Calcification patterns and morphology of Sella turcica are related to anteroposterior skeletal malocclusions: A cross-sectional study.

BACKGROUND: The sphenoid bone is an irregular, unpaired, symmetrical bone located in the middle of the anterior skull and is involved in craniofacial growth and development. Since the morphology of Sella turcica (ST) is associated with different craniofacial patterns, this study aimed to investigate if there is a correlation between ST morphology on the one hand and sagittal craniofacial patterns on the other hand. METHODS: This study was conducted with a convenience sample that included Brazilian individuals undergoing orthodontic treatment. Lateral cephalograms were used to evaluate the calcification pattern and morphology of ST, as well as skeletal class by analyzing the ANB angle. Pearson's chi-square test with Bonferroni post-hoc test was performed to evaluate the association between ST calcification pattern and morphology, and anteroposterior skeletal malocclusion. The established significance level was 0.05. RESULTS: The study collective was comprised of 305 orthodontic patients (178 (58.4 %) female, 127 (41.6 %) male), who had a mean age of 23.2 (±10.6) years. 131 participants (42.9 %) presented skeletal class I, 142 (46.6%) skeletal Class II, and 32 (10.5%) had a skeletal class III. The degree of prognathism of the mandible showed a homogenous distribution within the study collective (91 (29.9 %) orthognathic, 100 (32.9 %) retrognathic, 113 (37.2 %) prognathic mandible). Concerning the maxilla, 92 (30.2%) individuals presented an orthognathic upper jaw, whereas 60 (19.7%) showed maxillary retrognathism and 153 (50.2%) maxillary prognathism. Compared to patients with skeletal class I, skeletal class III individuals presented significantly more hypertrophic posterior clinoid process (p<0.007) and pyramidal shape of the dorsum of the ST (p<0.038). CONCLUSIONS: Our results suggest that the hypertrophic posterior clinoid process and pyramidal shape of the ST dorsum are more prevalent in individuals with skeletal class III malocclusion.

Unlocking the microbiome.

Individual species of bacteria and yeast present in the food of wild fruit flies work together to provide the nutrients needed for larval growth.

An investigation of digital skills of therapeutic radiographers/radiation therapists: A european survey of proficiency level and future educational needs.

INTRODUCTION: This study aims to assess the proficiency level of digital skills, the factors influencing that level and the training needs of Therapeutic Radiographers/Radiation Therapists (TR/RTTs), due to the differences in technology availability and accessibility, variations in the regulation and education of TR/RTTs in European countries, and the lack of a digital skills framework. METHODS: An online survey was distributed to TR/RTTs working in Europe to capture their self-assessment of proficiency levels of digital skills when performing their clinical role. Information was also gathered regarding training, work experience and level of information and communication technology (ICT) skills. Quantitative measures were analysed using descriptive statistics and correlation between variables, and qualitative responses using thematic analysis. RESULTS: 101 respondents from 13 European countries completed the survey. Digital skills in treatment planning followed by management and research were the least developed skills, while the most developed were transversal digital skills followed by digital skills in treatment delivery. The Radiotherapy areas of practice where TR/RTT has experience (e.g. Planning Image, Treatment Planning, Treatment), as well as the level of generic ICT skills (communication, content creation and problem-solving), was related to the level of proficiency of TR/RTT digital skills. Greater scope of practice and level of generic ICT were associated with a higher level of TR/RTT digital skills. Thematic analysis allowed the identification of new sub-themes to be included in the training of TR/RTTs. CONCLUSION: Education and training of TR/RTTs should be improved and adapted to the current needs of digitalisation to avoid differences in digital proficiency levels. IMPLICATIONS FOR PRACTICE: Aligning TR/RTTs' digital skill sets with emerging digitalisation will improve current practice and ensure the best care to all RT patients.

Barriers to patient recruitment in a poststroke neurorehabilitation multicenter trial in Brazil.

