BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers.

The demographic and clinical characteristics of patients who have BRCA 1/BRCA 2 pathogenic/likely pathogenic variants may differ from their relatives who had BRCA-related cancer. In this study, we aimed to demonstrate the clinical and demographic findings of patients who had BRCA-related cancer and to assess the differences comparing their relatives who had BRCA-related cancer with breast, genital tract, prostate, and pancreas cancers as well. The results of sequencing analysis of 200 cancer patients (190 women, 10 men) who have been directed to genetic counseling with an indication of BRCA1/BRCA2 testing from different regions across 9 medical oncology centers were retrospectively analyzed. A total of 200 consecutive cancer patients who harbored the BRCA1/BRCA2 pathogenic/likely pathogenic variant (130 (65%) patients harbored BRCA 1 pathogenic/likely pathogenic variant, and 70 harbored BRCA 2 pathogenic/likely pathogenic variant) were included. Of these, 64.0% had breast cancer (43.8% of them had the triple-negative disease, and about 2.3% had only the HER-2 mutant), 31.5% had genital cancers (92.1% of them had ovarian cancer, 3.2% had endometrium, and 1.6% had peritoneum cancer as the primary site and mostly serous adenocarcinoma was the most common histopathology and 14.3% of the patients had endometrioid adenocarcinoma), 3.5% had prostate (median time from metastasis to castration-resistant status was 28 months) and 1.0% had pancreas cancer. Newly diagnosed cancer (breast and ovary) patients who had BRCA 1/BRCA 2 pathogenic/ likely pathogenic variant were younger than their previous cancer diagnosed (breast, ovary, and pancreas) parents who harbored BRCA pathogenic/likely pathogenic variant. We suggest that the genetic screening of BRCA 1/ BRCA 2 pathogenic/likely pathogenic variant is needed as a routine screening for those with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. In addition, once BRCA 1 or BRCA 2 germline pathogenic variant has been identified in a family, testing of at-risk next-generation relatives earlier can identify those family members who also have the familial pathogenic variant, and thus need increased surveillance.

A food-responsive switch modulates TFEB and autophagy, and determines susceptibility to coxsackievirus infection and pancreatitis.

Almost a billion people worldwide are chronically undernourished. Herein, using a mouse model of coxsackievirus B3 (CVB3) infection, we report that a single day of food restriction (FR) markedly increases susceptibility to attenuated enterovirus infection, replication, and disease. These "pro-viral" effects, which are rapidly-reversed by the restoration of food, are mediated by several genes whose expression is altered by FR, and which support CVB3 replication. Central to this is TFEB, a protein whose expression and activation status are rapidly increased by FR. TFEB, which regulates the transcription of >100 genes involved in macroautophagy/autophagy and lysosomal biogenesis, responds similarly to both FR and CVB3 infection and plays a pivotal role in determining host susceptibility to CVB3. We propose that, by upregulating TFEB, FR generates an intracellular environment that is more hospitable to the incoming virus, facilitating its replication. This interplay between nutritional status and enterovirus replication has implications for human health and, perhaps, for the evolution of these viruses.Abbreviations: Atg/ATG: autophagy-related; CAR: Coxsackievirus and adenovirus receptor; Cas9: CRISPR associated protein 9; Cre: recombinase that causes recombination; CRISPR: clustered regularly interspaced short palindromic repeats; Ctsb/CTSB: cathepsin B; CVB3: coxsackievirus B3; DsRedCVB3: a recombinant CVB3 that encodes the Discosoma red fluorescent protein; EL: elastase; FR: food restriction; GFP: green fluorescent protein; gRNA: guide RNA; HBSS: Hanks Buffered Salt Solution; LYNUS: lysosomal nutrient sensing machinery; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; Nluc: nanoluciferase; NlucCVB3: a recombinant CVB3 encoding nanoluciferase; pfu: plaque-forming unit(s); p.i.: post infection; rCVB: recombinant coxsackievirus B3; RPS6KB/p70S6K: ribosomal protein S6 kinase; RT: room temperature; siRNA: small interfering RNA; TFEB: transcription factor EB; tg: transgenic; TUBB: ß-tubulin; UNINF: uninfected; wrt: with respect to; WT: wild type.

