Oral paracoccidioidomycosis: a retrospective study of 95 cases from a single center and literature review.

BACKGROUND: The ecoepidemiological panorama of paracoccidioidomycosis (PCM) is dynamic and still ongoing in Brazil. In particular, data about the oral lesions of PCM are barely explored. The aim of this study was to report the clinicopathological features of individuals diagnosed with oral PCM lesions at an oral and maxillofacial pathology service in Rio de Janeiro, Brazil, in the light of a literature review. MATERIAL AND METHODS: A retrospective study was conducted on oral biopsies obtained from 1958 to 2021. Additionally, electronic searches were conducted in PubMed, Embase, Scopus, Web of Science, Latin American and Caribbean Center on Health Sciences Information, and Brazilian Library of Dentistry to gather information from large case series of oral PCM. RESULTS: Ninety-five cases of oral PCM were surveyed. The manifestations were more frequent among males (n=86/90.5%), middle-aged/older adults (n=54/58.7%), and white individuals (n=40/51.9%). The most commonly affected sites were the gingiva/alveolar ridge (n=40/23.4%) and lip/labial commissure (n=33/19.3%); however, one (n=40/42.1%) or multiple sites (n=55/57.9%) could also be affected. In 90 (94.7%) patients, "mulberry-like" ulcerations/moriform appearance were observed. Data from 21 studies (1,333 cases), mostly Brazilian (90.5%), revealed that men (92.4%; male/female: 11.8:1) and individuals in the fifth and sixth decades of life were the most affected (range: 7-89 years), with the gingiva/alveolar ridge, palate, and lips/labial commissure being the sites most frequently affected. CONCLUSIONS: The features of oral PCM lesions are similar to those reported in previous studies from Latin America. Clinicians should be aware of the oral manifestations of PCM, with emphasis on the clinicodemographic aspects and differential diagnoses, especially considering the phenomenon of the emergence of reported cases in rural and/or urban areas of Brazil.

Periodontal outcomes of children and adolescents with attention deficit hyperactivity disorder: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to answer the following question: Are children and adolescents with attention deficit hyperactivity disorder (ADHD) more likely to have gingival or periodontal disease-related outcomes than their non-ADHD peers? METHODS: Searches were conducted in the following databases: Embase, Scopus, Web of Science, and PubMed. Google Scholar and OpenGrey were also verified. Observational studies were included in which children and adolescents with ADHD were compared with their healthy peers in terms of gingival and/or periodontal endpoints. Bias appraisal was performed using the Joann Briggs tool for case-control and cross-sectional studies. Meta-analysis was performed using R language. Results are reported as mean difference (MD) and odds ratio (OR). Statistical analyses were performed in RStudio. RESULTS: A total of 149 records were identified in the searches. Seven studies were included. The meta-analysis showed that children and adolescents with ADHD had a higher mean gingival bleeding index (percentage) than their non-ADHD peers (MD = 11.25; CI = 0.08-22.41; I2 = 73%). There was no difference between groups for plaque index (MD = 4.87; CI = - 2.56 to 12.30; I2 = 63%) and gingivitis (OR = 1.42; CI = 0.22-9.21; I2 = 76%). Regarding the assessment of risk of bias, the major issue found in the articles was the absence of analyses for the control of confounding factors. CONCLUSION: Children and adolescents with ADHD had more gingival bleeding than their non-ADHD peers, but no difference regarding plaque or gingivitis was detected between groups. CLINICAL REGISTRATION: CRD42021258404.

Physalin pool from Physalis angulata L. leaves and physalin D inhibit P2X7 receptor function in vitro and acute lung injury in vivo.

