pocket in the ring-aperture membrane-binding and oligomerization (RAMBO) domain, potentially interfering with the membrane binding and oligomerization of nsP1. Our cell-based and enzymatic assays, in combination with molecular docking and mapping of compound resistance mutations to the nsP1 structure, allowed us to group nsP1 inhibitors into functionally distinct classes. This study identified druggable pockets in the nsP1 dodecameric structure and provides a basis for the rational design, optimization, and combination of inhibitors of this unique and promising antiviral drug target.

Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of abdominal ultrasound in inflammatory bowel disease. / Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el empleo de la ecografía abdominal en la enfermedad inflamatoria intestinal.

Ultrasound has an excellent diagnostic performance when Crohn's disease is suspected, when performing an activity assessment, or determining the extension and location of Crohn's disease, very similar to other examinations such as MRI or CT. It has a good correlation with endoscopic lesions and allows the detection of complications such as strictures, fistulas or abscesses. It complements colonoscopy in the diagnosis and, given its tolerance, cost and immediacy, it can be considered as a good tool for disease monitoring. In ulcerative colitis, its role is less relevant, being limited to assessing the extent and activity when it is not possible with other diagnostic techniques or if there are doubts with these. Despite its advantages, its use in inflammatory bowel disease (IBD) is not widespread in Spain. For this reason, this document reviews the advantages and disadvantages of the technique to promote knowledge about it and implementation of it in IBD Units.

Efficacy and safety results from GEICO 1205, a randomized phase II trial of neoadjuvant chemotherapy with or without bevacizumab for advanced epithelial ovarian cancer.

BACKGROUND: Bevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery. OBJECTIVE: To evaluate neoadjuvant bevacizumab in a randomized phase II trial. METHODS: Patients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without ≥3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery. RESULTS: Of 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade ≥3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade ≥3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery. CONCLUSIONS: Adding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.

Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2H-Benzo[g]indazole Derivatives: Antiproliferative and Antibacterial Activity.

New substituted benzo[g]indazoles functionalized with a 6-nitro and 6-amino groups have been synthesized by the reaction of benzylidene tetralones with hydrazine in acetic acid. The resulting conformationally-constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. The nitro-based indazoles 11a, 11b, 12a and 12b have shown IC50 values between 5-15 µM against the lung carcinoma cell line NCI-H460. Moreover, the nitro compounds were tested for antibacterial activity where compounds 12a and 13b have shown MIC values of 250 and 62.5 µg/mL against N. gonorrhoeae with no hemolytic activity in human red blood cells (RBC).

Novel Polyphenols That Inhibit Colon Cancer Cell Growth Affecting Cancer Cell Metabolism.

New series of polyphenols with a hydrophilic galloyl-based head and a hydrophobic N-acyl tail, linked through a serinol moiety, have been synthesized and tested against colon cancer cell growth. Our structure activity relationship studies revealed that galloyl moieties are essential for growth inhibition. Moreover, the length of the N-acyl chain is crucial for the activity. Introduction of a (Z) double bond in the acyl chain increased the anticancer properties. Our findings demonstrate that 16, the most potent compound within this series, has inhibitory effects on colon cancer cell growth and metabolism (glycolysis and mitochondrial respiration) at the same time that it activates 5'AMP-activated kinase (AMPK) and induces apoptotic cell death. Based on these results, we propose that 16 might reprogram colon cancer cell metabolism through AMPK activation. This might lead to alterations on cancer cell bioenergy compromising cancer cell viability. Importantly, these antiproliferative and proapoptotic effects are selective for cancer cells. Accordingly, these results indicate that 16, with an unsaturated C18 chain, might be a useful prototype for the development of novel colon cancer cell growth inhibitors affecting cell metabolism.

A Novel Class of Cationic and Non-Peptidic Small Molecules as Hits for the Development of Antimicrobial Agents.

Cationic and non-peptide small molecules containing a total of six positive charges arranged on one side and a long aliphatic tail on the other have been synthesized and tested against Gram-positive and Gram-negative bacteria. The positive charges have been contributed by two aminophenol residues. These molecules have showed remarkable antimicrobial activity against Gram-positive bacteria including multidrug-resistant strains. Our structure⁻activity relationship studies demonstrated the importance of the length and flexibility of the hydrophobic tail for the antimicrobial activity. Importantly, these compounds are non-toxic to eukaryotic cells at the concentration affecting growth in bacteria, reflecting an acceptable margin of safety. The small size and easy synthetic accessibility of our molecules can be of interest for the further development of novel antimicrobials against Gram-positive bacterial pathogens, including multidrug-resistant strains.

Prevalence, Incidence, and Sex Ratio of Transsexualism in the Autonomous Region of Madrid (Spain) According to Healthcare Demand.

