bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Ex Vivo Assay to Select Homologous Recombination–Deficient Breast Tumors for PARP Inhibitor Treatment
Authors: Naipal Kishan A.T. , Verkaik Nicole S. , Ameziane Najim , van Deurzen Carolien H.M. , ter Brugge Petra , Meijers Matty , Sieuwerts Anieta M. , Martens John W. , O'Connor Mark J. , Vrieling Harry , Hoeijmakers Jan H.J. , Jonkers Jos , Kanaar Roland , de Winter Johan P. , Vreeswijk Maaike P. , Jager Agnes , van Gent Dik C.
Published: June 2014

Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are promising targeted treatment options for hereditary breast tumors with a homologous recombination (HR) deficiency caused by BRCA1 or BRCA2 mutations. However, the functional consequence of BRCA gene mutations is not always known and tumors can be HR deficient for other reasons than BRCA gene mutations. Therefore, we aimed to develop a functional test to determine HR activity in tumor samples to facilitate selection of patients eligible for PARP inhibitor treatment.

Experimental design: We obtained 54 fresh primary breast tumor samples from patients undergoing surgery. We determined their HR capacity by studying the formation of ionizing radiation induced foci (IRIF) of the HR protein RAD51 after ex vivo irradiation of these organotypic breast tumor samples. Tumors showing impaired RAD51 IRIF formation were subjected to genetic and epigenetic analysis.

Results: Five of 45 primary breast tumors with sufficient numbers of proliferating tumor cells were RAD51 IRIF formation deficient (11%, 95% CI, 5%–24%). This HR defect was significantly associated with triple-negative breast cancer (OR, 57; 95% CI, 3.9–825; P = 0.003). Two of five HR-deficient tumors were not caused by mutations in the BRCA genes, but by BRCA1 promoter hypermethylation.

Conclusion: The functional RAD51 IRIF assay faithfully identifies HR-deficient tumors and has clear advantages over gene sequencing. It is a relatively easy assay that can be performed on biopsy material, making it a powerful tool to select patients with an HR-deficient cancer for PARP inhibitor treatment in the clinic. Clin Cancer Res; 20(18); 4816–26. ©2014 AACR.
Demethylating Drugs as Novel Analgesics for Cancer Pain
Authors: Viet Chi T. , Dang Dongmin , Ye Yi , Ono Kentaro , Campbell Ronald R. , Schmidt Brian L.
Published: June 2014

Purpose: In this study, we evaluated the analgesic potential of demethylating drugs on oral cancer pain. Although demethylating drugs could affect expression of many genes, we focused on the mu-opioid receptor (OPRM1) gene pathway, because of its role in pain processing. We determined the antinociceptive effect of OPRM1 re-expression in a mouse oral cancer model.

Experimental Design: Using a mouse oral cancer model, we determined whether demethylating drugs produced antinociception through re-expression of OPRM1. We then re-expressed OPRM1 with adenoviral transduction and determined if, and by what mechanism, OPRM1 re-expression produced antinociception. To determine the clinical significance of OPRM1 on cancer pain, we quantified OPRM1 methylation in painful cancer tissues and nonpainful contralateral normal tissues of patients with oral cancer, and nonpainful dysplastic tissues of patients with oral dysplasia.

Results: We demonstrated that OPRM1 was methylated in cancer tissue, but not normal tissue, of patients with oral cancer, and not in dysplastic tissues from patients with oral dysplasia. Treatment with demethylating drugs resulted in mechanical and thermal antinociception in the mouse cancer model. This behavioral change correlated with OPRM1 re-expression in the cancer and associated neurons. Similarly, adenoviral-mediated OPRM1 re-expression on cancer cells resulted in naloxone-reversible antinociception. OPRM1 re-expression on oral cancer cells in vitro increased β-endorphin secretion from the cancer, and decreased activation of neurons that were treated with cancer supernatant.

Conclusion: Our study establishes the regulatory role of methylation in cancer pain. OPRM1 re-expression in cancer cells produces antinociception through cancer-mediated endogenous opioid secretion. Demethylating drugs have an analgesic effect that involves OPRM1. Clin Cancer Res; 20(18); 4882–93. ©2014 AACR.
The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a
Authors: Morrow Anne A. , Alipour Mohsen Amir , Bridges Dave , Yao Zemin , Saltiel Alan R. , Lee Jonathan M.
Published: June 2014

Emerging evidence now implicates phosphatidylinositol 4-kinases (PI4K), enzymes that generate PI(4)P from phosphatidylinositol (PtdIns), in cancer. In this study, we investigate the role of PI4KIIIβ, one of four mammalian PI4Ks, in breast cancer. Although PI4KIIIβ protein levels are low in normal breast tissue, we find that approximately 20% of primary human breast tumors overexpress it. Expression of PI4KIIIβ in breast carcinoma cells leads to increased Akt activation, dependent on increased PI(3,4,5)P3 production. However, a kinase-inactive version of PI4KIIIβ also led to increased Akt activation, and no changes in PI(4)P or PI(4,5)P2 lipid abundance were detected in the PI4KIIIβ-overexpressing cells. This implies that PI4KIIIβ regulates PI(3,4,5)P3 and Akt independent of PI(4)P production. We find that the PI4KIIIβ-binding protein, Rab11a, a small GTPase that regulates endosomal recycling, is involved in PI4KIIIβ-mediated activation of Akt, as RNAi depletion of Rab11a impairs Akt activation. Furthermore, ectopic PI4KIIIβ expression alters cellular Rab11a distribution and enhances recruitment of PI4KIIIβ and Rab11a to recycling endosomes. This work suggests that PI4KIIIβ affects PI3K/Akt signaling through Rab11a and endosomal trafficking, independent of its lipid kinase activity. Thus, PI4KIIIβ likely plays a role in breast oncogenesis and that cooperation between Rab11a and PI4KIIIβ represents a novel Akt activation pathway. Mol Cancer Res; 12(10); 1492–508. ©2014 AACR.
CD44-Mediated Adhesion to Hyaluronic Acid Contributes to Mechanosensing and Invasive Motility
Authors: Kim Yushan , Kumar Sanjay
Published: June 2014

