Eugenia pohliana leaves essential oil inhibits fungal virulence and restores antibiotic efficacy in multidrug-resistant bacterial strains.

This study aims to investigate the essential oil from leaves of E. pohliana (EOEP) in regard to its chemical composition, antimicrobial and drug-enhancing activity, as well as the reduction of fungal virulence capacity. Chemical characterization using GC-MS showed as major components the sesquiterpenes δ-cadinene, Epi-α-Muurolol, and bicyclogermacrene. The results of antibacterial tests indicated that Staphylococcus aureus was more sensitive to EOEP, that also enhanced the efficacy of gentamicin, erythromycin, and norfloxacin. EOEP exhibited antifungal properties against Candida albicans, in addition to potentiating the effectiveness of fluconazole against Candida tropicalis. It showed anti-virulence effects in all fungal strains. These findings underscore Eugenia pohliana as a potential candidate for the prospection of novel therapeutic agents to treat infectious diseases caused by resistant microbes.

Renal tubular acidosis in hereditary transthyretin amyloidosis (ATTRv).

INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRv) is a severe autosomal dominant systemic disease. It affects the peripheral and autonomic nervous systems, heart, kidneys, and eyes. Amyloid deposition has been demonstrated in the glomerular and tubulointerstitial compartments of the kidney. Therefore, urinary acidification disorders such as renal tubular acidosis (RTA) may be early manifestations of renal involvement in this population. OBJECTIVE: To evaluate the prevalence of RTA in individuals with ATTRv. METHODS: We included symptomatic and asymptomatic individuals with TTR mutation, older than 18 years, GFR >45 mL/min/1.73m2, without systemic metabolic acidosis. Urinary acidification protocol was performed with furosemide and fludrocortisone after 12 h of water deprivation (water deprivation test - WDT) and measurements of urine ammonium ( UNH 4 + ) and titratable acidity (UTA). Proximal RTA (pRTA) was diagnosed when FEHCO3>10%. Incomplete form distal RTA (dRTA) was diagnosed if UpH>5.3. RESULTS: We selected 49 individuals with a mean age of 40 (35.5-56.5) years, 63% of which were female, 84% were Caucasian, and mean GFR was 85.5 ± 20.5 mL/min/1.73m2. 94% had the genetic variant Val50Met and 57% were symptomatic. The prevalence of pRTA was 2% and of dRTA was 16.3%. In the subgroup with dRTA, there was no significant increase in excretion of UNH 4 + and UTA. We observed a good correlation between UpH by potentiometry and UpH dipstick. A UpH<5.5 on the dipstick had 100% sensitivity and negative predictive value to exclude dRTA. CONCLUSION: A high prevalence of RTA was found in individuals with TTR mutations. The UpH dipstick after WDT had good accuracy for screening for dRTA. Further studies are needed to evaluate the impact of early diagnosis and treatment of RTA in this population.

Fungal diversity associated with Goa's tarballs: Insights from ITS region amplicon sequencing.

This study explores the fungal diversity associated with tarballs, weathered crude oil deposits, on Goa's tourist beaches. Despite tarball pollution being a longstanding issue in Goa state in India, comprehensive studies on associated fungi are scarce. Our research based on amplicon sequence analysis of fungal ITS region fills this gap, revealing a dominance of Aspergillus, particularly Aspergillus penicillioides, associated with tarballs from Vagator and Morjim beaches. Other notable species, including Aspergillus sydowii, Aspergillus carbonarius, and Trichoderma species, were identified, all with potential public health and ecosystem implications. A FUNGuild analysis was conducted to investigate the potential ecological roles of these fungi, revealing a diverse range of roles, including nutrient cycling, disease propagation, and symbiotic relationships. The study underscores the need for further research and monitoring, given the potential health risks and contribution of tarball-associated fungi to the bioremediation of crude oil-contaminated beaches.

Renal tubular acidosis in hereditary transthyretin amyloidosis (ATTRv) / Acidose tubular renal na amiloidose hereditária por transtirretina (ATTRv)

