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Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match those of long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiological and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.
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Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.
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Engineering synthetic interfaces between membranes has potential applications in designing non-native cellular communication pathways and creating synthetic tissues. Here, InterSpy is introduced as a synthetic biology tool consisting of a heterodimeric protein engineered to form and maintain membrane-membrane interfaces between apposing synthetic as well as cell membranes through the SpyTag/SpyCatcher interaction. The inclusion of split fluorescent protein fragments in InterSpy allows tracking of the formation of a membrane-membrane interface and reconstitution of functional fluorescent protein in the space between apposing membranes. First, InterSpy is demonstrated by testing split protein designs using a mammalian cell-free expression (CFE) system. By utilizing co-translational helix insertion, cell-free synthesized InterSpy fragments are incorporated into the membrane of liposomes and supported lipid bilayers with the desired topology. Functional reconstitution of split fluorescent protein between the membranes is strictly dependent on SpyTag/SpyCatcher. Finally, InterSpy is demonstrated in mammalian cells by detecting fluorescence reconstitution of split protein at the membrane-membrane interface between two cells each expressing a component of InterSpy. InterSpy demonstrates the power of CFE systems in the functional reconstitution of synthetic membrane interfaces via proximity-inducing proteins. This technology may also prove useful where cell-cell contacts and communication are recreated in a controlled manner using minimal components.
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Bicamadas Lipídicas , Lipossomos , Animais , Membrana Celular , Membranas , Processamento de Proteína Pós-Traducional , Corantes , MamíferosRESUMO
Curcumin, one of the three principal curcuminoids found within turmeric rhizomes, has long been associated with numerous physiologically beneficial effects; however, its efficacy is limited by its inherently low bioavailability. Several novel formulations of curcumin extracts have been prepared in recent years to increase the systemic availability of curcumin; Longvida®, a solid lipid curcumin particle preparation, is one such formulation that has shown enhanced bioavailability compared with standard curcuminoid extracts. As part of a safety assessment of Longvida® for use as a food ingredient, a bacterial reverse mutation test (OECD TG 471) and mammalian cell erythrocyte micronucleus test (OECD TG 474) were conducted to assess its genotoxic potential. In the bacterial reverse mutation test, Longvida® did not induce base-pair or frame-shift mutations at the histidine locus in the genome of Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537, in the presence or absence of exogenous metabolic activation. Additionally, two gavage doses (24 h apart) of Longvida® to Swiss albino mice at 500, 1000, or 2000-mg/kg body weight/day did not cause structural or numerical chromosomal damage in somatic cells in the mammalian erythrocyte micronucleus test. It was therefore concluded that Longvida® is non-genotoxic.
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Aberrações Cromossômicas , Curcumina , Animais , Camundongos , Testes de Mutagenicidade , Aberrações Cromossômicas/induzido quimicamente , Curcumina/toxicidade , Mutação , Testes para Micronúcleos , Lipídeos , MamíferosRESUMO
Meiotic arrest is a common cause of human male infertility, but the causes of this arrest are poorly understood. Transactive response DNA-binding protein of 43 kDa (TDP-43) is highly expressed in spermatocytes in the preleptotene and pachytene stages of meiosis. TDP-43 is linked to several human neurodegenerative disorders wherein its nuclear clearance accompanied by cytoplasmic aggregates underlies neurodegeneration. Exploring the functional requirement for TDP-43 for spermatogenesis for the first time, we show here that conditional KO (cKO) of the Tardbp gene (encoding TDP-43) in male germ cells of mice leads to reduced testis size, depletion of germ cells, vacuole formation within the seminiferous epithelium, and reduced sperm production. Fertility trials also indicated severe subfertility. Spermatocytes of cKO mice showed failure to complete prophase I of meiosis with arrest at the midpachytene stage. Staining of synaptonemal complex protein 3 and γH2AX, markers of the meiotic synaptonemal complex and DNA damage, respectively, and super illumination microscopy revealed nonhomologous pairing and synapsis defects. Quantitative RT-PCR showed reduction in the expression of genes critical for prophase I of meiosis, including Spo11 (initiator of meiotic double-stranded breaks), Rec8 (meiotic recombination protein), and Rad21L (RAD21-like, cohesin complex component), as well as those involved in the retinoic acid pathway critical for entry into meiosis. RNA-Seq showed 1036 upregulated and 1638 downregulated genes (false discovery rate <0.05) in the Tardbp cKO testis, impacting meiosis pathways. Our work reveals a crucial role for TDP-43 in male meiosis and suggests that some forms of meiotic arrest seen in infertile men may result from the loss of function of TDP-43.