There is a high demand for stroke rehabilitation in the Brazilian public health system, but most studies that have addressed rehabilitation for unilateral spatial neglect (USN) after stroke have been performed in high-income countries. Therefore, the aim of this study was to analyze USN patient recruitment in a multicenter noninvasive brain stimulation clinical trial performed in Brazil and to provide study design recommendations for future studies. We evaluated the reasons for exclusion of patients from a multicenter, randomized, double-blinded clinical trial of rehabilitation of USN patients after stroke. Clinical and demographic variables were compared between the included and excluded patients. A descriptive statistical analysis was performed. Only 173 of the 1953 potential neglect patients (8.8%) passed the initial screening. After screening evaluation, 87/173 patients (50.3%) were excluded for clinical reasons. Cognitive impairment led to the exclusion of 21/87 patients (24.1%). Low socioeconomic status led to the exclusion of 37/173 patients (21.4%). Difficulty obtaining transportation to access treatment was the most common reason for their exclusion (16/37 patients, 43.3%). The analyzed Brazilian institutions have potential for conducting studies of USN. The recruitment of stroke survivors with USN was restricted by the study design and limited financial support. A history of cognitive impairment, intracranial stenting or craniectomy, and lack of transportation were the most common barriers to participating in a multicenter noninvasive brain stimulation trial among patients with USN after stroke.

Lung cancer survival and sex-specific patterns in Portugal: A population-based analysis.

INTRODUCTION: In Portugal, lung cancer (LC) is the first cause of cancer-related death and of death and disability combined. This study aims to analyze the overall survival (OS) and relative survival (RS) of patients diagnosed with LC in 2009-2011 by socio-demographic and tumor characteristics, and analyze sex-specific patterns. METHODS: We estimated 5-year OS using the Kaplan-Meier method and 5-year net survival through the RS framework. Cox regression modeling was used to determine the hazard ratio (HR) of death associated with each independent variable. FINDINGS: For the 11,523 cases analyzed, median 5-year OS was 264 days (95% confidence interval [CI]: 254.8-273.2), the cumulative OS was 13.6% and RS was 15.1%. Males had a lower median survival (237 days; 95% CI: 228.2-245.7) compared to females (416 days; 95% CI: 384.4-447.6) (p < 0.0001) and lower 5-year RS proportions (12.1% vs. 24.9%). RS progressively decreased with age (41.7% for age-group <40 to 7.2% for ≥80) and stage (66.6% for stage I to 2.4% for stage IV). As predictors of decreased survival, we identified male gender, increasing age >50, histologic types (squamous cell carcinoma, non-small cell lung cancer not otherwise specified, other unspecified and small cell lung cancer), and increasing stage. Compared to women, the risk of death in men was 37.7% higher (HR = 1.386; 95% CI: 1.295-1.484). CONCLUSIONS: The differences between OS and RS were small, reflecting the high lethality of LC. Male gender and older age are factors related to poor prognosis. Histology also plays a role in survival prognosis and varies with gender, but the factor related to the worst survival is stage. Although the study reflects data from a decade ago, and major changes occurred in diagnosis, staging and treatment, particularly for advanced disease, as LC mortality is strongly correlated with late stage diagnosis, all efforts should be made to secure early diagnosis and improve survival prospects.

Barriers to patient recruitment in a poststroke neurorehabilitation multicenter trial in Brazil

There is a high demand for stroke rehabilitation in the Brazilian public health system, but most studies that have addressed rehabilitation for unilateral spatial neglect (USN) after stroke have been performed in high-income countries. Therefore, the aim of this study was to analyze USN patient recruitment in a multicenter noninvasive brain stimulation clinical trial performed in Brazil and to provide study design recommendations for future studies. We evaluated the reasons for exclusion of patients from a multicenter, randomized, double-blinded clinical trial of rehabilitation of USN patients after stroke. Clinical and demographic variables were compared between the included and excluded patients. A descriptive statistical analysis was performed. Only 173 of the 1953 potential neglect patients (8.8%) passed the initial screening. After screening evaluation, 87/173 patients (50.3%) were excluded for clinical reasons. Cognitive impairment led to the exclusion of 21/87 patients (24.1%). Low socioeconomic status led to the exclusion of 37/173 patients (21.4%). Difficulty obtaining transportation to access treatment was the most common reason for their exclusion (16/37 patients, 43.3%). The analyzed Brazilian institutions have potential for conducting studies of USN. The recruitment of stroke survivors with USN was restricted by the study design and limited financial support. A history of cognitive impairment, intracranial stenting or craniectomy, and lack of transportation were the most common barriers to participating in a multicenter noninvasive brain stimulation trial among patients with USN after stroke.