The high-molecular-weight glycosaminoglycan, hyaluronic acid (HA), makes up a significant portion of the brain extracellular matrix. Glioblastoma multiforme (GBM), a highly invasive brain tumor, is associated with aberrant HA secretion, tissue stiffening, and overexpression of the HA receptor CD44. Here, transcriptomic analysis, engineered materials, and measurements of adhesion, migration, and invasion were used to investigate how HA/CD44 ligation contributes to the mechanosensing and invasive motility of GBM tumor cells, both intrinsically and in the context of Arg-Gly-Asp (RGD) peptide/integrin adhesion. Analysis of transcriptomic data from The Cancer Genome Atlas reveals upregulation of transcripts associated with HA/CD44 adhesion. CD44 suppression in culture reduces cell adhesion to HA on short time scales (0.5-hour postincubation) even if RGD is present, whereas maximal adhesion on longer time scales (3 hours) requires both CD44 and integrins. Moreover, time-lapse imaging demonstrates that cell adhesive structures formed during migration on bare HA matrices are more short lived than cellular protrusions formed on surfaces containing RGD. Interestingly, adhesion and migration speed were dependent on HA hydrogel stiffness, implying that CD44-based signaling is intrinsically mechanosensitive. Finally, CD44 expression paired with an HA-rich microenvironment maximized three-dimensional invasion, whereas CD44 suppression or abundant integrin-based adhesion limited it. These findings demonstrate that CD44 transduces HA-based stiffness cues, temporally precedes integrin-based adhesion maturation, and facilitates invasion.

Implications: This study reveals that the CD44 receptor, which is commonly overexpressed in GBM tumors, is critical for cell adhesion, invasion, and mechanosensing of an HA-based matrix. Mol Cancer Res; 12(10); 1416–29. ©2014 AACR.
Plasma Tocopherols and Risk of Prostate Cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT)
Authors: Albanes Demetrius , Till Cathee , Klein Eric A. , Goodman Phyllis J. , Mondul Alison M. , Weinstein Stephanie J. , Taylor Philip R. , Parnes Howard L. , Gaziano J. Michael , Song Xiaoling , Fleshner Neil E. , Brown Powel H. , Meyskens Frank L. , Thompson Ian M.
Published: June 2014

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We, therefore, examined whether presupplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case–cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0–7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88–1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44–1.62; P-trend = 0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29–3.22; P-trend = 0.005]. A positive plasma α-tocopherol–prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7–10; overall Q5 HR, 1.59; 95% CI, 1.13–2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32–3.40; P-trend = 0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between α-tocopherol and selenium itself or selenomethionine. Cancer Prev Res; 7(9); 886–95. ©2014 AACR.
Summary of bi-shRNAfurin/GM-CSF Augmented Autologous Tumor Cell Immunotherapy (FANG™) in Advanced Cancer of the Liver
Authors: Nemunaitis John , Barve Minal , Orr Douglas , Kuhn Joseph , Magee Mitchell , Lamont Jeffrey , Bedell Cynthia , Wallraven Gladice , Pappen Beena O. , Roth Alyssa , Horvath Staci , Nemunaitis Derek , Kumar Padmasini , Maples Phillip B. , Senzer Neil
Published: June 2014

Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2. Safety, mechanism, immunoeffectiveness, and suggested benefit were previously shown [Senzer et al.: Mol Ther 2012;20:679-689; Senzer et al.: J Vaccines Vaccin 2013;4:209]. We now provide further follow-up of a subset of 8 HCC patients. FANG manufacturing was successful in 7 of 8 attempts (one failure due to insufficient cell yield). Median GM-CSF expression was 144 pg/106 cells, TGFβ1 knockdown was 100%, and TGFβ2 knockdown was 93% of the vector-transported cells. Five patients were vaccinated (1 or 2.5 × 107 cells/intradermal injection, 6-11 vaccinations). No FANG toxicity was observed. Three of these patients demonstrated evidence of an immune response to the autologous tumor cell sample. Long-term follow-up demonstrated survival of 319, 729, 784, 931+, and 1,043+ days of the FANG-treated patients. In conclusion, evidence supports further assessment of the FANG immunotherapy in HCC.
Galantamine versus Risperidone for Agitation in People with Dementia: A Randomized, Twelve-Week, Single-Center Study
Authors: Freund-Levi Yvonne , Bloniecki Victor , Auestad Bjørn , Tysen Bäckström Ann Christine , Lärksäter Marie , Aarsland Dag
Published: June 2014

