tbuckley/cabot-search huggingface dataset:
Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt
Authors: Yasushi Mukai, Yoshiyuki Rikitake, Ichiro Shiojima, Sebastian Wolfrum, Minoru Satoh, Kyosuke Takeshita, Yukio Hiroi, Salvatore Salomone, Hyung Hwan Kim, Laura E. Benjamin, Kenneth Walsh, James K. Liao
Journal: Journal of Clinical Investigation (2006)

To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with N-nitro-L-arginine methyl ester (L-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with L-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.
The Role of Polypeptide Growth Factors in Human Carcinomas: New Targets for a Novel Pharmacological Approach
Authors: Roberto E. Favoni, Alessandra de Cupis
Journal: Pharmacological Reviews (2000)

The processes of cellular proliferation and progressive acquisition of a specialized phenotype show a high degree of coordination. In particular, these complex signaling networks mediating cell growth, differentiation, migration, and apoptosis are regulated in part by polypeptide growth factors that can act, by autocrine and/or paracrine mechanisms of action, as positive or negative modulators. Because these growth factors are unable to cross the hydrophobic cell membrane, they exert their effects via binding to cell surface receptors, most of which possess intrinsic tyrosine kinase activity. Owing to the interaction of polypeptide growth factors with their specific transmembrane receptors, a cascade of intracellular biochemical signals, resulting in the activation and repression of various subsets of genes, is triggered. One of the major incentives for studying factors that regulate processes of proliferation and differentiation is the recognition of their involvement in tumorigenesis. Genetic aberrations in growth factors signaling pathways are, in fact, inextricably linked to cancer. Malignant cells arise as a result of a stepwise progression of genetic events characterized by the unregulated expression of growth factors or components of their signaling networks. The main aim of this review is to examine the current understanding of the crucial contribution that several growth factors may have on transformation, tumorigenesis, and progression in several human tumors among the most widespread in western countries. For this purpose, we will analyze the chemistry and the molecular organization of the most important growth factors and their specific receptors. In addition, we will focus on the mechanisms of signal transduction, the complex cascade of biochemical events ensued from the growth factor/receptor binding. The present knowledge of the role of growth factor biochemical signaling networks in cancer leads to improvements not only in diagnosis and prognosis for this disease, but also for new and more targeted therapeutic intervention. The second part of this review will focus on the novel pharmacological approaches for cancer therapy that have been developed already or are being developed with the aim to specifically interfere at various steps of the growth factors signaling pathways.
Features of HIV-1 That Could Influence Maternal-Child Transmission
Authors: Srisakul C. Kliks, Diane W. Wara, Daniel V. Landers, Jay A. Levy
Journal: JAMA (1994)

To evaluate the biological and serological properties of the human immunodeficiency virus type 1 (HIV-1) for factors potentially involved in the mother-to-child transmission of HIV-1.Isolates of HIV-1 were recovered from the blood of 12 of 44 nontransmitting mothers and six of eight transmitting mothers and their corresponding infants. These 24 HIV-1 isolates were compared for their biological and immunologic properties to discern any parameters that correlate with vertical transmission of HIV-1.Replication capabilities of the above-mentioned HIV-1 isolates in human peripheral blood mononuclear cells (PBMCs), human macrophages, and various T-cell lines and the susceptibilities of the viruses to neutralization or enhancement by anti-HIV-1 antibodies in autologous serum samples from mothers and infants.San Francisco Bay Area, California.A cohort of 52 HIV-1-infected women and their infants in a prospective study on perinatal HIV transmission by the Bay Area Perinatal AIDS Center.The viral isolates from the transmitting mothers and their infants differed from the isolates from the nontransmitting mothers in their efficient replication in human PBMCs and in their ability to infect one or more human T-lymphocytic cell lines. All the HIV-1 isolates were able to infect human macrophages with only low-level replication and were unable to form syncytia in the MT-2-lymphocytic cells. No correlation between transmission and reactivity of maternal serum samples to the peptide corresponding to the principal neutralization domain of the third hypervariable region of the viral envelope was observed. However, the majority (9/12) of maternal isolates from the nontransmitters were neutralized by their autologous serum samples compared with only two among six in the transmitter group (P < .07). Moreover, five infant isolates were resistant to neutralization by their respective mother's serum samples, and one was sensitive to infection enhancement by the mother's serum. Another infant isolate was enhanced by his autologous serum.Viral factors that appeared to correlate with mother-to-child transmission of HIV-1 observed in a small cohort included rapid or high-titered replication in human PBMCs, T-cell line tropism, and resistance to neutralization or a sensitivity to enhancement of infection by the maternal serum.
Points from Letters: Onycholysis and Detergents
Authors: J. McL. Philp
Journal: BMJ (1971)

