Publications by authors named "Ana C Santos"

56 Publications

Secreted reporter assay enables quantitative and longitudinal monitoring of neuronal activity.

eNeuro 2021 Sep 16. Epub 2021 Sep 16.

Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA

The ability to measure changes in neuronal activity in a quantifiable and precise manner is of fundamental importance to understand neuron development and function. Repeated monitoring of neuronal activity of the same population of neurons over several days is challenging and, typically, low-throughput. Here, we describe a new biochemical reporter assay that allows for repeated measurements of neuronal activity in a cell type-specific manner. We coupled activity-dependent elements from the gene with a secreted reporter, luciferase, to quantify neuronal activity without sacrificing the neurons. The reporter predominantly senses calcium and NMDA receptor-dependent activity. By repeatedly measuring the accumulation of the reporter in cell media, we can profile the developmental dynamics of neuronal activity in cultured neurons from male and female mice. The assay also allows for longitudinal analysis of pharmacological treatments, thus distinguishing acute from delayed responses. Moreover, conditional expression of the reporter allows for monitoring cell type-specific changes. This simple, quantitative, cost-effective, automatable, and cell type-specific activity reporter is a valuable tool to study the development of neuronal activity in normal and disease-model conditions, and to identify small molecules or protein factors that selectively modulate the activity of a specific population of neurons.Neurological and neurodevelopmental disorders are prevalent worldwide. Despite significant advances in our understanding of synapse formation and function, developing effective therapeutics remains challenging, in part due to the lack of simple and robust high-throughput screening assays of neuronal activity. Here, we describe a simple biochemical assay that allows for repeated measurements of neuronal activity in a cell type-specific manner. Thus, filling the need for assays amenable to longitudinal studies, such as those related to neural development. Other advantages include its simple and quantitative nature, cell type-specificity, and being multiplexed with other invasive techniques.
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http://dx.doi.org/10.1523/ENEURO.0518-20.2021DOI Listing
September 2021

Obesity and Cancer: the Profile of a Population who Underwent Bariatric Surgery.

Obes Surg 2021 Aug 9. Epub 2021 Aug 9.

Faculdade de Medicina, Universidade do Porto, Porto, Portugal.

Introduction: Obesity is a significant risk factor for cancer incidence and mortality. The number of patients with obesity who undergo bariatric surgery is increasing; however, the impact of such a procedure in affecting the risk of cancer is not completely understood yet.

Methods: We conducted a retrospective unicentric cohort study to characterize the occurrence of cancer in patients who underwent bariatric surgery from January 2010 to December 2018. For cases of cancer identified after bariatric surgery, we performed a cancer-free survival analysis over time. We also performed a cross-sectional analysis of demographic and clinical characteristics at the time of surgery and compared patients with or without a cancer diagnosis.

Results: Of the 2578 patients who underwent bariatric surgery, 117 patients (4.5%) were diagnosed with a cancer. Fifty-nine cases were diagnosed before surgery, and the remaining 58 cases occurred after the bariatric procedure. The prevalence of cancer was more accentuated in women (4.9%) than among men (2.7%). Thyroid and breast cancer were the most frequent before and after bariatric surgery, respectively. On average, patients with cancer diagnosis were older (49.0 vs 43.3 years, p<0.001) and with a lower level of education (7.4 vs 8.6 school years, p=0.002).

Conclusion: Almost all the cases of cancer identified in this study were obesity-related cancers. Further prospective studies are needed to extend the current knowledge regarding the cancer risk profile of patients who undergo bariatric surgery.
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http://dx.doi.org/10.1007/s11695-021-05626-0DOI Listing
August 2021

Case Report: A Severe SARS-CoV-2 Infection in a Teenager With Angelman Syndrome.

Front Med (Lausanne) 2021 12;8:629112. Epub 2021 Mar 12.

Hospital Sírio-Libanês, São Paulo, Brazil.

Teenagers generally present mild to no symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present report, we present the case of a 14-year-old boy with Angelman syndrome (AS) who presented with severe COVID-19 symptoms. He spent 20 days in the ICU with elevated inflammatory biomarkers (C-reactive protein and D-dimer) and increased peaks of neutrophil-to-lymphocyte ratio, which is uncommon for teenagers diagnosed with COVID-19. Although he showed physiological instability, he was able to produce neutralizing antibodies, suggesting a functional immune response. The literature concerning the immune response to infections in patients with AS is still poor, and to our knowledge, this was the first report of a patient with AS diagnosed with COVID-19. As such, the present study may alert other patients with AS or other rare diseases that they lack a competent immune response and could suffer severe consequences of SARS-CoV-2 infection.
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http://dx.doi.org/10.3389/fmed.2021.629112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994262PMC
March 2021

Congenital right coronary fistula to right ventricle.

Cardiol Young 2021 04 2;31(4):639-640. Epub 2021 Mar 2.

Department of Radiology, Santa Cruz Hospital, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.

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http://dx.doi.org/10.1017/S1047951121000457DOI Listing
April 2021

Regeneration of pulp-dentin complex using human stem cells of the apical papilla: in vivo interaction with two bioactive materials.

Clin Oral Investig 2021 Sep 25;25(9):5317-5329. Epub 2021 Feb 25.