Aims: To examine the effects of galantamine and risperidone on agitation in patients with dementia. Methods: A total of 100 patients with dementia and neuropsychiatric symptoms (mean age ± SD: 78.6 ± 7.5 years; 67% female) were included in this 12-week, randomized, parallel-group, controlled, single-center trial. The participants received galantamine (n = 50; target dose: 24 mg) or risperidone (n = 50; target dose: 1.5 mg) for 12 weeks. Results: Both galantamine and risperidone treatment resulted in reduced agitation. However, risperidone showed a significant advantage over galantamine both at week 3 (mean difference in total Cohen-Mansfield Agitation Inventory score: 3.7 points; p = 0.03) and at week 12 (4.3 points; p = 0.01). Conclusions: Agitation improved in both groups, even if the treatment effects were more pronounced in the risperidone group; however, the effects on cognition and other aspects of tolerability were stronger with galantamine.
Advice on Lifestyle Changes (Diet, Red Wine and Physical Activity) Does Not Affect Internal Carotid and Middle Cerebral Artery Blood Flow Velocity in Patients with Carotid Arteriosclerosis in a Randomized Controlled Trial
Authors: Droste Dirk W. , Iliescu Catalina , Vaillant Michel , Gantenbein Manon , De Bremaeker Nancy , Lieunard Charlotte , Velez Telma , Meyer Michèle , Guth Tessy , Kuemmerle Andrea , Chioti Anna
Published: June 2014

Background: A Mediterranean diet, with and without small daily amounts of red wine, and physical activity reduce the risk of cerebrovascular disease and improve cognition. An increase in cerebral blood flow may be the underlying mechanism. Under normal conditions, cerebral blood flow velocity changes in the internal carotid arteries and in large basal cerebral arteries correlate closely with cerebral blood flow changes, as the diameter of these vessels hardly changes and only the smaller vessels downstream change their diameter. Methods: A prospective randomized controlled trial was performed in 108 patients with carotid atherosclerosis (mean age 64 years, 67% men, 66% on statin therapy). Half of them were advised to follow a polyphenol-rich modified Mediterranean diet including 1-2 tomatoes, 3-5 walnuts and a bar of dark chocolate (25 g) a day and to perform moderate physical exercise for 30 min/day (lifestyle changes). Within these two groups, half of the patients were randomized either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. Bilateral middle cerebral and internal carotid blood flow velocity (peak systolic, peak end-diastolic and mean) was measured at baseline and after 4 and 20 weeks using colour-coded duplex ultrasound. Insonation depth and insonation angle were used to identically place the sample volume during follow-up investigations. A general linear model with Tukey-Kramer adjustment for multiple comparisons was used to assess the primary end points. For the analysis we used the mean values of the right and left artery. Results: Neither lifestyle changes nor red wine had an effect on peak systolic, peak end-diastolic or mean cerebral blood flow velocity. Conclusions: Advice on lifestyle changes, including a modified polyphenol-rich Mediterranean diet, a glass of red wine daily and physical exercise, did not affect middle cerebral and internal carotid blood flow velocity in our patient group with carotid atherosclerosis. An increase in cerebral blood flow is thus unlikely to be the cause of the reduced risk of cerebrovascular disease and improved cognitive functioning described in the literature. One possible explanation for the fact that blood flow velocity was not affected by red wine, diet and physical activity advice is that two thirds of our patients were already on statin therapy. Statins increase cerebral blood flow and vasomotor reactivity via nitric oxide.
Renal Toxicity Associated with Weekly Cisplatin and Gemcitabine Combination Therapy for Treatment of Advanced Biliary Tract Cancer
Authors: Kobayashi Satoshi , Ueno Makoto , Ohkawa Shinichi , Irie Kuniyasu , Goda Yoshihiro , Morimoto Manabu
Published: June 2014

Objective: A combination of weekly cisplatin plus gemcitabine is a new standard regimen for patients with advanced biliary tract cancer (BTC). This regimen does not require prolonged hydration schedules; however, the long-time safety profile has not been evaluated so far. In particular, the aim of this study was to evaluate the renal function during this regimen. Methods: We reviewed 79 consecutive patients with BTC who received the weekly cisplatin plus gemcitabine regimen. The incidence of adverse events was evaluated by CTCAE v4.0. Results: A total of 402 courses were administered. The median cumulative dose of cisplatin was 250 mg (range: 25-825). The renal function was exacerbated gradually throughout the treatment course. The incidence of a decreased glomerular filtration rate (GFR) at <50 ml/min was significantly related to a pretreatment GFR at <80 ml/min and a total dose of cisplatin >400 mg [p = 0.011, odds ratio (OR) 58.2, 95% confidence interval (CI): 2.5-1334.0 and p = 0.021, OR 18.3, 95% CI: 1.6-215.5]. Conclusions: The combination of weekly cisplatin and gemcitabine for advanced BTC gradually affected the renal function, and it was highly recommended to focus on both the change of GFR and total dose of cisplatin during this regimen.
The Neuroprotective Effect and Probable Mechanism of DL-3-n-Butylphthalide in Brain Diseases
Authors: Sun Yinyi , Liu Kangyong , Zhang Ting , Sun Yanmeng , Chen Wenqi , Li Qian , Chen Rongfu , Sun Xiaojiang
Published: June 2014

3-n-Butylphthalide (NBP), one of the chemical constituents of celery oil, is used for the treatment of many central nervous system diseases, including Parkinson's disease, Alzheimer's disease and cerebral ischemia. NBP showed potent neuroprotective effects by decreasing oxidative damage, inhibiting inflammatory responses, improving mitochondrial function, and reducing neuronal apoptosis.
Initially Localized Synovial Sarcoma in Adults: A Retrospective Single-Center Analysis of 26 Patients Registered at the Department of Oncology, University of Vienna between 2004 and 2013
Authors: Lamm Wolfgang , Schur Sophie , Köstler Wolfgang J. , Amann Gabriele , Pokrajac Boris , Funovics Philipp , Panotopoulos Joannis , Brodowicz Thomas
Published: June 2014

