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O uso indiscriminado do método contraceptivo de emergência, popularmente conhecido como pílula do dia seguinte tem sido frequentemente utilizado, uma vez que é obtido de forma facilitada pelas redes de saúde, sejam elas Unidades Básicas de Saúde (UBS) ou farmácias comerciais, pois trata-se de um contraceptivo de emergência, somente eficaz se usado dentro de um curto espaço de tempo após a relação sexual desprotegida, não existindo uma triagem detalhada para sua dispensação, ou seja, não há necessidade de consulta, tampouco receita médica para obtê-la, tendo em vista que quanto antes houver a sua ingestão, maiores são as possibilidades de sua eficácia. Sendo assim, diante do fácil acesso muitas mulheres têm adotado apenas esse método contraceptivo como forma de prevenção de gravidez ao invés de utilizá-lo somente em casos de falha da primeira alternativa de contracepção. Não levando em consideração a exposição às IST's, sobrecarga hormonal do organismo, uma vez que ainda não se tem estudos conclusivos da dose limite recomendada para seu consumo. Com respeito a este tema, foram realizados entrevistas e questionários online de forma anônima e através das respostas obtidas foram elaborados gráficos de comparação para analisar as informações levantadas sobre o perfil das mulheres que mais consomem essa medicação, como idade, escolaridade, estado civil, região em que mora, dentre outras, para realizar um mapeamento do consumo e perfil das mulheres que mais consomem o referido medicamento. A partir disso, conscientizar tanto às mulheres que consomem quanto aos seus parceiros o quão prejudicial à saúde da mulher, evitando ao máximo o consumo deste.

A inserção da biotecnologia aplicada na indústria de cosmetologia gerou grande impacto em diversos aspectos, proporcionando as empresas cosméticas descobrir, desenvolver e produzir componentes de formulações cosméticas e avaliando a atividade destes na pele, sendo uma ferramenta alternativa para desenvolvimento de ativos com ação renovadora das células, preventiva e no combate ao envelhecimento, no tratamento de distúrbios relacionados à pele facial. Tem como objetivo ressaltar a necessidade do autocuidado facial e mostrar os benefícios de dermocosméticos fermentados no tratamento da pele devido ao uso prolongado de máscara de proteção. Foi realizado um levantamento dos dados online no período de junho a novembro de 2022. Através da busca em plataformas de pesquisa cientificas confiáveis como Google Acadêmico, Scientific Eletronic Library Online (SciELO), Biblioteca Virtual em Saúde (BVS), sites governamentais, a partir dos descritores “biotecnologia, cosméticos, hidroxiácidos, doenças da pele, autocuidado”. O uso prolongado de máscara fez com que a umidade, vapor, sujeira, suor, saliva ou muco ficassem presos entre a máscara e a pele causando irritação e sensibilidade do local, além do atrito da máscara no rosto, sendo assim um dos fatores que acarretou a danificação da barreira cutânea e sensibilização facial. Salienta-se sobre os ácidos que o uso de forma errônea pode desencadear outros distúrbios de pele, assim recomenda-se sempre consultar um profissional da saúde, como o dermatologista antes da aplicação dos produtos. Vale ressaltar também que apenas o uso de dermocosméticos fermentados não é o suficiente para uma pele saudável, e sim um conjunto de ações para equilibrar o organismo.

The literature on caregiver burden tends to focus on children and teenagers with epilepsy and less on adults. As caregiving is a dynamic, complex process across the trajectories, this study aims to examine the factors associated with caregiving burden in those caring for adults with epilepsy.This is a cross-sectional, survey-based study in which participants responded to questionnairesregarding perceived burden (ZBI), quality of life (IEQoL), psychological distress (DASS-21), family functioning (FAD) and perceived social support (MSPSS). Additional measures include socio-demographics and clinical characteristics of the care-recipient.A total of 111 caregivers participated, of whom 72.1% were females, 55% parents, 59.5% Chinese, 51.4% unemployed and 46.0% with tertiary education.Approximately half (42.3%) reported mild-to-moderate levels of burden (mean ZBI score 29.93, SD 16.09).Furthermore, multiple regression analysisidentified10 predictors of caregiver burden, namely family functioning, weekly caregiving hours, number of caregivers per family, attitude towards epilepsy, family support, caregivers' gender, personal income and as well as care-recipients' age of onset, seizure frequency and ADL dependency (F(10, 85) = 11.37, p 0.001). Stepwise regression highlighted family functioning as the main predictor (β = 0.299, p 0.001). The total ZBI score was positively correlated with caregivers' reported levels of depression (r = 0.549, p 0.001), anxiety (r = 0.599, p 0.001) and stress (r = 0.576, p 0.001) subscales in DASS-21, and negatively correlated with IEQoL (r=-0.637, p 0.001).This study shows that caregivers' burden is highly associated with the family system (family functioning, support and number of caregivers), besides demographics, psychosocial and clinical characteristics. Future research is required to learn how to support this sub-group of caregivers within the family system.

