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Paromita Majumder,Cleber A Trujillo,Camila G Lopes,Rodrigo R Resende,Katia N Gomes,Katia K Yuahasi,Luiz R G Britto,Henning Ulrich Ionotropic P2X and metabotropic P2Y purinergic receptors are expressed in the central nervous system and participate in the synaptic process particularly associated with acetylcholine, GABA, and glutamate neurotransmission. As a result of activation, the P2 receptors promote the elevation of free i... ( view more )ntracellular calcium concentration as the main signaling pathway. Purinergic signaling is present in early stages of embryogenesis and is involved in processes of cell proliferation, migration, and differentiation. The use of new techniques such as knockout animals, in vitro models of neuronal differentiation, antisense oligonucleotides to induce downregulation of purinergic receptor gene expression, and the development of selective inhibitors for purinergic receptor subtypes contribute to the comprehension of the role of purinergic signaling during neurogenesis. In this review, we shall discuss the participation of purinergic receptors in developmental processes and in brain physiology, including neuron-glia interactions and pathophysiology. ( view less ) Geneviève Goy,Vincent Thomas,Katia Rimann,Katia Jaton,Guy Prod'hom,Gilbert Greub Virulent Mycobacterium kansasii (mainly subtype 1) may cause lung infections, whereas certain other strains (essentially subtype 3) are commonly non-pathogenic mycobacteria colonizing the human lower respiratory tract of patients. Determining the clinical significance of a strain isolated from a re... ( view more )spiratory sample represents a major challenge for clinicians. Since some mycobacteria may use free-living amoebae as a training ground to select virulence traits, we wondered whether the Acanthamoeba castellanii amoeba could be used to determine the virulence of these intracellular bacteria. We investigated whether the growth and cytopathic effect of M. kansasii in A. castellanii correlate with the virulence of M. kansasii determined clinically and by subtyping. Pathogenic subtype 1 M. kansasii strains grew better in A. castellanii than non-pathogenic subtype 3 strains when considering both the number of bacteria per amoeba and the percentage of infected amoebae. Moreover, a subtype 3 M. kansasii strain isolated from blood culture, and thus considered pathogenic, was revealed to grow in A. castellanii similarly to pathogenic subtype 1 strains. These results suggest that amoebae may represent useful tools for testing the virulence of intracellular mycobacteria and other amoeba-resisting bacteria. This is important, since identification of novel bacterial virulence factors relies largely on in vitro assessment of virulence. ( view less ) Flavia I V Errera,Luís Henrique Canani,Maria Elisabeth R Silva,Erika Yeh,Walter Takahashi,Katia G Santos,Katia E P Souto,Balduíno Tschiedel,Israel Roisenberg,Jorge Luis Gross,Maria Rita Passos-Bueno OBJECTIVE: The purpose of this study was to evaluate the effect of the single nucleotide polymorphism (SNP) -634G>C at the 5' regulatory region of the vascular endothelial growth factor (VEGF) in the risk of proliferative diabetic retinopathy (PDR) in the Brazilian population of European ancestry w... ( view more )ith type 2 diabetes. RESEARCH DESIGN AND METHODS: A case-control study was conducted in 501 type 2 diabetic patients of European ancestry. Patients underwent a standardized clinical, ophthalmological, and laboratory evaluation. Of these, 167 patients had PDR (case patients), and 334 were considered as control subjects (patients without PDR) for PDR. A reference population (110 individuals of European ancestry) was also evaluated. RESULTS: No evidence of association between -634G>C/VEGF and the presence of diabetic retinopathy or type 2 diabetes was observed (P > 0.05). However, CC homozygous for the SNP -634G>C was significantly more frequent in patients with PDR (37 of 167; 22.2%) than in the corresponding control group (40 of 334; 12%) in accordance with a recessive model (P = 0.003). This effect was further observed when creatinine, BMI, sex, duration of type 2 diabetes, HDL cholesterol, and systolic blood pressure were taken into account (odds ratio 1.9 [95% CI 1.01-3.79], P = 0.04). CONCLUSIONS: The presence of the allele -634C/VEGF in homozygosity is an independent risk factor for the development of PDR in type 2 diabetic patients of European ancestry. ( view