tbuckley/cabot-search huggingface dataset:
Importance of Efferent Arteriolar Vascular Tone in Regulation of Proximal Tubule Fluid Reabsorption and Glomerulotubular Balance in the Rat
Authors: Iekuni Ichikawa, Barry M. Brenner
Journal: Journal of Clinical Investigation (1980)

Micropuncture study was performed in 21 mildly volume-expanded Munich-Wistar rats before and during partial aortic constriction to examine the effects of endogenous prostaglandins (PG) and angiotensin II (AII) on single nephron glomerular filtration rate (SNGFR) and absolute proximal reabsorption rate (APR). Animals received either vehicle (group 1), indomethacin (group 2), or indomethacin plus saralasin (group 3). Before aortic constriction, these inhibitors were without effect on values of SNGFR and APR. In group 1 rats, reduction in mean renal arterial perfusion pressure (R̄ĀP̄) to ∼65 mm Hg resulted in marked and proportional declines in SNGFR and APR. With equivalent reduction in R̄ĀP̄ in group 2 rats, however, SNGFR fell to a lesser extent and APR tended to increase slightly above preconstriction values. Indomethacin administration was therefore associated with disruption of glomerulotubular balance. In view of the roughly equivalent declines in afferent arteriolar resistance measured in groups 1 and 2, the magnitude of increase in efferent arteriolar resistance (RE) appeared to be of major importance in determining the observed presence or absence of glomerulotubular balance. Thus, the lesser fall in SNGFR in group 2 than in group 1 was a result of the higher value for glomerular capillary hydraulic pressure in group 2, a consequence of the higher value of RE. The higher average value for APR during reduced R̄ĀP̄ in group 2 than in group 1 is also attributable to this pronounced rise in RE, the effect of which was to augment the net reabsorptive pressure both by favoring higher postglomerular oncotic pressure and lower downstream (peritubular capillary) hydraulic pressure. Since intrarenal release of AII is enhanced when R̄ĀP̄ declines, and because AII is known to raise RE selectively, it is likely that endogenous AII brought about the marked increase in RE in group 2, which was readily demonstrable only in indomethacin-treated rats, presumably because endogenous PG synthesis was suppressed.
Alu elements mediate <i>MYB</i> gene tandem duplication in human T-ALL
Authors: Jennifer O'Neil, Joelle Tchinda, Alejandro Gutierrez, Lisa Moreau, Richard S. Maser, Kwok-Kin Wong, Wei Li, Keith McKenna, X. Shirley Liu, Bin Feng, Donna Neuberg, Lewis Silverman, Daniel J. DeAngelo, Jeffery L. Kutok, Rodney Rothstein, Ronald A. DePinho, Lynda Chin, Charles Lee, A. Thomas Look
Journal: The Journal of Experimental Medicine (2007)

Recent studies have demonstrated that the MYB oncogene is frequently duplicated in human T cell acute lymphoblastic leukemia (T-ALL). We find that the human MYB locus is flanked by 257-bp Alu repeats and that the duplication is mediated somatically by homologous recombination between the flanking Alu elements on sister chromatids. Nested long-range PCR analysis indicated a low frequency of homologous recombination leading to MYB tandem duplication in the peripheral blood mononuclear cells of ∼50% of healthy individuals, none of whom had a MYB duplication in the germline. We conclude that Alu-mediated MYB tandem duplication occurs at low frequency during normal thymocyte development and is clonally selected during the molecular pathogenesis of human T-ALL.
Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging
Authors: Dao-Fu Dai, Luis F. Santana, Marc Vermulst, Daniela M. Tomazela, Mary J. Emond, Michael J. MacCoss, Katherine Gollahon, George M. Martin, Lawrence A. Loeb, Warren C. Ladiges, Peter S. Rabinovitch
Journal: Circulation (2009)