OBJECTIVE: We assessed whether providing detailed clinical information alongside computed tomography (CT) images improves their interpretation for acute stroke. METHODS: Using the prospective Cornell AcutE Stroke Academic Registry, we randomly selected 100 patients who underwent noncontrast head CT within 6 hours of transient ischemic attack or minor acute ischemic stroke and underwent magnetic resonance imaging (MRI) within 6 hours of the CT. Three radiologist investigators evaluated each of the 100 CT studies twice, once with and once without accompanying information on medical history, signs, and symptoms. In random sequence, each study was interpreted in one condition (ie, with or without detailed accompanying information) and then after a 4-week washout period, in the opposite condition. Using MRI diffusion-weighted imaging (DWI) as the reference standard, we classified CT interpretations as correct (true positives or negatives) or incorrect (false positives or negatives). We used logistic regression with sandwich estimators to compare the proportion of correct interpretations. RESULTS: In patients with DWI-defined infarcts, acute ischemia was called on 20% of CTs with detailed history and 18% without history. In patients without infarcts, the absence of ischemia was called on 77% of CTs with history and 77% without history. The proportion of correct interpretations of CTs accompanied by detailed clinical history (49%) did not differ significantly from those without history (47%; odds ratio: 1.1; 95% confidence interval: 0.8-1.4). CONCLUSIONS: Reported findings on head CT for evaluation of suspected acute ischemic stroke were similar regardless of whether detailed clinical history was provided.

Case series have reported reversible left ventricular dysfunction, also known as stress cardiomyopathy or Takotsubo cardiomyopathy (TCM), in the setting of acute neurological diseases such as subarachnoid hemorrhage. The relative associations between various neurological diseases and Takotsubo remain incompletely understood. We performed a cross-sectional study of all adults in the National Inpatient Sample, a nationally representative sample of US hospitalizations, from 2006 to 2014. Our exposures of interest were primary diagnoses of acute neurological disease, defined by ICD-9-CM diagnosis codes. Our outcome was a diagnosis of TCM. Binary logistic regression models were used to examine the associations between our pre-specified neurological diagnoses and TCM after adjustment for demographics. Among acute neurological diagnoses, the strongest associations were seen with subarachnoid hemorrhage (odds ratio [OR] 11.7; 95% confidence interval [CI] 10.2–13.4), status epilepticus (OR 4.9; 95% CI 3.7–6.3), and seizures (OR 1.3; 95% CI 1.1–1.5). In a sensitivity analysis including secondary diagnoses of acute neurological diagnoses, associations were also seen with transient global amnesia (OR 2.3; 95% CI 1.5–3.6), meningoencephalitis (OR 2.1; 95% CI 1.7–2.5), migraine (OR 1.7; 95% CI 1.5–1.8), intracerebral hemorrhage (OR 1.3; 95% CI 1.1–1.5), and ischemic stroke (OR 1.2; 95% CI 1.1–1.3). In addition, female sex was strongly associated with Takotsubo (OR 5.1; 95% CI 4.9–5.4). TCM appears to be associated with varying degrees with several acute neurological diseases besides subarachnoid hemorrhage.

AIM To compare trampoline injuries and injury costs sustained at a commercial trampoline park versus private homes presenting to a major Australian children's hospital over a 12-month period. METHODS Children presenting with a trampoline injury to the paediatric emergency department in 2015 were identified using a keyword search of triage information. A comparison of injuries sustained at a commercial trampoline park and private homes was performed. RESULTS A total of 392 children presented with injuries, and the majority of injuries (68.9%) occurred at a private home; 19.4% were from a commercial trampoline park. Significant differences were seen between patients from a private home and commercial park for median age (5.6 vs. 12.8 years; P