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Proteínas de Ligação a DNA/deficiência , Regulação da Expressão Gênica , Infertilidade Masculina/metabolismo , Prófase Meiótica I , Epitélio Seminífero/metabolismo , Espermatócitos/metabolismo , Espermatogênese , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos KnockoutRESUMO
BACKGROUND: Primary hyperparathyroidism is a common endocrine disorder with adenomas being the most frequent cause. The condition is conventionally treated by a bilateral neck exploration through a cervical incision with removal of the affected glands. Intra-operative parathyroid hormone (IOPTH) monitoring and pre-operative Tc99m MIBI scans are facilitating focused approaches like minimally invasive video-assisted parathyroidectomy (MiVAP) and totally endoscopic parathyroidectomy (TOEP). METHODS: Patients with primary hyperparathyroidism were tested for location of diseased gland and accordingly selected for endoscopic parathyroidectomy by either trans-vestibular or trans-axillary approach. Those having undergone prior neck surgery or irradiation and those with an enlarged thyroid were excluded. All patients underwent IOPTH measurement to confirm the completeness of diseased gland resection. RESULTS: Eleven cases meeting selection criteria underwent endoscopic trans-vestibular parathyroidectomy and 16 cases underwent endoscopic trans-axillary parathyroidectomy. The mean operative time and blood loss were 104 min and 34 mL in trans-vestibular approach, respectively, while they were 47 min and 68 mL for the trans-axillary approach. All patients had post-operative resolution of hypercalcaemia. A single conversion to cervical approach was performed due to unsatisfactory IOPTH fall. A single patient suffered transient recurrent laryngeal nerve palsy which resolved with steroids. CONCLUSION: Endoscopic parathyroidectomy is a safe and feasible surgical procedure when combined with pre-operative imaging and intra-operative parathyroid hormone monitoring. There is a steady rise in the number of patients with primary hyperparathyroidism, a majority of whom have solitary gland affliction. Focused exploration is the current standard, wherein endoscopic surgery can be an important tool to improve outcomes.
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Endoscopia/métodos , Paratireoidectomia/métodos , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
PURPOSE: Reliable molecular diagnostic tools are still unavailable for making informed treatment decisions and monitoring the response in patients with castration resistant prostate cancer. We evaluated the significance of whole blood circulating androgen receptor transcripts of full length (AR-FL) and splice variants (AR-V1, AR-V3 and AR-V7) as biomarkers of abiraterone acetate treatment resistance in patients with castration resistant prostate cancer. MATERIALS AND METHODS: After retrospective analysis in 112 prostate specimens AR-FL, AR-V1, AR-V3 and AR-V7 were evaluated in 185 serial blood samples, prospectively collected from 102 patients with castration resistant prostate cancer before and during abiraterone acetate therapy via reverse transcription quantitative polymerase chain reaction. RESULTS: AR-FL was present in all samples while AR-V1, AR-V3, AR-V7 and at least 1 of them was detected in 17%, 55%, 65% and 81% of castration resistant prostate cancer blood samples, respectively. The highest amount of AR-V1 was found in blood of patients whose response time was short and medium in comparison to extended. Patients with a higher level of AR-FL and/or AR-V1 had the shortest progression-free survival and overall survival (p <0.0001). CONCLUSIONS: Blood circulating AR-FL or AR-V1 can serve as blood based biomarkers for identification of the primary resistance to abiraterone acetate and the tool to monitor de novo resistance development during abiraterone acetate treatment.
