Synergistic effect of the verapamil and amphotericin B against Cryptococcus neoformans.

Cryptococcus neoformans is an encapsulated yeast that can cause cryptococcosis and cryptococcal meningitis, which conventional treatment involves antifungal drugs such as polyenes, flucytosine, azoles, and their combinations. However, the high cost, toxicity, and increase in fungi resistance to antifungal agents stimulate the search for therapeutic strategies such as drug repurposing and combination therapy. This study evaluated the activity of the antihypertensive verapamil (VEH) alone and combined with amphotericin B (AmB) against C. neoformans. VEH exhibited antifungal activity against C. neoformans with minimum inhibitory concentration and minimum fungicidal concentration of 118 µg per mL. The combination of VEH and AmB exhibited synergism, reducing at least eightfold both drugs' concentrations. Moreover, the combination decreased the size and glucuronoxylomannnan content of C. neoformans capsule. However, no difference was observed in ergosterol levels of C. neoformans after treatment with VEH and AmB in combination. Altogether, VEH in combination with AmB exhibits potential as a candidate as for the development of anti-cryptococcal drug.

Synergistic Antibiofilm Action of Cinnamomum verum and Brazilian Green Propolis Hydroethanolic Extracts against Multidrug-Resistant Strains of Acinetobacter baumannii and Pseudomonas aeruginosa and Their Biocompatibility on Human Keratinocytes.

The accumulated dental biofilm can be a source of oral bacteria that are aspirated into the lower respiratory tract causing ventilator-associated pneumonia in hospitalized patients. The aim of this study was to evaluate the synergistic antibiofilm action of the produced and phytochemically characterized extracts of Cinnamomum verum and Brazilian green propolis (BGP) hydroethanolic extracts against multidrug-resistant clinical strains of Acinetobacter baumannii and Pseudomonas aeruginosa, in addition to their biocompatibility on human keratinocyte cell lines (HaCaT). For this, High-performance liquid chromatography analysis of the plant extracts was performed; then the minimum inhibitory and minimum bactericidal concentrations of the extracts were determined; and antibiofilm activity was evaluated with MTT assay to prevent biofilm formation and to reduce the mature biofilms. The cytotoxicity of the extracts was verified using the MTT colorimetric test, evaluating the cellular enzymatic activity. The data were analyzed with one-way ANOVA and Tukey's tests as well as Kruskal-Wallis and Dunn's tests, considering a significance level of 5%. It was possible to identify the cinnamic aldehyde in C. verum and p-coumaric, caffeic, and caffeoylquinic acids as well as flavonoids such as kaempferol and kaempferide and Artepillin-C in BGP. The combined extracts were effective in preventing biofilm formation and reducing the mature biofilms of A. baumannii and P. aeruginosa. Moreover, both extracts were biocompatible in different concentrations. Therefore, C. verum and BGP hydroethanolic extracts have bactericidal and antibiofilm action against multidrug resistant strains of A. baumannii and P. aeruginosa. In addition, the combined extracts were capable of expressively inhibiting the formation of A. baumannii and P. aeruginosa biofilms (prophylactic effect) acting similarly to 0.12% chlorhexidine gluconate.

Using survey data to estimate the impact of the omicron variant on vaccine efficacy against COVID-19 infection.