585 leads to considerable loss of efficiency and difficulties both in administration and medical care.It is one of the best health services that I have seen abroad, but does not come near to matching our own service.It is quite true that IsraAi medical students are not educated in general practice, but I cannot agree with Dr. Smith that this is "through no fault of the authors of the book."Dr. K. J. Mann is the D`rector-General of thv Hadassah (not Hadassar) University Hospital and could un- doubtedly have influenced the Medical School to permit students to attend the communal health centre.Perhaps the reason why the medical school authorities were unwilling to do so is because it is a well-known fact in Israel that the standard of medicine in health centres is very poor compared with the hospitals, largely owing to the obstinate refusal of the politicians to allow the various health insurance schemes to be nationalized.I do not believe that socialized medicine can work without nationalization.-Iam, etc.,
Severe chronic active hepatitis (autoimmune type) mimicked by coinfection of hepatitis C and human immunodeficiency viruses.
Authors: L Berk, S W Schalm, R A Heijtink
Journal: Gut (1991)

Severe chronic active hepatitis, defined as the presence of a fivefold increase in serum aminotransferases and a twofold rise in gamma globulin for at least 10 weeks, is considered a progressive immunological liver disease requiring corticosteroid treatment, particularly when serum autoantibodies and a severe lymphoplasmacellular periportal infiltrate are found in the liver biopsy specimen. A 38 year old man who fulfilled the criteria for severe chronic active hepatitis is described. His sex, his homosexuality, and the presence of antibodies against HIV, however, led to the suspicion of a coinfection with hepatitis C virus (HCV) rather than autoimmune disease. The rapid and complete response to alpha interferon treatment and a recently available positive antibody test for HCV supported this view. These findings indicate that a HCV related chronic active hepatitis can present as the severe autoimmune type of chronic active hepatitis. Moreover, as in HBV infection, the response to treatment differs from that of autoimmune severe chronic active hepatitis.
The Reliability of Clinical Diagnoses: State of the Art
Authors: Helena Chmura Kraemer
Journal: Annual Review of Clinical Psychology (2014)

Reliability of clinical diagnosis is essential for good clinical decision making as well as productive clinical research. The current review emphasizes the distinction between a disorder and a diagnosis and between validity and reliability of diagnoses, and the relationships that exist between them. What is crucial is that reliable diagnoses are essential to establishing valid diagnoses. The present review discusses the theoretical background underlying the evaluation of diagnoses, possible designs of reliability studies, estimation of the reliability coefficient, the standards for assessment of reliability, and strategies for improving reliability without compromising validity.
Reproductive history, hormonal factors and the incidence of hip and knee replacement for osteoarthritis in middle-aged women
Authors: B Liu, A Balkwill, C Cooper, A Roddam, A Brown, V Beral
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objectives:</h3> To examine the effect of reproductive history and use of hormonal therapies on the risk of hip and knee joint replacement for osteoarthritis. <h3>Methods:</h3> A prospective study of 1.3 million women aged on average 56 years at recruitment and followed-up through linkage to routinely collected hospital admission records was conducted. The adjusted relative risk (RR) of hip and knee replacement for osteoarthritis was examined in relation to parity, age at menarche, menopausal status, age at menopause and use of hormonal therapies. <h3>Results:</h3> Over a mean of 6.1 person-years of follow-up, 12 124 women had a hip replacement and 9977 a knee replacement. The risk of joint replacement increased with increasing parity and the effect was greater for the knee than the hip: increase in RR of 2% (95% CI 1 to 4%) per birth for hip replacement and 8% (95% CI 6 to 10%) for knee replacement. An early age at menarche slightly increased the risk of hip and knee replacement (relative risk for menarche ⩽11 years versus 12 years, 1.09 (95% CI 1.03 to 1.16) and 1.15 (95% CI 1.08 to 1.22), respectively). Menopausal status and age at menopause were not clearly associated with risk. Current use of postmenopausal hormone therapy was associated with a significant increase in the incidence of hip and knee replacement (RR 1.38 (95% CI 1.30 to 1.46) and RR 1.58 (95% CI 1.48 to 1.69), respectively) while previous use of oral contraceptives was not (RR 1.02 (95% CI 0.98 to 1.06) and RR 1.00 (95% CI 0.96 to 1.04) for hip and knee, respectively). <h3>Conclusions:</h3> Hormonal and reproductive factors affect the risk of hip and knee replacement, more so for the knee than the hip. The reasons for this are unclear.
"No Connexion Whatsoever"?
Authors: H. B. Wright
Journal: BMJ (1959)