Institute of Endodontics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Objectives: To compare the regenerative properties of human stem cells of the apical papilla (SCAPs) embedded in a platelet-rich plasma (PRP) scaffold, when implanted in vivo using an organotypic model composed of human root segments, with or without the presence of the bioactive cements - ProRoot MTA or Biodentine.

Material And Methods: SCAPs were isolated from third molars with incomplete rhizogenesis and expanded and characterized in vitro using stem cell and surface markers. The pluripotency of these cells was also assessed using adipogenic, chondrogenic, and osteogenic differentiation protocols. SCAPs together with a scaffold of PRP were added to the root segment lumen and the organotypic model implanted on the dorsal region of immunodeficient rats for a period of 4 months.

Results: Presence of SCAPs induced de novo formation of dentin-like and pulp-like tissue. A barrier of either ProRoot MTA or Biodentine did not significantly affect the fraction of sections from roots segments observed to contain deposition of hard material (P > 0.05). However, the area of newly deposited dentin was significantly greater in segments containing a barrier of Biodentine compared with ProRoot MTA (P < 0.001).

Conclusions And Clinical Relevance: SCAPs offer a viable alternative to other dental stem cells (DSCs) in their regenerative properties when enclosed in the microenvironment of human tooth roots. The present study also suggests that the presence of bioactive materials does not hinder or impede the formation of new hard tissues, but the presence of Biodentine may promote greater mineralized tissue deposition.
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http://dx.doi.org/10.1007/s00784-021-03840-9DOI Listing
September 2021

Subcutaneous Implantation Assessment of New Calcium-Silicate Based Sealer for Warm Obturation.

Biomedicines 2021 Jan 1;9(1). Epub 2021 Jan 1.

Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Calcium silicate-based sealers were recently introduced as a new class of endodontic sealers, with potential further benefits due to their bioactivity. The aim of this study was to evaluate the biocompatibility of two new hydraulic calcium silicate-based sealers, TotalFill BC Sealer (FKG, La Chaux-des-Fonds, Switzerland) and TotalFill BC Sealer HiFlow (FKG, La Chaux-des-Fonds, Switzerland) through subcutaneous implantation in connective tissue of rats. Subcutaneous implantation was performed in 16 young Wistar rats. Four polyethylene tubes were implanted in each animal, one empty to serve as a control, and three filled with tested sealers: AH Plus as reference (Dentsply DeTrey, Konstanz, Germany), TotalFill BC Sealer (BC) and TotalFill BC Sealer HiFlow (HiFlow). Eight rats were euthanized at 8 days and the remaining eight at 30 days. Hematoxylin-eosin staining was used to score the inflammatory reaction, macrophage infiltrate and to measure the thickness of the fibrous capsule. von Kossa staining was performed to evaluate the mineralization level. Kruskal-Wallis test followed by Dunn's test was used to analyze non-parametric data. To analyze the influence of the implantation time within each material, a Mann-Whitney U test was performed. At eight days post-implantation, AH Plus induced a more intense inflammatory reaction when compared both with the control ( ≤ 0.001) and BC ( ≤ 0.01). HiFlow presented a higher score of macrophage infiltrate than control ( ≤ 0.01) and BC ( ≤ 0.05). The fibrous capsule thickness in this period was significantly higher for the BC group when compared to control ( ≤ 0.01) and AH Plus ( ≤ 0.05). The mineralization potential was higher for the HiFlow group when compared with the control ( ≤ 0.001) and AH Plus ( ≤ 0.001). At 30 days post-implantation, the score for the inflammatory reaction remained higher for the AH Plus group when compared both to control ( ≤ 0.01) and BC ( ≤ 0.001). The macrophage infiltrate of the HiFlow was significantly higher than control ( ≤ 0.001) and AH Plus groups ( ≤ 0.01), additionally, the fibrous capsule of the BC ( ≤ 0.001) and HiFlow ( ≤ 0.01) groups were both thicker than control. Mineralization potential was observed only on BC ( ≤ 0.05) and HiFlow groups ( ≤ 0.001), when compared to control). BC exhibited the best biocompatibility performance of all tested sealers and HiFlow provided the greatest induction of mineralized tissues. Both TotalFill BC Sealer and TotalFill BC Sealer HiFlow are biocompatible and show potential bioactivity when implanted in the subcutaneous tissue. Bioactivity was not found in AH Plus.
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http://dx.doi.org/10.3390/biomedicines9010024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824331PMC
January 2021

Genetic and Virulence Characteristics of a Hybrid Atypical Enteropathogenic and Uropathogenic (aEPEC/UPEC) Strain.

Front Cell Infect Microbiol 2020 29;10:492. Epub 2020 Sep 29.

Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

Hybrid strains of combine virulence traits of diarrheagenic (DEC) and extraintestinal pathogenic (ExPEC), but it is poorly understood whether these combined features improve the virulence potential of such strains. We have previously identified a uropathogenic (UPEC) strain (UPEC 252) harboring the gene that encodes the adhesin intimin and is located in the locus of enterocyte effacement (LEE) pathogenicity island. The LEE-encoded proteins allow enteropathogenic (EPEC) and enterohemorrhagic (EHEC) to form attaching and effacing (A/E) lesions in enterocytes. We sought to characterize UPEC 252 through whole-genome sequencing and phenotypic virulence assays. Genome analysis unveiled that this strain harbors a complete LEE region, with more than 97% of identity comparing to E2348/69 (EPEC) and O157:H7 Sakai (EHEC) prototype strains, which was functional, since UPEC 252 expressed the LEE-encoded proteins EspB and intimin and induced actin accumulation foci in HeLa cells. Phylogenetic analysis performed comparing 1,000 single-copy shared genes clustered UPEC 252 with atypical EPEC strains that belong to the sequence type 10, phylogroup A. Additionally, UPEC 252 was resistant to the bactericidal power of human serum and colonized cells of the urinary (T24 and HEK293-T) and intestinal (Caco-2 and LS174T) tracts. Our findings suggest that UPEC 252 is an atypical EPEC strain that emerges as a hybrid strain (aEPEC/UPEC), which could colonize new niches and potentially cause intestinal and extraintestinal infections.
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http://dx.doi.org/10.3389/fcimb.2020.00492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550682PMC
May 2021

Hope is a crucial factor for patients facing cancer treatment.

Evid Based Nurs 2020 Aug 27. Epub 2020 Aug 27.

Nursing, Universidade Federal de Alagoas - Campus Arapiraca, Arapiraca, Alagoas, Brazil.

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http://dx.doi.org/10.1136/ebnurs-2020-103299DOI Listing
August 2020

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

PLoS Med 2020 08 18;17(8):e1003182. Epub 2020 Aug 18.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.

Background: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight.

Methods And Findings: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations.

Conclusions: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.
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http://dx.doi.org/10.1371/journal.pmed.1003182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433860PMC
August 2020

Secular trend in age at menarche in women in Portugal born between 1920 and 1992: Results from three population-based studies.

Am J Hum Biol 2020 09 25;32(5):e23392. Epub 2020 Jan 25.

EPIUnit-Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.

Objectives: Worldwide data on age at menarche suggest a gradually earlier maturation, which is stabilizing in some societies. The interplay between socioeconomic, behavioral, and environmental factors generates uncertainty about the current status and future trend of age at menarche in most societies. Therefore, we aimed to describe trends in age at menarche during the 20th century in Portugal.

Methods: A sample of 11 274 women born between 1920 and 1992 in northern Portugal, recruited to participate in three population-based cohorts (EPIPorto, EPITeen, and Generation XXI) was evaluated. Age at menarche across birth year categories was compared using ANOVA and the rate of change over time using linear regression.

Results: Age at menarche decreased with birth year (-31.1 days per 5 years; β = -.017, P < .001), women born before 1930 having a significantly higher age at menarche than those who were born after 1990 (mean (SD) = 13.1 (1.83) vs 12.0 (1.25), P < .001).

Conclusions: The decrease in age at menarche in northern Portugal suggests that a plateau is yet to be reached. Attention to time trends in age at menarche is relevant for health promotion since there is a possible relationship between pubertal timing and the later development of the metabolic syndrome.
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http://dx.doi.org/10.1002/ajhb.23392DOI Listing
September 2020

Emotions after stroke: A narrative update.

Int J Stroke 2020 04 3;15(3):256-267. Epub 2019 Oct 3.

Hospital do Mar - Cuidados Especializados Lisboa, Bobadela, Portugal.

Aim: In this narrative review we aimed to describe how stroke affects emotions and update the readers on the emotional disturbances that occur after stroke.

Methods: We searched Medline from 1.1.2013 to 1.7.2019, personal files and references of selected publications. All retrieved systematic reviews and randomized controlled trials were included. Other references were selected by relevance.

Summary Of Review: The emotional response includes a reactive behavior with arousal, somatic, motivational and motor components, and a distinctive cognitive and subjective affective experience. Emotional category responses and experiences after stroke can show dissociations between the behavioral response and the cognitive and affective experiences. Emotional disturbances that often occur after stroke include fear, anger, emotional indifference, lack of understanding of other emotions, and lack of control of emotional expression. Emotional disturbances limit social reintegration of the persons with stroke and are a source of caregiver burnout. The evidence to support the management of the majority of emotional disorders in stroke survivors is currently weak and of low or very low methodologic quality. An exception are the disorders of emotional expression control where antidepressants can have a strong beneficial effect, by reducing the number and duration of the uncontrollable episodes of crying or laughing.

Conclusion: Our current knowledge of the emotional disorders that occurs in acute stroke patients and in stroke survivors is heterogeneous and limited. Joint efforts of different research approaches, methodologies and disciplines will improve our current understanding on emotional disorder after stroke and indicate rational pathways to manage them.
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http://dx.doi.org/10.1177/1747493019879662DOI Listing
April 2020

Association of Pubertal Development With Adiposity and Cardiometabolic Health in Girls and Boys-Findings From the Generation XXI Birth Cohort.

J Adolesc Health 2019 10 31;65(4):558-563. Epub 2019 Jul 31.

EPIUnit - Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal; Departamento de Ciências da Saúde Pública e Forenses e Educação Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.

Purpose: Early timing of pubertal development is associated with worse cardiometabolic health in adulthood. We aimed to evaluate this association in 10-year-old girls and boys and clarify if it is independent of previous body mass index (BMI).

Methods: Pubertal development was evaluated through the Tanner scale in 4,548 children from the birth cohort Generation XXI. Data on anthropometrics, body composition, blood pressure, lipid profile, fasting plasma glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein were collected. Bonferroni correction was applied, using an alpha of .004 for statistical significance. Regression coefficients and 99.6% confidence intervals were computed using linear regression models.