less ) Katia G Santos,Balduino Tschiedel,João Schneider,Katia Souto,Israel RoisenbergWe investigated the relationship between diabetic retinopathy (DR) and three polymorphisms, C(-106)T in the aldose reductase (ALR2) gene, 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene and C677T in the methylenetetrahydrofolate reductase (MTHFR) gene, in 210 Euro-Brazilian type 2 diabe... ( view more )tic patients. Retinopathy was evaluated by funduscopic examination and genotype analysis was performed using the polymerase chain reaction and allele-specific restriction. Retinopathy was detected in 47% of the patients. There were no significant differences in allele or genotype distributions between patients with or without retinopathy for all polymorphisms. Thus, the three polymorphisms are not related to the presence of DR in Euro-Brazilian type 2 diabetic patients. ( view less ) Katia Scotlandi,Piero Picci PURPOSE OF REVIEW: The present review examines the rationale for targeting insulin-like growth factor-I receptor in sarcoma therapy and highlights some key issues that need to be addressed as clinical trials targeting insulin-like growth factor-I receptor proceed. RECENT FINDINGS: Preclinical evide... ( view more )nce supports proof of principle for targeting insulin-like growth factor-I receptor signaling in sarcomas. The insulin-like growth factor system is activated by or associated with most of the fusion oncoproteins that genetically characterize a group of sarcomas, but alterations in this pathway appear as a common feature. Correlation of cancer risk with insulin-like growth factor-I receptor signaling expression and polymorphisms has also been described. Blockade of insulin-like growth factor-I receptor functions results in an inhibition of tumor growth and metastasis, both when the targeted drugs were used as single agents and in combined therapies. Antibodies against insulin-like growth factor-I receptor and small kinase inhibitors represent, at this point, the most probable clinical options. SUMMARY: Sarcomas are good candidates for the design of a clinical study targeting insulin-like growth factor-I receptor. An attention to schedule with chemotherapy agents and new drugs, measurement of relevant indicators of response and better molecular understanding of the metabolic functions of insulin-like growth factor-I receptor and its functional relationship with insulin receptor are necessary to proceed safely with the design of anti-insulin-like growth factor strategies. ( view less ) Scot T Bateman,Jacques Lacroix,Katia Boven,Peter Forbes,Roger Barton,Neal J Thomas,Brian Jacobs,Barry Markovitz,Brahm Goldstein,James H Hanson,H Agnes Li,Adrienne G Randolph,Pediatric Acute Lung Injury and Sepsis Investigators Network  RATIONALE: Minimizing exposure of children to blood products is desirable. OBJECTIVES: We aimed to understand anemia development, blood loss, and red blood cell (RBC) transfusions in the pediatric intensive care unit (PICU). Methods: Prospective, multicenter, 6-month observational study in 30 PICUs... ( view more ). Data were collected on consecutive children (<18 yr old) in the PICU for 48 hours or more. MEASUREMENTS AND MAIN RESULTS: Anemia development, blood loss, and RBC transfusions were measured. A total of 977 children were enrolled. Most (74%) children were anemic in the PICU (33% on admission, 41% developed anemia). Blood draws accounted for 73% of daily blood loss; median loss was 5.0 ml/day. Forty-nine percent of children received transfusions; 74% of first transfusions were on Days 1-2. After adjusting for age and illness severity, compared with nontransfused children, children who underwent transfusion had significantly longer days of mechanical ventilation (2.1 d, P < 0.001) and PICU stay (1.8 d, P = 0.03), and had increased mortality (odds ratio [OR], 11.6; 95% confidence interval [CI], 1.43-90.9; P = 0.02), nosocomial infections (OR, 1.9; 95% CI, 1.2-3.0; P = 0.004), and cardiorespiratory dysfunction (OR, 2.1; 95% CI, 1.5-3.0; P < 0.001). High blood loss per kilogram body weight from blood draws (OR, 1.11; 95% CI, 1.03-1.2; P = 0.01) was associated with RBC transfusion more than 48 hours after admission. The most common indication for transfusion was low hemoglobin (42%). Pretransfusion hemoglobin values varied greatly (mean, 9.7 +/- 2.7 g/dl). CONCLUSIONS: Critically ill children are at significant risk for developing anemia and receiving blood transfusions. Transfusion in the PICU