BRffI=s 1183 records) usually gave a negative Wassermann reaction in the blood but a positive reaction in the cerebrospinal fluid.In view of this consistent finding it is, of course, possible that some cases were referred to an institution for mental defectives rather than to a special V.D. children's unit, since they showed few, if any, other signs of congenital syphilis.Nevertheless, I would wish to support the findings of Drs.
DISQUISITIONS ON ORIGINAL ANTIGENIC SIN
Authors: S. Fazekas de St.Groth, R. G. Webster
Journal: The Journal of Experimental Medicine (1966)

When primary immunity is boosted not by the homologous but by a crossreacting vaccine, the newly formed antibodies react better with the primary antigen than with the antigen actually eliciting the response. This phenomenon bears the name of Original Antigenic Sin (1). It is shown that the number of antibody molecules produced against the original and the vaccinating antigen is the same; that each of these molecules is capable of reacting with both antigens; that the activity of an antiserum can be completely absorbed with either antigen; that both residual and adsorbed-dissociated fractions of antibody exhibit the same relative affinities towards the two antigens as did the native serum; that, unlike standard primary and secondary responses, the population of antibody molecules characterizing the Original Antigenic Sin is homogeneous; that each molecule has a lower equilibrium constant (i.e. higher avidity) against the original antigen than against the antigen stimulating the present response; and that all equilibrium constants are typical of secondary antibody. It is concluded that the Original Antigenic Sin is a partial anamnestic response, a related antigen stimulating that sector only of the originally primed cells which is destined to produce cross-reacting antibody. A hypothesis is developed according to which the basic difference between primary and secondary reactivity rests on the presence of a trapping mechanism that allows anamnestic production of antibody against lower doses of the homologous antigen. Such a mechanism is capable of cross-trapping related antigens, thus preventing a standard primary response and allowing manifestations of Original Antigenic Sin.
Role of a BCL9-Related β-Catenin-Binding Protein, B9L, in Tumorigenesis Induced by Aberrant Activation of Wnt Signaling
Authors: Shungo Adachi, Takafumi Jigami, Toshio Yasui, Tetsuhiro Nakano, Susumu Ohwada, Yoshihiro Omori, Sumio Sugano, Bisei Ohkawara, Hiroshi Shibuya, Tsutomu Nakamura, Tetsu Akiyama
Journal: Cancer Research (2004)

Abstract Wnt signaling plays a crucial role in a number of developmental processes and in tumorigenesis. β-Catenin is stabilized by Wnt signaling and associates with the TCF/LEF family of transcription factors, thereby activating transcription of Wnt target genes. Constitutive activation of β-catenin-TCF–mediated transcription resulting from mutations in adenomatous polyposis coli (APC), β-catenin, or Axin is believed to be a critical step in tumorigenesis among divergent types of cancers. Here we show that the transactivation potential of the β-catenin-TCF complex is enhanced by its interaction with a BCL9-like protein, B9L, in addition to BCL9. We found that B9L is required for enhanced β-catenin-TCF–mediated transcription in colorectal tumor cells and for β-catenin–induced transformation of RK3E cells. Furthermore, expression of B9L was aberrantly elevated in about 43% of colorectal tumors, relative to the corresponding noncancerous tissues. These results suggest that B9L plays an important role in tumorigenesis induced by aberrant activation of Wnt signaling.
Cetuximab-Based Immunotherapy and Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma
Authors: Gang Niu, Xilin Sun, Qizhen Cao, Donald Courter, Albert Koong, Quynh-Thu Le, Sanjiv Sam Gambhir, Xiaoyuan Chen
Journal: Clinical Cancer Research (2010)

To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.
Biomarker analysis in a phase III study of pemetrexed–carboplatin versus etoposide–carboplatin in chemonaive patients with extensive-stage small-cell lung cancer
Authors: E.F. Smit, M.A. Socinski, B.P. Mullaney, S.P. Myrand, G.V. Scagliotti, P. Lorigan, M. Reck, T. Ciuleanu, J. von Pawel, N.A. Karaseva, A. Szczesna, D. Ohannesian, E. Powell, R.R. Hozak, S. Hong, S.C. Guba, N. Thatcher
Journal: Annals of Oncology (2011)
Government must win over doctors to changes to NHS
Authors: Adrian O'Dowd
Journal: BMJ (2007)