In recent years, different studies have provided estimates of the prevalence of transsexualism with very diverse results. The purpose of this study was to ascertain the prevalence, incidence, and sex ratio of transsexualism in the autonomous region of Madrid (Spain). A total of 1234 patients who attended from 2007 to the end of 2015 in the only Gender Identity Unit (GIU) in Madrid were analyzed. Sixty-three patients were excluded for various reasons; thus, 1171 could be included: 803 male-to-female (MtF) and 368 female-to-male (FtM) transsexual patients. Transsexualism was diagnosed based on the ICD-10, World Health Organization, 1992, and/or gender identity disorder based on the DSM-IV-TR, American Psychiatric Association, 2000. The demographic statistics were calculated on the basis of the population over 15 years old of Madrid. Based on healthcare demand, the prevalence of transsexualism was 22.1 in 100,000 inhabitants: 31.2 for MtF and 12.9 for FtM, making the MtF/FtM ratio approximately 2.2:1. The incidence rate was 2.5 in 100,000 inhabitants, representing an annual average of 130 demands. Although transsexualism occurs in all countries with different rates of prevalence, in our area, this prevalence was higher than reported from other European countries. We believe that two main circumstances might influence this high prevalence: the easy accessibility and the absence of a waiting list to the GIU, and the permissive social and legal climate and openness of Spain, especially in Madrid.

Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.

Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.

Thymidine phosphorylase participates in platelet signaling and promotes thrombosis.

RATIONALE: Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes mellitus. OBJECTIVE: To test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. METHODS AND RESULTS: By using a ferric chloride (FeCl3)-induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp(-/-) and Tymp(+/-) mice compared with wild-type mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet TYMP was responsible for the antithrombotic phenomenon in the TYMP-deficient mice. Collagen-, collagen-related peptide-, adenosine diphosphate-, or thrombin-induced platelet aggregation were significantly attenuated in Tymp(+/-) and Tymp(-/-) platelets, and in wild type or human platelets pretreated with TYMP inhibitor KIN59. Tymp deficiency also significantly decreased agonist-induced P-selectin expression. TYMP contains an N-terminal SH3 domain-binding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn, and Yes in platelets. TYMP-associated Lyn was inactive in resting platelets, and TYMP trapped and diminished active Lyn after collagen stimulation. Tymp/Lyn double haploinsufficiency diminished the antithrombotic phenotype of Tymp(+/-) mice. TYMP deletion or inhibition of TYMP with KIN59 dramatically increased platelet-endothelial cell adhesion molecule 1 tyrosine phosphorylation and diminished collagen-related peptide- or collagen-induced AKT phosphorylation. In vivo administration of KIN59 significantly inhibited FeCl3-induced carotid artery thrombosis without affecting hemostasis. CONCLUSIONS: TYMP participates in multiple platelet signaling pathways and regulates platelet activation and thrombosis. Targeting TYMP might be a novel antiplatelet and antithrombosis therapy.

Sigmoid stenosis caused by diverticulitis vs. carcinoma: usefulness of sonographic features for their differentiation in the emergency setting.

OBJECTIVE: To retrospectively evaluate the accuracy of ultrasound as a diagnostic method for differentiating acute diverticulitis from colon cancer in patients with sigmoid colon stenosis. MATERIALS AND METHODS: Ultrasound examinations of 91 consecutive patients with sigmoid stenosis (50 diverticulitis and 41 colon cancers) were reviewed by two trained radiologists. Sixty-five (71%) patients presented with acute abdominal symptoms. Thirteen sonographic criteria retrieved from the literature were evaluated to differentiate benign from malignant strictures. A score including all parameters which showed significant differences between benign vs. malignant was built. Sensitivity, specificity, accuracy, and positive or negative predictive values of each sonographic sign, the overall diagnosis, and sonographic score were calculated. RESULTS: Loss of the bowel wall stratification was the most reliable criteria for the diagnosis of malignancy (92% and 94% of sensitivity and specificity, respectively), and the best inter-radiologist agreement (κ = 0.848). Adjacent lymph nodes were the most specific feature (98%) for colon cancer, but its sensitivity was low. Global assessment could differentiate both diseases with high sensitivity (92-94.9%) and specificity (98-100%). Sonographic score >3 enabled differentiation of carcinoma from diverticulitis with 95% sensitivity and 92-94% specificity, with an area under the ROC curve of 0.98-0.987. There were no significant differences in the results between patients with acute and nonacute abdominal symptoms. CONCLUSION: The combination of several morphological sonographic findings using a score can differentiate most cases of diverticulitis from colon carcinoma in sigmoid strictures.

Is it feasible to diagnose catheter-related candidemia without catheter withdrawal?