Abstract Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe autosomal dominant systemic disease. It affects the peripheral and autonomic nervous systems, heart, kidneys, and eyes. Amyloid deposition has been demonstrated in the glomerular and tubulointerstitial compartments of the kidney. Therefore, urinary acidification disorders such as renal tubular acidosis (RTA) may be early manifestations of renal involvement in this population. Objective: To evaluate the prevalence of RTA in individuals with ATTRv. Methods: We included symptomatic and asymptomatic individuals with TTR mutation, older than 18 years, GFR >45 mL/min/1.73m2, without systemic metabolic acidosis. Urinary acidification protocol was performed with furosemide and fludrocortisone after 12 h of water deprivation (water deprivation test - WDT) and measurements of urine ammonium ( UNH 4 +) and titratable acidity (UTA). Proximal RTA (pRTA) was diagnosed when FEHCO3>10%. Incomplete form distal RTA (dRTA) was diagnosed if UpH>5.3. Results: We selected 49 individuals with a mean age of 40 (35.5-56.5) years, 63% of which were female, 84% were Caucasian, and mean GFR was 85.5 ± 20.5 mL/min/1.73m2. 94% had the genetic variant Val50Met and 57% were symptomatic. The prevalence of pRTA was 2% and of dRTA was 16.3%. In the subgroup with dRTA, there was no significant increase in excretion of UNH 4 + and UTA. We observed a good correlation between UpH by potentiometry and UpH dipstick. A UpH<5.5 on the dipstick had 100% sensitivity and negative predictive value to exclude dRTA. Conclusion: A high prevalence of RTA was found in individuals with TTR mutations. The UpH dipstick after WDT had good accuracy for screening for dRTA. Further studies are needed to evaluate the impact of early diagnosis and treatment of RTA in this population.

Resumo Introdução: A amiloidose hereditária por transtirretina (ATTRv) é uma doença sistêmica autossômica dominante grave. Afeta os sistemas nervoso periférico e autônomo, coração, rins e olhos. A deposição de amiloide foi demonstrada nos compartimentos glomerular e tubulointersticial do rim. Portanto, distúrbios de acidificação urinária, como acidose tubular renal (ATR), podem ser manifestações precoces de envolvimento renal nessa população. Objetivo: Avaliar a prevalência de ATR em indivíduos com ATTRv. Métodos: Incluímos indivíduos sintomáticos e assintomáticos com mutação na TTR, maiores de 18 anos, TFG >45 mL/min/1,73m2, sem acidose metabólica sistêmica. Realizou-se protocolo de acidificação urinária com furosemida e fludrocortisona após 12 horas de privação hídrica (teste de restrição hídrica - TRH) e medições de amônia urinária ( uNH 4 +) e acidez titulável (uTA) na urina. ATR proximal (ATRp) foi diagnosticada quando FEHCO3>10%. ATR distal (ATRd) de forma incompleta foi diagnosticada se pHu>5,3. Resultados: Selecionamos 49 indivíduos com idade média de 40 (35,5-56,5) anos, 63% mulheres, 84% caucasianos e TFG média de 85,5 ± 20,5 mL/min/1,73m2. 94% apresentaram a variante genética Val50Met; 57% eram sintomáticos. A prevalência de ATRp foi 2% e a de ATRd foi 16,3%. No subgrupo com ATRd, não houve aumento significativo na excreção de uNH 4 + e uTA. Observamos uma boa correlação entre pHU por potenciometria e pHU por fita reagente. Um pHU<5,5 na fita reagente apresentou 100% de sensibilidade e valor preditivo negativo para excluir a ATRd. ConclusÃO: Uma alta prevalência de ATR foi encontrada em indivíduos com mutações na TTR. O pHU por fita reagente após TRH teve boa precisão para triagem de ATRd. São necessários mais estudos para avaliar o impacto do diagnóstico e tratamento precoces da ATR nessa população.

Phytochemical Analysis, Antibacterial Activity and Modulating Effect of Essential Oil from Syzygium cumini (L.) Skeels.

One of the main global problems that affect human health is the development of bacterial resistance to different drugs. As a result, the growing number of multidrug-resistant pathogens has contributed to an increase in resistant infections and represents a public health problem. The present work seeks to investigate the chemical composition and antibacterial activity of the essential oil of Syzygium cumini leaves. To identify its chemical composition, gas chromatography coupled to mass spectrometry was used. The antibacterial activity test was performed with the standard strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 25853 and Staphylococcus aureus ATCC 25923 and multidrug-resistant clinical isolates E. coli 06, P. aeruginosa 24 and S. aureus 10. The minimum inhibitory concentration (MIC) was determined by serial microdilution as well as the verification of the modulating effect of the antibiotic effect. In this test, the oil was used in a subinhibitory concentration. The test reading was performed after 24 h of incubation at 37 °C. The results show that the major chemical constituent is α-pinene (53.21%). The oil showed moderate activity against E. coli ATCC 25922, with the MIC of 512 µg/mL; there was no activity against the other strains. The oil potentiated the effect of antibiotics demonstrating possible synergism when associated with gentamicin, erythromycin and norfloxacin against E. coli 06 and S. aureus 10.