was associated with worse outcomes. It is imperative to minimize blood loss from blood draws and to set clear transfusion thresholds. ( view less ) Gerardo Maria de Araújo Filho,Vivianne Pellegrino Rosa,Katia Lin,Luís Otávio Sales Ferreira Caboclo,Américo Ceiki Sakamoto,Elza Márcia Targas Yacubian We evaluated the frequency of psychiatric disorders (PDs) in a homogenous series of patients with temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS), as compared with patients with juvenile myoclonic epilepsy (JME), aiming to determine possible differences in psychiatric diagnoses betw... ( view more )een these two epileptic syndromes. Data from 170 patients with refractory TLE-MTS and from 100 patients with JME were reviewed and compared. The prevalence of PDs was high in both groups of patients with epilepsy: PDs were present in 85 patients with TLE-MTS (50%) and 49 patients with JME (49%). Among the TLE-MTS group, mood (25.8%), psychotic (15.8%), and anxiety (14.1%) disorders were the most frequent diagnoses, whereas anxiety and mood disorders (23 and 19%, respectively) were the most common among patients with JME. Psychoses were significantly associated with MTS (P<0.01) and anxiety disorders with JME (P<0.05). These findings suggest the existence of an anatomic correlation between PDs and brain structures involved in both epilepsy syndromes. ( view less ) Katia Dyrda,Paul Khairy Current medical guidelines have prompted implementation of increasing numbers of implantable rhythm devices, be they pacemakers, internal cardioverter-defibrillators or loop recorders. These devices rely on complex microcircuitry and use electromagnetic waves for communication. They are, therefore,... ( view more ) susceptible to interference from surrounding electromagnetic radiation and magnetic energy. Hermetic shielding in metallic cases, filters, interference rejection circuits and bipolar sensing have contributed to their relative resistance to electromagnetic interference (EMI) in household and workplace environments. Device interactions have occurred in hospitals where EMI sources are ubiquitous, including radiation, electrocautery and MRI exposures. However, with rapidly evolving technology, devices and potential sources of EMI continue to change. This review provides a contemporary overview of the current state of knowledge regarding risks attributable to EMI; highlights current limitations of implantable rhythm devices; and attempts to distinguish myths from realities. ( view less ) Flora S Kano,Katia Tamekuni,Adriana L Coelho,João Luis Garcia,Odilon Vidotto,Eiko Nakagawa Itano,Marilda C Vidotto The outer membrane proteins of Anaplasma marginale have been the focus of research to obtain an improved vaccine against bovine anaplasmosis. We evaluated the capacity of the recombinant plasmids pcDNA-msp1alpha, pcDNA-msp1beta, and pcDNA-mp5 to express MSP1a, MSP1b, and MSP5 proteins, and to deter... ( view more )mine the immunogenicity of BALB/c mice immunized with these plasmids individually or in association. Expression of proteins was confirmed in Vero cells by IFA. The combination of recombinant plasmids showed high antibodies response, produced better induction of Th1 response than individual plasmids, and induced significant proliferation of splenocytes. The mice sera immunized with A. marginale showed seroconversion and reacted with all native MSPs, but demonstrated predominance of the humoral IgG1 isotype and did not induce significant proliferation of splenocytes. The use of association of recombinant plasmid can be an effective strategy for the immunoprophylaxis of anaplasmosis. ( view less ) Luca Paoluzzi,Mithat Gonen,Jeffrey R Gardner,Jill Mastrella,Dajun Yang,Jon Holmlund,Mel Sorensen,Lance Leopold,Katia Manova,Guido Marcucci,Mark L Heaney,Owen A O'Connor Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic... ( view more ) known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy. ( view less ) Katia Ramos Moreira Leite,Luiz Heraldo Camara-Lopes,José Cury,Marcos F Dall'oglio,Adriana Sañudo,Miguel Srougi INTRODUCTION: Sextant prostate biopsy remains the standard technique for the detection of prostate cancer. It is well known that after a diagnosis of small acinar proliferation (ASAP) or high grade prostate intraepithelial neoplasia (HGPIN), the possibility of finding cancer is approximately 40% an... ( view more )d 30%, respectively. OBJECTIVE: We aim to analyze follow-up biopsies on patients who initially received a benign