Polymyxin Resistance in Clinical Isolates of K. pneumoniae in Brazil: Update on Molecular Mechanisms, Clonal Dissemination and Relationship With KPC-Producing Strains.

In Brazil, the production of KPC-type carbapenemases in Enterobacteriales is endemic, leading to widespread use of polymyxins. In the present study, 502 Klebsiella pneumoniae isolates were evaluated for resistance to polymyxins, their genetic determinants and clonality, in addition to the presence of carbapenem resistance genes and evaluation of antimicrobial resistance. Resistance to colistin (polymyxin E) was evaluated through initial selection on EMB agar containing 4% colistin sulfate, followed by Minimal Inhibitory Concentration (MIC) determination by broth microdilution. The susceptibility to 17 antimicrobials was assessed by disk diffusion. The presence of blaKPC, blaNDM and blaOXA-48-like carbapenemases was investigated by phenotypic methods and conventional PCR. Molecular typing was performed by PFGE and MLST. Allelic variants of the mcr gene were screened by PCR and chromosomal mutations in the pmrA, pmrB, phoP, phoQ and mgrB genes were investigated by sequencing. Our work showed a colistin resistance frequency of 29.5% (n = 148/502) in K. pneumoniae isolates. Colistin MICs from 4 to >128 µg/mL were identified (MIC50 = 64 µg/mL; MIC90 >128 µg/mL). All isolates were considered MDR, with the lowest resistance rates observed for amikacin (34.4%), and 19.6% of the isolates were resistant to all tested antimicrobials. The blaKPC gene was identified in 77% of the isolates, in consonance with the high rate of resistance to polymyxins related to its use as a therapeutic alternative. Through XbaI-PFGE, 51 pulsotypes were identified. MLST showed 21 STs, with ST437, ST258 and ST11 (CC11) being the most prevalent, and two new STs were determined: ST4868 and ST4869. The mcr-1 gene was identified in 3 K. pneumoniae isolates. Missense mutations in chromosomal genes were identified, as well as insertion sequences in mgrB. Furthermore, the identification of chromosomal mutations in K. pneumoniae isolates belonging from CC11 ensures its success as a high-risk epidemic clone in Brazil and worldwide.

Digital skills of therapeutic radiographers/radiation therapists - Document analysis for a European educational curriculum.

INTRODUCTION: It is estimated that around 50% of cancer patients require Radiotherapy (RT) at some point during their treatment, hence Therapeutic Radiographers/Radiation Therapists (TR/RTTs) have a key role to play in patient management. It is essential for TR/RTTs to keep abreast with new technologies and continuously develop the digital skills necessary for safe RT practice. The RT profession and education is not regulated at European Union level, which leads to heterogeneity in the skills developed and practised among countries. This study aimed to explore the white and grey literature to collate data on the relevant digital skills required for TR/RTTs practice. METHODS: An exhaustive systematic search was conducted to identify literature discussing digital skills of TR/RTTs; relevant grey literature was also identified. A thematic analysis was performed to identify and organise these skills into themes and sub-themes. RESULTS: 195 digital skills were identified, organised in 35 sub-themes and grouped into six main themes: (i) Transversal Digital Skills, (ii) RT Planning Image, (iii) RT Treatment Planning, (iv) RT Treatment Administration, (v) Quality, Safety and Risk Management, and (vi) Management, Education and Research. CONCLUSION: This list can be used as a reference to close current gaps in knowledge or skills of TR/RTTs while anticipating future needs regarding the rapid development of new technologies (such as Artificial Intelligence or Big Data). IMPLICATIONS FOR PRACTICE: It is imperative to align education with current and future RT practice to ensure that all RT patients receive the best care. Filling the gaps in TR/RTTs skill sets will improve current practice and provide TR/RTTs with the support needed to develop more advanced skills.

Beta-hydroxy-beta-methylbutyrate associated with low-intensity exercise training improves skeletal muscle regeneration through the IGF-Akt pathway.