To classify the appearance of the optic disc seen on fundus photographs of healthy subjects and patients with or suspected glaucoma whose diagnosis was based upon visual fields (VFs) and spectral-domain optical coherence tomography (sdOCT) results.One eye of 100 patients with or suspected glaucoma and 62 healthy subjects were prospectively tested with 24-2 and 10-2 VF and macular and disc sdOCT cube scans. All eyes with or suspected glaucoma had a 24-2 mean deviation better than -6.0 dB and an abnormal appearing disc on stereophotographs. The retinal ganglion cell plus inner plexiform layer (RGC+) from the macular scans and the retinal nerve fiber layer (RNFL) from the macular and disc scans were segmented and converted to probabilities plots. An eye was considered "glaucoma" if the sdOCT probability plots showed an abnormality in a region that corresponded to a defect seen on the 24-2 and/or 10-2 VF total deviation plot. Similarly, an eye was considered "suspect" only if both the sdOCT and VF plots were normal. Healthy subjects (normal VFs and sdOCT) were classified as "controls" and used as reference for comparisons. Glaucoma specialists reviewed the stereophotographs and classified eyes based on the presence of signs suggestive of glaucomatous optic neuropathy.The pattern of clinical signs of glaucomatous optic neuropathy seen on stereophotographs was statistically different between glaucoma (P0.001) and suspects (P0.001) vs. controls and explained up to 68% of the total variance of the diagnosis based upon sdOCT and VFs. Vertical cup-to-disc0.6, focal neuroretinal rim thinning, focal RNFL loss, and violation of the ISNT rule had the best performance to differentiate glaucoma and suspects from controls. Compared with the suspect group, glaucoma eyes (abnormal sdOCT and VF tests) were more likely to have vertical cup-to-disc0.6 (92% vs. 69%, P=0.003), diffuse rim (53% vs. 9%, P0.001) and RNFL (61% vs. 26%, P0.001) thinning, and β-zone parapapillary atrophy (68% vs. 17%, P0.001).Focal and diffuse signs of glaucoma damage seen on stereophotographs often match damage shown on VFs and sdOCT. In addition, damage shown on VFs and sdOCT is often missed during clinical evaluation. Longitudinal studies ought to differentiate focal signs of glaucoma damage seen on stereophotography from false-positives or very early loss.

Introduction: We examined the association between prior antiplatelet therapy and outcomes in patients with lobar versus deep intracerebral hemorrhage (ICH) versus intraventricular hemorrhage (IVH). Methods: We performed a retrospective cohort study using data from patients with lobar and deep ICH registered in the Virtual International Stroke Trials Archive (VISTA-ICH), and patients with IVH enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial. We excluded patients in the intervention arms of the trials, and those on prior anticoagulation therapy. The exposure was antiplatelet therapy prior to ICH/IVH. Primary outcomes were hematoma expansion and death/major disability in the VISTA-ICH cohort, and ventriculostomy tract hemorrhage, hematoma expansion, and death/major disability in the CLEAR III cohort. We used separate sets of logistic regression models in each group—lobar ICH, deep ICH, and IVH—to examine the association between antiplatelet therapy and our outcomes. Results: Among 548 ICH patients in the VISTA-ICH cohort, there were 416 (75.9%) lobar and 121 (22.1%) deep hematomas. Median baseline ICH volumes were 19 ml (IQR, 11-26) in lobar and 8 ml (IQR, 4-13) in deep bleeds. Prior antiplatelet therapy was reported in 92 patients with lobar (22.1%) and 26 patients (20.8%) patients with deep ICH. After adjustment for demographics, comorbidities, and hematoma characteristics, antiplatelet therapy was not associated with hematoma expansion or poor functional outcomes after lobar (OR, 0.8; 95% CI, 0.5-1.8) or deep (OR, 1.3; 95% CI, 0.4-3.8) ICH. In the CLEAR cohort, the 62 of 222 IVH patients (27.9%) with prior antiplatelet therapy had similar odds of hematoma expansion (OR, 0.6; 95% CI, 0.2-1.7) or poor functional outcomes (OR, 0.9; 95% CI, 0.4-2.1), but higher odds of ventriculostomy tract hemorrhage (OR, 3.2; 95% CI, 1.3-7.7). Conclusions: Prior antiplatelet therapy was not associated with hematoma expansion or functional outcomes after lobar or deep ICH or IVH, but was associated with ventriculostomy tract hemorrhage.