diagnosis after exclusion of HGPIN and ASAP. METHODS: From July 2000 to December 2003, 1177 patients were submitted to sextant extended prostate biopsy in our hospital. The mean patient age was 65.5 years old, and the median number of fragments collected at biopsy was 13. HGPIN and ASAP were excluded from our study. We only considered patients who had a diagnosis of benign at the first biopsy and were subjected to rebiopsies up until May 2005 because of a maintained suspicion of cancer. RESULTS: Cancer was initially detected in 524 patients (44.5%), and the diagnosis was benign in 415 (35.3%). Rebiopsy was indicated for 76 of the latter patients (18.3%) because of a persistent suspicion of cancer. Eight cases of adenocarcinoma (10.5%) were detected, six (75%) at the first rebiopsy. Six patients were submitted to radical prostatectomy, and all tumors were considered clinically significant. CONCLUSION: Our data indicate that in extended prostate biopsy, the first biopsy detects more cancer, and the first, second, and third rebiopsies after an initial benign diagnosis succeed in finding cancer in 7.9% (6/55), 5.9% (1/15) and 20% (1/4) of patients, respectively. ( view less ) Katia Grillo Padilha,Regina Márcia Cardoso de Sousa,Alda Ferreira Queijo,Ana Márcia Mendes,Dinis Reis Miranda BACKGROUND: High costs of intensive care as well as quality of care and patient safety demand measurement of nursing workload in order to determine nursing staff requirements. It is also important to be aware of the factors related to high patient care demands in order to help forecast staff requir... ( view more )ements in intensive care units (ICUs). OBJECTIVES: To describe nursing workload using the Nursing Activities Score (NAS); to explore the association between NAS and patients variables, i.e. gender, age, length of stay (LOS), ICU discharge, treatment in the ICU, Simplified Acute Physiology Score II (SAPS II) and Therapeutic Interventions Scoring System-28 (TISS-28). METHODS: NAS, demographic data, SAPS II and TISS-28 were analysed among 200 patients from four different ICUs in a private hospital in São Paulo, Brazil. RESULTS: NAS median were 66.4%. High NAS scores (> 66.4%) were associated with death (p-value 0.006) and LOS (p-value 0.015). Logistic regression analysis demonstrated that TISS-28 scores above 23 and SAPS II scores above 46.5 points, classified as high, increased 5.45 and 2.78 times, respectively, the possibility of a high workload as compared to lower values of the same indexes. CONCLUSION: This study shows that the highest NAS scores were associated with increased mortality, LOS, severity of the patient illness (SAPS II), and particularly to TISS-28 in the ICU. ( view less ) Marianne Goyer,Ludwig-Serge Aho,Jean-Baptiste Bour,Katia Ambert-Balay,Pierre PothierLittle is known about the epidemiology of Aichi virus, which is a new member of the family Picornaviridae, in the genus Kobuvirus. We report here on seroprevalence in France. Sera were screened using an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G. Of 972 sera tested, seroprevalen... ( view more )ce ranged from 25% for the 7-month-to-9-year-old age group to about 85% for the 30-to-39-year-old age group and older age groups. Our ELISA correlated well with the microneutralization technique. This study shows that Aichi virus is quite frequent in France and that seroconversion occurs before the age of 40. ( view less ) Marco Gobbi,Marcella Funicello,Klaus Gerstbrein,Marion Holy,Pablo R Moya,Ramón Sotomayor,María Inés Forray,Katia Gysling,Silvio Paluzzi,Giambattista Bonanno,Miguel Reyes-Parada,Harald H Sitte,Tiziana Mennini We studied two non-neurotoxic amphetamine derivatives (methyl-thioamphetamine, MTA and N,N-dimethylMTA, DMMTA) interacting with serotonin (5-HT) transporters (SERTs) with affinities comparable to that of p-Cl-amphetamine (pCA). The rank order for their maximal effects in inducing both [(3)H]5-HT re... ( view more )lease from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA >> MTA > or = DMMTA. A correlation between drug-induced release and currents is also strengthened by the similar bell shape of the dose-response curves. Release experiments indicated that MTA and DMMTA are SERT substrates although MTA is taken up by HEK-293 cells with a V(max) 40% lower than pCA. The weak effects of MTA and DMMTA in vitro might therefore be due to their properties as 'partial substrates' on the mechanisms, other than translocation, responsible for currents