The effect of beta-hydroxy-beta-methylbutyrate (HMB) supplementation associated with exercise training at different intensities and frequencies on skeletal muscle regeneration of muscle-injured rats was investigated. Male Wistar rats were divided into sedentary and trained groups. The sedentary groups were subdivided into non-injured (SED-Ct), non-injured supplemented with HMB (SED-Ct-HMB), injured (SED), and injured with HMB (SED-HMB), and the trained groups were injured, supplemented with HMB, and then divided into training three times a week without load (HT3) or with load (HT3L) and training five times a week without load (HT5) and with load (HT5L). The rats received a daily dose of HMB associated with 60 min of swimming with or without 5% body mass load for 14 days. On the 15th day, cryoinjury was performed in the right tibialis anterior muscle (TA), and 48 h later, supplementation and training continued for 15 days. After the last session, the TA was dissected and a cross-sectional area (CSA) of muscle fibers was used to determine the percentage of CSA fibers and connective tissue (%CT), as well as the total and phosphorylated protein contents. SED-HMB showed increased CSA and decreased %CT and TGF-ß when compared to SED. HT3 showed increased CSA and reduced %CT accompanied by increased IGF-1/Akt, myogenin, and MuRF1, and decreased TGF-ß. The CSA of HT5L also increased, but at the cost of a higher %CT compared to the other groups. Our results demonstrated that HMB associated with training without load and with lower frequency per week may be a valuable strategy for skeletal muscle regeneration.

Beta-hydroxy-beta-methylbutyrate associated with low-intensity exercise training improves skeletal muscle regeneration through the IGF-Akt pathway

The effect of beta-hydroxy-beta-methylbutyrate (HMB) supplementation associated with exercise training at different intensities and frequencies on skeletal muscle regeneration of muscle-injured rats was investigated. Male Wistar rats were divided into sedentary and trained groups. The sedentary groups were subdivided into non-injured (SED-Ct), non-injured supplemented with HMB (SED-Ct-HMB), injured (SED), and injured with HMB (SED-HMB), and the trained groups were injured, supplemented with HMB, and then divided into training three times a week without load (HT3) or with load (HT3L) and training five times a week without load (HT5) and with load (HT5L). The rats received a daily dose of HMB associated with 60 min of swimming with or without 5% body mass load for 14 days. On the 15th day, cryoinjury was performed in the right tibialis anterior muscle (TA), and 48 h later, supplementation and training continued for 15 days. After the last session, the TA was dissected and a cross-sectional area (CSA) of muscle fibers was used to determine the percentage of CSA fibers and connective tissue (%CT), as well as the total and phosphorylated protein contents. SED-HMB showed increased CSA and decreased %CT and TGF-β when compared to SED. HT3 showed increased CSA and reduced %CT accompanied by increased IGF-1/Akt, myogenin, and MuRF1, and decreased TGF-β. The CSA of HT5L also increased, but at the cost of a higher %CT compared to the other groups. Our results demonstrated that HMB associated with training without load and with lower frequency per week may be a valuable strategy for skeletal muscle regeneration.

The role of two-component regulatory systems in environmental sensing and virulence in Salmonella.

Adaptation to environments with constant fluctuations imposes challenges that are only overcome with sophisticated strategies that allow bacteria to perceive environmental conditions and develop an appropriate response. The gastrointestinal environment is a complex ecosystem that is home to trillions of microorganisms. Termed microbiota, this microbial ensemble plays important roles in host health and provides colonization resistance against pathogens, although pathogens have evolved strategies to circumvent this barrier. Among the strategies used by bacteria to monitor their environment, one of the most important are the sensing and signalling machineries of two-component systems (TCSs), which play relevant roles in the behaviour of all bacteria. Salmonella enterica is no exception, and here we present our current understanding of how this important human pathogen uses TCSs as an integral part of its lifestyle. We describe important aspects of these systems, such as the stimuli and responses involved, the processes regulated, and their roles in virulence. We also dissect the genomic organization of histidine kinases and response regulators, as well as the input and output domains for each TCS. Lastly, we explore how these systems may be promising targets for the development of antivirulence therapeutics to combat antibiotic-resistant infections.

Association between genetic polymorphisms in the promoter region of the defensin beta 1 gene and persistent apical periodontitis.

