Trends in 3D models of inflammatory bowel disease.

Inflammatory bowel disease (IBD) encompasses a set of chronic inflammatory conditions, namely Crohn's disease and ulcerative colitis. Despite all advances in the management of IBD, a definitive cure is not available, largely due to a lack of a holistic understanding of its etiology and pathophysiology. Several in vitro, in vivo, and ex vivo models have been developed over the past few decades in order to abbreviate remaining gaps. The establishment of reliable and predictable in vitro intestinal inflammation models may indeed provide valuable tools to expedite and validate the development of therapies for IBD. Three-dimensional (3D) models provide a more accurate representation of the different layers of the intestine, contributing to a stronger impact on drug screening and research on intestinal inflammation, and bridging the gap between in vitro and in vivo research. This work provides a critical overview on the state-of-the-art on existing 3D models of intestinal inflammation and discusses the remaining challenges, providing insights on possible pathways towards achieving IBD mimetic models. We also address some of the main challenges faced by implementing cell culture models in IBD research while bearing in mind clinical translational aspects.

All layers matter: Innovative three-dimensional epithelium-stroma-endothelium intestinal model for reliable permeability outcomes.

Drug development is an ever-growing field, increasingly requesting reliable in vitro tools to speed up early screening phases, reducing the need for animal experiments. In oral delivery, understanding the absorption pattern of a new drug in the small intestine is paramount. Classical two-dimensional (2D) in vitro models are generally too simplistic and do not accurately represent native tissues. The main goal of this work was to develop an advanced three-dimensional (3D) in vitro intestinal model to test absorption in a more reliable manner, by better mimicking the native environment. The 3D model is composed of a collagen-based stromal layer with embedded fibroblasts mimicking the intestinal lamina propria and providing support for the epithelium, composed of enterocytes and mucus-secreting cells. An endothelial layer, surrogating the absorptive capillary network, is also present. The cellular crosstalk between the different cells present in the model is unveiled, disclosing key players, namely those involved in the contraction of collagen by fibroblasts. The developed 3D model presents lower levels of P-glycoprotein (P-gp) and Multidrug Resistance Protein 2 (MRP2) efflux transporters, which are normally overexpressed in traditional Caco-2 models, and are paramount in the absorption of many compounds. This, allied with transepithelial electrical resistance (TEER) values closer to physiological ranges, leads to improved and more reliable permeability outcomes, which are observed when comparing our results with in vivo data.

Mucus-producing 3D cell culture models.

In vitro cell-based models have been used for a long time since they are normally easily obtained and have an advantageous cost-benefit. Besides, they can serve a variety of ends, from studying drug absorption and metabolism to disease modeling. However, some in vitro models are too simplistic, not accurately representing the living tissues. It has been shown, mainly in the last years, that fully mimicking a tissue composition and architecture can be paramount for cellular behavior and, consequently, for the outcomes of the studies using such models. Because of this, 3D in vitro cell models have been gaining much attention, since they are able to better replicate the in vivo environment. In this review we focus on 3D models that contain mucus-producing cells, as mucus can play a pivotal role in drug absorption. Being frequently overlooked, this viscous fluid can have an impact on drug delivery. Thus, the aim of this review is to understand to which extent can mucus affect mucosal drug delivery and to provide a state-of-the-art report on the existing 3D cell-based mucus models.

Building three-dimensional lung models for studying pharmacokinetics of inhaled drugs.

Drug development is a critical step in the development pipeline of pharmaceutical industry, commonly performed in traditional cell culture and animal models. Though, those models hold critical gapsin the prediction and the translation of human pharmacokinetic (PK) and pharmacodynamics (PD) parameters. The advances in tissue engineering have allowed the combination of cell biology with microengineering techniques, offering alternatives to conventional preclinical models. Organ-on-a-chips and three-dimensional (3D) bioprinting models present the potentialityof simulating the physiological and pathological microenvironment of living organs and tissues, constituting this way,more realistic models for the assessment of absorption, distribution, metabolism and excretion (ADME) of drugs. Therefore, this review will focus on lung-on-a-chip and 3D bioprinting techniques for developing lung models that can be usedfor predicting PK/PD parameters.