and/or release. After either local or systemic in vivo administration, MTA and DMMTA release 5-HT in a manner comparable to pCA. These findings confirm that the neurotoxic properties of some amphetamine derivatives are independent of their 5-HT-releasing activity in vivo. It is worth noting that only those amphetamine derivatives with high efficiency in inducing 5-HT release and currents in vitro have neurotoxic properties. ( view less ) Guido A M Tiberio,Laura Tiberio,Anna Benetti,Edoardo Cervi,Nadia Montani,Michel Dreano,Gianni Garotta,Katia Cerea,Nathalie Steimberg,GianPietro Pandolfo,Andrea Ferrari-Bravo,Giovanna Mazzoleni,Stefano M Giulini,Luisa Schiaffonati Major hepatic resection in cirrhotic patients is associated with impaired liver regeneration and failure, leading to high peri-operative mortality. In this work, the causes of defective regeneration in cirrhotic liver and the utility of IL-6 treatment were investigated in an experimental model comb... ( view more )ining cirrhosis and partial hepatectomy in the rat. Relative to normal controls, decompensated cirrhotic animals showed decreased survival, while compensated cirrhotic animals showed similar survival but reduced hepatic DNA synthesis and newly regenerated liver mass amount. Defective liver regeneration was associated with a decrease in STAT3 and NF-kB activation, consistent with an increased accumulation of their respective inhibitors PIAS3 and IkBalpha, and with a decreased induction of Bcl-xL. Treatment with recombinant IL-6 enhanced survival of decompensated cirrhotic animals, while it did not affect survival of compensated cirrhotic animals but sustained liver regeneration, by restoring STAT3 and NF-kB activation and Bcl-xL induction to the levels found in normal controls. The pro-growth effects exerted by IL-6 treatment in cirrhotic liver were attained also at low, pharmacologically acceptable doses. In conclusion, our results suggest that IL-6 treatment may be therapeutic in major resection of cirrhotic liver. ( view less ) Stanislava Stosic-Grujicic,Ivana Stojanovic,Danijela Maksimovic-Ivanic,Miljana Momcilovic,Dusan Popadic,Ljubica Harhaji,Djordje Miljkovic,Christine Metz,Katia Mangano,Gianpaolo Papaccio,Yousef Al-Abed,Ferdinando Nicoletti Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine of the innate immune system that plays a major role in the induction of immunoinflammatory responses. To examine the role of endogenous MIF in the pathogenesis of type 1 diabetes (TID) we evaluated the effects of administrat... ( view more )ion of neutralizing anti-MIF antibodies to NOD mice with accelerated forms of diabetes induced by injection of cyclophosphamide or by transfer of diabetogenic spleen cells. Both accelerated forms of diabetes were markedly reduced by anti-MIF antibody. Furthermore, MIF-deficient (MIF(-/-)) mice were less susceptible to the induction of immunoinflammatory diabetes, insulitis and apoptosis within the endocrine pancreas by multiple low doses of streptozotocin (MLD-STZ) than genetically matched wild type (WT) mice. MIF deficiency resulted in lower proliferation and lymphocyte adhesion, as well as reduced production from the spleens and peritoneal cells of a variety of inflammatory mediators typically associated with development of the disease including IL-12, IL-23, TNF-alpha, and IL-1beta. Furthermore, MIF deletion affected the production of IL-18, TNF-alpha, IL-1beta, and iNOS in the islets of Langerhans. These data, along with the higher expression of IL-4 and TGF-beta observed in the periphery and in the pancreas of MLD-STZ-challenged MIF(-/-) mice as compared to WT controls suggest that MIF deficiency has induced an immune deviation towards protective type 2/3 response. These results suggest that MIF participates in T1D by controlling the functional activity of monocytes/macrophages and T cells and modulating their secretory capacity of pro- and anti-inflammatory molecules. ( view less ) Alberto A Antunes,Katia Ramos Leite,Marcos F Dall'Oglio,Jose Cury,Miguel Srougi CONTEXT: Studies analyzing the concordance of biopsy and radical prostatectomy (RP) Gleason scores have limitations. Some included 2 or more centers, used historical controls from the early prostate specific antigen era or lacked a clear definition of the biopsy schemes. Furthermore, most did not c... ( view more )ontrol the results for prostate volume. OBJECTIVE: To confirm whether prediction of RP Gleason score can be optimized by taking more biopsy cores in