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Acetato de Abiraterona/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/sangue , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Intervalo Livre de Progressão , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Isoformas de Proteínas/sangue , RNA/sangue , Receptores Androgênicos/genéticaRESUMO
The purpose of this study was to characterize and develop a primate model of chronic retinal neovascularization and vascular leakage that can be employed to assess efficacy of experimental therapeutics targeting retinal ischemic and neovascular diseases. African green monkeys received bilateral intravitreal (IVT) injection of DL-alpha-aminoadipic acid (DLAAA; 5 mg) following ophthalmic examination, color fundus photography, fluorescein angiography (FA) and optical coherence tomography (OCT). Imaging was repeated to evaluate progression and subsequent stabilization of retinal vascular pathology elicited by DLAAA. Aflibercept (Eylea) was administered IVT (1.4 mg) to assess effects on vascular leakage. Ocular tissue was collected for histopathology and glial fibrillary acidic protein (GFAP), von Willebrand Factor (vWF), CD105/endoglin, VEGF and CD68 immunohistochemistry to study retinal degeneration and vascular remodeling. IVT DLAAA administration resulted in telangiectatic vessel formation as early as two-weeks post-injection, followed by retinal vascular leakage and inner retinal edema. Neovascular lesion progression was evident up to 8-10 weeks post-injection before stabilizing into a vascular leakage state that persisted beyond 90 weeks. Histopathology and immunostaining revealed retinal degeneration and neovascularization, increased expression of vWF, CD105/endoglin, VEGF and CD68 immunoreactivities in addition to Müller cell loss. Aflibercept significantly attenuated vascular leakage for 2-4 weeks before progressive return of leakage from weeks 4-8. Lesions remained responsive to anti-VEGF administration at 90 weeks after DLAAA injection. Findings support application of the primate DLAAA-induced retinal vascular leakage model for efficacy evaluations of candidate therapeutics and sustained release strategies targeting exudative AMD, diabetic retinopathy, macular telangiectasia and other retinal ischemic and neovascular diseases. Findings confirm relevance of the DLAAA primate phenotype to understanding shared retinal vascular disease mechanisms and macular susceptibility to vascular and metabolic insults.
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Angiofluoresceinografia/métodos , Neovascularização Retiniana/diagnóstico , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Animais , Chlorocebus aethiops , Doença Crônica , Modelos Animais de Doenças , Feminino , Fundo de Olho , MasculinoRESUMO
Di-(2-ethylhexyl) phthalate (DEHP) is a chemical that is widely used as a plasticizer. Exposure to DEHP has been shown to alter ovarian function in humans. Additionally, foods high in fat content, regularly found in the western diet, have been shown to be another potential disruptor of fetal ovarian function. Due to DEHP's lipophilicity, high-fat foods can be easily contaminated. Therefore, exposure to DEHP and a high-fat diet are both health concerns, especially in pregnant women, and the effects of these exposures on fetal oocyte quality and quantity should be elucidated. In this study, our goal was to determine if there are synergistic effects of DEHP exposure at an environmentally relevant level (20 µg/kg body weight/day) and high-fat diet on oogenesis and folliculogenesis. Dams were fed with a high-fat diet (45 kcal% fat) or a control diet (10 kcal% fat) 1 week before mating and during pregnancy and lactation. The pregnant mice were dosed with DEHP (20 µg/kg body weight/day) or vehicle control from E10.5 to litter birth. We found that treatment with an environmentally relevant dosage of DEHP and consumption of high-fat diet significantly increases synapsis defects in meiosis and affects folliculogenesis in the F1 generation.
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Dieta Hiperlipídica/efeitos adversos , Dietilexilftalato/toxicidade , Feto/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Gorduras na Dieta/farmacologia , Sinergismo Farmacológico , Disruptores Endócrinos/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Meiose/efeitos dos fármacos , Meiose/genética , Camundongos , Oogênese/fisiologia , Folículo Ovariano/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genéticaRESUMO
BACKGROUND: Chronic pancreatitis (CP) is a debilitating condition resulting in severe pain with progressive deterioration of pancreatic function. "Tropical" pancreatitis represents a variant of the disease with widely dilated ducts, numerous calculi, and few strictures. Traditionally, modified Puestow's procedure has been the treatment of choice for a dilated pancreatic ductal system. However, it has only recently been adapted to laparoscopic approach which is a technically demanding procedure primarily due to need for extensive intra-corporeal suturing. METHODS: Symptomatic cases of CP presenting at our center with minimum 8 mm mean ductal diameter at body and head were selected for laparoscopic modified Puestow's procedure. Those with prior pancreatic surgery, pancreatic head masses, endoscopic pancreatic stenting, and portal hypertension were excluded. Twenty-eight cases meeting selection criteria underwent a laparoscopic procedure. RESULTS: Seven patients (25%) underwent a stapled pancreaticojejunal anastomosis, 17 (60.7%) received a sutured anastomosis. Four patients (14.3%) were converted to open surgery due to failure to localize the pancreatic duct with percutaneous needle aspiration. Of those patients who underwent a successful laparoscopic procedure, a single patient developed a pancreatic fistula which resolved spontaneously; another patient had a difficult post-operative course with prolonged intensive care. We suffered no mortality within the series and no patient had any long-term disability. Anastomotic patency rates of 100% were achieved by the third post-operative month. CONCLUSION: Lateral pancreaticojejunostomy is an effective surgical management for CP with a dilated ductal system. Its laparoscopic adoption is the rational next surgical step. It allows effective duct decompression with low mortality and morbidity. The procedure demands an advanced surgical skill set with an emphasis on intra-corporeal suturing. Those patients suffering from tropical CP with wide ductal dilatation greater than 12 mm are suited to an endostapled anastomosis which helps significantly reduce operative time without any corrosion of outcomes.