Results: Girls with a Tanner stage ≥2 presented statistically significant higher values of BMI, waist circumference (WC), waist-to-height ratio, fat mass index, blood pressure, glucose, insulin, HOMA-IR, triglycerides, and high-sensitivity C-reactive protein and lower values of high-density lipoprotein cholesterol. Boys with a Tanner stage ≥2 presented statistically significant higher values of BMI, WC, systolic blood pressure, and HOMA-IR and lower values of high-density lipoprotein cholesterol. After adjustment, including previous BMI, a Tanner stage ≥2 remained associated with BMI z-score (girls β = .41 [.32, .50]; boys β = .10 [.01, .19]) and WC (girls β = 2.64 cm [1.86, 3.43]; boys β = .81 cm [.11, 1.51]), and only in girls with waist-to-height ratio (β = .01 [.00, .01]), fat mass index (β = .31 kg/m [.08; .54]), glucose (β = 1.59 mg/dL [.85, 2.33]), insulin (β = 1.73 μU/mL [.68, 2.78]), and HOMA-IR (β = .40 [.16, .64]).

Conclusions: Independently of previous BMI, preteens with early puberty already had more adiposity at age 10 years. In addition, girls had higher glucose, insulin, and HOMA-IR, which may predict a worse glucose metabolism. These preteens should be a target for public health interventions.
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http://dx.doi.org/10.1016/j.jadohealth.2019.05.014DOI Listing
October 2019

Association of Gestational Weight Gain With Adverse Maternal and Infant Outcomes.

JAMA 2019 05;321(17):1702-1715

Division of Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway.

Importance: Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges.

Objectives: To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories.

Design, Setting, And Participants: Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015.

Exposures: Gestational weight gain.

Main Outcomes And Measures: The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth.

Results: Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, ≥40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79).

Conclusions And Relevance: In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed.
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http://dx.doi.org/10.1001/jama.2019.3820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506886PMC
May 2019

Biocompatibility of a bioceramic silicone-based sealer in subcutaneous tissue.

J Oral Sci 2019 ;61(1):171-177

Institute of Biophysics, Faculty of Medicine, University of Coimbra.

This study evaluated the biocompatibility of a new silicone-based sealer (GuttaFlow Bioseal) in rat subcutaneous tissue and compared the results with those for GuttaFlow2 and AH Plus. Each of 16 Wistar rats received four subcutaneous tissue implants, namely, GuttaFlow Bioseal, GuttaFlow2, AH Plus, and one empty polyethylene tube. Eight rats were euthanized at day 8 and the remaining eight at day 30. Histological sections were stained with haematoxylin and eosin and analysed with a light microscope. Scores were established for inflammatory reaction, macrophage infiltrate, thickness of the fibrous capsule, and vascular changes. Differences between groups were assessed by using the Friedman test with Bonferroni correction. Histological analysis showed that GuttaFlow Bioseal had the lowest inflammatory reaction of all tested sealers at day 8. At day 30, the silicone-based sealers had similar inflammation profiles, but inflammation scores were nonsignificantly higher for AH Plus than for the negative control. The inflammatory reaction decreased from day 8 to day 30 in all sealers. GuttaFlow Bioseal had the most macrophage infiltrate. Under the present experimental conditions, GuttaFlow Bioseal induced limited inflammatory reactions at days 8 and 30, and initial inflammatory reactions to GuttaFlow2 and AH Plus subsided within 30 days. All tested sealers exhibited satisfactory biocompatibility at day 30 after subcutaneous implantation.
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http://dx.doi.org/10.2334/josnusd.18-0145DOI Listing
August 2019

Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis.

PLoS Med 2019 02 11;16(2):e1002744. Epub 2019 Feb 11.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.

Background: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.

Methods And Findings: We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations.

Conclusions: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
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http://dx.doi.org/10.1371/journal.pmed.1002744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370184PMC
February 2019

Subcutaneous delivery of biotherapeutics: challenges at the injection site.

Expert Opin Drug Deliv 2019 02 24;16(2):143-151. Epub 2019 Jan 24.

a Department of Pharmaceutical Technology, Faculty of Pharmacy , University of Coimbra , Coimbra , Portugal.

Introduction: Biotherapeutics are primarily delivered subcutaneously due to better compliance and prolonged rate of absorption compared to other parenteral administration routes. Recent research has allowed for the development of biotherapeutic formulations for subcutaneous delivery that require a lower frequency of administration by increasing drug half-life. Formulations determine shelf-life stability as well as features and transient behaviors that influence stability once implanted in the subcutaneous space.

Areas Covered: This review provides an overview of the factors affecting subcutaneous absorption with a focus on transient effects at the injection site following administration of biotherapeutics and the subsequent impact on absorption and stability.

Expert Opinion: Advances have been made in understanding subcutaneous tissue and the complex interplay of factors that regulate its homeostasis. The issue of poor stability after injection has been neglected, and many biotherapeutics are hampered by low bioavailability. With the advent of new in vitro techniques that account for properties of the injection site, stability studies evaluating subcutaneous tissues and impacts on pharmacokinetics of biotherapeutics may be useful in the development of new formulations.
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http://dx.doi.org/10.1080/17425247.2019.1568408DOI Listing
February 2019

Prevalence of vitamin D deficiency amongst soccer athletes and effects of 8 weeks supplementation.