Symptoms-based detection of SARS-CoV-2 infection is not a substitute for precise diagnostic tests but can provide insight into the likely level of infection in a given population. This study uses symptoms data collected in the Global COVID-19 Trends and Impact Surveys (UMD Global CTIS), and data on variants sequencing from GISAID. This work, conducted in January of 2022 during the emergence of the Omicron variant (subvariant BA.1), aims to improve the quality of infection detection from the available symptoms and to use the resulting estimates of infection levels to assess the changes in vaccine efficacy during a change of dominant variant; from the Delta dominant to the Omicron dominant period. Our approach produced a new symptoms-based classifier, Random Forest, that was compared to a ground-truth subset of cases with known diagnostic test status. This classifier was compared with other competing classifiers and shown to exhibit an increased performance with respect to the ground-truth data. Using the Random Forest classifier, and knowing the vaccination status of the subjects, we then proceeded to analyse the evolution of vaccine efficacy towards infection during different periods, geographies and dominant variants. In South Africa, where the first significant wave of Omicron occurred, a significant reduction of vaccine efficacy is observed from August-September 2021 to December 2021. For instance, the efficacy drops from 0.81 to 0.30 for those vaccinated with 2 doses (of Pfizer/BioNTech), and from 0.51 to 0.09 for those vaccinated with one dose (of Pfizer/BioNTech or Johnson & Johnson). We also extended the study to other countries in which Omicron has been detected, comparing the situation in October 2021 (before Omicron) with that of December 2021. While the reduction measured is smaller than in South Africa, we still found, for instance, an average drop in vaccine efficacy from 0.53 to 0.45 among those vaccinated with two doses. Moreover, we found a significant negative (Pearson) correlation of around - 0.6 between the measured prevalence of Omicron in several countries and the vaccine efficacy in those same countries. This prediction, in January of 2022, of the decreased vaccine efficacy towards Omicron is in line with the subsequent increase of Omicron infections in the first half of 2022.

Synergistic combination of duloxetine hydrochloride and fluconazole reduces the cell growth and capsule size of Cryptococcus neoformans.

This study aimed to evaluate the effect of duloxetine hydrochloride (DH) on Cryptococcus neoformans. DH minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were 18.5 µg/mL, and the combination with fluconazole (FLZ) reduced the MIC value by 16-and 4-fold for DH and FLZ, respectively. The capsule size decreased by 67% ​​and 16% when treated with DH and DH with FLZ, respectively. Therefore, this study showed that DH is active against C. neoformans alone and in combination with FLZ, leading to the reduction of the capsule size of this yeast.

Spatio-temporal analysis of land use/land cover change dynamics in Paraguai/Jauquara Basin, Brazil.

Although global climate change is receiving considerable attention, the loss of biodiversity worldwide continues. In this study, dynamics of land use/land cover (LULC) change in the Paraguai/Jauquara Basin, Mato Grosso, Brazil, were investigated. Two analyses were performed using R software. The first was a comparative study of LULC among the LULC classes at the polygon scale, and the second was a spatio-temporal analysis of moving polygons restricted to the agricultural regions in terms of topology, size, distance, and direction of change. The data consisted of Landsat images captured in 1993, 1997, 2001, 2005, 2009, 2013, and 2016 and processed using ArcGIS software. The proposed analytical approach handled complex data structures and allowed for a deeper understanding of LULC change over time. The results showed that there was a statistically significant change from regions of natural vegetation to pastures, agricultural regions, and land for other uses, accompanied by a significant trend of expansion of agricultural regions, appearing to stabilize from 2005. Furthermore, different patterns of LULC change were found according to soil type and elevation. In particular, the purple latosol soil type presented the highest expansion indexes since 2001, and the elevated agricultural areas have been expanding and/or stabilizing since 1997.

Estimating the COVID-19 Prevalence in Spain With Indirect Reporting via Open Surveys.

During the initial phases of the COVID-19 pandemic, accurate tracking has proven unfeasible. Initial estimation methods pointed toward case numbers that were much higher than officially reported. In the CoronaSurveys project, we have been addressing this issue using open online surveys with indirect reporting. We compare our estimates with the results of a serology study for Spain, obtaining high correlations (R squared 0.89). In our view, these results strongly support the idea of using open surveys with indirect reporting as a method to broadly sense the progress of a pandemic.

In vitro synergistic effects of fluoxetine and paroxetine in combination with amphotericin B against Cryptococcus neoformans.

Cryptococcus neoformans is a yeast that mainly affects immunocompromised individuals and causes meningoencephalitis depending on the immune status of the host. The present study aimed to validate the efficacy of selective serotonin reuptake inhibitors, fluoxetine hydrochloride (FLH) and paroxetine hydrochloride (PAH), alone and in combination with amphotericin B (AmB) against C. neoformans. Susceptibility tests were conducted using the broth microdilution method and synergistic effects of combining FLH and PAH with AmB were analyzed using the checkerboard assay. Effects of minimum inhibitory concentration (MIC) and synergistic concentration were evaluated in biofilms by quantifying the biomass, measuring the viability by counting the colony-forming units (CFU/mL) and examining the size of the induced capsules. Cryptococcus neoformans was susceptible to FLH and PAH and the synergistic effect of FLH and PAH in combination with AmB reduced the MIC of AmB by up to 8-fold. The isolated substances and combination with AmB were able to reduce biofilm biomass and biofilm viability. In addition, FLH and PAH alone or in combination with AmB significantly decreased the size of the yeast capsules. Collectively, our results indicate the use of FLH and PAH as a promising prototype for the development of anti-cryptococcal drugs.