Introduction: Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is an increasingly recognized cause of left ventricular dysfunction after acute brain injury. Previously considered a benign disease, recent small, single-center case series suggest that Takotusubo cardiomyopathy may be a risk factor for ischemic stroke. The strength and temporal profile of this association remain uncertain. Methods: We performed a cohort-crossover study using administrative claims data on all emergency department visits and acute care hospitalizations from 2005-2015 in California New York, and Florida. We identified patients with Takotsubo cardiomyopathy using a previously validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code. We excluded patients with a prior or concomitant stroke diagnosis. We compared the risk of ischemic stroke in the first year after Takotsubo cardiomyopathy to the risk of ischemic stroke in the second year after. The absolute risk increase and odds ratio (OR) were calculated using McNemar’s test for matched data. Results: Among 5,283 patients with Takotsubo cardiomyopathy (mean age, 67 years; 92% female), we identified 49 ischemic strokes during the year after Takotsubo cardiomyopathy versus 19 ischemic strokes in the control period 2 years later. The risk of stroke was significantly higher in the year after Takotsubo cardiomyopathy (absolute increase, 0.6%; 95% CI, 0.2%-0.9%) (OR, 2.6; 95% CI, 1.5-4.6) as compared to the control period. Conclusion: We found a heightened risk of ischemic stroke in the year after a diagnosis of Takotsubo cardiomyopathy, although the absolute risk increase was small.

Background: Real-world data on long-term trends in the use of tracheostomy after stroke are limited. Methods: Patients who underwent tracheostomy for acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH) were identified from the 1994 through 2013 releases of the National Inpatient Sample using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. Survey weights were used to report nationally representative estimates. Our primary outcome was the trend in tracheostomy use during the index stroke hospitalization over the last 20 years. Additionally, we evaluated trends in in-hospital mortality, timing of placement, and discharge disposition among patients who received a tracheostomy. Results: We identified 9.9 million patients with AIS, ICH, or SAH in the United States from 1994 to 2013, of which 170 255 (1.7%; 95% confidence interval [CI]: 1.6%-1.8%) underwent tracheostomy. Among all patients with stroke, tracheostomy use increased from 1.2% (95% CI: 1.1%-1.4%) in 1994 to 1.9% (95% CI: 1.8%-2.1%) in 2013, with similar trends across stroke types. From 1994 to 2013, the timing of tracheostomy decreased from 16.5 days (95% CI: 14.9-18.1 days) to 10.3 days (95% CI: 9.9-10.8 days) after mechanical ventilation. In-hospital mortality decreased from 32.6% (95% CI: 29.1%-36.1%) to 13.8% (95% CI: 12.3%-15.3%) among tracheostomy patients; however, discharge to a nonacute care facility increased from 42.9% (95% CI: 38.0%-47.8%) to 83.3% (95% CI: 81.6%-85.0%) and home discharge declined from 9.3% (95% CI: 7.3%-11.3%) to 2.9% (95% CI: 2.1%-3.7%). Conclusion: Over the past 2 decades, tracheostomy use has increased among patients with stroke. This increase was associated with earlier placement, reduced in-hospital mortality, and lower rates of home discharge.

Objective Seizures can be provoked by systemic diseases associated with metabolic derangements, but the association between liver disease and seizures remains unclear. Methods We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. The primary exposure variable was cirrhosis, and the secondary exposure was mild, noncirrhotic liver disease. The primary outcome was seizure, and the secondary outcome was status epilepticus. Diagnoses were ascertained using validated International Classification of Diseases, Ninth Edition, Clinical Modification codes. Survival statistics were used to calculate incidence rates, and Cox proportional hazards models were used to examine the association between exposures and outcomes while adjusting for seizure risk factors. Results Among 1 782 402 beneficiaries, we identified 10 393 (0.6%) beneficiaries with cirrhosis and 19 557 (1.1%) with mild, noncirrhotic liver disease. Individuals with liver disease were older and had more seizure risk factors than those without liver disease. Over 4.6 ± 2.2 years of follow-up, 49 843 (2.8%) individuals were diagnosed with seizures and 25 patients (0.001%) were diagnosed with status epilepticus. Cirrhosis was not associated with seizures (hazard ratio [HR] = 1.1, 95% confidence interval [CI] = 1.0-1.3), but there was an association with status epilepticus (HR = 1.9, 95% CI = 1.3-2.8). Mild liver disease was not associated with a higher risk of seizures (HR = 0.8, 95% CI = 0.6-0.9) or status epilepticus (HR = 1.1, 95% CI = 0.7-1.5). Significance In a large, population-based cohort, we found an association between cirrhosis and status epilepticus, but no overall association between liver disease and seizures.