J Sports Med Phys Fitness 2019 Apr 31;59(4):693-699. Epub 2018 Oct 31.

Department of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background: High prevalence of vitamin D deficiency is well known around the world in risk populations. Although less is known about the athletic population, some studies report vitamin D deficiency amongst athletic population and adequate vitamin D levels are crucial for athletic population as they can prevent injuries such as stress fractures and might even have ergogenic effects for example on muscle function. The main objectives were to evaluate the basal serum levels of 25(OH)D and calcium in professional soccer athletes on the latitude 40°N, to evaluate the effects in 25(OH)D and calcium serum levels following supplementation of 1667 IU/day of cholecalciferol during a period of 8 weeks and evaluate eventual toxicity arising from it.

Methods: Twenty-eight professional athletes were evaluated according to the skin type. Basal serum levels of 25(OH)D and calcium were evaluated during winter months. Athletes were then supplemented with cholecalciferol 25.000 IU every two weeks. Serum levels of 25(OH)D and calcium were evaluated after supplementation.

Results: 25(OH)D initially ranged between 9.9 ng/mL and 32.9 ng/mL with a median of 19.2 IQR 7.24 ng/mL. A statistically significant inverse correlation exists between vitamin D deficiency and the Fitzpatrick Scale (ρ=-0.555 P=0.003). After 8 weeks, 25(OH)D ranged between 10.6 ng/mL and 43.4 ng/mL with a median of 33.2 ng/mL IQR 6.1 ng/mL. We verified a statistically significant increase of serum 25(OH) D levels (11.74±5.988; CI 95% [9,02; 14,47]; P<0.001. In addition, there was a statistically significant reduction of calcium: -0.36±0.457; CI 95% [- 0.57; -0.15]; P=0.002.

Conclusions: Professional athletes have a high prevalence of vitamin D deficiency. Supplementation with cholecalciferol in winter months during 8 weeks is safe and effective in raising 25(OH)D serum levels. However, it may not be sufficient for athletes to reach adequate vitamin D levels.
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http://dx.doi.org/10.23736/S0022-4707.18.08551-1DOI Listing
April 2019

Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania.

BMC Med 2018 11 5;16(1):201. Epub 2018 Nov 5.

Departments of Public Health Sciences and Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Background: Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies.

Methods: We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape.

Results: We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications.

Conclusions: Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.
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http://dx.doi.org/10.1186/s12916-018-1189-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217770PMC
November 2018

Visceral Obesity and Metabolic Syndrome Are Associated with Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors.

Cancers (Basel) 2018 Aug 27;10(9). Epub 2018 Aug 27.

Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal.

The determinants for gastroenteropancreatic neuroendocrine tumors (GEP-NET) recent burden are matters of debate. Obesity and metabolic syndrome (MetS) are well established risks for several cancers even though no link with GEP-NETs was yet established. Our aim in this study was to investigate whether well-differentiated GEP-NETs were associated with obesity and MetS. Patients with well-differentiated GEP-NETs ( = 96) were cross-matched for age, gender, and district of residence with a control group ( = 96) derived from the general population in a case-control study. Patients presented gastro-intestinal (75.0%) or pancreatic (22.9%) tumors, grade G1 (66.7%) or G2 (27.1%) with localized disease (31.3%), regional metastasis (16.7%) or distant metastasis (43.8%) at diagnosis, and 45.8% had clinical hormonal syndromes. MetS was defined according to Joint Interim Statement (JIS) criteria. Well-differentiated GEP-NETs were associated with MetS criteria as well as the individual components' waist circumference, fasting triglycerides, and fasting plasma glucose ( = 0.003, = 0.002, = 0.011 and < 0.001, respectively). The likelihood of the association was higher when the number of individual MetS components was greater than four. MetS and some individual MetS components including visceral obesity, dyslipidemia, and increased fasting glucose are associated with well-differentiated GEP-NET. This data provides a novel insight in unraveling the mechanisms leading to GEP-NET disease.
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http://dx.doi.org/10.3390/cancers10090293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162651PMC
August 2018

Linalool bioactive properties and potential applicability in drug delivery systems.

Colloids Surf B Biointerfaces 2018 Nov 3;171:566-578. Epub 2018 Aug 3.

Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address:

The medicinal properties of essential oils from aromatic plants are known since antiquity. Currently, the technological innovation enabled the reinvention of the ancient plant knowledge leading to the identification and extraction of organic compounds present in essential oils. These organic compounds belong mainly to the terpene group and are accountable for the wide range of bioactive properties attributed to essential oils. Linalool (CHO), so-called 3,7-dimethyl-1,6-octadien-3-ol, is a monoterpene alcohol broadly present as a major constituent of plant essential oils, particularly lavender and coriander. Linalool per se is non-toxic and, according to recent in vitro and in vivo scientific studies, it has demonstrated to have a comprehensive range of bioactive properties, which can be exploited for pharmaceutic and cosmetic applications. The present review focuses on the anti-inflammatory, anticancer, anti-hyperlipidemic, antimicrobial, antinoceptive, analgesic, anxiolytic, antidepressive and neuroprotective properties of linalool. The advantages of the loading in nanotechnology-based drug delivery systems, with the purpose of enhancing its bioactive properties are also discussed.
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http://dx.doi.org/10.1016/j.colsurfb.2018.08.001DOI Listing
November 2018

Subcutaneous delivery of monoclonal antibodies: How do we get there?