Antifungal and anti-biofilm effect of the calcium channel blocker verapamil on non-albicans Candida species.

Candida is a human fungal pathogen that causes a wide range of diseases. Candida albicans is the main etiologic agent in these diseases; however, infections can be caused by non-albicans Candida species. Virulence factors such as biofilm production, which protect the fungus from host immunity and anti-fungal drugs, are important for the infection. Therefore, available antifungal drugs for candidiasis treatment are limited and the investigation of new and effective drugs is needed. Verapamil is a calcium channel blocker with an inhibitory effect on hyphae development, adhesion, and colonization of C. albicans. In this study, we investigated the effect of verapamil on cell viability and its antifungal and anti-biofilm activity in non-albicans Candida species. Verapamil was not toxic to keratinocyte cells; moreover, C. krusei, C. parapsilosis, and C. glabrata were susceptible to verapamil with a minimal inhibitory concentration (MIC) of 1250 µM; in addition, this drug displayed fungistatic effect at the evaluated concentrations. After treatment with verapamil, reduced viability, biomass, and mitochondrial activity were observed in biofilms of the non-albicans Candida species C. krusei, C. glabrata, and C. parapsilosis. These findings highlight the importance of the study of verapamil as an alternative treatment for infections caused by non-albicans Candida species.

Alcohol consumption does not increase the risk of surgical wound complications in breast cancer patients.

Alcohol consumption, despite influencing several organic processes, has been scarcely studied regarding the risk of developing surgical wound complications after surgical breast cancer treatment. The aim of this study was to analyse the association between alcohol consumption and the development of surgical wound complications in women undergoing surgical treatment for breast cancer. A prospective cohort study was conducted, comprising 486 women between 40 and 69 years old, interviewed during the preoperative period and followed up for 30 days. The occurrence of seroma, necrosis, surgical site infection (SSI), dehiscence, ecchymosis, and hematoma were considered as outcomes. Alcohol consumption during the 30 days prior to surgery was reported by 20.8% of the patients, with 8.4% being occasional consumers and 12.4% regular consumers. Binge drinking was reported by 10.2% of the women. The presence of surgical wound complications was observed in 65.2%. The most frequent complications were seroma (54.3%), necrosis (17.7%), and SSI (7.8%). No statistically significant association between alcohol consumption and the development of cicatricial complications was observed.

Efeito do cloridrato de duloxetina frente a Cryptococcus neoformans: abordagem in vitro e in vivo / Evaluation of the antifungal activity of duloxetine hydrochloride in Cryptococcus neoformans: in vitro and in vivo approach