Background: Synovial sarcoma is a rare subgroup of all soft-tissue sarcomas. The aim of this retrospective single-center analysis was to investigate the outcome of patients with initially localized disease. Patients and Methods: Twenty-six patients were enrolled in this retrospective single-center analysis. Baseline characteristics, treatment and outcome were evaluated. Results: In 13 patients (50%), the tumor was located in the lower extremity and in 4 patients (15%) in the upper extremity. Surgical resection was done in all but 2 patients (92%). Re-resection was done in 7 patients (27%). Fourteen patients (54%) received adjuvant chemotherapy. After a median follow-up of 23.3 months (range: 2.6-150.3), median disease-free survival was not reached at the time of analysis. Eight patients (31%) relapsed after initial therapy. Surgery was done in 2 patients, amputation in 1 patient, palliative chemotherapy was administered in 3 and radiation therapy in 2 patients. Median overall survival (OS) for all patients was not reached at the time of analysis. The estimated 5-year OS rate was 62%. Conclusion: Patients with initially localized synovial sarcoma who were included in this retrospective single-center analysis have an estimated 5-year OS rate of 62%.
The Metabolic Syndrome Is Associated with an Increased Risk of Colorectal Polyps Independent of Plasma Homocysteine
Authors: Chen Fang-Pei , Wang Hwei-Ming , Chiang Feng-Fan , Lin Chun-Che , Huang Shih-Chien , Huang Yi-Chia
Published: June 2014

Background/Aims: The links between the metabolic syndrome and homocysteine in relation to the risk of colorectal polyps are not understood. The purpose of this study was to investigate the association between the metabolic syndrome and homocysteine and further analyze the relationship between these two factors and the risk of colorectal polyps. Methods: This was a case-control study. A total of 135 participants with colorectal polyps (cases) and 110 participants without polyps (controls) were recruited. Results: There were 59 participants with the metabolic syndrome in the case group and 36 participants with the metabolic syndrome in the control group. The metabolic syndrome and its individual components, except for serum triglycerides, and homocysteine were associated with the risk of colorectal polyps. When the association of the metabolic syndrome and homocysteine with the risk of colorectal polyps was simultaneously considered, the association between homocysteine and the risk of colorectal polyps disappeared, but waist circumference, systolic and diastolic blood pressure, high-density lipoprotein cholesterol, and the metabolic syndrome itself were still significant risk factors for the development of colorectal polyps. Conclusion: Although the metabolic syndrome and plasma homocysteine were individually related to the risk of colorectal polyps, the metabolic syndrome was a major contributing factor in relation to the risk of colorectal polyps independent of plasma homocysteine.
Acute Myelogenous Leukemia without Maturation with a Retinoic Alpha-Receptor Deletion: A Case Report
Authors: Trosclair Christopher , Pollen Maressa , Capraro Gerald , Cotelingam James , Shackelford Rodney E.
Published: June 2014

Acute promyelocytic leukemia (APL) is characterized by a t(15;17) which fuses the 17q retinoic acid alpha-receptor sequence to the 15q PML gene sequence. The resulting fusion product plays a role in the development and maintenance of APL, and is very rarely found in other acute myeloid leukemia (AML) subtypes. Rare complex APL genomic rearrangements have retinoic acid alpha-receptor sequence deletions. Here we report a retinoic acid alpha-receptor sequence deletion in a case of AML without differentiation. To our knowledge, this is the first example of a retinoic acid alpha-receptor sequence deletion in this AML subtype.
Rapidly Growing Esophageal Carcinosarcoma Reduced by Neoadjuvant Radiotherapy Alone
Authors: Ogasawara Naotaka , Tamura Yasuhiro , Funaki Yasushi , Yamaguchi Yoshiharu , Shimozato Akihiro , Yanamoto Kenichiro , Takahashi Emiko , Miyachi Masahiko , Sasaki Makoto , Kasugai Kunio
Published: June 2014

Esophageal carcinosarcoma is a rare malignant neoplasm consisting of both carcinomatous and sarcomatous components. It is generally treated by surgery, radiotherapy and chemotherapy according to the protocols used for other esophageal cancers. However, the treatment of esophageal carcinosarcoma by radiotherapy alone before surgery has not been previously described. We report a patient with a rapidly growing esophageal carcinosarcoma that was efficiently reduced by neoadjuvant radiotherapy alone. A previously healthy 69-year-old man was admitted with dysphagia. Initial esophagogastroduodenoscopy (EGD) revealed a small nodular polypoid lesion of about 10 mm in the middle esophagus. A second EGD 1 month later showed that the tumor had expanded into a huge mass. A biopsy specimen revealed that the tumor comprised squamous cell carcinoma with spindle cell components, and the tumor was diagnosed as carcinosarcoma which was diagnosed as stage I (T1bN0M0). Due to renal dysfunction, the patient was treated with neoadjuvant radiotherapy (40 Gy) without chemotherapy. A third EGD 1 month later revealed remarkable tumor reduction. He then underwent total esophagectomy with regional lymph node dissection (pStage 0, pT1aN0M0). After surgical operation, the patient was followed up without adjuvant therapy. Whole body computed tomography revealed lung metastasis 14 months after surgery, and the patient died 2 months later. The neoadjuvant radiotherapy for esophageal carcinosarcoma was considered to have contributed to the subsequent surgery and his prolonged survival time. Thus, radiotherapy alone might be a suitable neoadjuvant therapy for esophageal carcinosarcomas.
Traqueo-oclusão intra-útero: técnica cirúrgica associada à corticoterapia promove aumento nos receptores de VEGF (Vascular Endothelial Growth Factor) em pulmões de fetos de ratas
Authors: Iscaife Alexandre , Gonçalves Anderson , Silveira Mariana Ribeiro Marcondes , Carvalho Hernandes Faustino de , Pereira Luís A. V. , Sbragia Neto Lourenço
Published: June 2014

