Microplastics Biodegradation by Estuarine and Landfill Microbiomes.

Plastic pollution poses a worldwide environmental challenge, affecting wildlife and human health. Assessing the biodegradation capabilities of natural microbiomes in environments contaminated with microplastics is crucial for mitigating the effects of plastic pollution. In this work, we evaluated the potential of landfill leachate (LL) and estuarine sediments (ES) to biodegrade polyethylene (PE), polyethylene terephthalate (PET), and polycaprolactone (PCL), under aerobic, anaerobic, thermophilic, and mesophilic conditions. PCL underwent extensive aerobic biodegradation with LL (99 ± 7%) and ES (78 ± 3%) within 50-60 days. Under anaerobic conditions, LL degraded 87 ± 19% of PCL in 60 days, whereas ES showed minimal biodegradation (3 ± 0.3%). PE and PET showed no notable degradation. Metataxonomics results (16S rRNA sequencing) revealed the presence of highly abundant thermophilic microorganisms assigned to Coprothermobacter sp. (6.8% and 28% relative abundance in anaerobic and aerobic incubations, respectively). Coprothermobacter spp. contain genes encoding two enzymes, an esterase and a thermostable monoacylglycerol lipase, that can potentially catalyze PCL hydrolysis. These results suggest that Coprothermobacter sp. may be pivotal in landfill leachate microbiomes for thermophilic PCL biodegradation across varying conditions. The anaerobic microbial community was dominated by hydrogenotrophic methanogens assigned to Methanothermobacter sp. (21%), pointing at possible syntrophic interactions with Coprothermobacter sp. (a H2-producer) during PCL biodegradation. In the aerobic experiments, fungi dominated the eukaryotic microbial community (e.g., Exophiala (41%), Penicillium (17%), and Mucor (18%)), suggesting that aerobic PCL biodegradation by LL involves collaboration between fungi and bacteria. Our findings bring insights on the microbial communities and microbial interactions mediating plastic biodegradation, offering valuable perspectives for plastic pollution mitigation.

Evaluation of axial displacement and torque loss of Morse-type prosthetic abutments of different angular tapers to their respective implants.

STATEMENT OF PROBLEM: The biomechanical stability of the implant-prosthesis assembly and its maintenance under function is a determining factor in the success of implant prosthesis rehabilitation, but studies of different angular tapers are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the axial displacement and torque loss of prosthetic abutments with Morse-type connections of different angular tapers after thermomechanical cycling by using microcomputed tomography (µCT) and a digital torque wrench. MATERIAL AND METHODS: Eighteen Ø3.5×11.5-mm implants were embedded in polyvinyl chloride cylinders, and the 3 different types of abutments (n=6) with angular tapers of 11.5 degrees - Alvim Cone Morse (ACM-11.5), 16.0 degrees - Helix Gran Morse (HGM-16), and 24.0 degrees - Nobel Replace Conical Connection (NRC-24) were installed with the torque recommended by the manufacturers. To calculate the axial displacements of the abutments about the implants, zirconia maxillary canine crowns were fabricated using a computer-aided design and computer-aided manufacturing (CAD-CAM) system and cemented onto the abutments. Before and after thermomechanical cycling, the assemblies were scanned using microtomography (micro-CT) to assess axial displacement, and the torque losses were calculated after the abutments were finally unscrewed. A load of 100 N, frequency of 2 Hz, and 106 cycles with temperature variation of 5 °C to 55 °C were used for the thermomechanical cycling. Analysis of variance and the Tukey post hoc test (α=.05) were used for analysis. RESULTS: A significant difference was observed between the abutments for axial displacement, measured after thermomechanical cycling (P=.002). The ACM-11.5 abutment showed the highest mean value (134.1 ±58.7 µm), different from HGM-16 (63.3 ±26.1 µm) (P=.013) and NRC-24 (42.7 ±8.7 µm) (P=.002); the 2 latter groups were similar to each other (P=.618). For the torque losses, no significant difference was found among the abutments (P=.928), but there were significant differences for the thermomechanical cycling (before and after) (P<.001) in that the loss of torque was greater after thermocycling. CONCLUSIONS: The smaller the taper angle of the Morse-type prosthetic abutment, the greater its axial displacement, and the thermomechanical cycling significantly reduced pretorque, regardless of taper.