Objectives People with epilepsy were (PWE) reported to have poorer employment rate. However, the methodologies used differ greatly from one study to another, making global comparison difficult. We aimed to determine the employment rate of PWE globally using a unified definition of employment rate and to summarize the reported positive and negative factors affecting employability in PWE, using a systematic review. Methods All studies reporting employment rate of PWE were independently assessed. Employment rate was recalculated according to the standard definition by the Bureau of Labor statistics (BLS) of United States and the International Labour Organization i.e. employment rate is the percentage of employed person over the labor force. Results Of 95 papers reported on employment status of PWE, adjusted employment rate (aER) was shown to be as low as 14% to as high as 89% with a mean adjusted employment rate of 58%. No significant differences in mean of aER was found between continents, or among Asian countries. Employment rate of people with uncontrolled seizures were reported in 16 papers, with a mean adjusted employed rate of 58%. Psychological factors were less frequently reported as compared to clinical and socio-demographical factors, seen in a total of 25 (26%) out of 97 studies. The positive factors leading to successful career in PWE were understudied and needed to be further explored. Conclusion Employability is multifactorial, including clinical, psychological and social factors. The adjusted employment rate of people with uncontrolled seizures is comparable to those with controlled seizures, supporting the need to explore non-clinical factors.

Purpose This study aimed to explore positive and negative factors affecting the employability in patients with uncontrolled seizures. Method Semistructured interviews with 21 patients with uncontrolled seizures were analyzed using interpretative phenomenological analysis. Result Eleven (52.4%) of the participants interviewed were employed; 7 were holding full-time position with more than 4 years of working experience. The mean age was 34.6 years, 71.4% were female, 38% were married, 71.4% had at least 11 years of education, 38% had a driving license, 19% received government monetary aid, 66.7% had seizure onset before reaching 17 years of age, 66.7% experienced monthly seizures, and 76% were on polytherapy. A total of 6 main themes were found to be affecting the employability among people with uncontrolled seizures: (a) ability to work ; (b) intention to work ; (c) support and stigma at workplace ; (d) family support, overdependence, and protection ; (e) life event ; and (f) government and welfare support . Subthemes under the main theme ability to work included education, cognitive and physical functions, ability to continue working after seizures, ability to travel to work, self-perceived ability to work, and ability to cope with stress. Many shared the same idea that employment is important, but their intention to work varied. The employed group tended to work for a future goal and self-satisfaction, and the unemployed group tended to have no or lack intention to work. Positive factors were noted in the following themes: ability to work; intention to work; support and stigma at workplace; and family support, overdependence, and protection. Conclusion There were internal and external factors affecting the employability among people with uncontrolled seizures both positively and negatively. Positive internal factors such as ability and intention to work require further exploration.

To compare trampoline injuries and injury costs sustained at a commercial trampoline park versus private homes presenting to a major Australian children's hospital over a 12-month period.Children presenting with a trampoline injury to the paediatric emergency department in 2015 were identified using a keyword search of triage information. A comparison of injuries sustained at a commercial trampoline park and private homes was performed.A total of 392 children presented with injuries, and the majority of injuries (68.9%) occurred at a private home; 19.4% were from a commercial trampoline park. Significant differences were seen between patients from a private home and commercial park for median age (5.6 vs. 12.8 years; P 0.001), gender (48.2 vs. 61.8% female; P = 0.03) and season of injury. Of the injuries, 27.3% occurred when children fell off the trampoline, and fractures (39.5%) were the most common injury; 17.4% required hospital admission, and 12.8% required surgical intervention. Commercial park injuries had a significantly longer median length of stay (37.4 vs. 22.8 h; P = 0.03). The estimated total acute cost for these trampoline injuries in 1 year was $546 786. Commercial trampoline park injuries accounted for 21.7% of the estimated cost and private homes for 68.2%.Paediatric trampoline injuries remain a common source of hospital presentation and admission, despite the introduction of a Voluntary Australian Standard. Paediatric trampoline injuries usually occur in private homes; however, the increasing popularity of commercial trampoline parks contributes to a change in the profile of trampoline injuries. Commercial park injuries were more expensive to treat.

The flavonoid quercetin holds promise as an antitumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown.The antiproliferative effects of quercetin alone or in combination with gemcitabine were tested in 2 human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet.Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared with quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation.Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer.