Introdução: A hérnia diafragmática congênita (HDC) causa hipoplasia e hipertensão pulmonar e em geral leva a alta morbidade e mortalidade neonatal. Traqueo-oclusão fetal (TO) e corticoterapia pré-natal são alternativas para acelerar o crescimento pulmonar fetal e diminuir a hipoplasia na HDC. A produção de VEGF (Vascular Endothelial Growth Factor) está relacionada com a maturidade pulmonar e sofre alterações na HDC ainda não elucidadas. Materiais e métodos: Seis grupos de 12 fetos de ratos Spreague-Dawley foram comparados: TO, Sham, Controle, TO+Dex, Sham+Dex e Controle+Dex. No dia 18,5º foi realizada TO com e sem corticoterapia utilizando dexametasona. No 21,5º dia gestacional os pesos corporal e pulmonar foram mensurados. Realizou-se imunohistoquímica para VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), seguida de morfometria. Resultados: O VEGFR-1 estava aumentado no TO (p<0.05)e na TO+Dex (p<0.05). O VEGFR-2 teve aumento significativo quando comparamos TO e TO+Dex com o controle (p<0,05). Conclusão: A TO associada ao uso de corticoesteróide aumentou o número de VEGFR-1 e VEGFR-2 em pulmões de fetos de ratas.
A medicina na Grécia antiga
Authors: Barbosa Denise F. , Lemos Pedro Carlos Piantino
Published: June 2014

Na Grécia Antiga, até o surgimento do pensamento filosófico-médico, quase nada era conhecido sobre a anatomia interna e a fisiologia humanas. O cuidado dos doentes era feito com métodos religiosos, com o objetivo de manutenção da “energia vital”, indispensável à vida. O novo pensamento passou a pregar a necessidade de se conhecer a essência natural do homem. A partir de então, textos foram escritos e, posteriormente, reunidos no “Corpus Hipocraticum”, que tem como principais valores, os relacionados à ética médica.
O teste de apnéia no diagnóstico de morte encefálica
Authors: Andrade Almir Ferreira de , Paiva Wellingson Silva , Amorim Robson Luis Oliveira , Figueiredo Eberval Gadelha , Silva Leonardo Borges de Barros e , Teixeira Manoel Jacobsen
Published: June 2014

O teste de apnéia é um passo mandatório na determinação de morte encefálica, fazendo parte do exame dos reflexos de tronco cerebral e que não pode ser dissociado do exame neurológico no diagnóstico de morte encefálica. Neste artigo realizamos uma revisão crítica sobre o teste de apnéia, ressaltando os aspectos técnicos, éticos e suas complicações.
Resultado perinatal na macrossomia fetal
Authors: Fiorelli Lilian Renata , Zugaib Marcelo
Published: June 2014

Introdução: A gestação de fetos macrossômicos aumenta o risco complicações perinatais. Método: Análise retrospectiva de 306 partos ocorridos no HU/USP entre 2002 e 2004, cujos recém-nascidos apresentaram peso = 4000 gramas. Resultados: A idade das gestantes foi de 14 a 43 anos (27,4 ± 6,0 anos) e 33,9% com paridade > 2 partos. A idade gestacional variou de 36 a 43 semanas (40,1 ± 1,1) sendo 54,2% gestações pós-data, e o peso ao nascimento variou de 4000 a 5085 gramas (4195,5 ± 188,9). O tipo de parto foi vaginal em 141 (46,1%) gestantes e cesárea em 165 (53,9%) gestantes. As principais intercorrências materno-fetais foram mecôneo (4,9%), traumatismo no recém-nascido (2,3%), laceração vaginal (1,9%), atonia uterina (1,6%) e distocia do bisacromial (1,6%). Não houve diferenças ignificativa na ocorrência de intercorrências (OR = 0,95; IC = 0,52-1,74) entre partos cesáreo e vaginal, e entre recém-nascidos com peso < ou > a 4500 gramas (OR = 1,09; IC = 0,38-3,10). Conclusão: Identificou-se o pós-datismo, a multiparidade e a idade materna avançada relacionados a macrossomia. Esta também associa-se a cesárea, a trauma de parto e a morbidade perinatal, porém, não demostrou-se a correlação entre a via de parto ou peso de nascimento< ou > de 4500gramas e a freqüência de intercorrências materno-fetais.
Endopróteses: opção terapêutica para estenoses traqueobrônquicas adquiridas
Authors: Anjos Daniel Marchi dos , Junqueira Jader Joel Machado , Gomes Diogo Bugano Diniz , Terra Ricardo Mingarini , Minamoto Hélio , Jatene Fabio Biscegli
Published: June 2014

A estenose traqueobrônquica é uma condição que cursa com dispnéia, estridor epneumonia obstrutiva, causada por diversas condições como tumores, compressão extrínseca e traqueobroncomalacia, porém a causa mais freqüente é a complicação resultante de intubação prolongada, sendo que ocorre em aproximadamente 1% das intubações. O tratamento de escolha para esta condição é a ressecção cirúrgica do segmento atingido, entretanto este procedimento não é possível em todos os pacientes e isto levou à adoção de técnicas endoscópicas paliativas. O uso de endopróteses para manter uma via aérea pérvia está entre as técnicas endoscópicas com melhores resultados. As endopróteses utilizadas atualmente dividem-se, principalmente, em próteses de silicone e metálicas expansíveis, cada uma com vantagens e desvantagens específicas. A presente monografia visa apresentar os principais modelos de endopróteses, comparando suas vantagens e desvantagens e índices de complicações, procurando sistematizar as indicações ideais para cada tipo de prótese.
O estetoscópio e os sons pulmonares: uma revisão da literatura
Authors: Carvalho Vitor Oliveira , Souza Germano Emílio Conceição
Published: June 2014