Many bloodstream infections (BSI) in patients with central venous catheters (CVC) are not catheter-related (CR). Assessment of catheter involvement without catheter withdrawal has not been studied in candidemia. We assessed the value of conservative techniques to evaluate catheters as the origin of candidemia in patients with CVC in a prospective cohort study (superficial Gram stain and culture, Kite technique (Gram stain and culture of the first 1 cm blood drawn from the CVC), proportion of positive blood cultures (PPBCs), differential time to positivity (DTP), and minimal time to positivity (MTP)). All catheters were cultured at withdrawal. From June 2008 to January 2012, 22 cases fulfilled the inclusion criteria. CR-candidemia (CRC) was confirmed in 10. Validity values for predicting CRC were: superficial Gram stain (S, 30%; Sp, 81.83%; PPV, 60%; NPV, 56.3%; Ac, 57.1%), superficial cultures (S, 40%; Sp, 75%; PPV, 57.1%; NPV, 60%; Ac, 59.1%), Kite Gram stain (S, 33.3%; Sp, 66.7%; PPV, 50%; NPV, 50%; Ac, 50%), Kite culture (S, 80%; Sp, 66.7%; PPV, 66.7%; NPV, 80%; Ac, 72.7%), PPBC (S, 50%; Sp, 41.7%; PPV, 41.7%; NPV, 50.0%; Ac, 45.5%), DTP (S, 100%; Sp, 33.3%; PPV, 55.6%; NPV, 100%; Ac, 63.6%), and MTTP (S, 70%; Sp, 58.3%; PPV, 58.3%; NPV, 70%; Ac, 63.6%). While combinations of two tests improved sensitivity and NPV, more than two tests did not improve validity values. Classic tests to assess CR-BSI caused by bacteria cannot be reliably used to diagnose CRC. Combinations of tests could be useful, but more and larger studies are required.

Multivalent agents containing 1-substituted 2,3,4-trihydroxyphenyl moieties as novel synthetic polyphenols directed against HIV-1.

The synthesis and the assessment of the anti-HIV activity of a set of molecules inspired by the multivalent structures of some naturally-occurring polyphenols (tannins) are reported. Different multibranched scaffolds have been derived from pentaerythritol as the central core which distribute spatially synthetic polyphenolic subunits based on 1-substituted 2,3,4-trihydroxyphenyl moieties. A tetrapodal compound () bearing four N-(2,3,4-trihydroxyphenyl)amide groups, exhibits remarkable selective activity against HIV-1 with EC50 values in the micromolar scale, in the same range as those reported for the most representative anti-HIV tannins. Preliminary SAR studies emphasize the importance of the 1-substituted 2,3,4-trihydroxyphenyl moiety, the presence of an amide as the linker and the multivalent architecture of these molecules, since the anti-HIV activity increases with the number of polyphenolic moieties. The data support the interest in synthetic polyphenols and represent a promising starting point for further design and development of selective HIV-1 inhibitors.

The bacteremia of dental origin and its implications in the appearance of bacterial endocarditis.

Numerous systemic diseases may affect the oral cavity and vice versa,in particular severe diseases that involve the heart valve. In these cases, additional measures or a modification to our dental treatment need to be taken. We are aware of various diseases that can cause the emergence of bacterial endocarditis (BE), such as; rheumatic fever, valve lesions due to intravenous drug use, Kawasaki disease and valve surgery, among others. Due to its severity when it is not taken into account in dental treatment, we intend to show the evolution of the antimicrobial prophylaxis towards this condition. Furthermore, we intend to publish the current guidelines of institutions and societies which increasingly encourage rational antimicrobial use. In addition, we intend to examine the evidence of the possible origins of this disease during dental treatment and at the same time describe the necessary considerations that need to be taken during dental treatment.

Implants in disabled patients: a review and update.

The range of indications for dental implants has broadened enormously owing to their predictability and the improvement of patient satisfaction in terms of stability, comfort, aesthetics and functionality. The aim of this article is to review those indications in patients with mental or physical disabilities as the difficulty to cope with oral hygiene often leads to teeth extraction, adding edentulousness to the impairments already present. Following that goal, available literature in Pubmed database, Scopus, Web of Knowledge and The Cochrane Library database about dental implants placement in these patients has been reviewed, assessing the variables of each study: number of patients, sex, average age, oral hygiene, parafunctional habits, impairment, bone quality, protocol of implant surgery, necessity of deep intravenous sedation or general anesthesia, follow-up period and number of failures. The comparison with studies involving other patient populations without mental or physical impediments did not show statistically significant differences in terms of the failure rate recorded. Although there is not much literature available, the results of this review seem to suggest that osseointegrated oral implants could be a therapeutic option in patients who suffer from any physical or psychological impairment. The success of an oral rehabilitation depends mainly on an adequate selection of the patients.