Gouregine, an α-Gem-Dimethyltetradehydrocularine Alkaloid, and Other Aporphinoid Alkaloids from the Bark of Guatteria olivacea (Annonaceae) and Their In Vitro Cytotoxic Activities.

Guatteria olivacea R.E. Fries is an Amazonian species known as 'envira-bobó' and 'envira-fofa' and is common in the states of Amazonas, Acre, and Pará. Recently, the essential oil from the leaves of this species has shown promising antitumor activity both in vitro and in vivo. The presence of isoquinoline-derived alkaloids, including aporphinoids and tetrahydroprotoberberine alkaloids, has also been previously reported. In our ongoing search for bioactive compounds from Annonaceae Amazonian plants, the bark of G. olivacea was investigated via classical chromatography techniques, which revealed nine compounds, eight isoquinoline-derived alkaloids, a rare alkaloid with a α-gem-dimethyltetradehydrocularine structure known as gouregine, seven known aporphinoid alkaloids: isopiline, O-methylisopiline, melosmine, 9-hydroxyiguattescine, dihydromelosmine, lysicamine, and guattouregidine, and one known pimaradiene diterpene: acanthoic acid. All the isolated compounds were described for the first time in the bark of G. olivacea, and their structures were elucidated by extensive analyses of their 1D and 2D NMR spectra in combination with MS data. The NMR data of the alkaloids isopiline, O-methylisopiline, melosmine, dihydromelosmine, and guattouregidine were revised due to incomplete data in the literature and some ambiguities. The in vitro cytotoxic activities of the isolated compounds were evaluated against human cancer (HepG2, KG-1a, and HCT116) and noncancerous (MRC-5) cell lines via the Alamar blue assay after 72 h of incubation. Among the compounds evaluated against human cancer cell lines, the most active was the oxoaporphine alkaloid lysicamine, which has strong activity against HCT116 cells, with an IC50 value of 6.64 µg/mL (22.79 µmol/L). Melosmine had a moderate effect on HCT116 cells, with an IC50 value of 16.77 µg/mL (49.70 µmol/L), whereas acanthoic acid had moderate effects on HepG2 and HCT116 cells, with IC50 values of 14.63 µg/mL (48.37 µmol/L) and 21.25 µg/mL (70.25 µmol/L), respectively.

Terbuthylazine herbicide: an alternative to atrazine for weed control in glyphosate-tolerant maize.

It is proposed that the herbicide terbuthylazine is more effective than atrazine in controlling weeds in maize. This study aimed to evaluate the efficacy of terbuthylazine and atrazine in a mixture with glyphosate in glyphosate-tolerant maize for post-emergence application. The experiment was conducted over three trials using randomized blocks with 4 repetitions and 10 treatments, composed by terbuthylazine rates + glyphosate, atrazine rates + glyphosate, [atrazine + mesotrione] + glyphosate, atrazine + tembotrione, isolated glyphosate, and nontreated control. Trial 1 were infested with Bidens subalternans DC. and Commelina benghalensis L; trial 2 with Urochloa plantaginea (Link) R. D. Webster, Ipomoea spp., volunteer soybean, B. subalternans, and grasses; and trial 3 infestation with C. benghalensis, U. plantaginea, Ipomoea spp., volunteer soybean, B. subalternans, Amaranthus hybridus L., and grasses. Weed control, crop injury, and yield were evaluated. Terbuthylazine + glyphosate showed an efficacy equivalent to that of atrazine or [atrazine + mesotrione] + glyphosate in the control of broadleaves and C. benghalensis. In contrast, the efficacy of terbuthylazine was similar or greater than that observed for atrazine in controlling grasses, depending on the location. Terbuthylazine is an important partner of glyphosate in controlling weeds in maize and is an alternative to atrazine.

Virtual Reality Exposure Treatment in Phobias: a Systematic Review.