A ausculta torácica é uma técnica diagnóstica muito antiga, amplamente usada na atualidade pelo seu baixo custo, grande praticidade e sensibilidade. Os diversos sons audíveis pelo estetoscópio sugerem condições pulmonares de grande importância para o tratamento dos enfermos. Estes sons são resultados das vibrações pulmonares e das respectivas vias aéreas transmitidas à parede torácica. Eles podem ser divididos primeiramente em: bronquiais (traqueobronquiais) ou vesiculares, não existindo padronização na sua descrição. Esta revisão tem como objetivo mostrar o que existe sobre os sons pulmonares e seus significados.
Perfil biofísico fetal e dopplervelocimetria da circulação fetal e fetoplacentária em gestantes hipertensas: estudo comparativo das variáveis perinatais
Authors: Fiorelli Lilian Renata , Figueira Paula Gabriela Marin , Dracxler Roberta Caetano , Miyadahira Seizo , Nomura Roseli , Zugaib Marcelo
Published: June 2014

Introdução: A síndrome hipertensiva, incluindo a Doença Hipertensiva Específi cada Gestação (DHEG), a Hipertensão Arterial Sistêmica Crônica (HAC) e a HAC com DHEGsuperajuntada, pode resultar em insufi ciência placentária que, por sua vez, está fortementerelacionada à restrição de crescimento intra-uterino (RCIU), patologia associada a elevado riscode morbi-mortalidade perinatal. Avaliar as condições intra-útero é de grande importância paraa conduta, seguimento e até mesmo interrupção dessas gestações, e é nesse momento quea cardiotocografi a (CTG), o perfi l biofísico fetal (PBF) e a dopplervelocimetria ganham papéisde destaque no acompanhamento pré-natal. Objetivo: Avaliar o papel da CTG, do PBF e dadopplervelocimetria nas síndromes hipertensivas, comparando os grupos DHEG e não DHEGe analisando seus valores com os resultados pós-natais. Materiais e métodos: Trata-se de umestudo retrospectivo em que foram analisados prontuários de 247 gestantes hipertensas quetiveram seus partos no HCFMUSP entre nov/2005 e nov/2006. Os seguintes métodos diagnósticosforam analisados: cardiotocografi a anteparto, perfi l biofísico fetal, dopplervelocimetriasda artéria umbilical (A/B e PI) e da artéria cerebral media, e ultrassonografi a. As variáveisperinatais estudadas foram: índice de Apgar, gasometria da artéria umbilical e classifi cação dopeso do recém-nascido de acordo com a idade gestacional. Os estudos estatísticos utilizadosforam o teste de Fisher e o de qui-quadrado (x2), considerados signifi cativos quando p < 0,05.Resultados: Pacientes com DHEG apresentaram resultados anormais de Dopplervelocimetriade artérias umbilicais pelo índice A/B (p = 0,0424) e PI (p = 0,028613), maior proporçãode RCF pela USG (p = 0,0294) e proteinúria de 24 horas alterada (p<0,0001). Esse métodotambém mostrou correlação com o PIG (p 0,0032), Apgar (p 0,01806) e pH (p 0,0086). A CTGtambém mostrou maior correlação com ocorrência de PIG (p 0,0017). Conclusão: Apenas adopplervelocimetria das artérias umbilicais correlacionou-se com DHEG, assim como com oApgar e pH < 7,20. Além disso, essa e a CTG correlacionaram-se com a ocorrência de RNPIG. Dessa forma, notou-se nítida superioridade dessa primeira na predição dos resultadosneonatais adversos.
Análise das características dos pulmões disponibilizados para transplante no Estado de São Paulo
Authors: Junqueira Jader Joel Machado , Waisberg Daniel Reis , Noleto Gustavo Sousa , Samano Marcos Naoyuki , Pêgo-Fernandes Paulo Manuel , Jatene Fabio Biscegli
Published: June 2014

Objetivos: Analisar a taxa de aproveitamento de pulmões disponibilizados em SãoPaulo em 2006, bem como caracterizar o perfi l dos doadores de pulmão deste período. Métodos: Estudo retrospectivo de 497 prontuários de doadores de pulmão, no período de jan/2006a dez/2006. Resultados: Dos 497 prontuários analisados, 149 (30%) não tiveram os pulmõesdoados, sendo excluídos do estudo. Dos 348 doadores eleitos para o estudo, 56,9% eram dosexo masculino, com idade média de 37,4±16,1anos. As principais causas da morte cerebralforam: AVC (40,5%), TCE (34,2%) e HSA (10,9%). A grande maioria recebia drogas vasoativas (90,5%), sendo que 13,5% haviam apresentado parada cárdio-respiratória. Do ponto de vistainfeccioso, o leucograma médio foi de 15008 ± 6467mm3, 67,8% recebiam antibioticoterapia e26,1% apresentavam infecção pulmonar. Quase 40% dos doadores apresentavam alteraçõesradiográfi cas. Apenas 4,9% dos doadores foram aceitos, representando 28 pulmões (taxa deaproveitamento de órgãos de 4,0%). Os motivos de recusa foram: alteração gasométrica (30,1%),infecção (23,7%) e distância (10,9%). Conclusão: A taxa de aproveitamento de pulmões emnosso meio é baixa. Além disso, mais de 50% das recusas deveram-se a gasometria arterialinadequada e infecção pulmonar. Aliar melhor cuidado ao potencial doador à menor rigidez noscritérios de seleção poderia aumentar a utilização dos órgãos doados.
Insuficiência cardíaca e transplante cardíaco
Authors: Fiorelli Alfredo Inácio , Coelho Guilherme Henrique Bianchi , Oliveira Junior José de Lima , Oliveira Adriana Santos
Published: June 2014