AIM: To evaluate the association between the promoter region of defensin beta 1 (DEFB1) genetic polymorphisms and persistent apical periodontitis (PAP) in Brazilian patients. METHODOLOGY: Seventy-three patients with post-treatment PAP (PAP group) and 89 patients with root filled teeth with healed and healthy periradicular tissues (healed group) were included (all teeth had apical periodontitis lesions at the beginning of the treatment). Patients who had undergone at least 1 year of follow-up after root canal treatment were recalled, and their genomic DNA was extracted from saliva. Two single nucleotide polymorphisms (SNPs) in DEFB1 at the g. -52G>A (rs1799946) and g. -20G>A (rs11362) positions were analysed using real-time polymerase chain reaction. The chi-squared test was performed, and the odds ratios were calculated using Epi Info 3.5.2. Logistic regression analysis in the codominant model, using the time of follow-up as a variable, was used to evaluate the SNP-SNP interaction. All tests were performed with an established alpha of 0.05 (P = 0.05). RESULTS: For the rs11362 polymorphism in the codominant and recessive models, patients who carried two copies of the T allele had a significantly lower risk of developing PAP (P = 0.040 and P = 0.031, respectively). For the rs1799946 polymorphism in DEFB1 in the codominant and recessive models, carrying one copy of the T allele significantly increased the risk of developing PAP (P = 0.007 and P = 0.031, respectively). In the logistic regression, both polymorphisms were associated with PAP as well as the SNP-SNP interaction (P < 0.0001). CONCLUSIONS: Polymorphisms in DEFB1 genes were associated with the development of post-treatment persistent apical periodontitis.

Metabolic profiles of multidrug resistant and extensively drug resistant Mycobacterium tuberculosis unveiled by metabolomics.

Although treatable with antibiotics, tuberculosis is a leading cause of death. Mycobacterium tuberculosis antibiotic resistance is becoming increasingly common and disease control is challenging. Conventional drug susceptibility testing takes weeks to produce results, and treatment is often initiated empirically. Therefore, new methods to determine drug susceptibility profiles are urgent. Here, we used mass-spectrometry-based metabolomics to characterize the metabolic landscape of drug-susceptible (DS), multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis. Direct infusion mass spectrometry data showed that DS, MDR, and XDR strains have distinct metabolic profiles, which can be used to predict drug susceptibility and resistance. This was later confirmed by Ultra-High-Performance Liquid Chromatography and High-Resolution Mass Spectrometry, where we found that levels of ions presumptively identified as isoleucine, proline, hercynine, betaine, and pantothenic acid varied significantly between strains with different drug susceptibility profiles. We then confirmed the identification of proline and isoleucine and determined their absolute concentrations in bacterial extracts, and found significantly higher levels of these amino acids in DS strains, as compared to drug-resistant strains (combined MDR and XDR strains). Our results advance the current understanding of the effect of drug resistance on bacterial metabolism and open avenues for the detection of drug resistance biomarkers.

Immunoexpression of bone resorption biomarkers in apical periodontitis in diabetics and normoglycaemics.

AIM: To compare the immunoexpression of RANK, MMP-9 and PTHrP in apical periodontitis lesions of diabetic and normoglycaemic individuals. METHODOLOGY: Primary chronic apical periodontitis lesions associated with teeth indicated for extraction in 13 type 2 diabetic individuals and 13 normoglycaemic individuals who were screened for the glycaemic index and glycated haemoglobin (HbA1c) were analysed. Individuals with other systemic diseases and users of anti-inflammatories and/or antibiotics in the previous 3 months were excluded. Silanized slides with paraffin sections were used for immunohistochemical reactions and stained with haematoxylin and eosin for histopathological classification. The images were analysed with an optical microscope, and the slides were subdivided into five large fields assigning scores (0-2), according to the number of positive markings for each antibody. Fisher's exact test evaluated the parameters: gender, type of lesion, location and position in the arch. Nonparametric Mann-Whitney test was used for age, HbA1c values and comparison of marker expression. The chi-squared test was used to associate the expression of the markers. And the Spearman's coefficient correlated the markers with the size of the periapical lesion. RESULTS: The samples consisted of 69% periapical granulomas and 31% periapical cysts in each group. RANK expression was considered weak/moderate and strong in, respectively, 62% and 38% of the cases in both groups. MMP-9 expression was weak/moderate and strong in, respectively, 38% and 62% of the cases from the diabetic group, in comparison with 38% and 38% in the normoglycaemics (24% cases from this group were negative). In contrast, PTHrP expression was negative, weak/moderate and strong in, respectively, 46%, 46% and 8% of the cases from the diabetic group, in comparison with 38% negative and 62% weak/moderate in normoglycaemics. Quantitative analysis revealed that there were no significant differences in the immunoexpression of RANK (P = 0.26), MMP-9 (P = 0.17) and PTHrP (P = 0.43) between the groups. There was no significant correlation between the expression of bone resorption markers and the macroscopic size of the periapical lesions (P > 0.05). CONCLUSIONS: The bone resorption mediators analysed had similar immunoexpression in the periapical lesions of diabetic and normoglycaemic individuals.