Purpose People with epilepsy (PWE) are negatively prejudiced in their ability to work. This study aimed to examine demographic, clinical and psychological factors associated with employability in PWE. Methods This study recruited epilepsy patients from a neurology clinic in Malaysia. Employability was measured using employment ratio, with a ratio ≥90% (ER90) classified as high employability. Basic demographic data such as age, gender, marital status, religion, education level and household income was collected. Clinical measures consisted of age of seizure onset, seizure frequency, type of epilepsy, aura, polytherapy, nocturnal seizures and seizure control. Psychological measures included Work Self-Determination Index (WSDI), Rosenberg Self-Esteem Scale (SES), and Multidimensional Scale of Perceived Social Support (MSPSS). Results Of 146 PWE, 64.4% had high employability. The participants were predominantly female (52%), Chinese (50.7%), single (50%), having tertiary education (55.5%) and focal epilepsy (72.6%). Clinically, only type of epilepsy was significantly correlated to employability of PWE. Employability of PWE was associated with ability to work (indicated by education level, work performance affected by seizures, ability to travel independently and ability to cope with stress at work) and family overprotection. The high employability group was found to have lower self-perceived stigma (ESS), higher self-determined motivation (WSDI), self-esteem (SES) and perceived social support (MSPSS), than the low employability group. Logistic regression analysis showed that tertiary education level (AOR 3.42, CI: 1.46–8.00), higher self-determination (WSDI, AOR 1.09, CI: 1.012–1.17), lower family overprotection (AOR 0.76, CI: 0.61–0.95), and generalised epilepsy (AOR 4.17, CI: 1.37–12.70) were significant predictors for higher employability in PWE. Conclusion Ability to work (education level), clinical factor (type of epilepsy) and psychological factor (self-determined motivation and family overprotection) were important factors affecting employability in PWE.

The rationale of this dose matching/dose escalating study was to compare a panel of flavonoids-luteolin, resveratrol, and quercetin-against the metabolite flux-controlling properties of a synthetic targeted fatty acid synthase inhibitor drug C75 on multiple macromolecule synthesis pathways in pancreatic tumor cells using [1,2-(13)C(2)]-d-glucose as the single precursor metabolic tracer. MIA PaCa-2 pancreatic adenocarcinoma cells were cultured for 48 h in the presence of 0.1% DMSO (control), or 50 or 100 μM of each test compound, while intracellular glycogen, RNA ribose, palmitate and cholesterol as well as extra cellular (13)CO(2), lactate and glutamate production patterns were measured using gas chromatography/mass spectrometry (GC/MS) and stable isotope-based dynamic metabolic profiling (SiDMAP). The use of 50% [1,2-(13)C(2)]-d-glucose as tracer resulted in an average of 24 excess (13)CO(2) molecules for each 1,000 CO(2) molecule in the culture media, which was decreased by 29 and 33% (P0.01) with 100 μM C75 and luteolin treatments, respectively. Extracellular tracer glucose-derived (13)C-labeled lactate fractions (Σm) were between 45.52 and 47.49% in all cultures with a molar ratio of 2.47% M + 1/Σm lactate produced indirectly by direct oxidation of glucose in the pentose cycle in control cultures; treatment with 100 μM C75 and luteolin decreased this figure to 1.80 and 1.67%. The tracer glucose-derived (13)C labeled fraction (Σm) of ribonucleotide ribose was 34.73% in controls, which was decreased to 20.58 and 8.45% with C75, 16.15 and 6.86% with luteolin, 27.66 and 19.25% with resveratrol, and 30.09 and 25.67% with quercetin, respectively. Luteolin effectively decreased nucleotide precursor synthesis pentose cycle flux primarily via the oxidative branch, where we observed a 41.74% flux (M + 1/Σm) in control cells, in comparison with only a 37.19%, 32.74%, or a 26.57%, 25.47% M + 1/Σm flux (P0.001) after 50 or 100 μM C75 or luteolin treatment. Intracellular de novo fatty acid palmitate (C16:0) synthesis was severely and equally blocked by C75 and luteolin treatments indicated by the 5.49% (control), 2.29 or 2.47% (C75) and 2.21 or 2.73% (luteolin) tracer glucose-derived (13)C-labeled fractions, respectively. On the other hand there was a significant 192 and 159% (P0.001), and a 103 and 117% (P0.01) increase in tracer glucose-derived cholesterol after C75 or luteolin treatment. Only resveratrol and quercetin at 100 μM inhibited tracer glucose-derived glycogen labeling (Σm) and turnover by 34.8 and 23.8%, respectively. The flavonoid luteolin possesses equal efficacy to inhibit fatty acid palmitate de novo synthesis as well as nucleotide RNA ribose turnover via the oxidative branch of the pentose cycle in comparison with the targeted fatty acid synthase inhibitor synthetic compound C75. Luteolin is also effective in stringently controlling glucose entry and anaplerosis in the TCA cycle, while it promotes less glucose flux towards cholesterol synthesis than that of C75. In contrast, quercetin and resveratrol inhibit glycogen synthesis and turnover as their underlying mechanism of controlling tumor cell proliferation. Therefore the flavonoid luteolin controls fatty and nucleic acid syntheses as well as energy production with pharmacological strength, which can be explored as a non-toxic natural treatment modality for pancreatic cancer.