Traditional Uses, Phytochemistry, and Bioactivities of Mesosphaerum suaveolens (L.) Kuntze.

Mesosphaerum suaveolens (L.) Kuntze is a species widely used traditionally in the treatment of ailments, such as stomach pain, hemorrhoids, cough, verminosis, ulcer, liver disease, fever, influenza, nasal congestion, and inflammation. This review aims to provide a survey of available information on seven international electronic databases (Google Scholar, Medline, ResearchGate, Web of Science, Scopus, Science Direct, and PubMed) about botanical aspects, traditional uses, phytochemistry, and biological activities of M. suaveolens. Mesosphaerum suaveolens is a tropical America native species, but it can be found in several parts of the world as a ruderal plant. The species is the most studied species of the genus Lamiaceae due its phytochemical aspect, especially regarding the chemical composition of its essential oil. Besides the essential oils, M. suaveolens is a source of numerous secondary compounds such as triterpenes, diterpenes, and phenolic compounds, which are related to its biological activities, such as allelopathic, antibacterial, antifungal, insecticidal, and larvicidal activities as described in the literature.

Chemical Constituents and Biological Activities of Croton heliotropiifolius Kunth.

Croton heliotropiifolius Kunth (Euphorbiaceae), whose occurrence has already been registered in the most varied Brazilian biomes, is commonly found in the Chapada do Araripe, Ceará. The species is traditionally used to treat fungal, parasitic, and degenerative diseases. This study investigated the chemical composition and pharmacological potential (antioxidant, antifungal, antiparasitic, and cytotoxic) of an aqueous extract obtained from the roots of C. heliotropiifolius. Following a qualitative phytochemical screening, the chemical constituents were identified by ultra-efficiency liquid chromatography coupled witha quadrupole/time-of-flight system (UPLC-QTOF). The antioxidant potential was verified by thin-layer chromatography (TLC). The direct and combined antifungal activity of the extract against opportunistic Candida strains was investigated using the microdilution method. The minimal fungicidal concentration (MFC) was determined by subculture, while the modulation of the morphological transition (fungal virulence) was evaluated by light microscopy. The in vitro antiparasitic activity was analyzed using epimastigotes of Trypanosoma cruzi and promastigotes of Leishmania braziliensis and Leishmania infantum, while cytotoxicity was determined in cultures of mouse fibroblasts. The phytochemical analysis identified the presence of acids, terpenes, flavonoids, lignans, and alkaloids. Among these constituents, the presence of polar and non-polar phenolic compounds with known antioxidant action was highlighted. While the extract showed clinically ineffective antifungal effects, it could enhance the effectiveness of fluconazole, in addition to inhibiting the morphological transition associated with increased virulence in Candida strains. Although the extract showed low cytotoxicity against fibroblasts, it also had weak antiparasitic effects. In conclusion, Croton heliotropiifolius is a source of natural products with antifungal and antioxidant potential.

Assessment of Mechanical Root Canal Preparation with Centric Reciprocating or Eccentric Rotary Kinematics: A Micro-computed Tomographic Study.

INTRODUCTION: The aim of this study was to compare, using micro-computed tomographic imaging, the preparation of mesial canals of mandibular molars with the Reciproc (VDW GmbH, Munich, Germany) and XP-endo Shaper (FKG, La Chaux-de-Fonds, Switzerland) systems, evaluating changes in dentin and canal volume, the percentage of untouched walls, the volume of accumulated hard tissue debris, and root canal deviation in the apical third. METHODS: Twenty-four mandibular molars with 2 mesial root canals and a single foramen were anatomically paired and divided into 2 experimental groups (n = 12) according to the system used. The specimens were scanned before and after preparation with the SkyScan 1176 microtomographic scanner (Bruker-microCT, Kontich, Belgium) at a resolution of 17.42 µm. The resulting data were statistically compared at a significance level of 5% using the Student t test and the Mann-Whitney test. RESULTS: A significant difference was observed in the untouched surface area for the total canal and the cervical and middle thirds, with the lowest untouched surface area in the XP-endo Shaper group (P < .05). The volume of accumulated hard tissue debris was significantly higher in the Reciproc group in the total canal as well as in the middle and apical thirds. There was no significant difference between the groups regarding the volume of dentin removed or the increase in canal volume and surface area (P > .05). CONCLUSIONS: The XP-endo Shaper touched more walls and left less accumulated hard tissue debris in the root canal system than the Reciproc group. Although the XP-endo Shaper showed superior results, neither system was able to fully prepare the root canal.