We compare the relative efficacy of virtual reality therapy exposure (VRET) versus in vivo therapy exposure among individuals suffering from phobias. A systematic search was completed up to 03 April 2020, using the following databases: ACM Digital Library, ResearchGate, IEEE, Science Direct, MIT PressJournals, Center for Direct Scientific Communication (CCSD) and Mary Ann Liebert Publishers. Five authors searched the databases using the following terms: Virtual Reality, Phobia, Mental health, Computing, Therapy, HMD, CAVE, Virtual ambient, in virtuo, Avoidance, Exposure, VRET, in vivo, Anxiety, Agoraphobia, Social Phobia, Stimuli, Cognitive-behaviour. All studies that evaluate the effect of in virtuo exposure towards phobia rehabilitation were selected. By reviewing the article, each author then applied the inclusion and exclusion criteria, and 30 articles were selected. Data extracted included the number of samples, amount of sessions, study variables that may affect the final outcome, therapy technology. The data provided was synthesized using a meta-analysis based on the results. The results demonstrated a positive outcome of Virtual Reality Exposure Treatment in the treatment of most phobias. In contrast, some of these treatments did not work for a few specific phobias in which the standard procedures were more effective. The findings suggest that for some specific phobias treatment, Virtual Reality Exposure Treatment does not reach the in vivo exposure level of immersion and presence. Further research is needed to perform studies with higher-dimension samples, since many papers report a low sample size and that is probably why many of them have inconclusive results.

Performance, biochemical and physiological parameters of Dorper × Santa Ines lambs fed with three levels of metabolizable energy.

This study aimed to evaluate the performance and the blood biochemical and physiological parameters of Dorper × Santa Ines lambs receiving three levels of metabolizable energy (ME). A completely randomized design with three treatments (ME levels) and eight replicates (lambs) was used. Twenty-four non-castrated male lambs of four months of age and 21.07 ± 3.91 kg body weight (BW) received a diet composed of 40% Tifton 85 hay and 60% concentrate feed, on a dry matter basis. The amount of feed supplied was adjusted to meet 115, 201, and 288 kcal ME per kg of metabolic weight (MW = BW0.75) daily. Average daily gain and the intake of dry matter (g/day and % BW0.75/day), nutrients, and energy increased linearly (P < 0.001) with ME level. The dry matter intake relative to BW (% BW/day) and feed conversion ratio showed quadratic responses (P < 0.05) to ME level. Serum creatinine decreased linearly (P = 0.038), whereas plasma glucose increased linearly (P = 0.045) with ME level. Serum urea presented a high variation (standard error range = ±1.98-6.07 mg/dL) in response to 288 kcal/kg0.75/day of ME supply, and did not stabilize during the trial. Respiratory rate increased linearly (P < 0.001) with ME level at each time of day (morning/afternoon), but with higher intensity in the afternoon. Heart rate and rectal temperature increased linearly (P < 0.001) with ME level. Given that the range of ME level simulated a restricted-to-ad libitum ME intake, the best response in terms of feed efficiency can be obtained with 252 kcal/kg0.75/day of ME supply, which probably reflects the best balance of metabolic and physiological parameters. Thus, in order to achieve high productive performance in tropical environments, feedlot lambs should be fed with high-concentrate diets.

Sinergism between alkaloids piperine and capsaicin with meglumine antimoniate against Leishmania infantum.

The primary choice of drugs to treat Leishmaniasis are the pentavalent antimony-based compounds, nevertheless these drugs presented undesirable side effects. However, safe natural compounds could be used in combination with these drugs to enhance their activity. The aim of this study was to evaluate the sinergism of capsaicin and piperine, isolated from Capsicum frutescens and Piper nigrum, respectively, in combination with meglumine antimoniate against Leishmania infantum promastigote and amastigote forms. Each compound was mixed with the standard drug in several percentage mixtures and tested at various concentrations. Capsaicin and piperine in combination with meglumine antimoniate (25% + 75%) showed better anti-leishmanial activity with EC50 = 4.31 ±â€¯0.44 e 7.25 ±â€¯4.84 µg/mL against promastigote and amastigote forms, respectively. The results point that these spice alkaloids are suitable compounds to be administered in combinations with antileishmanial drugs to improve their action.

Lenalidomide is effective and safe for the treatment of patients with relapsed multiple myeloma and very severe renal impairment.