3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs.

Three-dimensional cell culture models, such as spheroids, can be used in the process of the development of new anticancer agents because they are able to closely mimic the main features of human solid tumors, namely their structural organization, cellular layered assembling, hypoxia, and nutrient gradients. These properties imprint to the spheroids an anticancer therapeutics resistance profile, which is similar to that displayed by human solid tumors. In this review, an overview of the drug resistance mechanisms observed in 3D tumor spheroids is provided. Furthermore, comparisons between the therapeutics resistance profile exhibited by spheroids, and 2D cell cultures are presented. Finally, examples of the therapeutic approaches that have been developed to surpass the drug resistance mechanisms exhibited by spheroids are described.

Establishment of 2D Cell Cultures Derived From 3D MCF-7 Spheroids Displaying a Doxorubicin Resistant Profile.

In vitro 3D cancer spheroids generally exhibit a drug resistance profile similar to that found in solid tumors. Due to this property, these models are an appealing for anticancer compounds screening. Nevertheless, the techniques and methods aimed for drug discovery are mostly standardized for cells cultured in 2D. The development of 2D cell culture models displaying a drug resistant profile is required to mimic the in vivo tumors, while the equipment, techniques, and methodologies established for conventional 2D cell cultures can continue to be employed in compound screening. In this work, the response of 3D-derived MCF-7 cells subsequently cultured in 2D in medium supplemented with glutathione (GSH) (antioxidant agent found in high levels in breast cancer tissues and a promoter of cancer cells resistance) to Doxorubicin (DOX) is evaluated. These cells demonstrated a resistance toward DOX closer to that displayed by 3D spheroids, which is higher than that exhibited by standard 2D cell cultures. In fact, the 50% inhibitory concentration (IC50 ) of DOX in 3D-derived MCF-7 cell cultures supplemented with GSH is about eight-times higher than that obtained for conventional 2D cell cultures (cultured without GSH), and is only about two-times lower than that attained for 3D MCF-7 spheroids (cultured without GSH). Further investigation revealed that this improved resistance of 3D-derived MCF-7 cells may result from their increased P-glycoprotein (P-gp) activity and reduced production of intracellular reactive oxygen species (ROS).

Presença de mordida aberta anterior na dentadura mista ­ relação com hábitos bucais deletérios / Anterior open bite presence in mixed dentition: relationship with deleterious oral habits

O objetivo desta pesquisa foi identificar a presença de mordida aberta anterior (MAA) em pacientes que se encontram no período de dentadura mista e que apresentam hábitos bucais deletérios. Trata-se de um estudo transversal retrospectivo, no qual a amostra foi composta por prontuários de pacientes, de ambos os gêneros, atendidos no curso de especialização em Ortodontia da Faculdade de Odontologia do Recife. Para a avaliação dos dados, foram coletadas as informações como gênero, etnia, idade, perfil facial, hábitos bucais, tipo de deglutição, medida cefalométrica de Ricketts quanto ao trespasse vertical, além da observação das fotos extra e intrabucais iniciais. Foram avaliados 412 prontuários, sendo 34 selecionados por estarem de acordo com os critérios de inclusão da amostra. Desses, 11 (32,4%) apresentavam MAA, encontrando-se mais elevada no gênero feminino (50%). Além disso, ela foi mais prevalente nos pacientes que tinham o hábito de sucção digital e chupeta (72,7%), sendo menos elevada nos que apresentavam o hábito de roer unhas (11,8%). Em relação à deglutição atípica, a MAA variou de 66,7%, nas deglutições com pressionamento lingual, a 71,4%, nas deglutições com participação da musculatura peribucal e pressionamento lingual. Assim, foi possível concluir que na amostra estudada a MAA encontrou-se mais elevada no gênero feminino, apresentando associação estatisticamente significante com o hábito de sucção digital e chupeta e com tipo de deglutição atípica, sendo mais prevalente nos pacientes que tinham participação da musculatura peribucal e pressionamento lingual durante a deglutição.(AU)