Identification of Common CD8+ T Cell Epitopes from Lassa Fever Survivors in Nigeria and Sierra Leone.

Early and robust T cell responses have been associated with survival from Lassa fever (LF), but the Lassa virus-specific memory responses have not been well characterized. Regions within the virus surface glycoprotein (GPC) and nucleoprotein (NP) are the main targets of the Lassa virus-specific T cell responses, but, to date, only a few T cell epitopes within these proteins have been identified. We identified GPC and NP regions containing T cell epitopes and HLA haplotypes from LF survivors and used predictive HLA-binding algorithms to identify putative epitopes, which were then experimentally tested using autologous survivor samples. We identified 12 CD8-positive (CD8+) T cell epitopes, including epitopes common to both Nigerian and Sierra Leonean survivors. These data should be useful for the identification of dominant Lassa virus-specific T cell responses in Lassa fever survivors and vaccinated individuals as well as for designing vaccines that elicit cell-mediated immunity.IMPORTANCE The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine.

Exertional dyspnoea in a 28-year-old woman.

CLINICAL INTRODUCTION: A 28-year-old woman with a history of critical pulmonic stenosis, status postsurgical valvotomy and subsequent pulmonary valve replacement, presented to the cardiology clinic with 1 year of progressive exertional dyspnoea. She has a heart rate of 75 bpm and blood pressure of 110/55 mm Hg. Cardiac auscultation reveals a 1/6 systolic ejection murmur along the left sternum and an early 3/6 diastolic decrescendo murmur. A transthoracic echocardiogram is obtained (figure 1). QUESTIONS: Which of the following would be most likely found during right heart catheterisation?Ratio of pulmonary to systemic blood flow (Qp:Qs) >1.5Pulmonary vascular resistance >3 Wood unitsRight atrial pressure >10mm HgPulmonary artery systolic pressure >45mm Hg E. Pulmonary artery diastolic pressure <10mm Hg.

Sulfated polysaccharide extracted of the green algae Caulerpa racemosa increase the enzymatic activity and paw edema induced by sPLA2 from Crotalus durissus terrificus venom

Sulfated polysaccharides derived from seaweed have shown great potential for use in the development of new drugs. In this study, we observed that a low-molecular-weight sulfated polysaccharide from Caulerpa racemosa, termed CrSP, could interact with secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus terrificus venom. When native sPLA2 (14 kDa) was incubated with CrSP, they formed a molecular complex (sPLA2:CrSP) with a molecular mass of 32 kDa, approximately. Size exclusion chromatography experiments suggested that CrSP formed a stable complex with sPLA2. We belived that sPLA2 and SPCr are involved an ionic interaction between negatively charged CrSP and the positively charged basic amino acid residues of sPLA2, because this interaction induced significant changes in sPLA2 enzymatic and pharmacological activities. CrSP caused a significant increase in sPLA2 enzymatic and bactericidal activity and increased its edematogenic effect. A pharmacological assay showed that the myotoxic activity of sPLA2:CrSP is unrelated to its enzymatic activity and that sPLA2:CrSP may have a practical application as a natural antibacterial agent for use in humans and commercially raised animals.

Nerve sparing-distally based sural flap.

The management of soft-tissue defects in the ankle and foot area is a challenging task. Distally based sural flap is widely used, however it leaves donor area paresthesia. For this purpose, the sural nerve was dissected and preserved in the distally based sural flap in five cases of ankle and foot soft tissue reconstruction. This modification did not cause any compromise in flap circulation. All flaps survived with one partial distal necrosis. We suggest that, the distally based nerve sparing sural flap can be securely elevated with only a 3-4 cm wide subcutaneous pedicle without any compromise in flap circulation.

[Influence of current smoking on adherence and responses to pulmonary rehabilitation in patients with COPD]. / Influência do tabagismo atual na aderência e nas respostas à reabilitação pulmonar em pacientes com DPOC.