A criptococose se destaca pela alta incidência principalmente em pacientes imunocomprometidos, sendo responsável por um terço de todas as mortes em pacientes HIV positivos. Cryptococcus neoformans é o agente etiológico dessas infecções e possui uma cápsula composta, principalmente, por glucuronoxilomanana (GXM) e galactoxilomanana (GalXM) e é o maior fator de virulência dessa levedura. Devido ao limitado número de antifúngicos disponíveis, a toxicidade e a resistência a esses fármacos, o reposicionamento de medicamentos, ou seja, o uso de fármacos convencionalmente utilizados para outras finalidades no tratamento de uma nova doença, bem como a combinação entre os mesmos, podem ser opções importantes para o tratamento da criptococose. Os animais invertebrados têm sido amplamente utilizados na avaliação de eficácia e toxicidade de compostos. Assim, o objetivo deste estudo foi avaliar a atividade antifúngica do composto cloridrato de duloxetina (CD) isolado e em combinação com o antifúngico fluconazol (FLZ) utilizando técnicas in vitro e in vivo. Para determinar a Concentração Inibitória Mínima (CIM) e a Concentração Fungicida Mínima (CFM) foi realizada a técnica de microdiluição de acordo com a European Committee for Antimicrobial Susceptibility Testing (EUCAST). Em seguida, foi realizada a avaliação da atividade sinérgica de CD em combinação com FLZ. Além disso, foram avaliados os efeitos isolados de CD bem como as combinações sinérgicas com FLZ em cápsula induzida desta levedura e também na liberação de GXM. Em relação aos ensaios in vivo, o efeito tóxico de CD foi avaliado nos modelos de Caenorhabditis elegans e em Galleria mellonella. Além disso, a eficácia de CD por análise de curva de sobrevivência e o efeito na concentração de hemócitos também foram avaliados em G. mellonella. O fármaco CD apresentou o valor de CIM e CFM de 18,5 µg/mL e quando em combinação com FLZ resultaram em 12 concentrações sinérgicas reduzindo o valor de CIM em 4 a 16 vezes para CD e 4 vezes para FLZ. A análise do efeito de CD e combinações com FLZ mostrou diminuição de 12,5% a 67% no tamanho da cápsula quando avaliadas em concentração sub-inibitória, e em combinação com o FLZ. CD foi capaz de induzir a liberação de GXM em concentração dose-dependente. Em C. elegans e G. mellonella, CD não apresentou efeito tóxico. A dose 18,5 µg/larva de CD em G. mellonella diminuiu 35 vezes a concentração de hemócitos em relação ao grupo PBS. O tratamento isolado e em combinação com FLZ não aumentou o porcentual de sobrevivência de G. mellonella em relação ao grupo controle, fato que pode estar relacionado à alta lipossolubilidade do composto mantendo ligado ao corpo de gordura e impedindo assim seu efeito. Portanto, esse estudo mostrou que CD é ativo frente a C. neoformans in vitro, quando isolado e em combinação com fluconazol, sendo ainda capaz de agir na cápsula desta levedura e liberação de GXM(AU)

Cryptococcosis stands out for its high incidence, mainly in immunocompromised patients, being responsible for one third of all deaths in HIV positive patients. Cryptococcus neoformans is the etiological agent of these infections and has a capsule composed mainly of glucuronoxylomannan (GXM) and galactoxylomannan (GalXM), being considered the major virulence factor of this yeast. Due to the limited number of antifungals available, the toxicity and resistance to these drugs, the repositioning of drugs, that is, the use of drugs conventionally used for other purposes in the treatment of a new disease, as well as the combination between them, may be important options for the treatment of cryptococcosis. Invertebrate animals have been widely used to evaluate the efficacy and toxicity of compounds. Thus, the objective of this study was to evaluate the antifungal activity of the compound duloxetine hydrochloride (DH) isolated and in combination with the antifungal fluconazole (FLZ) using in vitro and in vivo techniques. To determine the Minimum Inhibitory Concentration (MIC) and the Minimum Fungicidal Concentration (MFC), the microdilution technique was performed according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST). Then, the evaluation of the synergistic activity of DC in combination with FLZ was performed. In addition, the effects of DH as well as synergistic combinations with FLZ in capsule induced from this yeast and also in the release of glucuroxylomannan (GXM) were evaluated. In relation to in vivo tests, the toxic effect of DH was evaluated in the models of Caenorhabditis elegans and in Galleria mellonella. In addition, DH efficacy by survival curve analysis and also the effect on hemocyte concentration were also evaluated in G. mellonella. The drug DH showed a MIC and MFC value of 18.5 µg/mL and when in combination with FLZ resulted in 12 synergistic concentrations, reducing the MIC value by 4 to 16 times for DH and 4 times for FLZ. The analysis of the effect of DH and combinations with FLZ showed a decrease of 12.5% to 67% in the size of the capsule when evaluated in sub-inhibitory concentration, and in combination with FLZ. DH was able to induce the release of GXM in dose-dependent concentration. In C. elegans and G. mellonella, DH had no toxic effect. When the treatment effect was evaluated with 18.5 µg / larva in G. mellonella, DH showed a 35-fold reduction compared to the PBS group. However, treatment alone and in combination with FLZ did not increase the percentage of G. mellonella survival in relation to the control group, a fact that may be related to the high liposolubility of the compound keeping it bound to the body of fat and thus preventing its effect. Thus, this study showed that DH is active against C. neoformans in vitro, when isolated and in combination with fluconazole, being able to act in the capsule of this yeast and release GXM(AU)

Exploring the Galleria mellonella model to study antifungal photodynamic therapy.