Malnourishment during early lactation disrupts the ontogenetic distribution of the CART and α-MSH anorexigenic molecules in the arcuate/paraventricular pathway and lateral hypothalamus in male rats.

Developmental malnourishment impacts the energetic metabolism control throughout life. In rat offspring, a 0% protein diet during the first 10 days of lactation results in leptin resistance and in alterations in: feeding behavior, serum leptin and neuropeptide Y (NPY) levels in the hypothalamic arcuate nucleus (ARC)/paraventricular (PVN) pathway. Here, the distributions of alpha-melanocyte stimulating hormone (α-MSH) and cocaine and amphetamine regulated transcript (CART), anorexigenic molecules, were immunohistochemically assessed in the ARC, PVN and lateral hypothalamus (LH) nuclei. Rat dams were subjected to one of the following diet protocols from postnatal day (P) 1-10: 1) Protein-free (PFG, 0% protein chow); 2) Pair-fed (UFG, normoprotein chow); 3) Control group (CG, normoprotein chow). PFG, UFG and CG male offspring were analyzed at different time points, from P5 to P180. In the ARC, PFG α-MSH and CART were increased from P10 to P45 when compared to CG and UFG. In the PVN, α-MSH and CART peaks in PFG animals were delayed from P20 to P30 when compared to CG. In the LH, CART was more intense in PFG animals than in UFG and CG ones by P20, and, by P30, UFG immunostaining became less intense than in CG. In conclusion, aproteic diet altered the ontogenetic distribution of both anorexigenic molecules. In the PVN, the peak was delayed to P30, which coincides with the leptin peak and follows the previously described NPY (orexigenic) peak in this model. The permanent LH CART and α-MSH increase may be associated with the previously observed PFG hypophagia.

Síndrome de Burnout em profissionais da hemodiálise / Burnout Syndrome in hemodialysis professionals

Objetivo: quantificar, dentre os profissionais que atuam no setor de hemodiálises, os que são acometidos pela Síndrome de Burnout. Método: estudo quantitativo, descritivo, transversal e de prevalência, com profissionais da saúde de hemodiálises. Os dados foram analisados por meio do software estatístico SPSS e apresentados em tabelas. Resultados: na Exaustão Emocional, 76,2% foram identificados como baixa; 20,2%, classificados como média e 3,6%, classificados como elevada. Em Despersonalização, 96,4% foram classificados como baixa; 2,4%, classificados como média e 1,2%, classificados como alta. Por fim, na Baixa Realização Profissional, 2,4% foram classificados como baixa; 4,8%, classificados como média e 92,9%, classificados como alta. Conclusão: há vulnerabilidade considerável dos profissionais de saúde das hemodiálises para a Síndrome de Burnout e suas dimensões, além de que há prevalências ligadas a algumas condições.(AU)

Sundown syndrome and symptoms of anxiety and depression in hospitalized elderly.

Sundown syndrome is characterized by the sudden appearance of neuropsychiatric symptoms such as agitation, confusion and anxiety in a chronologic fashion, usually during late afternoon or early evening. OBJECTIVE: To evaluate the prevalence of sundown syndrome in university hospital wards and its relationship with anxiety/depression symptoms, cognitive decline, and clinical and demographic variables. METHODS: We evaluated 70 patients admitted to the Lauro Wanderley University Hospital (HULW), João Pessoa-PB, Brazil. Data collection instruments were the Confusion Assessment Method (CAM), the Mini-Mental State Exam (MMSE) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Mean patient age was 68.4±6.4 years, 55.7% were male, 67.1% were illiterate or had incomplete primary education. It was observed that 14.3% of patients had delirium, 15.7% had cognitive deficits, while 21.4% and 18.6% had anxious and depressive symptoms, respectively. The age of patients with delirium (71.9±8.7) was significantly higher than those without (67.8±5.8). At 95% confidence, there was a significant difference in the groups with and without delirium for the MMSE and HADS-D scales. CONCLUSION: We verified the occurrence of delirium compatible with the sundown syndrome and associated with depressive symptoms and cognitive deficit, with no apparent relationship with infectious processes or fever, number of drugs used, hospital stay or anxious symptomatology.