a contemporary series of patients, with pathologic samples analyzed by the same pathologist, and controlling these results for prostate volume. DESIGN: The study comprised a retrospective case-control analysis of 393 patients with prostate cancer treated with RP. Patients were divided into 3 groups: those in group 1 underwent a 6-core biopsy; group 2, an 8-core biopsy; and group 3, a 10 or more-core biopsy. Concordance rates between biopsy and RP Gleason scores, as well as the rates of undergrading and overgrading, were determined for each biopsy scheme. RESULTS: Concordance rates were 60.9%, 58.3%, and 64.6% for patients from groups 1, 2, and 3, respectively (P = .18). When we analyzed patients with prostate volumes of less than 50 cm(3), concordance rates were 58.3%, 58.3%, and 65.1% for each group, respectively (P = .03). Among patients with prostate volumes of 50 cm(3) or more, concordance rates were 70%, 58.1%, and 63.6%, respectively (P = .66). CONCLUSIONS: Taking 10 or more cores can improve the prediction of RP Gleason score in patients with prostate volumes of less than 50 cm(3). For patients with prostate volumes of 50 cm(3) or more, increasing the biopsy cores to 10 or more did not improve prediction of RP Gleason score. ( view less ) Katia Mangano,Niranjan Sardesai,Maria D'Alcamo,Massimo Libra,Lucia Malaguarnera,Marco Donia,Klaus Bendtzen,Pierluigi Meroni,Ferdinando Nicoletti VGX-1027 is an isozaxoline compound that has recently been found to primarily target the function of murine macrophages but not of T cells, inhibiting secretion of tumor necrosis factor (TNF)-alpha in response to different Toll-like receptor agonists in vitro and in vivo. The well-defined role of i... ( view more )nnate immunity in inflammatory bowel diseases prompted us to consider the use of VGX-1027 in these diseases leading us to in vitro and in vivo test the drug in related experimental conditions. These consist, respectively, of the proliferation assay of CD4+CD25- T cells to enterobacteria, and the acute inflammatory colitis induced in mice by intracolonic challenge with dinitrobenzene sulfonic acid. The data from the two sets of experiments revealed that VGX-1027 inhibited both proliferation of enterobacterial antigen-reactive CD4+CD25- T cells in vitro and the development of clinical and histological signs of colitis in vivo. The beneficial effect in this model was associated with reduced colonic production of proinflammatory cytokines such as interleukin (IL)-1beta, TNF-alpha, IL-12p70 and interferon (IFN)-gamma and lower content of nuclear factor (NF)-kappaB (p65). These findings seem to warrant investigations of VGX-1027 for use in human. ( view less ) Chantal Henry,Donatienne Van den Bulke,Frank Bellivier,Isabelle Roy,Joël Swendsen,Katia M'Baïlara,Larry J Siever,Marion Leboyer Bipolar disorders are usually defined by alternative mood states, but a more precise characterization of the euthymic period could provide further insights into the pathophysiology of bipolar disorders. Surprisingly, few studies have investigated core affective dimensions in euthymic bipolar patien... ( view more )ts. In this study, we assessed 179 euthymic bipolar patients (score<12 on the Montgomery-Asberg Depression Scale and a score<6 on the Bech-Rafaelsen Mania Scale) compared with 86 control subjects using French versions of the Affective Lability Scale (ALS) and the Affect Intensity Measure (AIM). Data were analyzed by logistic regression. Our results showed that euthymic bipolar subjects reported having more intense emotions than controls and also had a higher affective lability. High scores in both affective dimensions were associated with a significantly higher risk for psychiatric axis I comorbidity. Moreover, a high affective lability score was associated with an earlier age of onset for bipolar disease. Affective lability and affect intensity might be two core dimensions of bipolar disorder during euthymic periods, suggesting that bipolar disorder is not circumscribed to mood episodes but also affects emotional reactivity between episodes. Both dimensions could account for the stress reactivity of bipolar patients that may lead to relapses. ( view less ) Wenhong Li,Rong Fu,Robinson I Negrón Juárez,Katia Fernandes Observations show that the standard precipitation index (SPI) over the southern Amazon region decreased in the period of 1970-1999 by 0.32 per decade, indicating an increase in dry conditions. Simulations of constant pre-industrial