Background— Age is a major risk for cardiovascular diseases. Although mitochondrial reactive oxygen species have been proposed as one of the causes of aging, their role in cardiac aging remains unclear. We have previously shown that overexpression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17% to 21%. Methods and Results— We used echocardiography to study cardiac function in aging cohorts of wild-type and mCAT mice. Changes found in wild-type mice recapitulate human aging: age-dependent increases in left ventricular mass index and left atrial dimension, worsening of the myocardial performance index, and a decline in diastolic function. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions and mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, decreased cardiac SERCA2 protein, and activation of the calcineurin–nuclear factor of activated T-cell pathway. All of these age-related changes were significantly attenuated in mCAT mice. Analysis of survival of 130 mice demonstrated that echocardiographic cardiac aging risk scores were significant predictors of mortality. The estimated attributable risk to mortality for these 2 parameters was 55%. Conclusions— This study shows that cardiac aging in the mouse closely recapitulates human aging and demonstrates the critical role of mitochondrial reactive oxygen species in cardiac aging and the impact of cardiac aging on survival. These findings also support the potential application of mitochondrial antioxidants in reactive oxygen species–related cardiovascular diseases.
Mental health services in the Arab world
Authors: AHMED OKASHA, ELIE KARAM, TAREK OKASHA
Journal: World Psychiatry (2012)

This paper summarizes the current situation of mental health services in the Arab world. Out of 20 countries for which information is available, six do not have a mental health legislation and two do not have a mental health policy. Three countries (Lebanon, Kuwait and Bahrain) had in 2007 more than 30 psychiatric beds per 100,000 population, while two (Sudan and Somalia) had less than 5 per 100,000. The highest number of psychiatrists is found in Qatar, Bahrain and Kuwait, while seven countries (Iraq, Libya, Morocco, Somalia, Sudan, Syria and Yemen) have less than 0.5 psychiatrists for 100,000 population. The budget allowed for mental health as a percentage from the total health budget, in the few countries where information is available, is far below the range to promote mental health services. Some improvement has occurred in the last decade, but the mental health human resources and the attention devoted to mental health issues are still insufficient.
Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials
Authors: R. Conforti, T. Boulet, G. Tomasic, E. Taranchon, R. Arriagada, M. Spielmann, M. Ducourtieux, J.C. Soria, T. Tursz, S. Delaloge, S. Michiels, F. Andre
Journal: Annals of Oncology (2007)
Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes
Authors: Lisa S. Westerberg, Parool Meelu, Marisa Baptista, Michelle A. Eston, David A. Adamovich, Vinicius Cotta-de-Almeida, Brian Seed, Michael K. Rosen, Peter Vandenberghe, Adrian J. Thrasher, Christoph Klein, Frederick W. Alt, Scott B. Snapper
Journal: The Journal of Experimental Medicine (2010)

X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability.
Analysis of Integrin α7 Mutations in Prostate Cancer, Liver Cancer, Glioblastoma Multiforme, and Leiomyosarcoma
Authors: Baoguo Ren, Yan P. Yu, George C. Tseng, Chuanyue Wu, Ka Chen, Uma N. Rao, Joel Nelson, George K. Michalopoulos, Jian-Hua Luo
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundIntegrins are the major adhesive molecules in mammalian cells. Each integrin subtype plays a unique role in cell differentiation and embryo development. However, integrin involvement in carcinogenesis has not been well defined.
VEGF Trap induces antiglioma effect at different stages of disease
Authors: Candelaria Gomez-Manzano, Jocelyn Holash, Juan Fueyo, Jing Xu, Charles A. Conrad, Kenneth D. Aldape, John F. de Groot, B. Nebiyou Bekele, W. K. Alfred Yung
Journal: Neuro-Oncology (2008)