The aim of this research was to identify the presence of anterior open bite (AOB) in patients who are in mixed dentition period and who present deleterious oral habits. This is a retrospective cross-sectional study in which the sample was composed by medical records of patients of both genders, treated in the course of Specialization in Orthodontics of the Dentistry School of Recife. For data assessment, information such as gender, ethnicity, age, facial profile, oral habits, swallowing type, Ricketts cephalometric vertical trespass measure were collected, and also observation of initial extra and intra-oral photos was performed. For this research, 412 medical records were evaluated, 34 were selected as they were in accordance to sample inclusion criteria. Out of these, 11 (32.4%) had AOB, higher among female gender (50%). Moreover, it was more prevalent in patients who had digital sucking and pacifier use habits (72.7%), being lower in those with nail biting habit (11.8%). Regarding atypical swal- lowing, AOB ranged from 66.7%, in swallowing with lingual press to 71.4%, in swallowing with participation of perioral musculature and lingual press. Thus, it was possible to conclude in the studied sample that AOB was higher in the female gender, with statistically significant association to digital sucking and pacifier use habits and with atypical swallowing type, being more prevalent in patients who had participation of perioral musculature and lingual press during swallowing.(AU)

Comparative study of the therapeutic effect of Doxorubicin and Resveratrol combination on 2D and 3D (spheroids) cell culture models.

The assessment of drug-combinations for pancreatic cancer treatment is usually performed in 2D cell cultures. In this study, the therapeutic effect and the synergistic potential of a particular drug-combination towards 2D and 3D cell cultures of pancreatic cancer were compared for the first time. Thus, the effect of Doxorubicin:Resveratrol (DOX:RES) combinations (at molar ratios ranging from 5:1 to 1:5) in the viability of PANC-1 cells cultured as 2D monolayers and as 3D spheroids was analyzed. The results showed that the cells' viability was more affected when DOX:RES combinations containing higher contents of RES (1:2-1:5 molar ratios) were used. This can be explained by the ability of RES to reduce the P-glycoprotein (P-gp)-mediated efflux of DOX. Further, it was also revealed that the synergic effect of this drug combination was different in 2D and in 3D cell cultures. In fact, despite of the 1:4 and 1:5 DOX:RES ratios being both synergistic for both types of PANC-1 cell cultures, their Combination Indexes (CI) in the monolayers were lower than those attained in spheroids. Overall, the obtained results revealed that the DOX:RES combination is promising for pancreatic cancer treatment and corroborate the emergent need to evaluate drug combinations in 3D cell cultures.

Diffuse infantile hepatic haemangioma-how to manage an incidental but potentially lethal finding.

Infantile hepatic haemangioma (IHH) is a rare vascular tumour that is potentially lethal due to its associated complications, including heart failure, hepatic failure, hypothyroidism and abdominal compartment syndrome. The authors report a case of an asymptomatic diffuse IHH in a newborn male, which was presented as an incidental finding at the time that the patient was diagnosed with pyloric stenosis. The patient was treated with increasing doses of propranolol that were well tolerated. With the regression of the IHH by the time that the patient reached one year of age, there was a significant imagiologic improvement. Because there is no consensus on the optimal approach for the treatment of liver tumours in newborns, it is important to adopt a systematic approach. After the diagnosis of diffuse IHH has been established, the decision to initiate treatment and the therapeutic of choice is often controversial. Regular follow-up is recommended to monitor possible complications.