BACKGROUND: Antimicrobial photodynamic therapy (aPDT) shows antimicrobial activity on yeast of the genus Candida. In aPDT, the depth at which the light penetrates the tissue is extremely important for the elaboration of the treatment. The aim of this study was to evaluate the action of aPDT on experimental candidiasis and the laser impact in the tissue using Galleria mellonella as the infection model. METHODS: G. mellonella larvae were infected with different Candida albicans strains. After 30 min, they were treated with methylene blue-mediated aPDT and a low intensity laser (660 nm). The larvae were incubated at 37 °C for seven days and monitored daily to determine the survival curve, using the Log-rank test (Mantel Cox). To evaluate the distribution of the laser as well as its depth of action in the larva body, the Interactive 3D surface PLOT of Image J was used. The effects of aPDT on the immune system were also evaluated by the quantification of hemocytes in the hemolymph of G. mellonella after 6 h of Candida infection (ANOVA and Tukey's test). RESULTS: In both the ATCC 18,804 strain and the C. albicans clinical strain 17, aPDT prolonged the survival of the infected G. mellonella larvae by a lethal fungal dose. There was a statistically significant difference between the aPDT and the control groups in the ATCC strain (P = 0.0056). The depth of laser action in the insect body without the photosensitizer was 2.5 mm and 2.4 mm from the cuticle of the larva with the photosensitizer. In the larvae, a uniform distribution of light occurred along 32% of the body length for the group without the photosensitizer and in 39.5% for the group with the photosensitizer. In the immunological analysis, the infection by C. albicans ATCC 18,804 in G. mellonella led to a reduction in the number of hemocytes in the hemolymph. The aPDT and laser treatment induced a slight increase in the number of hemocytes. CONCLUSION: Both aPDT and laser treatment positively influenced the treatment of experimental candidiasis. G. mellonella larvae were a useful model for the study of light tissue penetration in antimicrobial photodynamic therapy.

Scalp microbiota alterations in children with pediculosis.

Pediculosis is a disease caused by the insect Pediculus humanus capitis that mainly occurs in childhood. A comparative study was carried out evaluating groups of schoolchildren with (group A) and without pediculosis (group B) to analyse the characteristics of the scalp microbiota. Samples were collected by swab using Stuart transport medium and incubate in Sabouraud dextrose agar with tetracycline to analyse the fungal microbiota and in blood agar to assess the bacterial microbiota. The isolates identity was confirmed by sequencing of the 16S and 18S regions of the ribosomal DNA gene for bacteria and fungi, respectively. The analysis of the 186 isolates led to the identification of 35 bacteria and 40 fungi in group A and 47 bacteria and 64 fungi in group B. The results indicate differences in bacterial and fungal species in the groups analysed. In the observed bacterial microbiota, Staphylococcus capitis occurred more frequently than Staphylococcus epidermidis in group A vs B. Among fungal isolates, Debaryomyces sp. was more frequent in group B vs A. Our findings showed scalp microbiota alterations in children with pediculosis, meriting future studies to analyse the relationship between these agents and their impact on human health.

Delay of neuropathic pain sensitization after application of dexamethasone-loaded implant in sciatic nerve-injured rats

Neuroimmune interactions underlying the development of pain sensitization in models of neuropathic pain have been widely studied. In this study, we evaluated the development of allodynia and its reduction associated with peripheral antineuroinflammatory effects induced by a dexamethasone-loaded biodegradable implant. Chronic constriction injury (CCI) of the sciatic nerve was performed in Wistar rats. The electronic von Frey test was applied to assess mechanical allodynia. The dexamethasone-loaded implant was placed perineurally at the moment of CCI or 12 days after surgery. Dorsal root ganglia (DRG; L4-L5) were harvested and nuclear extracts were assayed by Western blot for detection of nuclear factor (NF)-κB p65/RelA translocation. Dexamethasone delivered from the implant delayed the development of allodynia for approximately three weeks in CCI rats when the implantation was performed at day 0, but allodynia was not reversed when the implantation was performed at day 12. NF-κB was activated in CCI rat DRG compared with naïve or sham animals (day 15), and dexamethasone implant inhibited p65/RelA translocation in CCI rats compared with control. This study demonstrated that the dexamethasone-loaded implant suppresses allodynia development and peripheral neuroinflammation. This device can reduce the potential side effects associated with oral anti-inflammatory drugs.