Dental Caries, Developmental Defects of Enamel and Enamel Microhardness Associated with Genetic Polymorphisms in the RANK/RANKL/OPG System.

Purpose: Recent studies have suggested that disruptions in the RANKL/RANK/OPG system might be involved in enamel conditions. The aim of this study was to test whether genetic polymorphisms in RANK, RANKL and OPG are associated with dental caries, developmental defects of enamel (DDE) and enamel microhardness. Study design: Saliva samples were collected from two subsets for the purpose of genomic DNA extraction. In the first subset, composed of 248 children, dental caries and DDE were evaluated during their clinical examination. In the second subset, composed of 72 children, enamel samples from the buccal surface of primary teeth were used for enamel microhardness analysis. Genetic polymorphisms in RANK, RANKL and OPG were genotyped by real-time polymerase chain reactions in all samples from both populations. The chi-square test was used for dental caries and DDE analysis while, one-way ANOVA with Tukey's post-test was used for microhardness analysis. Hardy-Weinberg equilibrium was also calculated. The established alpha was 5%. Results: Caries experience analysis demonstrated a statistically-significant difference for OPG allele distribution in primary dentition (p=0.033). The studied polymorphisms in RANK, RANKL and OPG were not associated with DDE or enamel microhardness (p>0.05). Conclusion: The genetic polymorphism rs2073618 in OPG is associated with dental caries experience in primary dentition.

Cytotoxic, genotoxic, and oxidative stress-inducing effect of an l-amino acid oxidase isolated from Bothrops jararacussu venom in a co-culture model of HepG2 and HUVEC cells.

Hepatocellular carcinoma incidence rates have increased worldwide, which encouraged the development of new chemotherapeutic drugs. l-Amino acid oxidases from snake venoms are cytotoxic towards human tumor cells in in vitro monoculture systems, which do not simulate the tumor microenvironment. We examined the antitumor potential of BjussuLAAO-II, an l-amino acid oxidase from Bothrops jararacussu venom, in hepatocarcinoma cells (HepG2) in monoculture and co-culture with human umbilical vein endothelial cells (HUVEC) in vitro. All the concentrations tested (0.25-5.00 µg/mL) were cytotoxic (MTT and clonogenic survival assays) towards HepG2 and HUVEC cells in monoculture, and increased oxidative stress by 2',7'-dichlorofluorescin diacetate fluorescence assay. Only 1.00 and 5.00 µg/mL exerted these effects in HepG2 cells co-cultured with HUVEC cells, and were genotoxic (comet assay) to HUVEC cells in monoculture. BjussuLAAO-II at 5.00 µg/mL induced DNA, but not chromosomal damage (micronucleus assay) in HepG2 cells in mono- and co-culture. The cytotoxicity and genotoxicity was more pronounced in monoculture, indicating that the tumor microenvironment influences the cellular response. BjussuLAAO-II caused cell death and DNA damage in HepG2 cells in vitro by inducing oxidative stress. Therefore, BjussuLAAO-II is a promising molecule for the development of new antitumor drugs.

[Cutaneous metastases on the extremities]. / Métastases cutanées des extrémités.

BACKGROUND: Cutaneous metastases (CM) on the extremities are rare complication of cancer with poor prognosis. In general, lesions simulate an infection. Herein, we report two new cases with atypical presentation. PATIENTS AND METHODS: Case no 1: a 71-year-old man consulted for suspicion of left hand pyogenic granuloma present for 3 months. His history revealed two treated squamous-cell carcinomas (tongue and lung). On physical examination, he presented three budding and foul-smelling lesions on his left hand. Histopathology showed metastasis of squamous-cell carcinoma. Radiographic examination revealed spread of pulmonary nodules with suspicion of metastasis. Case no 2: a 68-year-old man was hospitalized for indurated edema of the right leg present for several months. Six months earlier, he had undergone surgery for left pulmonary adenocarcinoma without metastasis. Physical examination revealed an indurated edema on the right foot. Histopathology showed metastasis from adenocarcinoma. A scan revealed several osteolytic lesions in the right foot as well as lymphadenopathy. DISCUSSION: Herein, we report two original cases of CM of the extremities diagnosed as tumor progression. This is a rare complication of variable clinical presentation and impacts both cancer management and prognosis. It is important to consider the diagnosis when distal cutaneous lesions persist, particularly where there is a history of cancer.