J Control Release 2018 09 2;286:301-314. Epub 2018 Aug 2.

Faculty of Pharmacy, University of Coimbra, Portugal; I3S - Institute for Research and Innovation in Health, University of Porto, Portugal. Electronic address:

The convenience of subcutaneous (SC) administration and the increasing interest in monoclonal antibody (mAb)-based therapies for chronic diseases, hint their potential for SC delivery in a near future. In addition, there is a common interest among patients, clinicians and pharmaceutical industry in moving from intravenous to SC administration of mAbs due to benefits of improved patient compliance and reduced costs to the healthcare system. Despite the wide use of this route of administration in diseases like diabetes and rheumatoid arthritis, SC bioavailability of mAbs has been shown to be incomplete and variable in most preclinical and clinical studies. This evidences a gap in the understanding of SC absorption process of mAbs and in their drug development process. Likewise, challenges present in drug formulation, such as high viscosity and aggregation, and the inherent immunogenicity of mAbs have also been hampering the successful translation to clinical settings. This review provides a characterization of the subcutaneously delivered mAbs that have entered the market in the last 10 years as well as a snapshot of the landscape of currently undergoing clinical trials. Moreover, there is an overview of the factors influencing SC absorption of mAbs and the preclinical models in use to study SC pharmacokinetics. Considerations about drug formulation and immunogenicity of mAbs are also explored.
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http://dx.doi.org/10.1016/j.jconrel.2018.08.001DOI Listing
September 2018

Halloysite clay nanotubes for life sciences applications: From drug encapsulation to bioscaffold.

Adv Colloid Interface Sci 2018 Jul 31;257:58-70. Epub 2018 May 31.

Methodist Health System, Dallas, TX 75203, USA.

Natural forming clay halloysite is an emerging nanomaterial carrier for sustained drug delivery. These 50 nm diameter aluminosilicate tubes, with inner - alumina and outer - silica surface layers, can be loaded with 10-30 wt% of drug molecules, DNA and enzymes. The opposite charge of the inner and outer halloysite surface allow for selective drug adsorption inside or outside the clay nanotubes. The drug loaded halloysite enhanced the zeta potential of minus 50-60 mV allowing for stable aqueous nanocolloids. Halloysite nanoformulations provide an extended 10-20 h release profile, and may be functionalized (e.g., clogging tubes' end with polymers extending release time to 1-2 weeks or allowing for triggered release), which renders these clay nanostructures as promising controlled delivery systems. Recent studies demonstrate the potential of abundantly available halloysite clay nanotubes for life science applications, from drug delivery via oral or topical administration, to tissue scaffolds and regenerative medicine, while assessing their cellular internalization, stability, biosafety and biocompatibility are featured. The benefits and limitations of halloysite clay nanotubes are discussed, as well as the directions for future developments.
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http://dx.doi.org/10.1016/j.cis.2018.05.007DOI Listing
July 2018

Neoplastic Multifocal Skin Lesions: Biology, Etiology, and Targeted Therapies for Nonmelanoma Skin Cancers.

Skin Pharmacol Physiol 2018 21;31(2):59-73. Epub 2017 Dec 21.

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Coimbra, Portugal.

Neoplastic skin lesions are multifocal, diffuse skin infiltrations of particular relevance in the differential diagnosis of ulcerative, nodular, or crusting skin lesions. Nonmelanoma skin cancers (NMSCs), namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and also actinic keratosis (AK), are the most common malignant tumors in humans. BCCs do not proliferate rapidly and most of the times do not metastasize, while SCCs are more infiltrative, metastatic, and destructive. AKs are precursor lesions of cutaneous SCCs. The classical therapy of NMSCs makes use of photodynamic therapy associated with chemotherapeutics. With improved understanding of the pathological mechanisms of tumor initiation, progression, and differentiation, a case is made towards the use of targeted chemotherapy with the intent to reduce the cytotoxicity of classical treatments. The present review aims to describe the current state of the art on the knowledge of NMSC, including its risks factors, oncogenes, and skin carcinogenesis, discussing the classical therapy against new therapeutic options.
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http://dx.doi.org/10.1159/000479529DOI Listing
August 2018

Characterization of plasma labile heme in hemolytic conditions.

FEBS J 2017 10 11;284(19):3278-3301. Epub 2017 Sep 11.

Instituto Gulbenkian da Ciência, Oeiras, Portugal.

Extracellular hemoglobin, a byproduct of hemolysis, can release its prosthetic heme groups upon oxidation. This produces metabolically active heme that is exchangeable between acceptor proteins, macromolecules and low molecular weight ligands, termed here labile heme. As it accumulates in plasma labile heme acts in a pro-oxidant manner and regulates cellular metabolism while exerting pro-inflammatory and cytotoxic effects that foster the pathogenesis of hemolytic diseases. Here, we developed and characterized a panel of heme-specific single domain antibodies (sdAbs) that together with a cellular-based heme reporter assay, allow for quantification and characterization of labile heme in plasma during hemolytic conditions. Using these approaches, we demonstrate that when generated during hemolytic conditions labile heme is bound to plasma molecules with an affinity higher than 10 m and that 2-8% (~ 2-5 μm) of the total amount of heme detected in plasma can be internalized by bystander cells, termed here bioavailable heme. Acute, but not chronic, hemolysis is associated with transient reduction of plasma heme-binding capacity, that is, the ability of plasma molecules to bind labile heme with an affinity higher than 10 m. The heme-specific sdAbs neutralize the pro-oxidant activity of soluble heme in vitro, suggesting that these maybe used to counter the pathologic effects of labile heme during hemolytic conditions. Finally, we show that heme-specific sdAbs can be used to visualize cellular heme. In conclusion, we describe a panel of heme-specific sdAbs that when used with other approaches provide novel insights to the pathophysiology of heme.
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http://dx.doi.org/10.1111/febs.14192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978748PMC
October 2017

Maternal Smoking: A Life Course Blood Pressure Determinant?