OBJECTIVE: To investigate the modulating effects of current smoking on adherence and responses to pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In a prospective study, 18 ex-smokers and 23 current smokers (GOLD stages II-III) were enrolled in a 12-week multidisciplinary, supervised PR program. The patients were assessed clinically and as to subjective variables (dyspnea and health-related quality of life) and objective variables (body composition, pulmonary function and 6-min walking distance). The degree of nicotine dependence in current smokers was assessed by the Fagerström test. Program completion defined PR 'adherence'. RESULTS: There was a significant association between current smoking and non-adherence to PR with 30.4% vs. 11.1% and odds ratio=2.9 (1.6-4.1; p<0.01). However, the current smokers who completed the program (n=16) had a similar absentee rate to the ex-smokers, as well as similar gains in the subjective (quality of life) and objective (walked distance) items. Additionally, there was a significant reduction in daily cigarette consumption and in the degree of nicotine dependence in current smokers (p<0.05). CONCLUSIONS: Although current smoking is negatively related to PR adherence, COPD smokers who complete the PR can have similar gains in functionality and quality of life compared to ex-smokers. Moreover, PR may be related to decreased nicotine dependence, even without a formal smoking withdrawal program.

Influência do tabagismo atual na aderência e nas respostas à reabilitação pulmonar em pacientes com DPOC / Influence of current smoking on adherence and responses to pulmonary rehabilitation in patients with COPD

OBJETIVO: Investigar o possível efeito modulador do tabagismo atual na aderência e nos efeitos da reabilitação pulmonar (RP) em pacientes com doença pulmonar obstrutiva crônica (DPOC). MÉTODOS: Em um estudo prospectivo, 18 pacientes ex-tabagistas e 23 tabagistas atuais (GOLD estádios II-IV) foram incluídos num programa multidisciplinar de RP com duração de 12 semanas. Os pacientes foram submetidos à avaliação clínica e à de variáveis subjetivas (dispneia e qualidade de vida) e objetivas (composição corporal, função pulmonar e teste da caminhada de 6 minutos). Nos pacientes tabagistas, obteve-se o nível de dependência da nicotina pela escala de Fagerstrõm. A interrupção da RP antes do término previsto foi considerada indicativa de não aderência ao programa. RESULTADOS: A proporção de pacientes não-aderentes à RP foi maior nos tabagistas do que nos ex-tabagistas (30,4 por cento vs 11,1 por cento, respectivamente; razão de chance=2,9 (1,6-4,1); p<0,01). Entretanto, os tabagistas atuais que completaram o programa (n=16) apresentaram taxa de absenteísmo à RP similar ao observado nos ex-tabagistas, assim como ganhos equivalentes nas respostas subjetivas (qualidade de vida) e objetivas (distância caminhada). Adicionalmente, houve redução significante no número de cigarros consumidos diariamente e no grau de dependência da nicotina nos tabagistas atuais (p<0,05). CONCLUSÕES: Embora o tabagismo atual reduza a aderência à RP, pacientes tabagistas com DPOC que completam tais programas apresentam ganhos funcionais e na qualidade de vida equivalentes aos observados nos ex-tabagistas. A RP, mesmo sem um programa estruturado de cessação do tabagismo, pode associar-se com redução, ao menos a curto prazo, da dependência da nicotina.

OBJECTIVE: To investigate the modulating effects of current smoking on adherence and responses to pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In a prospective study, 18 ex-smokers and 23 current smokers (GOLD stages II-III) were enrolled in a 12-week multidisciplinary, supervised PR program. The patients were assessed clinically and as to subjective variables (dyspnea and health-related quality of life) and objective variables (body composition, pulmonary function and 6-min walking distance). The degree of nicotine dependence in current smokers was assessed by the Fagerstrõm test. Program completion defined PR "adherence". RESULTS: There was a significant association between current smoking and non-adherence to PR with 30.4 percent vs. 11.1 percent and odds ratio=2.9 (1.6-4.1; p<0.01). However, the current smokers who completed the program (n=16) had a similar absentee rate to the ex-smokers, as well as similar gains in the subjective (quality of life) and objective (walked distance) items. Additionally, there was a significant reduction in daily cigarette consumption and in the degree of nicotine dependence in current smokers (p<0.05). CONCLUSIONS: Although current smoking is negatively related to PR adherence, COPD smokers who complete the PR can have similar gains in functionality and quality of life compared to ex-smokers. Moreover, PR may be related to decreased nicotine dependence, even without a formal smoking withdrawal program.

Caracterização anatômica, química e antibacteriana de folhas de Brunfelsia uniflora (manacá) presentes na Mata Atlântica / Anatomical, chemical and antibacterial characterization of leaves of Brunfelsia uniflora (manacá) in the Atlantic Rainforest (Mata Atlântica)

Brunfelsia uniflora é uma espécie pertencente à família Solanaceae conhecida popularmente como manacá e empregada em medicina popular, suas folhas são empregadas contra artrite, reumatismo, sífilis, picadas de cobra, febre amarela, e ainda como diurética e antitérmica. Objetivou-se realizar um estudo anatômico foliar, através de microscopia de luz e de eletrônica de varredura, bem como análises químicas do extrato foliar através de cromatografia e testes microbiológicos com os extratos foliares para atividade antibacteriana frente a Escherichia coli e Staphylococcus aureus. O material biológico foi coletado em área de Mata Atlântica, nas proximidades da cidade de São Vicente - SP. O estudo da anatomia foliar de Brunfelsia uniflora, evidenciou parênquima paliçádico com duas camadas celulares e o parênquima lacunoso com seis camadas de células; foi observada grande quantidade de drusas no parênquima clorofiliano e predominância de esclerênquima na região da nervura central da folha. A epiderme abaxial apresentou grande quantidade de estômatos, sendo estes quase que ausentes na epiderme adaxial. Estudos através de microscopia eletrônica de varredura permitiram evidenciar uma camada de cera epicuticular ornamental bem característica na epiderme adaxial da folha, predominância de estômatos paracíticos, presença de tricomas capitados e muitos tricomas peltados na epiderme abaxial da folha. A análise química evidenciou alguns picos nos cromatogramas que correspondem a grupos de substâncias que não puderam ser analisadas de forma qualitativa, mas que se pode inferir a ocorrência de derivados de ácido cafeico. Os testes microbiológicos obtidos apresentaram resultados negativos no controle das espécies de bactérias testadas, nas concentrações utilizadas.

Brunfelsia uniflora is a species that belongs to the family Solanaceae, popularly known as manacá. In popular medicine the leaves are used for arthritis, rheumatism, syphilis, snake bites, yellow fever, and even as a diuretic and anti-thermal. The main objective of this work was the anatomical study through optical and electronic scanning microscopy, chemical analysis and microbiological tests using Escherichia coli and Staphylococcus aureus and Brunfelsia uniflora leaves extracts. The plants were collected in the Atlantic Rainforest (Mata Atlântica), nearby the city of São Vicente, SP. Brunfelsia uniflora presented palisade parenchyma with two cellular layers and lacunary parenchyma with six cellular layers; large quantities of crystals in mesophyll and sclerenchyma were observed. The lower epidermis presented large quantities of stomata while they were almost absent in the adaxial epidermis. The electronic scanning microscopy showed the presence of paracitic stomata, a waxy layer ornamented in the adaxial epidermis as well as the presence of few trichomes in the central vein region in the abaxial surface. However, in the vein region the trichomes were absent. A chemical analysis showed evidence of some spectral peaks concerning the occurrence of caffeic acid derivatives. The microbiological tests presented negative results for the two species of bacteria.

Caracterização anatômica e química da folha e do sistema radicular de Hydrocotyle umbellata (Apiaceae) / Anatomical and chemical characterization of the leaf and root system of Hydrocotyle umbellata (Apiaceae)