A síndrome de Sundown é caracterizada pelo aparecimento súbito de sintomas neuropsiquiátricos como agitação, confusão e ansiedade de forma cronológica, geralmente no final da tarde ou no início da noite. OBJETIVO: Avaliar a prevalência da síndrome do por do sol em enfermarias de um hospital universitário e sua relação com sintomatologia depressivo-ansiosa, déficit cognitivo e variáveis clínicas e demográficas. MÉTODOS: Foram avaliados 70 pacientes admitidos nas enfermarias Hospital Universitário Lauro Wanderley (HULW), João Pessoa-PB, Brasil. Os instrumentos de coleta de dados foram a Escala de Avaliação de Quadros Confusionais (Confusion Assessment Method - CAM), o Mini-Exame do Estado Mental (MEEM) e a Escala Hospitalar de Ansiedade e Depressão (HADS). RESULTADOS: A média de idade de 68,4±6,4 anos, 55,7% do sexo masculino, 67,1% não alfabetizados ou com instrução fundamental incompleta. Observou-se que 14,3% dos pacientes tinham delirium, 15,7% tinham déficit cognitivo, enquanto 21,4% e 18,6% apresentavam sintomas ansiosos e depressivos, respectivamente. A idade dos pacientes com delirium (71,9±8,7) foi significativamente maior que a dos que não apresentavam este quadro (67,8±5,8). Com 95% de confiança, há diferença significativa nos grupos com e sem delirium em relação das escalas do MEEM e do HADS-D. CONCLUSÃO: Verificamos a ocorrência de delirium compatível com a síndrome do pôr do sol e associado com sintomas depressivos e déficit cognitivo, sem relação aparente com processo infeccioso ou febre, número de medicamentos em uso, permanência hospitalar e sintomatologia ansiosa.

Sundown syndrome and symptoms of anxiety and depression in hospitalized elderly / Síndrome do pôr do sol e sintomas de ansiedade e depressão em idosos hospitalizados

ABSTRACT Sundown syndrome is characterized by the sudden appearance of neuropsychiatric symptoms such as agitation, confusion and anxiety in a chronologic fashion, usually during late afternoon or early evening. Objective: To evaluate the prevalence of sundown syndrome in university hospital wards and its relationship with anxiety/depression symptoms, cognitive decline, and clinical and demographic variables. Methods: We evaluated 70 patients admitted to the Lauro Wanderley University Hospital (HULW), João Pessoa-PB, Brazil. Data collection instruments were the Confusion Assessment Method (CAM), the Mini-Mental State Exam (MMSE) and the Hospital Anxiety and Depression Scale (HADS). Results: Mean patient age was 68.4±6.4 years, 55.7% were male, 67.1% were illiterate or had incomplete primary education. It was observed that 14.3% of patients had delirium, 15.7% had cognitive deficits, while 21.4% and 18.6% had anxious and depressive symptoms, respectively. The age of patients with delirium (71.9±8.7) was significantly higher than those without (67.8±5.8). At 95% confidence, there was a significant difference in the groups with and without delirium for the MMSE and HADS-D scales. Conclusion: We verified the occurrence of delirium compatible with the sundown syndrome and associated with depressive symptoms and cognitive deficit, with no apparent relationship with infectious processes or fever, number of drugs used, hospital stay or anxious symptomatology.

RESUMO A síndrome de Sundown é caracterizada pelo aparecimento súbito de sintomas neuropsiquiátricos como agitação, confusão e ansiedade de forma cronológica, geralmente no final da tarde ou no início da noite. Objetivo: Avaliar a prevalência da síndrome do por do sol em enfermarias de um hospital universitário e sua relação com sintomatologia depressivo-ansiosa, déficit cognitivo e variáveis clínicas e demográficas. Métodos: Foram avaliados 70 pacientes admitidos nas enfermarias Hospital Universitário Lauro Wanderley (HULW), João Pessoa-PB, Brasil. Os instrumentos de coleta de dados foram a Escala de Avaliação de Quadros Confusionais (Confusion Assessment Method - CAM), o Mini-Exame do Estado Mental (MEEM) e a Escala Hospitalar de Ansiedade e Depressão (HADS). Resultados: A média de idade de 68,4±6,4 anos, 55,7% do sexo masculino, 67,1% não alfabetizados ou com instrução fundamental incompleta. Observou-se que 14,3% dos pacientes tinham delirium, 15,7% tinham déficit cognitivo, enquanto 21,4% e 18,6% apresentavam sintomas ansiosos e depressivos, respectivamente. A idade dos pacientes com delirium (71,9±8,7) foi significativamente maior que a dos que não apresentavam este quadro (67,8±5,8). Com 95% de confiança, há diferença significativa nos grupos com e sem delirium em relação das escalas do MEEM e do HADS-D. Conclusão: Verificamos a ocorrência de delirium compatível com a síndrome do pôr do sol e associado com sintomas depressivos e déficit cognitivo, sem relação aparente com processo infeccioso ou febre, número de medicamentos em uso, permanência hospitalar e sintomatologia ansiosa.