Prostaglandin E2 (PGE2) is a product of cyclooxygenase (COX) and PGE synthase (PGES) and deactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). Down-regulation of PGDH contributes to PGE2 accumulation in lung and colon cancers but has not been identified in pancreatic cancer.Normal human pancreatic and tumor-matched tissues, as well as MiaPaCa-2 and BxPC-3 cell lines, were assessed for COX-2, microsomal PGES-1, PGDH, and snail homolog 1 (SNAI1) and SNAI2 expressions by real-time polymerase chain reaction and Western blotting and PGE2 by enzyme-linked immunosorbent assay.Normal tissues exhibited low COX-2 messenger RNA (mRNA) and protein expressions and high PGDH mRNA and protein expressions and PGE2 levels at 13 pg/mg of protein. In contrast, tumor tissues exhibited high COX-2 mRNA and protein expressions and low PGDH mRNA and protein expressions and PGE2 levels at 32 pg/mg of protein. Tumor tissues exhibited significantly elevated expressions of SNAI2 mRNA and protein but not SNAI1 because SNAI1 and SNAI2 reportedly down-regulate PGDH expression. The COX-2-positive BxPC-3 but not the COX-2-negative MiaPaCa-2 treated with 100-nmol/L PGE2 induced phosphorylated extracellular signal-related kinase that was blocked by the mitogen-activated protein kinase kinase inhibitor U0126, demonstrating the ability of PGE2 to activate ERK.These results suggest that enhanced PGE2 production proceeds through the expressions of COX-2 and microsomal PGES-1 and down-regulation of PGDH by SNAI2 in pancreatic tumors.

Purpose Omega-3 polyunsaturated fatty acids (PUFAs) are widely considered health promoting. We have previously reported that the omega-3 PUFA eicosapentaenoic acid (EPA) inhibits growth of pancreatic cancer (PaCa) cells in vitro and in vivo. However, the mechanism underlying the effects of EPA in PaCa cells is unknown. Methods

SummarySaturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.

To assess the extent to which glaucomatous damage of the macula can be detected using the summary statistics of a commercial report based upon the circumpapillary retinal nerve fiber layer (cpRNFL) thickness obtained with frequency domain optical coherence tomography (fdOCT).One hundred forty-three eyes of 143 open-angle glaucoma patients and suspects (56.4 ± 13.8 years) had 10-2 visual fields (VFs) and fdOCT macular and disc cube scans. RNFL and retinal ganglion cell plus inner plexiform layer thickness and probability maps were generated and combined with 10-2 VF information in a single-page, custom report previously described. Three graders evaluated these reports and classified each eye as "abnormal macula" or "normal macula." Commercially available fdOCT reports for cpRNFL thickness were generated using the automatic segmentation algorithm and norms from the machine. The ability of the reports to detect macular damage was analyzed in three ways: temporal quadrant (TQ) < 5%; TQ < 5% or clock hour 7 < 1% (TQ + CH7); and clock hours 7 through 10 with two sectors < 5% or one sector < 1% (CH7-10).Sixty-one (43%) eyes were classified "abnormal macula" and 41 (29%) as "normal macula"; the 10-2 VFs and OCT probability maps did not agree in the remaining eyes. Of the 61 abnormal eyes, the TQ criterion missed 47 (77%); TQ + CH7 missed 24 (39%); and CH7-10 missed 22 (36%).Conventional cpRNFL analyses on commercial OCT reports can miss macular (central field) damage.To detect glaucomatous damage of the macula, additional tests, such as macular cube scans and/or 10-2 VFs, should be performed.