P2X7 receptor promotes inflammatory response and neuropathic pain. New drugs capable of impairing inflammation and pain-reducing adverse effects extracted from plant extracts have been studied. Physalis angulate L. possesses traditional uses and exhibits antiparasitic, anti-inflammatory, antimicrobial, antinociceptive, antimalarial, antileishmanial, immunosuppressive, antiasthmatic. diuretic, and antitumor activities. The most representative phytochemical constituents identified with medicinal importance are the physalins and withanolides. However, the mechanism of anti-inflammatory action is scarce. Although some physalins and withanolides subtypes have anti-inflammatory activity, only four physalins subtypes (B, D, F, and G) have further studies. Therefore, we evaluated the crude ethanolic extract enriched with physalins B, D, F, and G from P. angulata leaves, a pool containing the physalins B, D, F, G, and the physalins individually, as P2X7 receptor antagonists. For this purpose, we evaluated ATP-induced dye uptake, macroscopic currents, and interleukin 1-ß (IL-1ß) in vitro. The crude extract and pool dose-dependently inhibited P2X7 receptor function. Thus, physalin B, D, F, and G individually evaluated for 5'-triphosphate (ATP)-induced dye uptake assay, whole-cell patch-clamp, and cytokine release showed distinct antagonist levels. Physalin D displayed higher potency and efficacy than physalin B, F, and G for all these parameters. In vivo mice model as ATP-induced paw edema was potently inhibited for physalin D, in contrast to physalin B, F, and G. ATP and lipopolysaccharide (LPS)-induced pleurisy in mice were reversed for physalin D treatment. Molecular modeling and computational simulation predicted the intermolecular interactions between the P2X7 receptor and physalin derivatives. In silico results indicated physalin D and F as a potent allosteric P2X7 receptor antagonist. These data confirm physalin D as a promisor source for developing a new P2X7 receptor antagonist with anti-inflammatory action.

Short-chain fatty acids and FFAR2 as suppressors of bone resorption.

Short-chain fatty acids (SCFAs) exert a variety of immune and metabolic functions by binding to G-protein-coupled receptors, mainly free fatty acid receptor 2 (FFAR2). However, the effects of SCFAs and FFARs on bone remodeling, especially in alveolar bone, have been less explored. In this study, we investigated the influence of the SCFA/FFAR2 axis on alveolar bone. Bone samples from wild-type (WT) and FFAR2-deficient mice (FFAR2-/-) were analyzed using micro-CT, histology and qPCR. WT and FFAR2-/- animals received a high-fiber diet (HFD) reported to increase circulating levels of SCFAs. Additionally, we analyzed the effects of SCFAs and a synthetic FFAR2 agonist, phenylacetamide-1 (CTMB), on bone cell differentiation. The participation of histone deacetylase inhibitors (iHDACs) in the effects of SCFAs was further assessed in vitro. CTMB treatment was also evaluated in vivo during orthodontic tooth movement (OTM). FFAR2-/- mice exhibited deterioration of maxillary bone parameters. Consistent with this, FFAR2-/- mice exhibited a significant increase of OTM and changes in bone cell numbers and in the expression of remodeling markers. The HFD partially reversed bone loss in the maxillae of FFAR2-/- mice. In WT mice, the HFD induced changes in the bone markers apparently favoring a bone formation scenario. In vitro, bone marrow cells from FFAR2-/- mice exhibited increased differentiation into osteoclasts, while no changes in osteoblasts were observed. In line with this, differentiation of osteoclasts was diminished by SCFAs and CTMB. Moreover, CTMB treatment significantly reduced OTM. Pretreatment of osteoclasts with iHDACs did not modify the effects of SCFAs on these cells. In conclusion, SCFAs function as regulators of bone resorption. The effects of SCFAs on osteoclasts are dependent on FFAR2 activation and are independent of the inhibition of HDACs. FFAR2 agonists may be useful to control bone osteolysis.

Linear and volumetric gain after vertical bone augmentation in the posterior mandible using an autologous cortical tenting method.

This study was performed to evaluate the linear and volumetric effects of a technique for reconstruction of the posterior atrophic mandible, including the final bone gain of the graft, by three-dimensional assessment. Thirteen individuals were recruited into the study and submitted to a total of 15 mandibular autogenous bone block surgeries. Cone beam computed tomography images were obtained at three different times. Bone graft length and thickness, and the volume, height, and width of the graft were measured. Data were compared statistically among the time points using the Friedman test, and cluster analysis was performed to identify the association between the study variables and the resorption rate (α = 0.05). Linear analysis of the width and height of the recipient area at the different time points revealed a statistically significant difference. The final average increase in height was 1.6 mm; all subjects showed an average volume gain of 3.412mm3, and 77% of the subjects showed an average graft resorption of 0.688mm3 construction of three-dimensional vertical defects of the posterior mandible resulted in good healing with minimal complications and minimal bone graft resorption, favouring vertical bone gain.

Forty cases of acquired oral syphilis and a review of the literature.