Pathological angiogenesis is a hallmark of cancer, specifically of glioblastomas, the most malignant and common primary brain tumor. Vascular endothelial growth factor (VEGF) is the key protein in the regulation of the hypervascular phenotype of primary malignant brain tumors. In this study, we tested VEGF Trap, a soluble decoy receptor for VEGF, in an intracranial glioma model. VEGF Trap was administered in short or prolonged schedules to animals bearing human gliomas at different stages of disease. Of importance, VEGF Trap treatment was efficacious in both initial and advanced phases of tumor development by significantly increasing overall survival. Furthermore, this effect was enhanced in animals treated with more prolonged regimens. In addition, we observed the emergence of a VEGF Trap-resistant phenotype characterized by tumor growth and increased invasiveness. Our results suggest that VEGF Trap will be effective in treating both patients with recurrent or progressive resectable glioblastoma and patients that have undergone extensive initial surgery. Finally, our results indicate that the clinical success of VEGF Trap may depend on a prolonged treatment in combined therapy aiming to simultaneously inhibit angiogenesis and tumor invasion.
Adiponectin Promotes Functional Recovery after Podocyte Ablation
Authors: Joseph M. Rutkowski, Zhao V. Wang, Ae Seo Deok Park, Jianning Zhang, Dihua Zhang, Ming Chang Hu, Orson W. Moe, Katalin Susztak, Philipp E. Scherer
Journal: Journal of the American Society of Nephrology (2013)

Low levels of the adipocyte-secreted protein adiponectin correlate with albuminuria in both mice and humans, but whether adiponectin has a causative role in modulating renal disease is unknown. Here, we first generated a mouse model that allows induction of caspase-8–mediated apoptosis specifically in podocytes upon injection of a construct-specific agent. These POD-ATTAC mice exhibited significant kidney damage, mimicking aspects of human renal disease, such as foot process effacement, mesangial expansion, and glomerulosclerosis. After the initial induction, both podocytes and filtration function recovered. Next, we crossed POD-ATTAC mice with mice lacking or overexpressing adiponectin. POD-ATTAC mice lacking adiponectin developed irreversible albuminuria and renal failure; conversely, POD-ATTAC mice overexpressing adiponectin recovered more rapidly and exhibited less interstitial fibrosis. In conclusion, these results suggest that adiponectin is a renoprotective protein after podocyte injury. Furthermore, the POD-ATTAC mouse provides a platform for further studies, allowing precise timing of podocyte injury and regeneration.
Diclofenac-Associated Hepatotoxicity
Authors: Simon M. Helfgott
Journal: JAMA (1990)

Diclofenac sodium, a phenylacetic acid—derived nonsteroidal anti-inflammatory drug (NSAID) recently released in the United States, was associated with the development of significant hepatitis in seven patients, with one associated death. Signs and symptoms developed within several weeks of initiation of drug use and generally resolved 4 to 6 weeks following discontinuation of use of the drug. The only patient rechallenged with the drug developed a recurrence of her hepatic abnormalities. In one patient, fatal, fulminant hepatitis developed despite early withdrawal of the drug. Review of the European literature disclosed three additional fatalities associated with diclofenac therapy. It is unclear whether the incidence of hepatotoxicity is higher with this drug compared with other nonsteroidal anti-inflammatory drugs. Careful patient monitoring is advised, and prompt discontinuation of the drug is suggested when signs or symptoms of liver disease develop. (<i>JAMA</i>. 1990;264:2660-2662)
Tumor Recurrence and Survival in Patients Treated for Thymomas and Thymic Squamous Cell Carcinomas: A Retrospective Analysis
Authors: Philipp Ströbel, Andrea Bauer, Bernhard Puppe, Til Kraushaar, Axel Krein, Klaus Toyka, Ralf Gold, Michael Semik, Reinhard Kiefer, Wilfred Nix, Berthold Schalke, Hans Konrad Müller-Hermelink, Alexander Marx
Journal: Journal of Clinical Oncology (2004)