Nicotine Tob Res 2018 05;20(6):674-680

EPIUnit, Institute of Public Health, University of Porto, Portugal.

Introduction: Exposure to maternal smoking early in life may affect blood pressure (BP) control mechanisms. We examined the association between maternal smoking (before conception, during pregnancy, and 4 years after delivery) and BP in preschool children.

Methods: We evaluated 4295 of Generation XXI children, recruited at birth in 2005-2006 and reevaluated at the age of 4. At birth, information was collected by face-to-face interview and additionally abstracted from clinical records. At 4-year follow-up, interviews were performed and children's BP measured. Linear regression models were fitted to estimate the association between maternal smoking and children's BP.

Results: Children of smoking mothers presented significantly higher BP levels. After adjustment for maternal education, gestational hypertensive disorders, and child's body mass index, children exposed during pregnancy to maternal smoking presented a higher systolic BP (SBP) z-score (β = 0.08, 95% confidence interval [CI] 0.04 to 0.14). In crude models, maternal smoking was associated with higher SBP z-score at every assessed period. However, after adjustment, an attenuation of the association estimates occurred (β = 0.08, 95% CI 0.03 to 0.13 before conception; β = 0.07, 95%CI 0.02 to 0.12; β = 0.04, 95%CI -0.02 to 0.10; and β = 0.06, 95%CI 0.00 to 0.13 for the first, second, and third pregnancy trimesters, respectively; and β = 0.07, 95%CI 0.02 to 0.12 for current maternal smoking). No significant association was observed for diastolic BP z-score levels.

Conclusion: Maternal smoking before, during, and after pregnancy was independently associated with systolic BP z-score in preschool children. This study provides additional evidence to the public health relevance of maternal smoking cessation programs if early cardiovascular health of children is envisaged.

Implications: Using observational longitudinal data from the birth cohort Generation XXI, this study showed that exposure to maternal smoking-before pregnancy, during pregnancy, and 4 years after delivery-was associated with a systolic BP-raising effect in children at the age of 4. The findings of this study add an important insight into the need to support maternal smoke-free environments in order to provide long-term cardiovascular benefit, starting as early as possible in life.
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http://dx.doi.org/10.1093/ntr/ntx117DOI Listing
May 2018

Sonication-Assisted Layer-by-Layer Assembly for Low Solubility Drug Nanoformulation.

ACS Appl Mater Interfaces 2015 Jun 27;7(22):11972-83. Epub 2015 May 27.

‡Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal.

Sonication-assisted layer-by-layer (LbL) self-assembly is a nanoencapsulation technique based on the alternate adsorption of oppositely charged polyelectrolytes, enabling the encapsulation of low solubility drugs. In this work, a top-down LbL technique was performed using a washless approach and ibuprofen (IBF) as a model class II drug. For each saturated layer deposition, polyelectrolyte concentration was determined by titration curves. The first layer was constituted by cationic poly(allylamine hydrochloride) (PAH), given the IBF negative surface charge, followed by anionic polystyrenesulfonate (PSS). This polyelectrolyte sequence was made up with 2.5, 5.5, and 7.5 bilayer nanoshells. IBF nanoparticles (NPs) coated with 7.5 bilayers of PAH/PSS showed 127.5 ± 38.0 nm of particle size, a PDI of 0.24, and a high zeta potential (+32.7 ± 0.6 mV), allowing for a stable aqueous nanocolloid of the drug. IBF entrapment efficiency of 72.1 ± 5.8% was determined by HPLC quantification. In vitro MTT assay showed that LbL NPs were biocompatible. According to the number of coating layers, a controlled release of IBF from LbL NPs was achieved under simulated intestinal conditions (from 5 h up to 7 days). PAH/PSS-LbL NPs constitute a potential delivery system to improve biopharmaceutical parameters of water low solubility drugs.
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http://dx.doi.org/10.1021/acsami.5b02002DOI Listing
June 2015

MDR ST2179-CTX-M-15 Escherichia coli co-producing RmtD and AAC(6')-Ib-cr in a horse with extraintestinal infection, Brazil.

J Antimicrob Chemother 2015 Apr 23;70(4):1263-5. Epub 2014 Dec 23.

Department of Microbiology, Institute of Biomedical Sciences, Universidade de São Paulo, São Paulo, Brazil Department of Clinical Analysis, School of Pharmacy, Universidade de São Paulo, São Paulo, Brazil

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http://dx.doi.org/10.1093/jac/dku520DOI Listing
April 2015

Use of Chamomilla recutita in the Prevention and Treatment of Oral Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplantation: A Randomized, Controlled, Phase II Clinical Trial.