Patients with multiple myeloma (MM) and severe renal impairment (SRI) have shorter survival than MM patients without renal failure. Although lenalidomide is a highly active drug, this immunomodulatory agent is frequently neglected in this context due to its predominant renal clearance and, consequently, an increased risk of toxicity. This risk might be overcome with the proper lenalidomide dose adjustment to renal function. This study evaluates the outcomes of 23 relapsed MM patients with SRI (baseline creatinine clearance (CrCl) <30 mL/min) treated with lenalidomide-dexamethasone (LenDex), including 56 % (13 patients) under hemodialysis. The median CrCl at start of LenDex was 19 mL/min; an overall response rate (partial response or better) of 56 % was obtained, with a median follow-up from start of LenDex of 52 months (8-79). The median time until maximal response was 4 months, and in 58 % (7/12), the response was longer than 2 years. Nine percent had renal improvement, but all the 13 patients on hemodialysis remained under treatment. LenDex was interrupted in three cases because of adverse events (infections and cutaneous events); 78 % of the patients were on thromboprophylaxis with aspirin. It is important to notice that, after initial dose adjustment of therapy, there should be a continuous process of dose adjustment, taking into account variations in renal function. Furthermore, lenalidomide dose adjustment should be made according to the individual tolerance, even with stable renal function. LenDex dose adjustment, according to these principles, does not negatively impact response and improves treatment tolerance. It has a clear potential to treat this group of patients and to induce long duration of responses [event-free survival (EFS) 20.5 m and overall survival (OS) 42.6 m].

Optical eye simulator for laser dazzle events.

An optical simulator of the human eye and its application to laser dazzle events are presented. The simulator combines optical design software (ZEMAX) with a scientific programming language (MATLAB) and allows the user to implement and analyze a dazzle scenario using practical, real-world parameters. Contrary to conventional analytical glare analysis, this work uses ray tracing and the scattering model and parameters for each optical element of the eye. The theoretical background of each such element is presented in relation to the model. The overall simulator's calibration, validation, and performance analysis are achieved by comparison with a simpler model based uponCIE disability glare data. Results demonstrate that this kind of advanced optical eye simulation can be used to represent laser dazzle and has the potential to extend the range of applicability of analytical models.

Variations in the structure and function of the soil fungal communities in the traditional cropping systems from Madeira Island.

Agricultural soils are responsible for ecological functions and services that include primary production of food, fiber and fuel, nutrient cycling, carbon cycling and storage, water infiltration and purification, among others. Fungi are important drivers of most of those ecosystem services. Given the importance of fungi in agricultural soils, in this study, we aimed to characterize and analyse the changes of the soil fungal communities of three cropping systems from Madeira Island, where family farming is predominant, and investigate the response of fungi and its functional groups to soil physicochemical properties. To achieve that, we sequenced amplicons targeting the internal transcribed spacer 1 (ITS1) of the rRNA region, to analyse soil samples from 18 agrosystems: 6 vineyards (V), 6 banana plantations (B) and 6 vegetable plantations (H). Our results showed that alpha diversity indices of fungal communities are similar in the three cropping systems, but fungal composition and functional aspects varied among them, with more pronounced differences in B. Ascomycota, Basidiomycota, and Mortierellomycota were the main phyla found in the three cropping systems. Agaricomycetes and Sordariomycetes are the predominant classes in B, representing 23.8 and 22.4%, respectively, while Sordariomycetes (27.9%) followed by Eurotiomycetes (12.3%) were the predominant classes in V and Sordariomycetes (39.2%) followed by Tremellomycetes (8.9%) in the H. Saprotrophs are the fungal group showing higher relative abundance in the three cropping systems, followed by plant pathogens. Regarding symbionts, endophytes were highly observed in B, while mycorrhizal fungi was predominant in V and H. The structure of fungal communities was mainly correlated with soil content of P, K, N, Fe, and Cu. In addition, we identified bioindicators for each cropping system, which means that cultivated crops are also drivers of functional groups and the composition of communities. Overall, the three cropping systems favored diversity and growth of taxa that play important roles in soil, which highlights the importance of conservative management practices to maintain a healthy and resilient agrosystem.

Microorganism community structure: A characterisation of agrosystems from Madeira Archipelago.