Implantação de um programa interdisciplinar para o controle da obesidade infantil na Secretaria de Saúde do Distrito Federal/DF / Implantation of an interdisciplinary program for the control of childhood obesity in the department of health of the Federal District / DF

A obesidade é caracterizada como uma condição de acúmulo anormalou excessiva de gordura no organismo. É uma patologia de origemmultifatorial, estando relacionada a fatores genéticos, ambientais,psicológicos e socioeconômicos. Frente as várias implicações associadasà obesidade infantil, o objetivo do artigo é descrever uma experiênciade implantação de um programa com uma abordagem interdisciplinar,no tratamento da obesidade infantil no DF. O programa é realizadopredominantemente na forma de grupos, com consultas individuais eoficinas temáticas. Após as intervenções, observamos uma melhora dasmedidas antropométricas, nos exames bioquímicos, na diminuição dosedentarismo, na autoestima, no sono, no convívio social, nos níveis deansiedade, agressividade, compulsão alimentar e nas relações familiares.Diante disso, programas de intervenção sobre essa temática devem fazerparte de políticas públicas.

Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-ß1, IL-13 and oxidative stress.

AIM: To evaluate the therapeutic effects of bone marrow-derived CD11b+CD14+ monocytes in a murine model of chronic liver damage. METHODS: Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay. RESULTS: CD11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6 and IL-1ß, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-ß1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin. CONCLUSION: Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.

In vivo study of schistosomicidal action of 1-benzyl-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one.

Praziquantel has been the drug most widely used therapy against different forms of schistosomiasis around the world. However, this treatment has shown ineffective in humans and in experimental models of Schistosoma mansoni. New therapeutic alternatives have been tested, including the imidazolidine derivative LPSF/PT-09, which has shown high therapeutic potential in vitro. In this work, we tested the schistosomal activity of this derivative in doses of 250mg/kg and 200mg/kg in mice experimentally infected with a high parasite load of S. mansoni. Parasitological evaluations related to the number of S. mansoni worms and their oviposition were performed during the acute phase of the disease and have demonstrated moderate effectiveness of 30-54,4%. However, LPSF/PT-09 did not influence oviposition of the parasites or the embryonic development of the eggs. The results obtained in this model showed that the imidazolidine derivative LPSF/PT-09 presented significant antischistosomal activity in vivo, posing as a potential candidate for this class of drugs. However, a better understanding of the pharmacokinetics and pharmacodynamics of the imidazolidine derivative LPSF/PT-09 is needed.

Pregnant women's oral health: knowledge, practices and their relationship with periodontal disease / Conhecimentos e práticas de saúde bucal de gestantes e sua relação com doença periodontal

ABSTRACT Objective To evaluate pregnant women's knowledge and perception of oral practices as well as their relationship with periodontal disease. Methods The project was developed in 27 units of the Family Health Strategy in the city of Picos, State of Piauí, Brazil, whose service prioritized providing the first dental appointment for pregnant women. A questionnaire was applied to 302 pregnant women, and a calibrated examiner (Kappa=0.96) performed the intraoral exam (CPI). Results the disease was present in 90.7% of them, although 96.4% had been to the dentist once, the majority have not seen a dentist during pregnancy, either because they feared the treatment would harm the baby, or lack of perceiving the need for doing so. Among those that had seen a dentist, did so because of pain or due to routine dental appointments. (19.9%). The belief that pregnancy could cause oral problems was mentioned by 39.7%, however, the majority (98.3%) stated they had received no guidance in this period, a fact which was shown to be associated with periodontal disease (p=0.0003). Conclusion It was concluded that there had been disease prevalence in the group, becoming persistent throughout pregnancy and also that the women presented many oral health care doubts during their gestational period.