A insuficiência cardíaca é uma síndrome complexa definida pela falência do coração em proporcionar suprimento adequado de sangue às necessidades metabólicas tissulares, ou fazê-lo por meio de elevadas pressões de enchimento. Geralmente, resulta de disfunção estrutural ou funcional do coração que compromete a sua capacidade de comportar o volume de enchimento diastólico de sangue ou de realizar sua ejeção. Caracteriza-se por disfunção ventricular e alterações da regulação neurohumoral, acompanhada de sintomas de cansaço aos esforços, retenção hídrica e redução da expectativa de vida. Em nosso meio, a sobrevida da insuficiência cardíaca com o tratamento clínico é estimada em 84%, 63% e 52%, em um, dois e cinco anos, respectivamente. Tem-se observado que a insuficiência cardíaca apresenta maior mortalidade do que muitas modalidades de câncer, como bexiga, mama e próstata,perdendo apenas ao câncer de pulmão. Na fase avançada da doença o transplante cardíaco é a única forma de tratamento capaz de restaurar as funções hemodinâmicas, melhorar a qualidade de vida e a sobrevida. O método foi empregado pioneiramente por Barnard em 1967 e ganhou ampla difusão com a introdução da ciclosporina no esquema imunossupressor. Todavia, ao lado das vantagens oferecidas pelo transplante existem limitações importantes que impedem a sua extensão universal aos pacientes com insuficiência cardíaca terminal. Dentre elas devem-se ressaltar a carência de doadores viáveis, a imunossupressão inespecífica, contra-indicações médicas e psicossociais.
Avaliação hemodinâmica macro e micro-circulatória no choque séptico
Authors: Figueiredo Luiz Francisco Poli de , Silva Eliézer , Corrêa Thiago Domingos
Published: June 2014

A avaliação da perfusão tecidual, especialmente à beira do leito, pode ser complexa em muitos pacientes sépticos. Assim, impõe-se, atualmente, uma reavaliação da monitoração das variáveis de perfusão tecidual. Oferta e consumo de oxigênio são variáveis importantes; no entanto, principalmente a oferta de oxigênio apresenta pouca relação com prognóstico. Da mesma forma, os níveis séricos de lactato e a análise da saturação venosa de oxigênio (SvO2ou ScO2), traduzem o equilíbrio sistêmico entre oferta e consumo de oxigênio. A monitoração da pCO2 da mucosa gástrica e a visualização direta da microcirculação são instrumentos que auxiliam a avaliação local da perfusão tecidual, podendo ser útil em estados de importante heterogeneidade na distribuição de fluxo.
Acupuntura: prática baseada em evidências
Authors: Lin Chin An , Hsing Wu Tu , Pai Hong Jin
Published: June 2014

A acupuntura está cada vez mais em evidência, além de ser uma especialidade em ascensão tanto entre os estudantes de medicina, como entre os médicos que buscam a sua especialização, ganhou destaque da Associação Médica Britânica que advogou a sua aprovação perante a comunidade médica britânica, além de recomendar o Sistema de Saúde Pública Britânica a aceitar o tratamento de cefaléia crônica por acupuntura, aconselha que o mesmo encoraje os médicos de atenção primária a passar por treinamento em acupuntura. Na revisão de trabalhos recentes, a acupuntura está sendo pesquisada para o tratamento de diversas moléstias ou condições clínicas diferentes daquelas a que eram indicadas. Situações como hipertensão arterial sistêmica e fertilização in vitro, a acupuntura tem sido estudada como opções de tratamento válidas. Essa situação coloca uma nova perspectiva para a especialidade acupuntura, que está sendo considerada cada vez como uma prática em saúde validada, dentro dos paradigmas da medicina ortodoxa.
A Large Permissive Regulatory Domain Exclusively Controls
Tbx3
Expression in the Cardiac Conduction System
Authors: van Weerd Jan Hendrik , Badi Ileana , van den Boogaard Malou , Stefanovic Sonia , van de Werken Harmen J.G. , Gomez-Velazquez Melisa , Badia-Careaga Claudio , Manzanares Miguel , de Laat Wouter , Barnett Phil , Christoffels Vincent M.
Published: June 2014

Rationale
:

The evolutionary conserved
Tbx3
/
Tbx5
gene cluster encodes T-box transcription factors that play crucial roles in the development and homeostasis of the cardiac conduction system in human and mouse. Both genes are expressed in overlapping patterns and function in strictly tissue-specific and dose-dependent manners, yet, their regulation is poorly understood.

Objective
:

To analyze the mechanism underlying the complex regulation of the
Tbx3
/
Tbx5
cluster.

Methods and Results
:

By probing the 3-dimensional architecture of the
Tbx3/Tbx5
cluster using high-resolution circular chromosome conformation capture sequencing in vivo, we found that its regulatory landscape is in a preformed conformation similar in embryonic heart, limbs, and brain.
Tbx3
and its flanking gene desert form a 1 Mbp loop between CCCTC-binding factor (CTCF)-binding sites that is separated from the neighboring
Tbx5
loop. However,
Ctcf
inactivation did not result in transcriptional regulatory interaction between
Tbx3
and
Tbx5
. Multiple sites within the
Tbx3
locus contact the promoter, including sites corresponding to regions known to contain variations in the human genome influencing conduction. We identified an atrioventricular-specific enhancer and a pan-cardiac enhancer that contact the promoter and each other and synergize to activate transcription in the atrioventricular conduction system.