Purpose: Angiogenesis is essential for physiological processes as well as for carcinogenesis. New approaches to cancer therapy include targeting angiogenesis. One target is VEGF-A and its receptor VEGFR2. In this study, we sought to investigate pancreatic cancer angiogenesis in a genetically modified VEGFR2-luc-KI mouse. Procedures: Live in vivo bioluminescence imaging of angiogenesis was performed continuously until sacrifice in subcutaneous tumors as well as in orthotopically transplanted tumors. Tumor tissue was immunostained for CD-31 and VEGFR2. Results: Peritumoral angiogenesis measured by light emission was detected beginning at week3 following subcutaneous injection. In the orthotopic model, light emission began at day4, which likely corresponds to wound healing, and continued throughout the experimental period during tumor growth. Peritumoral CD-31 vessel- and VEGFR2-staining were positive. Conclusions: The VEGFR2-luc-KI mouse is a valuable tool to demonstrate tumor angiogenesis and seems to be suitable to evaluate anti-angiogenic approaches in pancreatic cancer

BACKGROUND: Excess prostaglandin E2 (PGE2) mediates growth and survival of several cancers, including prostate and pancreatic cancers (PaCa). 15-Hydroxyprostaglandin dehydrogenase (PGDH) catalyzes PGE2 to an inactive 15-keto metabolite. We have previously shown that PGDH is down-regulated in human PaCa, contributing to accumulated levels of PGE2 that can subsequently feed back to suppress further PGDH expression. In contrast, PGDH expression has been reportedly up-regulated by vitamin D3 (VD3) in prostate cancer cells but has not been confirmed in pancreatic cancer cells. AIM: The study focuses on whether VD3 up-regulates PGDH expression in pancreatic cancer cells. METHODS: Human PaCa cell lines BxPC-3, HPAF-II and MIA PaCa-2 were treated with VD3 were analyzed for vitamin D receptor (VDR), cyclooxygenase-2 (COX-2) and PGDH expression by RT-PCR. Protein extracts were analyzed by Western blotting for VDR, COX-2, PGDH, SNAI1, SNAI2 and GAPDH expression. Cellular proliferation was analyzed by MTT assay. PGE2 was measured by ELISA. RESULTS: Dose-dependent treatment with VD3 at 1000 nM resulted in a maximal decrease in proliferation by 1.3 ± 0.1-fold in BxPC-3, 1.7 ± 0.3-fold in HPAF-II expressing elevated VDR and 1.1 ± 0.3-fold in MIA PaCa-2. VD3 at 10 nM resulted a time-dependent increase in PGDH mRNA expression by 3.8 ± 0.3-fold in BxPC-3 and 7.7 ± 0.6-fold in HPAF-II, whereas expression remained unchanged in MIA PaCa-2. Conversely, COX-2 mRNA expression decreased by 0.5 ± 0.1-fold in BxPC-3 and 0.6 ± 0.1-fold in HPAF-II, but not in MIA PaCa-2. PGDH protein expression increased at 96 and 120 hrs following treatment with VD3 in BxPC-3 and HPAF-II whereas COX-2 protein expression decreased in HPAF-II cells but was abolished by 96 and 120 hrs in BxPC-3 cells. PGDH protein expression was increased at 120 hrs in MIA PaCa-2 following addition of VD3 but COX-2 protein expression in this cell line was not detected. VD3 decreased the PGDH transcriptional regulators SNAI1 protein expression by 120 hrs in BxPC-3 and HPAF-II cells but not MIA PaCa-2 whereas SNAI2 decreased in all cell types by 96 hrs. Knockdown of SNAI by siRNA at 100 nM in HPAF-II resulted in a 1.3 ± 0.3-fold decrease proliferation and 1.4 ± 0.1-fold decrease in PGE2 production. Combined treatment with 100 nM of siSNAI and 10 nM of VD3 did not result in synergistic decrease in proliferation or PGE2 production. CONCLUSION: PaCa cells expressing vitamin D receptors responded to VD3 treatment with a corresponding increase in PGDH coupled with a decrease in COX-2 expression. VD3 or siSNAI resulted in a decrease in cellular proliferation and PGE2 production but the combined treatment did not augment further decreases, suggesting that the decrease by VD3 could be mediated through SNAI regulation of PGDH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 62. doi:1538-7445.AM2012-62

Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin—an abundant, naturally-occurring plant flavonoid—with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted.