Reports of substandard medicines: a lexicographic analysis of the Brazilian Health Surveillance Report System

Regulatory agencies are responsible for collecting and evaluating spontaneous reports of suspected problems related to medications, including those from substandard medicines (SM). Objectives: The aim was to evaluate the profile of SM reports submitted to the Brazilian Health Surveillance Notification System (Notivisa) and classify these reports objectively by means of lexicographic analysis. Methods: Was extracted all SM reports available in Notivisa during the period 1 January 2007 to 31 December 2017. Descriptive statistics were performed and the reasons for SM reporting were standardized (using OpenRefine and Microsoft Excel). The following analyses were performed using IRAMuTeQ 0.7 alpha2: lexicographic analysis to obtain the frequency of active words; descending hierarchical classification (DHC) to categorize the active words into lexical classes; factorial correspondence analysis (FCA) to obtain graphs of the classes. Approved by the Ethics Committee of the Hospital do Trabalhador/SES/PR CAAE 81873417.3.0000.5225 (protocol number: 2.506.594). Results: A total of 61,775 reports were analyzed, most of them reported by hospitals (46%). The DHC of the reasons for SM produced four classes visualized in the FCA: (i) packaging problems (16%) mainly leakages/opening issues; (ii) inadequate drug identification (22%), such as illegible label information; (iii) stability and contamination issues (11%) such as presence of particles; (iv) damaged tablets/blisters (23%) mainly broken tablets. Most SM (52%) were solutions for parenteral use; sodium chloride (9%), glucose and dipyrone (3%) were the products with most complaints. Conclusions: The reasons for SM reporting can be objectively classified into classes that represent the main problems submitted to Notivisa. This classification could guide the standardization of SM reporting and contribute to improving surveillance reporting systems worldwide

Functional characterization of 8-oxoguanine DNA glycosylase of Trypanosoma cruzi

The oxidative lesion 8-oxoguanine (8-oxoG) is removed during base excision repair by the 8-oxoguanine DNA glycosylase 1 (Ogg1). This lesion can erroneously pair with adenine, and the excision of this damaged base by Ogg1 enables the insertion of a guanine and prevents DNA mutation. In this report, we identified and characterized Ogg1 from the protozoan parasite Trypanosoma cruzi (TcOgg1), the causative agent of Chagas disease. Like most living organisms, T. cruzi is susceptible to oxidative stress, hence DNA repair is essential for its survival and improvement of infection. We verified that the TcOGG1 gene encodes an 8-oxoG DNA glycosylase by complementing an Ogg1-defective Saccharomyces cerevisiae strain. Heterologous expression of TcOGG1 reestablished the mutation frequency of the yeast mutant ogg1-/- (CD138) to wild type levels. We also demonstrate that the overexpression of TcOGG1 increases T. cruzi sensitivity to hydrogen peroxide (H2O2). Analysis of DNA lesions using quantitative PCR suggests that the increased susceptibility to H2O2 of TcOGG1-overexpressor could be a consequence of uncoupled BER in abasic sites and/or strand breaks generated after TcOgg1 removes 8-oxoG, which are not rapidly repaired by the subsequent BER enzymes. This hypothesis is supported by the observation that TcOGG1-overexpressors have reduced levels of 8-oxoG both in the nucleus and in the parasite mitochondrion. The localization of TcOgg1 was examined in parasite transfected with a TcOgg1-GFP fusion, which confirmed that this enzyme is in both organelles. Taken together, our data indicate that T. cruzi has a functional Ogg1 ortholog that participates in nuclear and mitochondrial BER. © 2012 Furtado et al

An in vivo control map for the eukaryotic mRNA translation machinery

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis

Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells

Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment‐based approach to create new flexible G‐quadruplex (G4) DNA‐interactive small molecules with good calculated oral drug‐like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)‐stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose‐ and DNA sequence‐dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G‐quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4′‐(4,4′‐(1,3‐phenylene)bis(1H‐1,2,3‐triazole‐4,1‐diyl))bis(1‐methylquinolin‐1‐ium) (1 d) showed the greater activity. Importantly, dose–response curves show that 1 d is cytotoxic in the human colon cancer HT‐29 cell line enriched in cancer stem‐like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells

Strength training to prevent falls in older adults: A systematic review with meta-analysis of randomized controlled trials