The aim of this study was to describe 40 cases of acquired oral syphilis (AOS) and to discuss the distribution of demographic characteristics, clinical features, and differential diagnosis of the disease. A retrospective study was conducted covering a 17-year period at a single institution in southern Brazil. Moreover, a literature review was performed through a search of the PubMed database for articles on AOS published between 1955 and March 2018. Data were analyzed descriptively. The predominant group within the case series was male patients in their twenties. The vast majority of cases (92.5%) were in the secondary stage of the disease. The lips were the most commonly affected site, with greyish-white mucous patches and reddish ulcers. In the literature review, the largest number of reported cases came from North America. Male patients in the third and fourth decades of life were most affected. AOS occurred more commonly as mucous patches and ulcers on the tongue and palate. Similarities regarding the distribution by sex, age, and anatomical location were found in the present study when compared to cases reported elsewhere. Clinicians, oral pathologists, and maxillofacial surgeons should familiarize themselves with the variable spectrum of signs and symptoms of AOS in their clinical practice to improve diagnosis and management.

Male idiopathic infertility and the TP53 polymorphism in codon 72.

Many environmental agents affect the development of male germ cells at different stages. Apoptosis is common during normal spermatogenesis; it plays an important role in controlling the number of germ cells and the disposal of defective stem cells to produce functional sperm. The presence of p53 in primary spermatocytes suggests that it plays a role in the prophase of meiosis. p53 is expressed in the testis in both spermatocytes and spermatogonia. This suggests that the p53 gene (TP53) is important for apoptosis regulation during spermatogenesis, and may be associated with male infertility. The main causes of male infertility are genetic, physical, and pathological abnormalities, intense and prolonged exercise, aging, drug use, and long periods of sexual abstinence. Approximately 20% of male infertility is idiopathic. The Trp53 gene is involved in meiosis in male rats and mice suggesting that the p53 plays a critical role in spermatogenesis. We investigated the association between the TP53 polymorphism in codon 72 and idiopathic male infertility in 208 semen samples: 106 showed abnormal semen analysis results and were from infertile men, and 102 were from fertile individuals (the control group). Changes in Trp53 expression are associated with the main phase regulating meiotic progression with a peak in the pachytene stage, and Trp53-deficient mice exhibit degenerative syndrome (giant cells). The genotypic and allelic frequencies were not significantly different among the groups in this study; the results suggest that the TP53 polymorphism in codon 72 is not associated with the pathogenesis of idiopathic male infertility or failure of spermatogenesis.

Great Ears: Low-Frequency Sensitivity Correlates in Land and Marine Leviathans.

Like elephants, baleen whales produce low-frequency (LF) and even infrasonic (IF) signals, suggesting they may be particularly susceptible to underwater anthropogenic sound impacts. Analyses of computerized tomography scans and histologies of the ears in five baleen whale and two elephant species revealed that LF thresholds correlate with basilar membrane thickness/width and cochlear radii ratios. These factors are consistent with high-mass, low-stiffness membranes and broad spiral curvatures, suggesting that Mysticeti and Proboscidea evolved common inner ear adaptations over similar time scales for processing IF/LF sounds despite operating in different media.

Cytokines release and oxidative status in semen samples from rabbits treated with bacterial lipopolysaccharide.

This study was aimed to evaluate the effects of a lipopolysaccharide- (LPS) induced inflammation on cytokines release and oxidative status of semen samples from buck rabbits at different times after treatment. Semen analysis was performed by optical microscopy and sperm motility evaluation by the computer-assisted sperm analyzer. The presence of activated macrophages and apoptotic/necrotic sperm was evaluated by fluorescent microscopy. A panel of cytokines, interleukin (IL)-6, IL-8, IL-1ß, and tumor necrosis factor-α, were detected and quantified in seminal plasma using the Bio-Plex Cytokine assay. Reactive oxygen metabolite and thiobarbituric acid-reactive substance determinations were carried out by spectrophotometry and tocopherol analysis by high performance liquid chromatography. The sperm motility and track speed were reduced in LPS-treated rabbits. The activated macrophages in LPS-treated buck rabbits significantly increased from 0.50 × 10(6)/mL (baseline) to 27 × 10(6)/mL on Day 21; successively, there was a progressive reduction. Apoptotic and necrotic sperm in LPS rabbits followed more or less the same trend. The reactive oxygen metabolite levels in semen from LPS-treated rabbits showed higher values compared with those evaluated in controls, particularly during the lag time, Days 1 to 3. The sperm thiobarbituric acid-reactive substances highlighted a peak in LPS-treated rabbits compared with those of controls on Day 1 after LPS treatment, and the different T isoforms (α, δ, and γ+ß) showed a similar trend with a significant decrease on Day 1 after injection and a recovery on Days 30 to 56. Until Days 3 to 21 from the treatment, higher levels of IL-1ß and tumor necrosis factor-α were detected in seminal plasma of LPS-treated rabbits. Interleukin-6 showed a peak on Day 3 after LPS treatment, and on Day 7, the value was similar to the control group. In conclusion, this study confirms that the buck rabbit is a good model for mimicking and understanding the inflammation mechanisms, which may induce male infertility, in particular that a systemic inflammatory status causes alterations to the sperm cells through a shift in the balance between the oxidant and antioxidant systems.

Resultados angiográficos e do seguimento clínico de 5 Anos após implante de stents farmacológicos com revestimento biodegradável em pacientes com alto risco de reestenose: análise de subgrupo do estudo randomizado PAINT / Angiographic and 5-year clinical follow-up after implantation of drug-eluting stents with biodegradable coating in patients at high risk of restenosis: the PAINT randomized trial

Introdução: Polímeros biodegradáveis foram desenvolvidos para reduzir a reação de hipersensibilidade associada aos polímeros duráveis dos stents farmacológicos de primeira geração, mantendo sua eficácia antiproliferativa e aumentado sua segurança. Avaliamos os resultados angiográficos de 9 meses e os resultados clínicos de longo prazo dos stents farmacológicos com polímeros biodegradáveis em pacientes com alto risco de reestenose. Métodos: Pacientes com diâmetro de referência ≤ 2,5 mm, extensão da lesão ≥ 15 mm, diabetes, ou uma combinação dessas características foram selecionados da população do estudo PAINT. Esses pacientes foram previamente randomizados e alocados para intervenção coronária percutânea recebendo os stents farmacológicos com polímeros biodegradáveis com sirolimus ou com paclitaxel ou stents metálicos, na razão 2:2:1. Resultados: Cento e setenta e oito pacientes foram tratados com stents farmacológicos com polímeros biodegradáveis (n = 142) ou stents metálicos (n = 36). No acompanhamento angiográfico de 9 meses, os primeiros mostraram menor perda tardia (0,40 ± 0,42 mm vs. 0,90 ± 0,47 mm; p < 0,01) e reestenose binária (7,4% vs. 25%; p < 0,01). No acompanhamento clínico de 5 anos, o grupo com stents farmacológicos com polímeros biodegradáveis mostrou menores taxas do desfecho combinado de morte cardíaca, infarto do miocárdio e revascularização do vaso-alvo (16,2% vs. 38,0%; p = 0,03), principalmente devido à redução da revascularização do vaso-alvo (9,9% vs. 36,1%; p < 0,01). Morte total, morte cardíaca e infarto do miocárdio não foram diferentes entre os grupos. A trombose do stent, provável ou definitiva, ocorreu em 2,8% vs. 0% (p = 0,30). Conclusões: Os stents farmacológicos com polímeros biodegradáveis eluidores de paclitaxel ou sirolimus foram eficazes na redução de reestenose angiográfica aos 9 meses e na necessidade de reintervenção por reestenose clínica em 5 anos, sem aumentar o risco de...

Background: Biodegradable polymers were developed to reduce the hypersensitivity reaction associated to durable polymers found with the first generation drug-eluting stents, while maintaining antiproliferative efficacy and increasing safety. This study evaluated the 9-month angiographic follow-up and long-term clinical outcomes of biodegradable polymer-coated drug-eluting stents compared with identical platform metallic stents in patients with high-risk for restenosis. Methods: Patients with a reference diameter ≤ 2.5 mm, lesion length ≥ 15 mm, diabetes, or a combination of these characteristics were selected from the population of the PAINT trial. These patients were previously randomized and allocated for percutaneous coronary intervention with either a sirolimus-eluting biodegradable polymer-coated stent, a paclitaxel-eluting biodegradable polymer-coated stent, or an identical metallic platform stent, at a ratio of 2:2:1. Results: One hundred and seventy-eight patients were treated with biodegradable polymer-coated drug-eluting stents (n = 142) or bare metal stents (n = 36). At the 9-month angiographic follow-up, biodegradable polymercoated drug-eluting stents had lower rates of late loss (0.40 ± 0.42 mm vs. 0.90 ± 0.47 mm; p < 0.01) and binary restenosis (7.4% vs. 25%; p <0.01). In the 5-year clinical follow-up, the group with biodegradable polymer-coated drug-eluting stents had lower rates of the composite endpoint of cardiac death, myocardial infarction, and target vessel revascularization (16.2% vs. 38.0%; p = 0.03), especially due to the reduction of target vessel revascularization (9.9% vs. 36.1%; (p 0.01). Total death, cardiac death and myocardial infarction were not different among groups. 0% (p = 0.30). Conclusions: Paclitaxel or sirolimus-eluting biodegradable polymer-coated stents were effective in reducing angiographic restenosis at 9 months and the need of reintervention for clinical restenosis in 5...

Very late outcomes of drug-eluting stents coated with biodegradable polymers: insights from the 5-year follow-up of the randomized PAINT trial.

BACKGROUND: Few studies have examined the very long-term outcomes after implantation of drug-eluting stents (DES) coated with biodegradable polymers (BP). This report presents the 5-year clinical follow-up of patients treated with BP-DES in the randomized PAINT trial. METHODS: The PAINT study is a prospective, multicenter randomized controlled trial that allocated 274 patients for treatment with two BP-DES formulations [paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES)] or bare metal stents (BMS) in a 1:2:2 ratio, respectively. The primary end-point of this sub-study was defined as the composite of the major cardiac adverse events (MACE) cardiac death, myocardial infarction (MI) or ischemia-driven target vessel revascularization (TVR) at 5 years. RESULTS: The 5-year MACE rates were different among the groups: 35.3%, 22.5% and 16.9% for BMS, PES and SES, respectively (P<0.05 for both DES vs. bare stent comparisons). The primary end-point was mainly driven by TVR: 31.8%, 14.1% and 12.2% for bare stents, PES and SES, respectively (P<0.05 for both DES vs. bare stent comparisons). The incidence of stent thrombosis (ST) was null for BMS during the entire follow-up. There was no definite or probable ST in the SES group after the second year, while one patient (1.0%) presented with a definite ST episode in the PES group between 4 and 5 years. CONCLUSIONS: The tested biodegradable-polymer coated stents releasing either paclitaxel or sirolimus, compared with same bare metal platform, sustained their effectiveness in reducing combined major adverse cardiac events and re-intervention without an increase in ST during 5 years of follow-up.

Efeito do extrato aquoso de camomila (Chamomilla recutita L. ) na prenhez de ratas e no desenvolvimento dos filhotes / Effect of aqueous extract of chamomile (Chamomilla recutita L. ) on rat pregnancy and offspring development

As plantas medicinais possuem substâncias ativas e, muitas vezes, o efeito tóxico sobre o organismo é desconhecido ou ignorado pelos usuários. A camomila é muito utilizada pela população, porém, contra-indicada para gestantes por possuir indícios de atividade emenagoga e relaxante da musculatura lisa. Por esses motivos, o objetivo do presente estudo foi avaliar os efeitos do extrato aquoso de camomila na gestação e nos filhotes gerados. Foram utilizadas 9 ratas da linhagem Wistar, divididas em 3 grupos, D1 e D2 que receberam infusão de camomila a 5% e 10% respectivamente, e o grupo controle que recebeu soro fisiológico. Os tratamentos foram administrados por via oral, desde o 1º ao 7º dia após o cruzamento. Os parâmetros estudados foram: prevalência de abortos, ganho de peso materno durante a prenhez, morte fetal e materna, malformações fetais grosseiras, número de recém-nascidos, peso dos filhotes, e análise de reflexos neurológicos dos filhotes (postural, preensão e orientação) no 1º, 3º, 5º e 10º dias de vida. Houve gestação em 70% do grupo controle, 40% do D1 e 80% do D2. Não houve diferença no ganho de peso materno no 7º e 21º dia, porém, os grupos tratados obtiveram ganho de peso menor em relação ao controle no 14º dia de gestação (p=0,04). As diferenças entre o número de recém-nascidos não foram significantes. Quanto ao peso dos recém-nascidos, os animais tratados apresentaram menor ganho de peso aos dias 1, 3, 5, e 10 após o nascimento (p=0,005; p=0,001; p<0,001; p<0,001; respectivamente). Ocorreram diferenças no reflexo postural no 1º dia, ocorrendo aceleração (p=0,005); já no reflexo de preensão (p=0,006), e no reflexo de orientação (p=0,01) houve retardo no desaparecimento, sem alteração nos demais dias sobre os outros parâmetros avaliados. A camomila pode influenciar, tanto no ganho de peso materno durante a gestação, como no dos filhotes após o nascimento, e pode provocar alterações nos reflexos neurológicos. Não se observou alteração nos demais parâmetros estudados.

Medicinal plants have active substances and their toxic effect on the organism is often unknown or ignored by users. Chamomile has been widely used by the population; however, it is contraindicated for pregnant women due to evidence of its emmenagogue and relaxing activity on smooth muscles. For these reasons, the aim of this study was to evaluate the effects of aqueous extract of chamomile on pregnancy and generated offspring. Nine Wistar rats were divided into three groups, D1 and D2, which received chamomile infusion at 5% and 10%, respectively, and the control group which received saline solution. Treatments were administered from the 1st to the 7th day after breeding. The studied parameters were abortion prevalence, maternal weight gain during pregnancy, fetal and maternal death, gross fetal malformation, newborn number, weight and neurological reflexes of the offspring on the 1st, 3rd, 5th and 10th days of life. There was pregnancy in 70% of control group, 40% of D1 and 80% of D2. There was no difference in maternal weight gain on the 7th and 21st days; however, treated groups had smaller weight gain, compared to control, on the 14th day of pregnancy (p=0.04). The differences among newborn numbers were not significant. As to weight of newborns, treated animals had smaller weight gain on days 1, 3, 5 and 10 after birth (p=0.005; p=0.001; p<0.001; p<0.001; respectively). For neurological effects, there were differences in postural reflex on the 1st day, resulting in acceleration; on the other hand, for grasp (p=0.006) and orienting reflex (p=0.01), there was a delay in disappearing, and no changes occurred on the remaining days for the other assessed parameters. Chamomile may influence maternal weight gain during pregnancy, as well as offspring weight gain after birth, and may cause changes in neurological reflexes. There was no alteration in the remaining studied parameters.

Late clinical outcomes after implantation of drug-eluting stents coated with biodegradable polymers: 3-year follow-up of the PAINT randomised trial.

AIMS: The long-term clinical performance of drug-eluting stents (DES) coated with biodegradable polymers is poorly known. METHODS AND RESULTS: A total of 274 coronary patients were randomly allocated to paclitaxel-eluting stents, sirolimus-eluting stents, or bare metal stents (2:2:1 ratio). The two DES used the same biodegradable polymers and were identical except for the drug. At three years, the pooled DES population had similar rates of cardiac death or myocardial infarction (9.0% vs. 7.1; p=0.6), but lower risk of repeat interventions (10.0% vs. 29.9%; p<0.01) than controls with bare stents. The cumulative 3-year incidence of definite or probable stent thrombosis in the pooled DES group was 2.3% (first year: 1.8%; second year: 0.4%; third year: zero). There were no significant differences in outcomes between paclitaxel- and sirolimus-eluting stents. CONCLUSIONS: The biodegradable-polymer coated DES releasing either paclitaxel or sirolimus were effective in reducing the 3-year rate of re-interventions.

Efficacy of chewed vs. crushed lanthanum on phosphorus binding in healthy volunteers.

BACKGROUND AND AIM: For effective dietary phosphorous (P) binding, patients are recommended to chew lanthanum tablets completely before swallowing, with or immediately after meals. However, some patients are unable to chew the tablets. It is not known if crushing the tablets prior to taking them with food is as efficacious as chewing them. This study was conducted to compare the efficacy of chewed vs. crushed lanthanum on P binding. METHODS: 12 healthy subjects were randomized and crossed-over to receive: (A) a standardized meal containing 1 g (32 mmol) of elemental P; (B) a single 1 g oral dose of lanthanum, chewed and taken with the standardized meal; (C) a single 1 g oral dose of lanthanum, crushed into a fine powder using a pestle and mortar, mixed with applesauce, and taken with the standardized meal. Blood and urine samples were collected from baseline to 8 hours after meal completion. The changes in serum P, urinary P excretion and fractional excretion of P (FePi) were compared among treatment arms using ANOVA. RESULTS: Co-administration of lanthanum with meal resulted in a smaller increase in serum P, compared with meal alone (p < 0.05). The smaller increase in serum P was similar for both chewed and crushed lanthanum. The amount of P excreted and FePi were also lower when chewed or crushed lanthanum was administered with meal, compared with meal alone (p = n.s. and p < 0.05, respectively). CONCLUSION: Both chewed and crushed lanthanum are effective in lowering P absorption after a dietary P load.

Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP).

The 5-lipoxygenase-activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose-dependent inhibition of blood LTB(4) production and dose-related inhibition of urinary LTE(4). After a single oral dose (50-1,000 mg) of AM103, the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-dependent manner. After multiple-dose administration (50-1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single- and multiple-dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

The objective of the present study was to assess the effects of the immunosuppressant rapamycin (Rapamune®, Sirolimus) on both resistance vessel responsiveness and atherosclerosis in apolipoprotein E-deficient 8-week-old male mice fed a normal rodent diet. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation of isolated mesenteric bed, and atherosclerotic lesions were evaluated. After 12 weeks of orally administered rapamycin (5 mg·kg-1·day-1, N = 9) and compared with untreated (control, N = 9) animals, rapamycin treatment did not modify either NE-induced vasoconstriction (maximal response: 114 ± 4 vs 124 ± 10 mmHg, respectively) or ACh- (maximal response: 51 ± 8 vs 53 ± 5 percent, respectively) and SNP-induced vasorelaxation (maximal response: 73 ± 6 vs 74 ± 6 percent, respectively) of the isolated vascular mesenteric bed. Despite increased total cholesterol in treated mice (982 ± 59 vs 722 ± 49 mg/dL, P < 0.01), lipid deposition on the aorta wall vessel was significantly less in rapamycin-treated animals (37 ± 12 vs 68 ± 8 µm² x 10³). These results indicate that orally administered rapamycin is effective in attenuating the progression of atherosclerotic plaque without affecting the responsiveness of resistance vessels, supporting the idea that this immunosuppressant agent might be of potential benefit against atherosclerosis in patients undergoing therapy.

Fundamento e desenho do teste randomizado PAINT / Rationale and design for the PAINT randomized trial / Fundamento y diseño del test randomizado PAINT

Fundamento: Descrevemos as bases teóricas e o formato do "Estudo PAINT - Intervenção percutânea com stents com eluição de paclitaxel ou sirolimus em polímero biodegradável comparados com stents sem recobrimento no tratamento de lesões coronárias de novo". Objetivo: Avaliar duas novas formulações de stents com eluição de paclitaxel ou sirolimus em comparação com um stent de estrutura metálica idêntica, porém sem recobrimento polimérico ou eluição de droga. Métodos: O PAINT é um estudo randomizado, multicêntrico, de 3 braços, conduzido em centros terciários brasileiros, que incluiu 275 pacientes alocados para tratamento com os stents InfinniumR (paclitaxel), the SupralimusR (sirolimus) ou Milennium MatrixR (sem recobrimento) na proporção 2:2:1 ratio. Os pacientes apresentavam lesões coronarianas de novo em vasos nativos com um diâmetro entre 2,5 e 3,5 mm, passíveis de tratamento com um único stent com comprimento de 29 mm ou menos. O objetivo primário era comparar a perda tardia aos nove meses de ambos stents com paclitaxel- ou sirolimus versus a perda luminal dos stents convencionais de controle. Objetivos secundários importantes incluíam a comparação angiográfica entre os dois tipos de stents farmacológicos, bem como a análise da ocorrência de eventos clínicos adversos. Resultados e conclusões: O estudo PAINT apresenta um formato peculiar e único que permitiu a avaliação da segurança e eficácia de duas novas formulações de stents farmacológicos, com carreador polimérico biodegradável, e liberação de paclitaxel ou sirolimus, os quais foram comparados contra um stent metálico convencional (objetivo primário). Uma vez que os stents farmacológicos diferiram entre sí somente pela droga, mas eram idênticos nas suas outras características, os estudo também permitiu a comparação do efeito anti-restenótico entre sirolimus e paclitaxel (objetivo secundário).