Integrated analysis of ethionamide resistance loci in Mycobacterium tuberculosis clinical isolates.

Tuberculosis patients taking second line drugs such as ethionamide (ETH) have often experienced previous treatment failure and usually have a complex history of disease and treatment that can span decades. Mutations in the ETH activating enzyme, EthA, confer resistance through undescribed mechanisms. To explore the impact of EthA mutations on ETH resistance, data from a total of 160 ETHR isolates was analysed. The most frequently mutated positions are within regions that display sequence conservation with the active site of OTEMO, another FAD-containing NADH-binding Baeyer-Villiger monooxygenase (BVMO), or with the sugar binding site of galectin-4N. Additionally, to look at a possible role of EthR on ETH resistance we purified an EthR mutant identified in a clinical isolate, F110L, and found it to bind the ethA-ethR intergenic region with higher affinity than the wild type regulator in gel shift assays. The ability of cyclic di-GMP to enhance DNA binding is maintained in the EthR mutant. To our knowledge, this is the first ETH resistance study that combines sequence and resistance data of clinical isolates with functional and structural information.

Laurus nobilis (laurel) aqueous leaf extract's toxicological and anti-tumor activities in HPV16-transgenic mice.

Cancers induced by human papillomavirus (HPV) infection remain a significant public health threat, fueling the study of new therapies. Laurel (Laurus nobilis) compounds and extracts recently showed in vitro activity against HPV-transformed cell lines. This work aims to evaluate the in vivo efficacy and hepatic toxicity of a laurel extract in a transgenic mouse model of HPV16-induced cancer. The extract was administered in drinking water (20 mg per animal per day) for three consecutive weeks, using four experimental groups (n = 10) (group I: HPV16-/- without treatment, group II: treated HPV16-/-, group III: HPV16+/- without treatment and group IV: treated HPV16+/-). Following the treatment period, animals were sacrificed and skin samples were used to classify skin lesions histologically. Toxicological parameters included hematological and biochemical blood markers, splenic and hepatic histology and hepatic oxidative stress. The extract did not prevent the progression of HPV16-induced cutaneous lesions in this model. The treated wild-type animals showed mild hepatitis, while transgenic animals suffered weight loss. However, there were no changes concerning hematological, biochemical and hepatic oxidative stress markers.

iNKT cells are increased in children with severe therapy-resistant asthma

Background: Invariant natural killer T (iNKT) cells play complex functions in the immune system, releasing both Th1 and Th2 cytokines. The role of iNKT cells in human asthma is still controversial and never described in severe therapy-resistant asthma in children. The objective of this work was to analyse iNKT frequency in peripheral blood of children with severe therapy-resistant asthma (STRA), compared to children with milder asthma and healthy controls. Methods: Children with asthma (n = 136) (non-severe and STRA) from a referral centre and healthy controls (n = 40) were recruited. Peripheral blood mononuclear cells were isolated, stained with anti-CD3 and anti-iNKT (Vα24Jα18), and analysed through flow cytometry. Atopic status was defined by measuring specific IgE in serum. Airway inflammation was assessed by induced sputum. Results: Children with asthma presented an increased frequency of CD3+iNKT+ cells (median 0.38% IQR 0.18-1.9), compared to healthy controls (median 0.26% IQR 0.10-0.43) (p = 0.025). Children with STRA also showed an increased frequency of iNKT cells (1.5% IQR 1.05-2.73) compared to healthy controls and non-severe asthmatic children (0.35% IQR 0.15-1.6; p = 0.002). The frequency of iNKT cells was not different between atopic and non-atopic children. In addition, iNKT cells were not associated with any inflammatory pattern of induced sputum studied. Conclusion: Our data suggests that iNKT cells play a role in paediatric asthma, which is also associated with the severity of disease, but independent of the atopic status (AU)

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