Thymic epithelial tumors (TET) are rare epithelial neoplasms of the thymus with considerable histologic heterogeneity. This retrospective study focused on the correlation of WHO-defined TET histotypes with survival and tumor recurrence in a large cohort of patients receiving different modes of treatment.Two hundred twenty-eight patients were followed for up to 21 years (median, 60 months; range, 1 to 252 months) after primary surgery. Forty-two patients received adjuvant radiotherapy (mean dose, 53 Gy), and 33 patients received adjuvant chemotherapy.Seventy-six (88%) of 86 patients with WHO type A, AB, and B1 thymomas were treated by surgery alone, with three tumor relapses after 3 to 10 years (median, 3.4 years). Twelve of 67 patients with WHO type B2 and B3 thymomas in Masaoka stages I and II were treated by adjuvant radiotherapy without evidence of tumor recurrence after 1 to 12 years (median, 4 years). Among 75 patients with B2 and B3 thymomas with incomplete resection or a tumor stage III or higher, the recurrence rate was 34% (n = 23) after 0.5 to 17 years (median, 5 years) in patients receiving adjuvant radiochemotherapy, compared to 78% (seven of nine patients) in patients without adjuvant radiochemotherapy. Incomplete tumor resection was associated with a high recurrence rate (65%) and a poor prognosis (P <.01).The long-term outcome of TET patients is related to tumor stage, WHO histotype, completeness of surgical removal, and type of treatment. Prospective trials are warranted to formally address the efficacy of adjuvant therapy in the treatment of localized and advanced malignant TETs.
Widespread Losses of Vomeronasal Signal Transduction in Bats
Authors: Huabin Zhao, Dong Xu, Shuyi Zhang, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2010)

The vertebrate vomeronasal system (VNS) detects intraspecific pheromones and environmental odorants. We sequenced segments of the gene encoding Trpc2, an ion channel crucial for vomeronasal signal transduction, in 11 species that represent all main basal lineages of Yinpterochiroptera, one of the two suborders of the order Chiroptera (bats). Our sequences show that Trpc2 is a pseudogene in each of the 11 bats, suggesting that all yinpterochiropterans lack vomeronasal sensitivity. The Trpc2 sequences from four species of Yangochiroptera, the other suborder of bats, suggest vomeronasal insensitivity in some but not all yangochiropterans. These results, together with the available morphological data from the bat VNS, strongly suggest multiple and widespread losses of vomeronasal signal transduction and sensitivity in bats. Future scrutiny of the specific functions of the VNS in the few bats that still retain the VNS may help explain why it is dispensable in most bats.
SERS‐Fluorescence Joint Spectral Encoded Magnetic Nanoprobes for Multiplex Cancer Cell Separation
Authors: Zhuyuan Wang, Shenfei Zong, Hui Chen, Chunlei Wang, Shuhong Xu, Yiping Cui
Journal: Advanced Healthcare Materials (2014)

A new kind of cancer cell separation method is demonstrated, using surface‐enhanced Raman scattering (SERS) and fluorescence dual‐encoded magnetic nanoprobes. The designed nanoprobes can realize SERS‐fluorescence joint spectral encoding (SFJSE) and greatly improve the multiplexing ability. The nanoprobes have four main components, that is, the magnetic core, SERS generator, fluorescent agent, and targeting antibody. These components are assembled with a multi‐layered structure to form the nanoprobes. Specifically, silica‐coated magnetic nanobeads (MBs) are used as the inner core. Au core‐Ag shell nanorods (Au@Ag NRs) are employed as the SERS generators and attached on the silica‐coated MBs. After burying these Au@Ag NRs with another silica layer, CdTe quantum dots (QDs), that is, the fluorescent agent, are anchored onto the silica layer. Finally, antibodies are covalently linked to CdTe QDs. SFJSE is fulfilled by using different Raman molecules and QDs with different emission wavelengths. By utilizing four human cancer cell lines and one normal cell line as the model cells, the nanoprobes can specifically and simultaneously separate target cancer cells from the normal ones. This SFJSE‐based method greatly facilitates the multiplex, rapid, and accurate cancer cell separation, and has a prosperous potential in high‐throughput analysis and cancer diagnosis.
Neuropilin-1 Expression on Regulatory T Cells Enhances Their Interactions with Dendritic Cells during Antigen Recognition
Authors: Milka Sarris, Kristian G. Andersen, Felix Randow, Luzia Mayr, Alexander G. Betz
Journal: Immunity (2008)