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Laparoscopia/métodos , Pancreaticojejunostomia/métodos , Pancreatite Crônica/cirurgia , Técnicas de Sutura , Adulto , Feminino , Humanos , Masculino , Ductos Pancreáticos/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Indo-Cyanine Green Fluorescence is an emerging technology with more frequent use in laparoscopic and robotic surgery. It relies on near-infrared (NIR) fluorescence to demonstrate tissue perfusion with demarcation of tissue planes and vascular pedicles. The aim of the study is to evaluate the role of this technology in laparoscopic adrenalectomy (LA). METHODS: 55 patients underwent laparoscopic adrenalectomy using NIR Fluorescence enabled laparoscope. All cases received a standard initial dose of 5-mg dye to aid tissue visualization. Surgery proceeded with "fluorescence mode" demonstrating real-time NIR images superimposed on standard white-light imaging. The timing, number of doses were dictated by the operating surgeon, which were recorded and correlated with intra-operative fluorescence visualization. RESULTS: 54 patients underwent successful LA, with one conversion in a case of large pheochromocytoma due to difficult hemostasis. The lag between ICG administration and visualization of adrenal fluorescence varied between 30 and 75 s. The total duration of adrenal parenchymal fluorescence after a single dose did not exceed 15 min in our series. Average total administered dose was 14.4 mg. We suffered no mortality. There were no adverse effects due to the dye. 5 patients suffered Grade I complications, with one patient suffering Grade II and IV complication each, as per Clavien-Dindo Classification. Final histopathology demonstrated pheochromocytoma, adrenocortical adenoma, adrenocortical carcinoma, cushing's adenoma, aldosteronoma, and myelolipoma. CONCLUSION: We describe our initial positive experience with ICG fluorescence in LA, with a detailed description of dye administration in our study. The technology offers real-time differentiation of tissues and identification of vascular structures, providing immediate guidance during surgery. Further evaluation of its role in adrenocortical malignancy is warranted. NIR fluorescence is a safe, useful addition in laparoscopic adrenalectomy which will undergo further refinement over time.
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Neoplasias das Glândulas Suprarrenais , Glândulas Suprarrenais/diagnóstico por imagem , Adrenalectomia/métodos , Verde de Indocianina/farmacologia , Laparoscopia/métodos , Imagem Óptica/métodos , Neoplasias das Glândulas Suprarrenais/classificação , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/patologia , Adulto , Corantes/farmacologia , Feminino , Humanos , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Estudos Retrospectivos , Cirurgia Assistida por Computador/métodosRESUMO
Acute rhabdomyolysis is a rare phenomenon in the emergency setting almost exclusively associated with trauma, drugs, and recent upper respiratory and gastrointestinal infection. Rare reports in the literature have highlighted adult patients presenting with rhabdomyolysis as 1 component in a constellation of symptoms in acute HIV-1 seroconversion; however, there are few reports of rhabdomyolysis as the sole presenting symptom. This case highlights the importance of investigating HIV and other sexually transmitted diseases in pediatric cases of rhabdomyolysis in the emergency care setting.