Cyclo-oxygenase-2 (COX 2) inhibitors should be used only as the last choice after other types of non-steroidal anti-inflammatory drugs (NSAIDs) to relieve chronic pain in people with heart disease or at high risk of it, the American Heart Association has recommended.Its statement, published online in Circulation on 26 February (http://circ.ahajournals.orgdoi:10.1161/circulationaha.106.181424), was designed to end any remaining confusion about the cardiovascular risk of these agents.The association has recommended a stepped approach to treatment.The first step should be non-pharmacological approaches, such as physical therapy and weight loss, for patients with known cardiovascular disease or with risk factors for ischaemic heart disease.Drug treatment should start with agents with the lowest reported risk of cardiovascular events, before other agents are prescribed, and at each step account should be taken of the risk-benefit balance.First line drug choices include paracetamol (acetaminophen), aspirin, tramadol, and short term use of other narcotic analgesics.If these fail to achieve adequate pain control, the next option is non-acetylated salicylates, such as naproxen.The association recommended NSAIDs that aren't COX 2 inhibitors if pain is still inadequately controlled, then NSAIDs with some COX 2 activity as the next step, and lastly COX 2 selective NSAIDs.The committee considered the risk of all three of these classes to be sufficiently high to require that patients taking them should be monitored regularly for sustained hypertension (or worsening of prior blood pressure control), oedema, worsening renal function, or gastrointestinal bleeding.See pp 436, 450. Save COX 2 inhibitors till last for cardiac patientsUK NEWS HFEA allows women to donate eggs for research, p445 World NEWS repeal law that puts "FdA on the payroll of the industry", p447 bmj.comUK government defeated on community treatment forms
Hyperphosphorylation of the Cardiac Ryanodine Receptor at Serine 2808 Is Not Involved in Cardiac Dysfunction After Myocardial Infarction
Authors: Hongyu Zhang, Catherine A. Makarewich, Hajime Kubo, Wei Wang, Jason M. Duran, Ying Li, Remus M. Berretta, Walter J. Koch, Xiongwen Chen, Erhe Gao, Héctor H. Valdivia, Steven R. Houser
Journal: Circulation Research (2012)

Abnormal behavior of the cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and heart failure (HF) after myocardial infarction (MI). It has been proposed that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a single residue, Ser-2808, is a critical mediator of RyR dysfunction, depressed cardiac performance, and HF after MI.We used a mouse model (RyRS2808A) in which PKA hyperphosphorylation of the RyR2 at Ser-2808 is prevented to determine whether loss of PKA phosphorylation at this site averts post MI cardiac pump dysfunction.MI was induced in wild-type (WT) and S2808A mice. Myocyte and cardiac function were compared in WT and S2808A animals before and after MI. The effects of the PKA activator Isoproterenol (Iso) on L-type Ca(2+) current (I(CaL)), contractions, and [Ca(2+)](I) transients were also measured. Both WT and S2808A mice had depressed pump function after MI, and there were no differences between groups. MI size was also identical in both groups. L type Ca(2+) current, contractions, Ca(2+) transients, and SR Ca(2+) load were also not significantly different in WT versus S2808A myocytes either before or after MI. Iso effects on Ca(2+) current, contraction, Ca(2+) transients, and SR Ca(2+) load were identical in WT and S2808A myocytes before and after MI at both low and high concentrations.These results strongly support the idea that PKA phosphorylation of RyR-S2808 is irrelevant to the development of cardiac dysfunction after MI, at least in the mice used in this study.
Management of Helicobacter pylori infection in children
Authors: G Oderda
Journal: Gut (1998)

When trying to decide which children withHelicobacter pylori infection should be treated and at what stage they should be tested, we should take into account the fact that eradication of the infection may be useful both to induce symptom remission and to prevent later complications in adulthood.However, well designed studies to identify those infected children who are at risk of developing complications or have symptoms due to the infection are still lacking.Current literature only gives information on how to treat children with H pylori infection.Treatment regimens that include two drugs are usually more eVective than in adults, and produce an eradication rate of 70-80%, but they should be given for at least two weeks, shorter treatments being less eVective.Antibiotic resistance can impair eradication rate and the frequency of resistant strains in children should be studied.Combinations of antibiotics with antisecretory drugs are highly eVective in adults, but triple therapy with two antibiotics and an antisecretory drug has been seldom tried in children; compliance is often poor so that the eradication rate is often similar to that produced by dual therapy.Compliance strongly influences eradication, and short simple treatment regimens that produce rapid symptom remission with few side eVects are needed to optimise patient compliance.After treatment, eradication must be proved.Serological tests can help, provided that pretreatment serum is available and three to six months have passed since the treatment.A 13 C-ureabreath test ( 13 C-UBT) should be performed at least six weeks after treatment, but false negative results can occur and cut-oV must be adjusted.