Conclusions
:

We provide a high-resolution model of the 3-dimensional structure and function of the
Tbx3
/
Tbx5
locus and show that the locus is organized in a preformed, permissive structure. The
Tbx3
locus forms a CTCF-independent autonomous regulatory domain with multiple combinatorial regulatory elements that control the precise pattern of
Tbx3
in the cardiac conduction system.
Thromboxane Prostaglandin Receptor Antagonist and Carotid Atherosclerosis Progression in Patients With Cerebrovascular Disease of Ischemic Origin
Authors: Bots Michiel L. , Ford Ian , Lloyd Suzanne M. , Laurent Stephane , Touboul Pierre J. , Hennerici Michael G.
Published: June 2014

Background and Purpose—

Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques.

Methods—

A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period.

Results—

Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, –0.004 to 0.016) and –0.005 mm per year (95% confidence interval, –0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, −0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77–1.07).

Conclusions—

Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%.

Clinical Trial Registration—

URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN66157730.
Vessel Wall Magnetic Resonance Imaging in Acute Ischemic Stroke
Authors: Power Sarah , Matouk Charles , Casaubon Leanne K. , Silver Frank L. , Krings Timo , Mikulis David J. , Mandell Daniel M.
Published: June 2014

Background and Purpose—

The aim of the study was to determine the effects of thromboembolism and mechanical thrombectomy on the vessel wall magnetic resonance imaging (VW-MRI) appearance of the intracranial arterial wall.

Methods—

This was a cross-sectional study of consecutive patients with acute intracranial arterial occlusion who underwent high-resolution contrast-enhanced VW-MRI within days of stroke presentation. For each patient, we categorized arterial wall thickening and enhancement as definite, possible, or none using contralateral arteries as a reference standard. We performed χ
2
tests to compare the effects of medical therapy and mechanical thrombectomy.

Results—

Sixteen patients satisfied inclusion criteria. Median time from symptom onset to VW-MRI was 3 days (interquartile range, 2 days). Among 6 patients treated with mechanical thrombectomy using a stent retriever, VW-MRI demonstrated definite arterial wall thickening in 5 (83%) and possible thickening in 1 (17%); there was definite wall enhancement in 4 (67%) and possible enhancement in 2 (33%). Among 10 patients treated with medical therapy alone, VW-MRI demonstrated definite arterial wall thickening in 3 (30%) and possible thickening in 2 (20%); there was definite wall enhancement in 2 (20%) and possible enhancement in 2 (20%). Arterial wall thickening and enhancement were more common in patients treated with mechanical thrombectomy than with medical therapy alone (
P
=0.037 and
P
=0.016, respectively).

Conclusions—

Mechanical thrombectomy results in intracranial arterial wall thickening and enhancement, potentially mimicking the VW-MRI appearance of primary arteritis. This arterial wall abnormality is less common in patients with arterial occlusion who have been treated with medical therapy alone.
Novel Factor Xa Inhibitor for the Treatment of Cerebral Venous and Sinus Thrombosis
Authors: Geisbüsch Christina , Richter Daniel , Herweh Christian , Ringleb Peter A. , Nagel Simon
Published: June 2014

Background and Purpose—

Thrombosis of cerebral veins and sinus (cerebral venous thrombosis) is a rare stroke pathogenesis. Pharmaceutical treatment is restricted to heparin and oral anticoagulation with vitamin K antagonists (VKAs).

Methods—

Between January 2012 and December 2013, we recorded data from our patients with cerebral venous thrombosis. The modified Rankin scale was used to assess clinical severity; excellent outcome was defined as modified Rankin scale 0 to 1. Recanalization was assessed on follow-up MR angiography. Patients were then divided into 2 treatment groups: phenprocoumon (VKA) and a novel factor Xa inhibitor. Clinical and radiological baseline data, outcome, recanalization status, and complications were retrospectively compared.

Results—

Sixteen patients were included, and 7 were treated with rivaroxaban. Overall outcome was excellent in 93.8%, and all patients showed at least partial recanalization. No statistical significant differences were found between the groups, except the use of heparin before start of oral anticoagulation (
P
=0.03). One patient in the VKA and 2 patients in the factor Xa inhibitor group had minor bleeding (
P
=0.55) within the median (range) follow-up of 8 months (5–26).

Conclusions—

Factor Xa inhibitor showed a similar clinical benefit as VKA in the treatment of cerebral venous thrombosis. Further systematic prospective evaluation is warranted.
Pourouma bergii (Urticaceae), a new species from South America
Authors: Gaglioti André Luiz , NETO SERGIO ROMANIUC
Published: June 2014

During the course of the taxonomic revision and molecular phylogeny of Pourouma, we encountered a new species from Peru and Ecuador. P. bergii Gaglioti & Romaniucis here described, illustrated and its morphological similarities to P. tomentosa subsp. persecta and P. petiolulata are discussed. A Conservation Assessment determines P. bergii to be Data Deficient (DD).
Palaquium bintuluense (Sapotaceae), a new species from Sarawak
Authors: CHANTARANOTHAI PRANOM
Published: June 2014

Palaquium bintuluense, a new species from Sarawak, is described and illustrated. The species appears most similar to P. rufolanigerum.