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Infecções por HIV/complicações , Infecções por HIV/diagnóstico , HIV-1/imunologia , Rabdomiólise/virologia , Soroconversão , Injúria Renal Aguda/etiologia , Adolescente , Homossexualidade Masculina , Humanos , Masculino , Rabdomiólise/complicaçõesRESUMO
Retinopathy of prematurity adversely affects premature infants because of oxygen-induced damage of the immature retinal vasculature, resulting in pathological neovascularization (NV). Our pilot studies using the mouse model of oxygen-induced retinopathy (OIR) showed marked increases in angiogenic mediators, including endothelins and endothelin receptor (EDNR) A. We hypothesized that activation of the endothelin system via EDNRA plays a causal role in pathological angiogenesis and up-regulation of angiogenic mediators, including vascular endothelial growth factor A (VEGFA) in OIR. Mice were exposed to 75% oxygen from post-natal day P7 to P12, treated with either vehicle or EDNRA antagonist BQ-123 or EDNRB antagonist BQ-788 on P12, and kept at room air from P12 to P17 (ischemic phase). RT-PCR analysis revealed increased levels of EDN2 and EDNRA mRNA, and Western blot analysis revealed increased EDN2 expression during the ischemic phase. EDNRA inhibition significantly increased vessel sprouting, resulting in enhanced physiological angiogenesis and decreased pathological NV, whereas EDNRB inhibition modestly improved vascular repair. OIR triggered significant increases in VEGFA protein and mRNA for delta-like ligand 4, apelin, angiopoietin-2, and monocyte chemoattractant protein-1. BQ-123 treatment significantly reduced these alterations. EDN2 expression was localized to retinal glia and pathological NV tufts of the OIR retinas. EDN2 also induced VEGFA protein expression in cultured astrocytes. In conclusion, inhibition of the EDNRA during OIR suppresses pathological NV and promotes physiological angiogenesis.
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Endotelinas/metabolismo , Retina/metabolismo , Neovascularização Retiniana/metabolismo , Retinopatia da Prematuridade/metabolismo , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Camundongos , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Retina/efeitos dos fármacos , Retina/patologia , Neovascularização Retiniana/patologia , Retinopatia da Prematuridade/patologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Hypoxia-induced arginase elevation plays an essential role in several vascular diseases but influence of arginase on hypoxia-mediated angiogenesis is completely unknown. In this study, in vitro network formation in bovine aortic endothelial cells (BAEC) was examined after exposure to hypoxia for 24h with or without arginase inhibition. Arginase activity, protein levels of the two arginase isoforms, eNOS, and VEGF as well as production of NO and ROS were examined to determine the involvement of arginase in hypoxia-mediated angiogenesis. Hypoxia elevated arginase activity and arginase 2 expression but reduced active p-eNOS(Ser1177) and NO levels in BAEC. In addition, both VEGF protein levels and endothelial elongation and network formation were reduced with continued hypoxia, whereas ROS levels increased and NO levels decreased. Arginase inhibition limited ROS, restored NO formation and VEGF expression, and prevented the reduction of angiogenesis. These results suggest a fundamental role of arginase activity in regulating angiogenic function.
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Arginase/metabolismo , Células Endoteliais/enzimologia , Hipóxia/patologia , Neovascularização Patológica , Animais , Aorta/citologia , Aorta/enzimologia , Arginase/antagonistas & inibidores , Bovinos , Hipóxia Celular , Endotélio Vascular/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Retinal neovascularization is a major cause of vision loss in diseases characterized by retinal ischemia and is characterized by the pathological growth of abnormal vessels. Vascular endothelial growth factor (VEGF) is known to play an important role in this process. Oxidative stress has been strongly implicated in up-regulation of VEGF associated with neovascularization in various tissues. Hence, compounds with anti-oxidant actions can prevent neovascularization. α-Mangostin, a component of mangosteen (Garcinia mangostana Linn), has been shown to have an anti-oxidant property in pathological conditions involving angiogenesis such as cancer. However, the effect of α-mangostin on ROS formation and angiogenic function in microvascular endothelial cells has not been studied. Hence, this study demonstrated the anti-angiogenic effects of α-mangostin in relation to ROS formation in bovine retinal endothelial cells (REC). α-Mangostin significantly and dose-dependently reduced formation of ROS in hypoxia-treated REC. α-Mangostin also significantly and dose-dependently suppressed VEGF-induced increases in permeability, proliferation, migration and tube formation in REC and blocked angiogenic sprouting in the ex vivo aortic ring assay. In addition, α-mangostin inhibited VEGF-induced phosphorylation of VEGFR2 and ERK1/2-MAPK. According to our results, α-mangostin reduces oxidative stress and limits VEGF-induced angiogenesis through a process involving abrogation of VEGFR2 and ERK1/2-MAPK activation.