Cytotoxic effects of alkaloids on cervical carcinoma cell lines: a review / Efeitos citotóxicos de alcaloides sobre linhagens de células do câncer cervical: uma revisão

Cervical cancer is the fourth type of women neoplasia, with thousands of new cases annually. It is closely related to human papillomavirus (HPV) infection, which has more than 13 oncogenic types, among them HPV 16 and 18 are implicated in 70% of cervical carcinoma cases. Alkaloids are nitrogenated and naturally occurring compounds, showing several uses in medical treatment, including cytotoxic and antineoplastic activities. In this work we aim to evaluate the cytotoxic and chemotherapeutic potential of alkaloids against cervical cancer. In order to accomplish this purpose, we have made a survey of potentially effective alkaloids with cytotoxic activities over HPV-16+ and HPV-18+ cells (HeLa cells). Through a literature review between the years of 1980 and 2015, we described the major alkaloid sources, distribution in nature and also discussed the mechanisms of action for their cytotoxicity. We found that alkaloids showed efficacy as cytotoxic agents, inhibiting cell growth of the HPV-transformed cells in vitro and in vivo by means of activation of intrinsic and extrinsic pathways of apoptosis, which included the clivage of caspases and PARP-1 (Poli-Adenosyl- Ribose Protease 1), increase in p53 expression, release of cytochrome C and increase of cell death receptors expression like Fas, mainly observed in HeLa (HPV- 18+) cell lines. Moreover, these secondary metabolites helped in modulating the MDR (Multi-Drug Resistance) against the cell lines studied, which lead us to suggest their possible use as chemotherapeutic agents on the lesions caused by these viruses

O câncer cervical é a quarta neoplasia incidente em mulheres, com o surgimento de milhares de novos casos anualmente. Está altamente relacionado à infecção pelo papilomavírus humano (HPV), que apresenta mais de 13 tipos oncogênicos, dentre os quais os tipos 16 e 18 são encontrados em 70% dos casos de câncer do colo do útero (câncer cervical). Alcaloides são substâncias naturais nitrogenadas que apresentam diversos usos na terapia, incluindo atividades antineoplásica e citotóxica. Neste sentido, objetivamos neste trabalho avaliar o potencial citotóxico e quimioterápico de alcaloides sobre o câncer cervical. Para tanto, relacionamos os alcaloides com potencial citotóxico sobre HPV- 16+ e HPV-18+ (células HeLa), bem como mostramos suas principais fontes de obtenção, distribuição na natureza e discutimos os mecanismos de ação pelos quais realizam seu efeito citotóxico, através de uma revisão bibliográfica realizada entre o período de 1980 e 2015. Os alcaloides mostraram-se eficazes como drogas citotóxicas, inibindo o crescimento de células alteradas pelo HPV tanto in vitro quanto in vivo, com ativação de mecanismos intrínsecos e extrínsecos de apoptose, tais como ativação das caspases, clivagem de PARP-1 (Poli-ADP-Ribose Protease 1), aumento da expressão de p53, liberação de citocromo C e aumento da expressão de receptores de morte como o Fas, principalmente em células das linhagens HeLa (HPV-18+). Adicionalmente, esses metabólitos secundários auxiliaram na modulação da resistência a múltiplas drogas pelas linhagens de células estudadas, o que nos leva a sugerir o seu possível uso na quimioterapia das lesões provocadas por estes vírus.

Polyglandular Syndrome Type III and Severe Peripheral Neuropathy: An Unusual Association.

INTRODUCTION: Polyglandular syndrome is characterized by the association of autoimmune, organ-specific, endocrine and non-endocrine diseases. OBJECTIVE: To present a case of polyglandular syndrome type III (b) accompanied by pernicious anemia and autoimmune thyroiditis. METHOD: Report the clinical case of a young patient that developed progressive and disabling peripheral neuropathy framework, triggered by vitamin B12 deficiency. DISCUSSION: It was proven that atrophic gastritis with positive intrinsic anti-factor was responsible for the framework of pernicious anemia, which in turn dangerously reduced the serum levels of vitamin B12, leading to myelopathy. There was a progressive neurological improvement after parenteral cyanocobalamin replacement, keeping the patient at ambulatory, under maintenance therapy. CONCLUSION: The importance of suspecting on polyglandular syndrome in the presence of autoimmune frameworks is important, especially those involving diabetes, thyroiditis, atrophic gastritis, pernicious anemia, vitiligo, among others.