SummaryThe interaction of T cells with dendritic cells (DCs) determines whether an immune response is launched or not. Recognition of antigen leads to formation of immunological synapses at the interface between the cells. The length of interaction is likely to determine the functional outcome, because it limits the number of MHC class II-peptide complexes that can be recruited into the synapse. Here, we show that regulatory T (Treg) cells and naive helper T (Th) cells interact differently with DCs in the absence of proinflammatory stimuli. Although differences in T cell receptor repertoire might contribute, Foxp3-induced phenotypic differences play a major role. We found that Neuropilin-1 (Nrp-1), which is expressed by most Treg cells but not naive Th cells, promoted prolonged interactions with immature DCs (iDCs), resulting in higher sensitivity to limiting amounts of antigen. This is likely to give Treg cells an advantage over naive Th cells, with the same specificity leading to a "default" suppression of immune responses in the absence of "danger signals."
Inhibition of MicroRNA-92a Prevents Endothelial Dysfunction and Atherosclerosis in Mice
Authors: Xavier Loyer, Stéphane Potteaux, Anne-Clémence Vion, Coralie L. Guérin, Sheerazed Boulkroun, Pierre-Emmanuel Rautou, Bhama Ramkhelawon, Bruno Esposito, Marion Dalloz, Jean-Louis Paul, Pierre Julia, Jean Maccario, Chantal M. Boulanger, Ziad Mallat, Alain Tedgui
Journal: Circulation Research (2013)

Rationale for Study: MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein expression at post-transcriptional level. We hypothesized that a specific pool of endothelial miRNAs could be selectively regulated by flow conditions and inflammatory signals, and as such be involved in the development of atherosclerosis. Objective: To identify miRNAs, called atheromiRs, which are selectively regulated by shear stress and oxidized low-density lipoproteins (oxLDL), and to determine their role in atherogenesis. Methods and Results: Large-scale miRNA profiling in HUVECs identified miR-92a as an atheromiR candidate, whose expression is preferentially upregulated by the combination of low shear stress (SS) and atherogenic oxLDL. Ex vivo analysis of atheroprone and atheroprotected areas of mouse arteries and human atherosclerotic plaques demonstrated the preferential expression of miR-92a in atheroprone low SS regions. In Ldlr −/− mice, miR-92a expression was markedly enhanced by hypercholesterolemia, in particular in atheroprone areas of the aorta. Assessment of endothelial inflammation in gain- and loss-of-function experiments targeting miR-92a expression revealed that miR-92a regulated endothelial cell activation by oxLDL, more specifically under low SS conditions, which was associated with modulation of Kruppel-like factor 2 (KLF2), Kruppel-like factor 4 (KLF4), and suppressor of cytokine signaling 5. miR-92a expression was regulated by signal transducer and activator of transcription 3 in SS- and oxLDL-dependent manner. Furthermore, specific in vivo blockade of miR-92a expression in Ldlr −/− mice reduced endothelial inflammation and altered the development of atherosclerosis, decreasing plaque size and promoting a more stable lesion phenotype. Conclusions: Upregulation of miR-92a by oxLDL in atheroprone areas promotes endothelial activation and the development of atherosclerotic lesions. Therefore, miR-92a antagomir seems as a new atheroprotective therapeutic strategy.
Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania
Authors: Michael H. Allen, Robert M. Hirschfeld, Patricia J. Wozniak, Jeffrey D. Baker, Ph.D., Charles L. Bowden
Journal: American Journal of Psychiatry (2006)

Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania.Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (< =55.0 microg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling.The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 microg/ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 microg/ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 microg/ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 microg/ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups.The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 microg/ml.