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Inibidores da Angiogênese/farmacologia , Células Endoteliais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Xantonas/farmacologia , Animais , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Bovinos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
To compare our innovative, cost-effective method of lacrimal surgery with other methods. A prospective cohort study. The study included 80 eyes of 80 consecutive patients who presented to our clinic between January 2009 and December 2011. The patients underwent surgery using a new technique with a specially designed cannula and were followed according to our protocol. Patency on irrigation. Of the 80 cases enrolled, the procedure was successful in 52.5 % with a mean follow-up of 247.2 days. The success rate was significantly affected by the preoperative conditions (p = 0.001) and follow-up duration (p = 0.006). This simple innovative technique was cost-effective and the results were comparable with those of other techniques.
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Dacriocistorinostomia , Dacriocistorinostomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo/instrumentação , Cateterismo/métodos , Análise Custo-Benefício , Dacriocistorinostomia/economia , Dacriocistorinostomia/instrumentação , Endoscopia/instrumentação , Feminino , Seguimentos , Humanos , Aparelho Lacrimal/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
A 58-year-old man presenting with angina was found to have a large coronary aneurysm on angiography. After coronary bypass and multiple ST-elevation myocardial infarctions over the following months, the decision was made to exclude the aneurysm with a flow-diverting stent, which reduced flow to the aneurysm and left the patient asymptomatic since the procedure. This is the first reported use of a cerebral flow-diverting stent for treatment of a coronary aneurysm.
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Objective In this study, we aimed to compare the efficacy and safety of the fixed-dose combination (FDC) of nimesulide (100 mg) + paracetamol (325 mg) [NP], ketorolac (10 mg) [Kt] alone, diclofenac (50 mg) + paracetamol (325 mg) [DP], and aceclofenac (100 mg) + paracetamol (325 mg) [AP] in patients with acute painful conditions. Methods This was a randomized, prospective, open-label, multicentre, active-controlled study involving patients aged ≥18 years, with acute painful conditions like low back pain, acute musculoskeletal disorders, and trauma such as tendinitis, tenosynovitis, bursitis, sprains and strains, migraine, dental pain, painful dental procedures, and post-surgical pain. Reduction in pain intensity and liver, renal, gastrointestinal, and cardiovascular safety were assessed on days seven and 14. Results A total of 600 patients were randomized into NP, Kt, DP, and AP groups in a 1:1:1:1 ratio. NP, DP, and AP were administered twice a day while Kt was given three times a day. The reduction of pain as measured by the numerical rating scale (NRS) scores at the end of day seven was 3.75 ± 1.58 in the NP group, 2.96 ± 1.18 in the Kt group, 3.42 ± 1.42 in the DP group, and 3.47 ± 1.30 in the AP group. The pain reduction in the NP group was significantly greater (p<0.001) as compared to the Kt group and non-inferior to the DP and AP groups on days seven and 14. Non-inferiority was concluded between the NP, DP, and AP groups as the lower limit of 95% CI of the difference in the change of pain intensity on both days seven and 14 was above the predefined margin of -1.0. All the drugs were well tolerated, but a significantly greater number of adverse events were reported in the DP group (32) as compared to the NP group (14) (p<0.05). The most common adverse events reported during the study were nausea, gastritis, and abdominal pain in all four groups. There was no significant alteration in liver and renal function tests except a rise in serum creatinine in the DP group. Conclusions The FDC of nimesulide with paracetamol is superior to ketorolac and non-inferior to the FDC of diclofenac with paracetamol and aceclofenac with paracetamol in the management of pain in patients with acute painful conditions. The tolerability profile of the FDC of nimesulide with paracetamol is similar to that of ketorolac but better than diclofenac with paracetamol and aceclofenac with paracetamol combinations.
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Hepatic angiosarcoma (HA) is a rare primary malignancy of hepatic endothelial and fibroblastic vascular tissue origin. Patients typically present with vague constitutional symptoms of fatigue, weight loss, abdominal pain, and ascites. Hemoperitoneum is a frequent clinical manifestation of HA associated with higher mortality and is underrecognized. Here, we report the case of a patient with HA that was complicated by a peritoneal bleed, its management, and associated poor prognosis.