Background: We describe the rationale and design for the "PercutAneous Intervention with biodegradable-polymer based paclitaxel-eluting or sirolimus-eluting versus bare stents for de novo coronary lesions - PAINT trial". Objectives: To evaluate two novel formulations of paclitaxel-eluting stent and the sirolimus-eluting stent against a stent with the same metallic structure but without polymer coating or drug elution. Methods: The PAINT is a multicenter 3-arm randomized trial, conducted in Brazilian tertiary institutions, which included 275 patients allocated for the InfinniumR paclitaxel-eluting stent, the SupralimusR sirolimus-eluting stent or the Milennium MatrixR bare metal stent in a 2:2:1 ratio. Patients had de novo coronary lesions in native vessels with a diameter between 2.5 and 3.5 mm, amenable for treatment with a single stent of 29 mm or less in length. The primary objetive was to compare the in-stent late loss at 9 months of both paclitaxel- and sirolimus-eluting versus the late loss of control bare metal stents. Important secondary objectives included the comparison in outcomes between sirolimus and paclitaxel stents, as well as the analysis of the incidence of major adverse cardiac events. Results amd conclusions: The PAINT trial had a unique design that allowed for the evaluation of the safety and efficacy profiles of two novel drug-eluting stent formulations, with a biodegradable-polymer carrier and releasing paclitaxel or sirolimus, which were compared against a bare metal stent (primary objective). As the drug-eluting stents differed by the drug, but were identical otherwise, the trial also allowed the comparison of the anti-restenosis effects of sirolimus versus paclitaxel (secondary objective).

Fundamento: Describimos las bases teóricas y el formato del "Estudio PAINT - Intervención percutánea con stents recubiertos de paclitaxel o sirolimus en polímero biodegradable comparados con stents no recubiertos en el tratamiento de lesiones coronarias de novo". Objetivo: Evaluar dos nuevas formulaciones de stents con liberación de paclitaxel o sirolimus en comparación con un stent de estructura metálica idéntica, pero sin recubierto polimérico o liberación de droga. Métodos: El PAINT es un estudio randomizado, multicéntrico, de 3 brazos, llevado a cabo en centros terciaros brasileños, que incluyó a 275 pacientes destinados a tratamiento con los stents InfinniumR (paclitaxel), the SupralimusR (sirolimus) o Milennium MatrixR (no recubierto) en la proporción 2:2:1. Los pacientes presentaban lesiones coronarias de novo en vasos nativos con un diámetro entre 2,5 y 3,5 mm, pasibles de tratamiento con un único stent de hasta 29 mm de longitud. El objetivo primario era comparar la pérdida luminal tardía a los nueve meses de ambos stents con paclitaxel- o sirolimus versus la pérdida luminal de los stents convencionales de control. Los objetivos secundarios importantes incluían la comparación angiográfica entre los dos tipos de stents farmacológicos, así como el análisis de la ocurrencia de eventos clínicos adversos. Resultados y conclusiones: El estudio PAINT presenta un formato peculiar y único que permitió la evaluación de la seguridad y eficacia de dos nuevas formulaciones de stents farmacológicos, con transportador polimérico biodegradable, y liberación de paclitaxel o sirolimus, los que fueron comparados con un stent metálico convencional (objetivo primario). Dado que los stents farmacológicos diferían entre sí solamente por la droga, pero eran idénticos en sus otras características, el estudio también permitió la comparación del efecto antireestenótico entre sirolimus y paclitaxel (objetivo secundario).

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice.

The objective of the present study was to assess the effects of the immunosuppressant rapamycin (Rapamune, Sirolimus) on both resistance vessel responsiveness and atherosclerosis in apolipoprotein E-deficient 8-week-old male mice fed a normal rodent diet. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation of isolated mesenteric bed, and atherosclerotic lesions were evaluated. After 12 weeks of orally administered rapamycin (5 mg.kg-1.day-1, N = 9) and compared with untreated (control, N = 9) animals, rapamycin treatment did not modify either NE-induced vasoconstriction (maximal response: 114 +/- 4 vs 124 +/- 10 mmHg, respectively) or ACh- (maximal response: 51 +/- 8 vs 53 +/- 5%, respectively) and SNP-induced vasorelaxation (maximal response: 73 +/- 6 vs 74 +/- 6%, respectively) of the isolated vascular mesenteric bed. Despite increased total cholesterol in treated mice (982 +/- 59 vs 722 +/- 49 mg/dL, P < 0.01), lipid deposition on the aorta wall vessel was significantly less in rapamycin-treated animals (37 +/- 12 vs 68 +/- 8 microm(2) x 10(3)). These results indicate that orally administered rapamycin is effective in attenuating the progression of atherosclerotic plaque without affecting the responsiveness of resistance vessels, supporting the idea that this immunosuppressant agent might be of potential benefit against atherosclerosis in patients undergoing therapy.