A família Apiaceae (Umbelliferae), também denominada de pioneira das praias, é capaz de habitar locais de alto teor de salinidade, além de suportar a ação dos ventos e das ondas. O presente trabalho teve como objetivo o estudo da anatomia foliar e radicular e analisar constituintes químicos das folhas e do sistema radicular, caracterizando grupos químicos biologicamente ativos presentes nesses órgãos que permitam aplicações farmacológicas. O material foi coletado na região de Proteção Ambiental Iguape, Cananéia, Peruíbe. As folhas são dorsiventrais, com epiderme unisseriada, bordo regular, parênquima paliçádico com duas a três camadas e parênquima lacunoso com oito e nove camadas de células. É anfiestomática, apresentando grandes câmaras subestomáticas com maior incidência de estômatos na epiderme abaxial. O feixe vascular é colateral apresentando células de esclerênquima em forma de meia lua ao redor do xilema e do floema. O pecíolo apresenta contorno irregular, está envolvido por colênquima em toda sua extensão e apresenta grande quantidade de canais secretores entre os feixes vasculares. O rizoma apresenta contorno irregular com variação de 10 a 15 camadas de células de parênquima constituindo o córtex. O cilindro central é constituído por feixes colaterais delimitados pela endoderme. O periciclo é sinuoso e envolve totalmente os feixes vasculares. Sob a epiderme há uma faixa contínua de colênquima. A medula é constituída de células de parênquima de parede fina. H. umbellata apresentou triterpenos, saponinas, flavonóides, compostos poliacetilênicos e leucoceramidas. Folhas e rizomas apresentaram constituintes químicos semelhantes, com diferenças apenas na intensidade dos picos, o que denota diferença quantitativa entre as substâncias presentes. O rendimento do extrato do rizoma é menor que o rendimento das folhas.

The Apiaceae family (Umbelliferae), also called pioneer of beaches, is capable to inhabit areas of high salinity levels. It supports the action of the winds as well as the waves. The objectives of the present work are the study of the foliar and root anatomy and its chemical constituents, in order to find biological active agents that allow pharmacological applications. The plants were collected in an environmental protected region (Área de Proteção Ambiental de Iguape, Cananéia, Peruíbe, SP). The leaves are dorsiventral, with one cellular layer epidermis, palisade parenchyma having two or three layers and lacunary parenchyma presenting eight or nine layers of cells. The leaves are amphistomatical, presenting great substomatal chambers with bigger incidence of stomata in abaxial epidermis. The vascular bundles are collateral, presenting half moon sclerenchyma form around the xylem and the phloem. Petiole shows irregular contour, involved by collenchyma in all extension and presents great amount of secretory ducts between vascular bundles. Rhizome presents irregular contour with ten to fifteen layers of cortical parenchyma cells. The central cylinder has collateral bundles delimited by the endodermis. Pericycle is sinuate and totally involves vascular bundles. Under the epidermis there is a continuous band of collenchyma. The medulla has thin wall parenchyma cells. H. umbellata presented triterpenoids, saponins, flavonoids, poliacetylenes compounds and leucoceramides. Leaves and rhizomes presented similar chemical components, with slightly differences on spectral peaks. The yield of rhizome extract was smaller than the leaves extract.

Septicemia e gastrenterite em crianças internadas: estudo clínico e anatomapatológico / Septicemia and gastroenteritis in hospitalized children: clinical and anatomopathological study

Os autores realizaram uma análise retrospectiva de 20 pacientes de idades entre cinco dias e sete anos, que foram necropsiados no Serviço de Patologia Infantil do HUAP e que tiveram diagnóstico histológico de gastroenterite e septicemia. Foram divididos em dois grupos: o primeiro, constituído por 11 crianças que adquiriram diarréia na comunidade e depois foram internadas e o segundo, por nove pacientes cuja infecçäo intestinal foi adquirida no hospital. Só foi possível determinar o agente etiológico em sete casos (E. coli em três, Klebsiella pneumoniae em um, Pseudomonas aeruginosa em um e Staphylococcus aureus em dois). Entre os achados anatomopatológicos, além da enterocolite, o achado mais comum foi pneumonia bacteriana. Concluíram que a septicemia conseqüente à infecçäo hospitalar ocorreu em 12 casos (60%), sendo três do grupo 1 e nove do grupo 2. A grande maioria dos pacientes foi medicada com associaçäo de antibióticos. Näo observaram diferenças significativas em relaçäo à gravidade das complicaçöes entre os dois grupos, através do exame anatomopatológico. Teriam sido evitados muitos desses casos se fossem observadas as regras contra infecçäo hospitalar