Microbial diversity profoundly influences soil ecosystem functions, making it vital to monitor community dynamics to comprehend its structure. Our study focused on six agrosystems in Madeira Archipelago, analysing bacteria, archaea, fungi and AMF through classical microbiology and molecular techniques. Despite distinct edaphoclimatic conditions and management practices, bacterial structures exhibited similarities, with Alphaproteobacteria at 18%-20%, Bacilli at 11%-18% and Clostridia at 9%-14%. The predominance of copiothrophic groups suggested that soil nutrient content was the driver of these communities. Regarding archaea, the communities changed among sites, and it was evident that agrosystems provided niches for methanogens. The Crenarchaeota varied between 15% and 29%, followed by two classes of Euryarchaeota, Methanomicrobia (17%-25%) and Methanococci (4%-32%). Fungal communities showed consistent composition at the class level but had differing diversity indices due to management practices and soil texture. Sordaryomycetes (21%-28%) and Agaricomycetes (15%-23%) were predominant. Conversely, AMF communities appeared to be also influenced by the agrosystem, with Glomus representing over 50% of the community in all agrosystems. These insights into microbial groups' susceptibilities to environmental conditions are crucial for maintaining healthy soil and predicting climate change effects on agrosystems' productivity, resilience and sustainability. Additionally, our findings enable the development of more robust prediction models for agricultural practices.

A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.

Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.

Metabolic tumor volume assessed by 18F FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates.

PURPOSE: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). EXPERIMENTAL DESIGN: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. RESULTS: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P<0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. CONCLUSION: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.

Biochemical and electrophysiological characterization of two sea anemone type 1 potassium toxins from a geographically distant population of Bunodosoma caissarum.

Sea anemone (Cnidaria, Anthozoa) venom is an important source of bioactive compounds used as tools to study the pharmacology and structure-function of voltage-gated K+ channels (KV). These neurotoxins can be divided into four different types, according to their structure and mode of action. In this work, for the first time, two toxins were purified from the venom of Bunodosoma caissarum population from Saint Peter and Saint Paul Archipelago, Brazil. Sequence alignment and phylogenetic analysis reveals that BcsTx1 and BcsTx2 are the newest members of the sea anemone type 1 potassium channel toxins. Their functional characterization was performed by means of a wide electrophysiological screening on 12 different subtypes of KV channels (KV1.1-KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; hERG and Shaker IR). BcsTx1 shows a high affinity for rKv1.2 over rKv1.6, hKv1.3, Shaker IR and rKv1.1, while Bcstx2 potently blocked rKv1.6 over hKv1.3, rKv1.1, Shaker IR and rKv1.2. Furthermore, we also report for the first time a venom composition and biological activity comparison between two geographically distant populations of sea anemones.

Dynamic modeling of the cellular senescence gene regulatory network.

Cellular senescence is a cell fate that prominently impacts physiological and pathophysiological processes. Diverse cellular stresses induce it, and dramatic gene expression changes accompany it. However, determining the interactions comprising the gene regulatory network (GRN) governing senescence remains challenging. Recent advances in signal processing techniques provide opportunities to reconstruct GRNs. Here, we describe a GRN for senescence integrating time-series transcriptome and transcription factor depletion datasets. Specifically, we infer a set of differential equations using the "Sparse Identification of Nonlinear Dynamics" (SINDy) algorithm, discriminate genes with potential hidden regulators, validate the inferred GRN for time-points not included in the training data, and comprehensively benchmark our approach. Our work is a proof of concept for a data-driven GRN reconstruction method, consolidating an iterative, powerful mathematical platform for senescence modeling that can be used to test hypotheses in silico and has the potential for future discoveries of clinical impact.

Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars.

Although oncogene-induced senescence (OIS) is a potent tumor-suppressor mechanism, recent studies revealed that cells could escape from OIS with features of transformed cells. However, the mechanisms that promote OIS escape remain unclear, and evidence of post-senescent cells in human cancers is missing. Here, we unravel the regulatory mechanisms underlying OIS escape using dynamic multidimensional profiling. We demonstrate a critical role for AP1 and POU2F2 transcription factors in escape from OIS and identify senescence-associated chromatin scars (SACSs) as an epigenetic memory of OIS detectable during colorectal cancer progression. POU2F2 levels are already elevated in precancerous lesions and as cells escape from OIS, and its expression and binding activity to cis-regulatory elements are associated with decreased patient survival. Our results support a model in which POU2F2 exploits a precoded enhancer landscape necessary for senescence escape and reveal POU2F2 and SACS gene signatures as valuable biomarkers with diagnostic and prognostic potential.