RESUMO Objetivo Avaliar o conhecimento, as práticas e a percepção em saúde bucal de gestantes e a sua relação com a doença periodontal. Métodos Foi aplicado um questionário à 302 gestantes nas 27 unidades da Estratégia Saúde da Família de Picos, Piauí, cujo serviço priorizava apenas a realização da 1ª consulta odontológica na gestante. Examinadora calibrada (Kappa=0,96) realizou o exame intra-oral (IPC). Resultados A doença estava presente em 90,7% das gestantes, apesar de 96,4% delas já terem ido ao dentista alguma vez, a maioria não o fez na gestação, seja por medo de que o tratamento fizesse mal ao bebê, seja por ausência de percepção de necessidade. Dentre as que procuraram, o fizeram por dor ou busca por consultas de rotina. A crença de que a gravidez pode causar problemas bucais foi citada por 39,7%. A maioria das gestantes (98,3%) declarou não ter recebido orientações sobre como evitar problemas bucais e essa variável mostrou-se associada à presença da doença periodontal (p=0,003). Conclusão A doença periodontal é muito prevalente no grupo, persistindo durante a gestação e existem muitas dúvidas sobre os cuidados em saúde bucal durante o período gestacional.

Periodontal disease as a risk factor for aspiration pneumonia: a systematic review / Doença periodontal como fator de risco para pneumonia aspirativa: uma revisão sistemática

The objective of this study was to systematically review the available literature, evaluating if periodontal disease is a risk factor for the development of aspiration pneumonia. The data sources were publications available between 01/01/1980 and 01/15/2011, on the following databases: MEDLINE, LILACS, Evidence Portal, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Academics. Inclusion criteria included randomized clinical trials, case-control and cohort studies, as well as cross sectional studies, in Portuguese and English. Teams of reviewers, independently and in duplicate, screened titles and abstracts of full text articles to determine eligibility. The selected articles were read in full and the variables evaluated independently and described in predetermined forms according to clinical outcomes. As a result, five studies out of 653 publications were included: three case-control studies and two cohort studies. Although these studies indicate a positive association between the presence of periodontal disease and the occurrence of aspiration pneumonia, the results must be interpreted with caution. They should not be taken as definitive conclusions due to variations in methodology and limitations, such as sample size, inadequate control of potential confounding variables, lack of calibration of periodontal measurements and inconsistent criteria for the establishment of aspiration pneumonia. There is little evidence to affirm that periodontal disease is a risk condition factor for aspiration pneumonia. Future studies are necessary to elucidate this association, as well as to establish the potential benefit of periodontal treatment with the goal of reducing the risk of developing aspiration pneumonia.

O Objetivo do estudo foi revisar sistematicamente a literatura disponível, avaliar se a doença periodontal é um fator de risco para o desenvolvimento de pneumonia por aspiração. As fontes de dados foram publicações disponíveis entre 01/01/1980 e 15/01/2011, nas seguintes bases de dados: Medline, Lilacs, Evidence Portal, Cochrane Central Register de Ensaios Controlados (CENTRAL) e Google Academics. Os estudos de seleção foram ensaios clínicos randomizados, estudos de caso-controle e coorte, assim como estudos transversais, em Português e Inglês. Equipes de revisores, independente e em duplicado fez os títulos de telas e resumos e do texto completo para determinar a elegibilidade. Os artigos selecionados foram lidos na íntegra e as variáveis avaliadas de forma independente e descrito em formas pré-determinadas de acordo com os resultados clínicos. Como resultado, cinco estudos de 653 publicações foram incluídos: três estudos de caso-controle, um estudo de coorte e um estudo prospectivo, com análise retrospectiva de dados. Embora esses estudos indicam uma associação positiva entre a presença de doença periodontal e a ocorrência de pneumonia aspirativa, os resultados devem ser interpretados com cautela. Eles não devem ser tomados como conclusões definitivas devido a variações nas metodologias e limitações, tais como tamanho da amostra, controle inadequado de potenciais variáveis de confusão, a falta de calibração das medições periodontais e sem critérios consistentes para o estabelecimento de pneumonia por aspiração. Há pouca evidência para afirmar que a doença periodontal é um fator condição de risco para pneumonia aspirativa. Futuros estudos são necessários para elucidar essa associação, bem como para estabelecer o potencial benefício do tratamento periodontal com o objetivo de reduzir o risco de desenvolver pneumonia por aspiração.