INTRODUÇÃO: A Síndrome Poliglandular é caracterizada pela associação de doenças autoimune órgão-específicas, endócrinas e não endócrinas. OBJETIVO: Apresentar um caso de Síndrome Poliglandular do tipo III (b) acompanhada de anemia perniciosa e tireoidite auto-imune. MÉTODO: Relata-se o caso clínico de uma paciente jovem que desenvolveu quadro de neuropatia periférica progressiva e incapacitante, desencadeada pela deficiência de vitamina B12. DISCUSSÃO: Ficou comprovado que a gastrite atrófica com anticorpo anti-fator intrínseco positivo foi responsável pelo quadro de anemia perniciosa, que por sua vez reduziu perigosamente os níveis séricos da vitamina B12. Houve melhora progressiva do quadro neurológico após reposição parenteral da cianocobalamina, mantendo-se a paciente, em seguimento ambulatorial, sob terapia de manutenção. CONCLUSÃO: Ressalta-se a importância de se suspeitar da síndrome poliglandular na vigência de quadros auto-imunes, especialmente aqueles envolvendo diabetes, tireoidites, gastrite atrófica, anemia perniciosa, vitiligo, entre outros.

Mutation Update for UBE3A variants in Angelman syndrome.

Angelman syndrome is a neurodevelopmental disorder caused by a deficiency of the imprinted and maternally expressed UBE3A gene. Although de novo genetic and epigenetic imprinting defects of UBE3A genomic locus account for majority of Angelman diagnoses, approximately 10% of individuals affected with Angelman syndrome are a result of UBE3A loss-of-function mutations occurring on the expressed maternal chromosome. The variants described in this manuscript represent the analysis of 2,515 patients referred for UBE3A gene sequencing at our institution, along with a comprehensive review of the UBE3A mutation literature. Of these, 267 (10.62%) patients had a report issued for detection of a UBE3A gene nucleotide variant, which in many cases involved family studies resulting in reclassification of variants of unknown clinical significance (VUS). Overall, 111 (4.41%) probands had a nucleotide change classified as pathogenic or strongly favored to be pathogenic, 29 (1.15%) had a VUS, and 126 (5.0%) had a nucleotide change classified as benign or strongly favored to be benign. All variants and their clinical interpretations are submitted to NCBI ClinVar, a freely accessible human variation and phenotype database.

Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.

BRCA1 and BRCA2 sequencing analysis detects variants of uncertain clinical significance in approximately 2 % of patients undergoing clinical diagnostic testing in our laboratory. The reclassification of these variants into either a pathogenic or benign clinical interpretation is critical for improved patient management. We developed a statistical variant reclassification tool based on the premise that probands with disease-causing mutations are expected to have more severe personal and family histories than those having benign variants. The algorithm was validated using simulated variants based on approximately 145,000 probands, as well as 286 BRCA1 and 303 BRCA2 true variants. Positive and negative predictive values of ≥99 % were obtained for each gene. Although the history weighting algorithm was not designed to detect alleles of lower penetrance, analysis of the hypomorphic mutations c.5096G>A (p.Arg1699Gln; BRCA1) and c.7878G>C (p.Trp2626Cys; BRCA2) indicated that the history weighting algorithm is able to identify some lower penetrance alleles. The history weighting algorithm is a powerful tool that accurately assigns actionable clinical classifications to variants of uncertain clinical significance. While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.

Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer.

BACKGROUND: This study sought to determine the prevalence of PALB2 mutations in a cohort referred for diagnostic testing for hereditary breast cancer. METHODS: Sanger sequencing was used to analyze the entire coding region and flanking introns of PALB2 in anonymized DNA samples from 1479 patients. Samples were stratified into a "high-risk" group, 955 samples from individuals predicted to have a high probability of carrying a mutation in BRCA1 or BRCA2 based on their personal and family history, and a "lower-risk" group consisting of 524 samples from patients with breast cancer, but fewer risk factors for being a BRCA1 or BRCA2 mutation carrier. All patients were known to be negative for deleterious sequence mutations and large rearrangements in BRCA1 and BRCA2. RESULTS: We identified 12 disease-associated PALB2 mutations among the 1479 patients (0.8%). The PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice-site mutation. The mutation prevalence for the high-risk population was 1.05% (95% CI = 0.5-1.92), whereas that for the lower-risk population was 0.38% (95% CI = 0.05-1.37). We identified 59 PALB2 variants of uncertain significance (VUS) among 57 of the 1479 patients (3.9%). CONCLUSIONS: These results suggest that PALB2 mutations occur at a frequency of ~1% in patients with hereditary breast cancer.

Pyramidal neurons are "neurogenic hubs" in the neurovascular coupling response to whisker stimulation.