Cancer Nurs 2015 Jul-Aug;38(4):322-9

Author Affiliations: Ribeiräo Preto College of Nursing, University of Säo Paulo, Ribeiräo Preto (Drs Braga, Silveira, C.B. Santos, and Carvalho); Amaral Carvalho Foundation, Jaú (Dr A.C.F. Santos), and the Ribeiräo Preto Faculty of Pharmaceutical Sciences, University of Säo Paulo, Ribeiräo Preto, Brazil (Drs Bueno and Bastos).

Background: Oral mucositis is a common inflammatory complication among patients undergoing hematopoietic stem cell transplantation (HSCT). Among its therapeutic properties, Chamomilla recutita has anti-inflammatory effects.

Objective: The aim of this study was to identify the dosage of the liquid extract of C recutita in mouthwash that is needed to reduce the incidence and intensity of oral mucositis in adult patients undergoing allogenic HSCT.

Methods: In a randomized phase II clinical trial, 40 patients were randomized to receive routine care plus mouthwash containing a liquid extract of C recutita at 0.5%, 1%, or 2% (experimental groups) or standard care alone (control group). Daily evaluation was performed using the measurement scale for oral toxicity defined by the World Health Organization. Statistical analysis was performed, in which the incidence, intensity, and duration of oral mucositis were compared between each experimental group and the control group.

Results: The experimental group at the 1% dosage demonstrated reduced incidence, intensity, and duration of oral mucositis compared with the control group. The formulation was well tolerated by patients and was safe, as no moderate or severe adverse effects were identified.

Conclusions: In this study, the use of mouthwash containing 1% C recutita extract can be associated with reduced incidence, intensity, and duration of mucositis in adults patients undergoing allogenic HSCT.

Implications For Practice: The results of this investigation will help nurses and other professionals in selecting the C recutita dosage used to manage oral mucositis in patients undergoing HSCT.
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http://dx.doi.org/10.1097/NCC.0000000000000194DOI Listing
January 2017

Lactococcus lactis carrying the pValac DNA expression vector coding for IL-10 reduces inflammation in a murine model of experimental colitis.

BMC Biotechnol 2014 Aug 9;14:73. Epub 2014 Aug 9.

Department of General Biology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Background: Inflammatory bowel diseases (IBD) are intestinal disorders characterized by inflammation in the gastrointestinal tract. Interleukin-10 is one of the most important anti-inflammatory cytokines involved in the intestinal immune system and because of its role in downregulating inflammatory cascades, its potential for IBD therapy is under study. We previously presented the development of an invasive strain of Lactococcus lactis (L. lactis) producing Fibronectin Binding Protein A (FnBPA) which was capable of delivering, directly to host cells, a eukaryotic DNA expression vector coding for IL-10 of Mus musculus (pValac:il-10) and diminish inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of intestinal inflammation. As a new therapeutic strategy against IBD, the aim of this work was to evaluate the therapeutic effect of two L. lactis strains (the same invasive strain evaluated previously and the wild-type strain) carrying the therapeutic pValac:il-10 plasmid in the prevention of inflammation in a dextran sodium sulphate (DSS)-induced mouse model.

Results: Results obtained showed that not only delivery of the pValac:il-10 plasmid by the invasive strain L. lactis MG1363 FnBPA+, but also by the wild-type strain L. lactis MG1363, was effective at diminishing intestinal inflammation (lower inflammation scores and higher IL-10 levels in the intestinal tissues, accompanied by decrease of IL-6) in the DSS-induced IBD mouse model.

Conclusions: Administration of both L. lactis strains carrying the pValac:il-10 plasmid was effective at diminishing inflammation in this murine model of experimental colitis, showing their potential for therapeutic intervention of IBD.
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http://dx.doi.org/10.1186/1472-6750-14-73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129430PMC
August 2014

Advance in methods studying the pharmacokinetics of polyphenols.

Curr Drug Metab 2014 Jan;15(1):96-115

Center for Pharmaceutical Studies, School of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.

Significant advances have been achieved during the past decade concerning the metabolism of polyphenol compounds in vitro, but scarce data has been presented about what really happens in vivo. Many studies on polyphenols to date have focused on the bioactivity of one specific molecule in aglycone form, often at supraphysiological doses, whereas foods contain complex, often poorly characterized mixtures with multiple additive or interfering activities. Whereas most studies up to the middle-late 1990s measured total aglycones in plasma and urine, after chemical or enzymatic deconjugation, or both, several recent works now report the polyphenol conjugate composition of plasma, urine, feces and/or tissues, after the administration of pure polyphenols or polyphenol-rich matrices. HPLC methods with electrochemical, mass spectrometric and fluorescence detection have adequate sensitivity. LC/UV-Vis methods have also been widely reported, but they are much less sensitive. Compared with electro-chemical and fluorescence detection, MS can quantify analytes without chromatographic separation, which leads to high throughput, presenting itself as the best choice to date. Regarding the experimental model to monitor the bioavailability of phenolic compounds, most published studies are based on human and animal models, with the majority using rodents, primates and recently the nematode Caenorhabditis elegans. This review focuses on the fundamentals of pharmacokinetic methods from the last 15 years and how the results are evaluated and validated. The types of analytical methods, animal models and biological matrices were used to better elucidate pharmacokinetics of polyphenols.
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http://dx.doi.org/10.2174/1389200214666131211155028DOI Listing
January 2014
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