We performed a systematic review with meta-analysis of randomized controlled trials (RCTs) to assess the effects of strength training (ST), as compared to alternative multimodal or unimodal exercise programs, on the number of falls in older adults (=60 years). Ten databases were consulted (CINAHL, Cochrane Library, EBSCO, EMBASE, PEDro, PubMed, Scielo, Scopus, SPORTDiscus and Web of Science), without limitations on language or publication date. Eligibility criteria were as follows: RCTs with humans =60 years of age of any gender with one group performing supervised ST and a group performing another type of exercise training, reporting data pertaining falls. Certainty of evidence was assessed with Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Meta-analysis used a random effects model to calculate the risk ratio (RR) for number of falls. Five RCTs with six trials were included (n = 543, 76% women). There was no difference between ST and alternative exercise interventions for falls (RR = 1.00, 95% CI 0.77–1.30, p = 0.99). The certainty of evidence was very low. No dose–response relationship could be established. In sum, ST showed comparable RR based on number of falls in older adults when compared to other multimodal or unimodal exercise modalities, but evidence is scarce and heteroge-neous, and additional research is required for more robust conclusions. Registration: PROSPERO CRD42020222908

Bayesian inference of biochemical kinetic parameters using the linear noise approximation

Background Fluorescent and luminescent gene reporters allow us to dynamically quantify changes in molecular species concentration over time on the single cell level. The mathematical modeling of their interaction through multivariate dynamical models requires the deveopment of effective statistical methods to calibrate such models against available data. Given the prevalence of stochasticity and noise in biochemical systems inference for stochastic models is of special interest. In this paper we present a simple and computationally efficient algorithm for the estimation of biochemical kinetic parameters from gene reporter data. Results We use the linear noise approximation to model biochemical reactions through a stochastic dynamic model which essentially approximates a diffusion model by an ordinary differential equation model with an appropriately defined noise process. An explicit formula for the likelihood function can be derived allowing for computationally efficient parameter estimation. The proposed algorithm is embedded in a Bayesian framework and inference is performed using Markov chain Monte Carlo. Conclusion The major advantage of the method is that in contrast to the more established diffusion approximation based methods the computationally costly methods of data augmentation are not necessary. Our approach also allows for unobserved variables and measurement error. The application of the method to both simulated and experimental data shows that the proposed methodology provides a useful alternative to diffusion approximation based methods

Osteochondral transplantation using autografts from the upper tibio-fibular joint for the treatment of knee cartilage lesions

Purpose Treatment of large cartilage lesions of the knee in weight-bearing areas is still a controversy and challenging topic. Autologous osteochondral mosaicplasty has proven to be a valid option for treatment but donor site morbidity with most frequently used autografts remains a source of concern. This study aims to assess clinical results and safety profile of autologous osteochondral graft from the upper tibio-fibular joint applied to reconstruct symptomatic osteochondral lesions of the knee. Methods Thirty-one patients (22 men and 9 women) with grade 4 cartilage lesions in the knee were operated by mosaicplasty technique using autologous osteochondral graft from the upper tibio-fibular joint, between 1998 and 2006. Clinical assessment included visual analog scale (VAS) for pain and Lysholm score. All patients were evaluated by MRI pre- and post-operatively regarding joint congruency as good, fair (inferior to 1 mm incongruence), and poor (incongruence higher than 1 mm registered in any frame). Donor zone status was evaluated according to specific protocol considering upper tibio-fibular joint instability, pain, neurological complications, lateral collateral ligament insufficiency, or ankle complaints. Results Mean age at surgery was 30.1 years (SD 12.2). In respect to lesion sites, 22 were located in weight-bearing area of medial femoral condyle, 7 in lateral femoral condyle, 1 in trochlea, and 1 in patella. Mean follow-up was 110.1 months (SD 23.2). Mean area of lesion was 3.3 cm 2 (SD 1.7), and a variable number of cylinders were used, mean 2.5 (SD 1.3). Mean VAS score improved from 47.1 (SD 10.1) to 20.0 (SD 11.5); p = 0.00. Similarly, mean Lysholm score increased from 45.7 (SD 4.5) to 85.3 (SD 7.0); p = 0.00. The level of patient satisfaction was evaluated, and 28 patients declared to be satisfied/very satisfied and would do surgery again, while 3 declared as unsatisfied with the procedure and would not submit to surgery again. These three patients had lower clinical scores and kept complaints related to the original problem but unrelated to donor zone. MRI score significantly improved at 18–24 months comparing with pre-operative (p = 0.004). No radiographic or clinical complications related to donor zone with implication in activity were registered. Conclusions This work corroborates that mosaicplasty technique using autologous osteochondral graft from the upper tibio-fibular joint is effective to treat osteochondral defects in the knee joint. No relevant complications related to donor zone were registered