Expansão rápida da maxila na dentadura mista ancorada em dentes decíduos – relato de caso / Rapid maxillary expansion in mixed dentition anchored on deciduous teeth – case report

A expansão rápida da maxila para a correção da atresia transversal do arco superior, associada ou não à mordida cruzada posterior, é um procedimento frequente na Ortodontia. Este artigo discute o emprego deste recurso nas fases iniciais da dentadura mista e ilustra um caso clínico no qual foi utilizado o expansor fixo tipo Hass modificado, ancorado nos caninos e segundos molares decíduos, para o tratamento de uma paciente de sete anos e dez meses de idade com atresia maxilar, mordida cruzada unilateral, desvio da linha média dentária superior e apinhamento dentário anterior. O expansor tipo Hass modificado mostrou-se eficaz para a expansão transversal precoce do arco superior, favorecendo o desenvolvimento normal da oclusão...

Rapid maxillary expansion for the correction of transversal atresia of the superior arch associated or not with posterior crossbite, is a frequent procedure in orthodontics. This article discusses the use of this feature in the early stages of mixed dentition and illustrates a clinical case in which a modified Hass-type fixed expander was used, anchored in maxillary deciduous canines and second molars on the treatment of a seven years and ten months old patient with maxillary atresia, unilateral crossbite, dental midline deviation, and anterior dental crowding. The modified Haas-type expander proved to be effective for the early transversal atresia of the superior arch, favoring the development of normal occlusion...

Absenteísmo por causa médica e odontológica em empresa de serviços gráficos e de informação / Absenteeism for medical and dental reasons in a graphic and information service company

O absenteísmo no trabalho tem sido considerado um obstáculo no mundo corporativo, incidindo negativamente sobre a produtividade das empresas e na saúde do trabalhador. Objetivo: Determinar o absenteísmo por causas médicas e odontológicas e suas associações com variáveis demográ- ficas e trabalhistas. Métodos: Foram analisados 387 prontuários de saúde dos funcionários de uma empresa de serviços gráficos e de informação, no período 24 meses, associando variáveis demográficas: gênero, idade e trabalhistas: tempo de admissão e categoria profissional, com a presença de atestados e declarações médicas e odontológicas, caracterizando respectivamente o absenteísmo doença e o absenteísmo saúde. Resultados: Foram identificados 749 documentos que justificavam a ausência no ambiente laboral, em 194 prontuários (50,1%), totalizando 1.604 dias de afastamento, sendo, 48,3% representados pelos atestados mé- dicos, 2,8% pelos atestados odontológicos, 37,7% declarações médicas e 11,2% declarações odontológicas. As principais causas de absenteísmo doença foram as relacionadas ao olho e seus anexos (16,2%) e ao sistema osteomuscular e tecido conjuntivo (14,1%). As morbidades de causa odontológica mais frequentes foram as exodontias (23,8%), pulpites (19,1%) e cárie dentária (19,1%). Observou-se associação entre o número de atestados médicos e o tempo de admissão e a categoria profissional e entre o número de declarações médicas e odontológicas com o gênero feminino e tempo de admissão. Conclusão: O absenteísmo médico foi superior ao odontológico, porém este último representou a 11ª causa de afastamento dos trabalhadores do seu ambiente laboral. O impacto dos problemas bucais causa limitações no desempenho funcional que pode ser mensurado através dos índices de absenteísmo saúde e doença...

Low transformation growth factor-β1 production and collagen synthesis correlate with the lack of hepatic periportal fibrosis development in undernourished mice infected with Schistosoma mansoni