Recent Advances in the Use of Galleria mellonella Model to Study Immune Responses against Human Pathogens.

The use of invertebrates for in vivo studies in microbiology is well established in the scientific community. Larvae of Galleria mellonella are a widely used model for studying pathogenesis, the efficacy of new antimicrobial compounds, and immune responses. The immune system of G. mellonella larvae is structurally and functionally similar to the innate immune response of mammals, which makes this model suitable for such studies. In this review, cellular responses (hemocytes activity: phagocytosis, nodulation, and encapsulation) and humoral responses (reactions or soluble molecules released in the hemolymph as antimicrobial peptides, melanization, clotting, free radical production, and primary immunization) are discussed, highlighting the use of G. mellonella as a model of immune response to different human pathogenic microorganisms.

Antiallodynic activity of leflunomide is partially inhibited by naltrexone and glibenclamide and associated with reduced production of TNF-α and CXCL-1.

Leflunomide, an immunosuppressive drug approved for the treatment of patients with rheumatoid arthritis, exhibits many mechanisms which may affect the nociceptive processing. Therefore, the present study aimed to evaluate the effect induced by leflunomide on the mechanical allodynia in models of inflammatory and neuropathic pain in mice and investigate mechanisms mediating such effects. Per os (p.o.) administration of leflunomide (25, 50 or 100mg/kg) inhibited the inflammatory edema and mechanical allodynia induced by intraplantar carrageenan. Even ongoing inflammatory edema and mechanical allodynia were reduced by leflunomide. Previous administration of naltrexone (10mg/kg, intraperitoneal) or glibenclamide (40mg/kg, p.o.) partially attenuated leflunomide antiallodynic activity. A single administration of leflunomide (50 or 100mg/kg, p.o.) also partially inhibited ongoing mechanical allodynia induced by chronic constriction injury (CCI) or repeated administrations of paclitaxel. The antiallodynic effect induced by leflunomide (50 or 100mg/kg, p.o.) in the model of neuropathic pain induced by CCI was associated with reduced production of tumor necrosis factor-α both at the injury site and ipsilateral paw. Leflunomide also reduced production of the chemokine CXCL-1 at the paw ipsilateral to the injury site. Concluding, leflunomide partially inhibited ongoing mechanical allodynia in models of inflammatory and neuropathic pain. The antiallodynic effect was associated with activation of opioidergic receptors and ATP-sensitive potassium channels and reduced production of inflammatory mediators. These data indicate leflunomide as a drug that should be further investigated aiming to identify a new analgesic pharmacotherapy and reinforces repositioning as an important strategy to identify new uses for approved drugs.

Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund's adjuvant.

BACKGROUND: The effects induced by thiamine and riboflavin, isolated or in association with corticosteroids, in models of chronic inflammation are not known. Thus, we evaluated the effect induced by these B vitamins, isolated or in association with dexamethasone, on the mechanical allodynia, paw edema and cytokine production induced by complete Freund's adjuvant (CFA) in rats. METHODS: Chronic inflammation was induced by two injections of CFA. Nociceptive threshold, paw volume and body temperature were evaluated for 21days. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) contents were determined in paw tissue. Riboflavin (125, 250 or 500mg/kg) or thiamine (150, 300 or 600mg/kg) were administered per os (po), twice daily. Dexamethasone (0.5mg/kgday, po) was administered every three days. RESULTS: CFA induced long lasting mechanical allodynia and paw edema. Elevation of body temperature was observed for a short period. Riboflavin reduced neither paw edema nor mechanical allodynia. Thiamine did not change paw edema, but partially inhibited mechanical allodynia. Riboflavin (500mg/kg) and thiamine (600mg/kg) exacerbated the anti-inflammatory activity of dexamethasone. Riboflavin, thiamine and dexamethasone reduced TNF-α and IL-6 production. The association of dexamethasone with thiamine induced greater inhibition of IL-6 production when compared with that induced by dexamethasone. CONCLUSIONS: Riboflavin and thiamine exacerbate the anti-inflammatory activity of dexamethasone and reduce production of TNF-α and IL-6.