[Multiple Myeloma Treatment Guidelines by the Portuguese Group of Multiple Myeloma]. / Recomendações do Grupo Português do Mieloma Múltiplo para Tratamento do Mieloma Múltiplo.

The treatment of multiple myeloma has profoundly changed with the introduction of several innovative therapies. The optimization of therapeutic sequencing through the combined use of the various drugs developed in recent years and the attention given to the characteristics of patients have allowed the reduction of toxicities and increased survival and quality of life of patients with multiple myeloma. These treatment recommendations from the Portuguese Multiple Myeloma Group offer guidance for first-line treatment and progression/relapse situations. These recommendations are given highlighting the data that justify each choice and referring to the respective levels of evidence that support these options. Whenever possible, the respective national regulatory framework is presented. These recommendations constitute an advance towards the best treatment of multiple myeloma in Portugal.

O tratamento do mieloma múltiplo tem sido amplamente alterado com introdução de várias terapêuticas inovadoras. A otimização da sequenciação terapêutica através do uso combinado dos vários fármacos desenvolvidos nos últimos anos e a atenção dada às características dos doentes têm permitido diminuir toxicidades e aumentar a sobrevivência dos doentes, bem como aumentar a sua qualidade de vida. As presentes recomendações terapêuticas do Grupo Português do Mieloma Múltiplo oferecem orientações para o tratamento de primeira linha e progressão/recaída. As recomendações são fundamentadas evidenciando os dados que justificam cada escolha e referindo os respetivos níveis de evidência que suportam essas opções. Sempre que possível é apresentado o respetivo enquadramento regulamentar nacional. Estas recomendações constituem um avanço para o melhor tratamento do mieloma múltiplo em Portugal.

Crotamine pharmacology revisited: novel insights based on the inhibition of KV channels.

Crotamine, a 5-kDa peptide, possesses a unique biological versatility. Not only has its cell-penetrating activity become of clinical interest but, moreover, its potential selective antitumor activity is of great pharmacological importance. In the past, several studies have attempted to elucidate the exact molecular target responsible for the crotamine-induced skeletal muscle spasm. The aim of this study was to investigate whether crotamine affects voltage-gated potassium (K(V)) channels in an effort to explain its in vivo effects. Crotamine was studied on ion channel function using the two-electrode voltage clamp technique on 16 cloned ion channels (12 K(V) channels and 4 Na(V) channels), expressed in Xenopus laevis oocytes. Crotamine selectively inhibits K(V)1.1, K(V)1.2, and K(V)1.3 channels with an IC(50) of ∼300 nM, and the key amino acids responsible for this molecular interaction are suggested. Our results demonstrate for the first time that the symptoms, which are observed in the typical crotamine syndrome, may result from the inhibition of K(V) channels. The ability of crotamine to inhibit the potassium current through K(V) channels unravels it as the first snake peptide with the unique multifunctionality of cell-penetrating and antitumoral activity combined with K(V) channel-inhibiting properties. This new property of crotamine might explain some experimental observations and opens new perspectives on pharmacological uses.

Relationship between occlusion and lisping in children with cleft lip and palate.

INTRODUCTION: The literature suggests that individuals with history of cleft lip and palate who present with midfacial growth deficiency are at higher risk of presenting lisping. The relationship between distortions during production of linguoalveolar fricative sounds and the severity of malocclusion, however, has not been established for the population with cleft. OBJECTIVE: To study the association between lisping and dental arch relationship. METHODOLOGY: Speech samples and dental arch casts were obtained from 106 children with operated unilateral cleft lip and palate (UCLP) during the stage of mixed dentition and before orthodontic treatment. Videotaped productions of the phrase /u saci saiw sedu/ were rated by speech-language pathologists for the identification of lisping during [s]. Dental arch casts were rated by orthodontists using the Goslon Yardstick and the Five-Year Index to establish dental arch relationship. RESULTS: Multiple logistic regression showed no significant association between lisping and dento-occlusal index (p  =  .802) and age (p  =  .662). Substantial interjudge agreement during auditory-perceptual ratings was found (kappa  =  .63). Almost perfect agreement was found between orthodontists while establishing the dental arch relationship (kappa  =  .81). DISCUSSION: This study failed to reveal an association between lisping and dental arch relationship in children with operated UCLP. Multiple variables may play a role in determining occurrence of lisping, warranting further investigation.