Undernourished mice infected (UI) submitted to low and long-lasting infections by Schistosoma mansoni are unable to develop the hepatic periportal fibrosis that is equivalent to Symmers’ fibrosis in humans. In this report, the effects of the host’s nutritional status on parasite (worm load, egg viability and maturation) and host (growth curves, biology, collagen synthesis and characteristics of the immunological response) were studied and these are considered as interdependent factors influencing the amount and distribution of fibrous tissue in hepatic periovular granulomas and portal spaces. The nutritional status of the host influenced the low body weight and low parasite burden detected in UI mice as well as the number, viability and maturation of released eggs. The reduced oviposition and increased number of degenerated or dead eggs were associated with low protein synthesis detected in deficient hosts, which likely induced the observed decrease in transformation growth factor (TGF)-β1 and liver collagen. Despite the reduced number of mature eggs in UI mice, the activation of TGF-β1 and hepatic stellate cells occurred regardless of the unviability of most miracidia, due to stimulation by fibrogenic proteins and eggshell glycoproteins. However, changes in the repair mechanisms influenced by the nutritional status in deficient animals may account for the decreased liver collagen detected in the present study.

Low transformation growth factor-ß1 production and collagen synthesis correlate with the lack of hepatic periportal fibrosis development in undernourished mice infected with Schistosoma mansoni.

Undernourished mice infected (UI) submitted to low and long-lasting infections by Schistosoma mansoni are unable to develop the hepatic periportal fibrosis that is equivalent to Symmers' fibrosis in humans. In this report, the effects of the host's nutritional status on parasite (worm load, egg viability and maturation) and host (growth curves, biology, collagen synthesis and characteristics of the immunological response) were studied and these are considered as interdependent factors influencing the amount and distribution of fibrous tissue in hepatic periovular granulomas and portal spaces. The nutritional status of the host influenced the low body weight and low parasite burden detected in UI mice as well as the number, viability and maturation of released eggs. The reduced oviposition and increased number of degenerated or dead eggs were associated with low protein synthesis detected in deficient hosts, which likely induced the observed decrease in transformation growth factor (TGF)-ß1 and liver collagen. Despite the reduced number of mature eggs in UI mice, the activation of TGF-ß1 and hepatic stellate cells occurred regardless of the unviability of most miracidia, due to stimulation by fibrogenic proteins and eggshell glycoproteins. However, changes in the repair mechanisms influenced by the nutritional status in deficient animals may account for the decreased liver collagen detected in the present study.

Evaluation of the anti-Schistosoma mansoni activity of thiosemicarbazones and thiazoles.

Schistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma and affects over 207 million people. Chemotherapy is the only immediate recourse for minimizing the prevalence of this disease and involves predominately the administration of a single drug, praziquantel (PZQ). Although PZQ has proven efficacy, there is a recognized need to develop new drugs as schistosomicides since studies have shown that repeated use of this drug in areas of endemicity may cause a temporary reduction in susceptibility in isolates of Schistosoma mansoni. Hydrazones, thiosemicarbazones, phthalimides, and thiazoles are thus regarded as privileged structures used for a broad spectrum of activities and are potential candidates for sources of new drug prototypes. The present study determined the in vitro schistosomicidal activity of 10 molecules containing these structures. During the assays, parameters such motility and mortality, oviposition, morphological changes in the tegument, cytotoxicity, and immunomodulatory activity caused by these compounds were evaluated. The results showed that compounds formed of thiazole and phthalimide led to higher mortality of worms, with a significant decline in motility, inhibition of pairing and oviposition, and a mortality rate of 100% starting from 144 h of exposure. These compounds also stimulated the production of nitric oxide and tumor necrosis factor alpha (TNF-α), thereby demonstrating the presence of immunomodulatory activity. The phthalyl thiazole LpQM-45 caused significant ultrastructural alterations, with destruction of the tegument in both male and female worms. According to the present study, phthalyl thiazole compounds possess antischistosomal activities and should form the basis for future experimental and clinical trials.

Campomelic dysplasia and malignant hyperthermia.

Campomelic dysplasia (CD) is a rare clinical entity, usually fatal in the first year of life. It is characterised by bowing and angulations of long bones, along with other congenital anomalies. The occurrence of malignant hyperthermia is rare, but it has been associated with skeletal dysplasias. The authors present the case of a boy, born at 40 weeks of gestational age, with multiple congenital anomalies and subsequently diagnosed with CD, who died at 16 months of age as a consequence of malignant hyperthermia.