2-Phthalimidethanol and 2-phthalimidethyl nitrate inhibit mechanical allodynia, neutrophil recruitment and cytokine and chemokine production in a murine model of articular inflammation.

BACKGROUND: Phthalimide analogs have been shown to exhibit anti-inflammatory, analgesic and immunomodulatory activities in different preclinical assays. This study aimed to investigate the potential role of 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO) in a murine model of antigen-induced articular inflammation. METHODS: Articular inflammation was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in the knee joint of immunized male C57BL/6J mice. The animals were pre-treated with PTD-OH or PTD-NO (500mg/kg, per os, - 1h). Nociceptive threshold was measured using an electronic von Frey apparatus. The total number of leukocytes in the synovial cavity was determined. Concentrations of tumor necrosis factor (TNF)-α and CXCL-1 and myeloperoxidase (MPO) activity were determined in periarticular tissue. RESULTS: Both PTD-OH and PTD-NO inhibited at similar extent the mechanical allodynia, neutrophil recruitment to the synovial cavity and periarticular tissue and TNF-α and CXCL-1 production induced by intra-articular challenge with mBSA in immunized mice. CONCLUSIONS: PTD-OH and PTD-NO exhibit a marked activity in a murine model of antigen-induced articular inflammation in immunized animals. These results reinforce the interest in the investigation of phthalimide analogs devoid of the glutarimide ring as candidates to analgesic and anti-inflammatory drugs.

Impact of Treatment Type on Overall Survival in ElderlyBrazilian Women with Breast Cancer

Objective: To analyze the survival of elderly patients with breast cancer according to the type of treatment used. Methods: A cohort study of women aged 80 or over with breast cancer registered with the Brazilian National Cancer Institute (Instituto Nacional do Câncer - INCA) between 2008 and 2009 was conducted. Prognosis was analyzed according to the cancer treatment performed: surgery, radiotherapy, or hormone therapy. Analysis of the overall 5-year survival rate was performed using the Kaplan - Meier method, and comparisons of curves were undertaken using the log-rank test. For multiple regression analysis, Cox regression was used, adjusting for age and clinical stage, considering values of p < 0.05 as significant. Data were all analyzed using the statistical package SPSS version 20. Results: 70 women with a mean age of 84.0 ± 3.7 years at diagnosis participated in the study. The median follow-up time was 37.1 months (range 0.5­75.5), and 31 deaths (44.3%) occurred during this time. The median survival time was 51.2 months (95% CI, 44.9­57.4), higher in those who underwent surgery (p = 0.012) and those who had hormone therapy (p=0.001). Treatment with surgery reduced the risk of death by 61.7% (HR 0.3; 95% CI, 0.1­0.6; p = 0.001) when adjusted for clinical stage and age at diagnosis. However, there was no significant benefit from radiotherapy (HR 1.2; 95% CI, 0.5­2.5; p = 0.694). Conclusion: Treatment with surgery and hormone therapy increased the survival of our Brazilian patients with breast cancer aged 80 or over.

Cancer cases attributable to alcohol consumption in Brazil.

This is the first study specifically estimating the proportion of new cancer cases that could be attributable to alcohol consumption in the year 2012 in Brazil. The proportion of exposed cases and the association between alcohol and lip and oral cavity, nasopharynx, other pharynx, larynx, esophagus, colorectum, female breast, liver, and intrahepatic bile ducts cancers was based on data made available by the Integrator System of Hospital Cancer Registries. The cancer incidence was obtained from the estimates produced by GLOBOCAN. In 2012 there were 437,592 new cancer cases in Brazil, excluding non-melanoma skin cancers. Of these, alcohol consumption was responsible for 4.8% of all new cases. The alcohol-attributable fraction was higher for men (7.0%) than for women (2.6%). A total of 21,000 new cancer cases, 15,554 in men and 5,646 in women, could be attributable to alcohol consumption. In Brazil, a significant fraction of cancer cases can be attributed to alcohol consumption, and public health measures to prevent heavy alcohol use should be implemented.