The whisker-to-barrel cortex is widely used to study neurovascular coupling, but the cellular basis that underlies the perfusion changes is still largely unknown. Here, we identified neurons recruited by whisker stimulation in the rat somatosensory cortex using double immunohistochemistry for c-Fos and markers of glutamatergic and GABAergic neurons, and investigated in vivo their contribution along with that of astrocytes in the evoked perfusion response. Whisker stimulation elicited cerebral blood flow (CBF) increases concomitantly with c-Fos upregulation in pyramidal cells that coexpressed cyclooxygenase-2 (COX-2) and GABA interneurons that coexpressed vasoactive intestinal polypeptide and/or choline acetyltransferase, but not somatostatin or parvalbumin. The evoked CBF response was decreased by blockade of NMDA (MK-801, -37%), group I metabotropic glutamate (MPEP+LY367385, -40%), and GABA-A (picrotoxin, -31%) receptors, but not by GABA-B, VIP, or muscarinic receptor antagonism. Picrotoxin decreased stimulus-induced somatosensory evoked potentials and CBF responses. Combined blockade of GABA-A and NMDA receptors yielded an additive decreasing effect (-61%) of the evoked CBF compared with each antagonist alone, demonstrating cooperation of both excitatory and inhibitory systems in the hyperemic response. Blockade of prostanoid synthesis by inhibiting COX-2 (indomethacin, NS-398), expressed by ∼40% of pyramidal cells but not by astrocytes, impaired the CBF response (-50%). The hyperemic response was also reduced (-40%) after inhibition of astroglial oxidative metabolism or epoxyeicosatrienoic acids synthesis. These results demonstrate that changes in pyramidal cell activity, sculpted by specific types of inhibitory GABA interneurons, drive the CBF response to whisker stimulation and, further, that metabolically active astrocytes are also required.

LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining.

Mucopolysaccharidosis type II (MPS II) is caused by mutations in the IDS gene, which encodes the lysosomal enzyme iduronate-2-sulfatase. In ∼20% of MPS II patients the disorder is caused by gross IDS structural rearrangements. We identified two male cases harboring complex rearrangements involving the IDS gene and the nearby pseudogene, IDSP1, which has been annotated as a low-copy repeat (LCR). In both cases the rearrangement included a partial deletion of IDS and an inverted insertion of the neighboring region. In silico analyses revealed the presence of repetitive elements as well as LCRs at the junctions of rearrangements. Our models illustrate two alternative consequences of rearrangements initiated by non-allelic homologous recombination of LCRs: resolution by a second recombination event (that is, Alu-mediated recombination), or resolution by non-homologous end joining repair. These complex rearrangements have the potential to be recurrent and may be present among those MSP II cases with previously uncharacterized aberrations involving IDS.

Impactação de prótese dentária em esôfago cervical: diagnóstico e tratamento / Giant colonic diverticulum, a rare disease with atypical localization

Corpo estranho esofágico é uma condição frequente que acomete todas as faixas etárias, predominando em crianças e idosos. O diagnóstico deve ser precoce, uma vez que o prognóstico é influenciado pelo tempo de permanência do corpo estranho no esôfago. Os autores relatam o caso de um paciente admitido com quadro de insuficiência respiratória, apresentando corpo estranho impactado em esôfago cervical, de difícil diagnóstico. Foram realizados exames laboratoriais e radiografias de tórax que não apresentaram alterações significativas. A EDA (Endoscopia Digestiva Alta) evidenciou estenose cerrada no nível do esôfago proximal, e a videonasofibrobroncoscopia visualizou tumoração vegetante em região de hipofaringe. A tomografia computadorizada de crânio e região cervical demonstrou imagem de corpo estranho em esôfago proximal, sugestiva de prótese dentária. A retirada da prótese foi realizada por laringoscopia direta, entretanto, o paciente evoluiu com complicações e óbito.

Esophageal foreign body is a common condition that affects all age groups, mainly in children and in the elderly. The diagnosis must be early, since the prognosis is influenced by the length of foreign body in the esophagus. The authors report the case of a patient admitted with respiratory insufficiency presenting a foreign body impacted in the cervical esophagus, difficult to diagnose. It was conducted laboratory tests and chest X-rays that showed no significant changes. Upper gastrointestinal endoscopy (upper endoscopy) revealed tight stenosis at the level of the proximal esophagus and the Videonasofibrobronchoscopy visualized a vegetating tumor in thehypopharynx. Computed tomography of the skull and neck showed an image of a foreign body in proximal esophagus, suggestive dental prosthesis. The removal of the prosthesis was performed by direct laryngoscopy, however, the patient evolved with complications and death.