climate with recent climate models indicate a low probability (p=0%... ( view more )) that the trends are due to internal climate variability. When the 23 models are forced with either anthropogenic factors or both anthropogenic and external natural factors, approximately 13% of sampled 30-year SPI trends from the models are found to be within the range of the observed SPI trend at 95% confidence level. This suggests a possibility of anthropogenic and external forcing of climate change in the southern Amazon. On average, the models project no changes in the frequency of occurrence of low SPI values in the future; however, those models which produce more realistic SPI climatology, variability and trend over the period 1970-1999 show more of a tendency towards more negative values of SPI in the future. The analysis presented here suggests a potential anthropogenic influence on Amazon drying, which warrants future, more in-depth, study. ( view less ) Katia C U Mugnol,Rômulo A Ando,Rafael Y Nagayasu,Adelaide Faljoni-Alario,Sergio Brochsztain,Paulo S Santos,Otaciro R Nascimento,Iseli L Nantes The alternative low-spin states of Fe(3+) and Fe(2+) cytochrome c induced by SDS or AOT/hexane reverse micelles exhibited the heme group in a less rhombic symmetry and were characterized by electron paramagnetic resonance, UV-visible, CD, magnetic CD, fluorescence, and Raman resonance. Consistent w... ( view more )ith the replacement of Met(80) by another strong field ligand at the sixth heme iron coordination position, Fe(3+) ALSScytc exhibited 1-nm Soret band blue shift and epsilon enhancement accompanied by disappearance of the 695-nm charge transfer band. The Raman resonance, CD, and magnetic CD spectra of Fe(3+) and Fe(2+) ALSScytc exhibited significant changes suggestive of alterations in the heme iron microenvironment and conformation and should not be assigned to unfold because the Trp(59) fluorescence remained quenched by the neighboring heme group. ALSScytc was obtained with His(33) and His(26) carboxyethoxylated horse cytochrome c and with tuna cytochrome c (His(33) replaced by Asn) pointing out Lys(79) as the probable heme iron ligand. Fe(3+) ALSScytc retained the capacity to cleave tert-butylhydroperoxide and to be reduced by dithiothreitol and diphenylacetaldehyde but not by ascorbate. Compatible with a more open heme crevice, ALSScytc exhibited a redox potential approximately 200 mV lower than the wild-type protein (+220 mV) and was more susceptible to the attack of free radicals. ( view less ) Reena Shakya,Matthias Szabolcs,Ellen McCarthy,Elson Ospina,Katia Basso,Subhadra Nandula,Vundavalli Murty,Richard Baer,Thomas Ludwig Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a ... ( view more )heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either Bard1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional Bard1- and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are "triple negative" for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of Bard1-, Brca1-, and Bard1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer. ( view less ) Emerson G Pontes,Paula Leite,David Majerowicz,Georgia C Atella,Katia C Gondim In insects, lipids are stored in the fat body, mainly as triacylglycerol (TAG). In Rhodnius prolixus, a hematophagous hemipteran, lipids are accumulated after blood meal to be used later on. In adult females, at the second day after feeding, the amount of TAG was 57+/-17mug/fat body, it increased a... ( view more )lmost five times and at fourth day it was 244+/-35mug/fat body. TAG content remained constant until day 13, but it then decreased and, at day 20th it was very low (31+/-4.9mug/fat body). Radiolabeled free fatty acid was used to follow lipid accumulation by the fat body, as it was previously shown that, in R. prolixus, injected free fatty acids associate with lipophorin, a major hemolymphatic lipoprotein. (3)H-palmitic acid was injected into the hemocoel of R. prolixus females. It disappeared from the hemolymph very rapidly, and radioactivity was incorporated by the fat body. Sixty minutes after injection, radioactivity in the fat body was found mainly in TAGs. The capacity of the fat body to incorporate fatty acids from the hemolymph varied according to the days after blood meal, and it was maximal around the fourth day. Lipophorin binding to specific sites in fat body membrane preparations also showed variation at different days. When membranes obtained from insects at the second, fifth and tenth days were compared, binding was highest at fifth day after feeding. ( view less ) Toshimi Yoshida,Idit Hazan,Jiangwen Zhang,Samuel Y Ng,Taku Naito,Hugo J Snippert,Elizabeth J Heller,Xiaoqing Qi,Lee N Lawton,Christine J Williams,Katia Georgopoulos The ability of somatic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that keep stem cell-specific genes active and key differentiation factors repressed but poised for activation. The epigenetic factors that provide this type ... ( view more )of regulation remain ill-defined. Here we provide the first evidence that the SNF2-like ATPase Mi-2beta of the Nucleosome Remodeling Deacetylase (NuRD) complex is required for maintenance of and multilineage differentiation in the early hematopoietic hierarchy. Shortly after conditional inactivation of Mi-2beta, there is an increase in cycling and a decrease in quiescence in an HSC (hematopoietic stem cell)-enriched bone marrow population. These cycling mutant cells readily differentiate into the erythroid lineage but not into the myeloid and lymphoid lineages. Together, these effects result in an initial expansion of mutant HSC and erythroid progenitors that are later depleted as more differentiated proerythroblasts accumulate at hematopoietic sites exhibiting features of erythroid leukemia. Examination of gene expression in the mutant HSC reveals changes in the expression of genes associated with self-renewal and lineage priming and a pivotal role of Mi-2beta in their regulation. Thus, Mi-2beta provides the hematopoietic system with immune cell capabilities as well as with an extensive regenerative capacity. ( view less ) Katia Mattarozzi,Claudia Bellucci,Claudio Campi,Carlo Cipolli,Raffaele Ferri,Christian Franceschini,Michela Mazzetti,Paolo Maria Russo,Stefano Vandi,Luca Vignatelli,Giuseppe Plazzi BACKGROUND: Cataplexy is the main motor symptom of narcolepsy/cataplexy and is considered a form of rapid eye movement (REM) sleep motor dyscontrol appearing during wakefulness and elicited by emotions. This study examined the relationship between the frequency of cataplectic attacks in patients wi... ( view more )th narcolepsy/cataplexy and (a) the clinical and behavioural characteristics of cataplectic attacks, including the emotional tone of trigger events, and (b) the polysomnographic characteristics of daytime sleepiness, nocturnal sleep structure and indices of motor disorders during sleep. METHODS: A consecutive series of 44 first-diagnosed drug-naive patients with narcolepsy/cataplexy, fulfilling the International Classification of Sleep Disorders, 2nd edition (ICSD-2) clinical and polysomnographic diagnostic criteria, were interviewed to estimate the frequency and clinical characteristics of cataplectic attacks and the occurrence of REM sleep behaviour disorder (RBD). All patients also underwent a video-polysomnographic recording to assess their sleep parameters and indices of altered motor control during sleep. RESULTS: Patients were divided into two groups on the basis of the frequency of cataplectic attacks, namely high-frequency (n=30) or low-frequency (n=14) depending on whether they estimated they had more or less than one attack per month. High-frequency patients (with a larger proportion of men) reported attacks more often affecting mainly the head, jaw and shoulder muscles and experienced more events among those listed as possible triggers of attacks. Sixty-one percent of patients reported RBD and 43% had an RBD episode at video-polysomnography regardless of the frequency of cataplectic attacks or gender. Lastly, the frequency of periodic leg movements (PLM) per hour was higher in men than women and increased with age. CONCLUSIONS: Patients with more than one cataplectic attack per month had more frequent involvement of head, jaw and shoulder muscles and were mainly men. The proportions of patients with clinically assessed RBD and an RBD episode documented by video-polysomnography, as well as conspicuous values of PLM per hour, are fairly consistent with those reported in recent small-group studies. Therefore, it seems legitimate to argue that RBD and PLM are nocturnal manifestations intrinsic to narcolepsy/cataplexy and that the gender-related differences in the frequency of attacks and the value of PLM per hour may be indicative of a larger difference in the clinical and polysomnographic characteristics of narcolepsy/cataplexy than hitherto suspected. ( view less )
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