tbuckley/cabot-search huggingface dataset:
Indomethacin enhances endothelial NO release — evidence for a role of PGI2 in the autocrine control of calcium-dependent autacoid production
Authors: Steffen-Sebastian Bolz, Ulrich Pohl
Journal: Cardiovascular Research (1997)

Objective: We studied whether NO or prostacyclin (PGI2), which are continuously released by endothelial cells, have autocrine/paracrine effects on the calcium-dependent autacoid production by modulating the intracellular Ca2+ concentration ([Ca2+]i). Methods: Histamine(His)-induced [Ca2+]i increases (Fura 2-method) and NO-dependent cGMP increase were measured in human umbilical vein endothelial cells (HUVECs) before and after cyclooxygenase inhibition or application of cAMP- and cGMP-elevating drugs. Results: 0.3 μM His increased endothelial [Ca2+]i from 77±2 nM to 418±59 nM. The His-induced [Ca2+]i increases were significantly attenuated following treatment with PGI2 (by 23%) and forskolin (by 33%), both increasing the cAMP release from HUVECs (by 49% and 66%). The His-induced [Ca2+]i increases were inhibited by the protein kinase A-activator cBIMPS (by 61%) which also abolished the His-induced PGI2 release. Conversely, inhibition of the PGI2 production with indomethacin significantly augmented the His-induced [Ca2+]i increases (by 32%), resulting in a significantly augmented NO production as indicated by an enhanced LNNA-sensitive cGMP increase in HUVECs. In contrast, neither increases of cGMP (basal 0.4±0.1 pmol/mg) elicited by 10 μM SNP (21±2 pmol/mg) or 10 μM C-type natriuretic peptide (CNP, 4.6±1.6 pmol/mg) nor its reduction by 30 μM LNNA had any effect on the His-induced [Ca2+]i increases. Conclusion: PGI2 attenuates agonist-induced [Ca2+]i increases by a cAMP-dependent mechanism, thereby modulating not only its own synthesis via a negative feedback but also that of NO. Consequently, reduced PGI2 levels result in an increased NO production. NO which does not cause a negative feedback control by cGMP might therefore compensate for the lack of PGI2.
Capitalizing on diversity: an integrative approach towards the multiplicity of cellular mechanisms underlying myogenic responsiveness
Authors: Darcy Lidington, Rudolf Schubert, Steffen-Sebastian Bolz
Journal: Cardiovascular Research (2012)

The intrinsic ability of resistance arteries to respond to transmural pressure is the single most important determinant of their function. Despite an ever-growing catalogue of signalling pathways that underlie the myogenic response, it remains an enigmatic mechanism. The myogenic response's mechanistic diversity has largely been attributed to 'hard-wired' differences across species and vascular beds; however, emerging evidence suggests that the mechanistic basis for the myogenic mechanism is, in fact, 'plastic'. This means that the myogenic response can change quantitatively (i.e. change in magnitude) and qualitatively (i.e. change in mechanistic basis) in response to environmental challenges (e.g. disease conditions). Consequently, understanding the dynamics of how the myogenic response capitalizes on its mechanistic diversity is key to unlocking clinically viable interventions. Using myogenic sphingosine-1-phosphate (S1P) signalling as an example, this review illustrates the remarkable plasticity of the myogenic response. We propose that currently unidentified 'organizational programmes' dictate the contribution of individual signalling pathways to the myogenic response and introduce the concept that certain signalling elements act as 'divergence points' (i.e. as the potential higher level regulatory sites). In the context of pressure-induced S1P signalling, the S1P-generating enzyme sphingosine kinase 1 serves as a divergence point, by orchestrating the calcium-dependent and -independent signalling pathways underlying microvascular myogenic responsiveness. By acting on divergence points, the proposed 'organizational programmes' could form the basis for the flexible recruitment and fine-tuning of separate signalling streams that underlie adaptive changes to the myogenic response and its distinctiveness across species and vascular beds.
Prostate-Specific Antigen Kinetics as a Measure of the Biologic Effect of Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Serologic Progression of Prostate Cancer
Authors: Brian I. Rini, Vivian Weinberg, Robert Bok, Eric J. Small
Journal: Journal of Clinical Oncology (2002)

Purpose: To determine the biologic effect of granulocyte-macrophage colony-stimulating factor (sangramostim, GM-CSF; Immunex Corporation, Seattle, WA) as measured by prostate-specific antigen (PSA) kinetics in patients with serologic progression of prostate cancer after definitive local therapy. Patients and Methods: Patients with prostate cancer who had undergone previous definitive surgical or radiation therapy with nonmetastatic, recurrent disease as manifested by a rising PSA between 0.4 ng/mL and 6.0 ng/mL were enrolled on this phase II trial. Patients received 250 μg/m 2 /day of subcutaneous GM-CSF on days 1 through 14 of a 28-day cycle. PSA was measured at day 1 of each cycle. Results: Thirty patients with serologic progression of prostate cancer were treated. The median pretreatment PSA was 2.9 ng/mL. Of the 29 evaluable patients, three patients (10%; 95% confidence interval, 2% to 27%) achieved a 50% reduction in PSA. For the patients (n = 26) in whom the on-treatment PSA doubling time could be calculated, the median PSA doubling time increased from 8.4 months to 15 months (P = .001), and the median slope of the PSA versus time curve decreased with treatment (P = .004). Therapy was well tolerated by all patients, with an average treatment duration of 16.5 cycles (range, 5 to 33). Conclusion: GM-CSF has a biologic effect in patients with serologic progression of prostate cancer after definitive local therapy, as measured by PSA declines and modulation of PSA kinetics.
1144-104 The novel organic nitroxyl donor, isopropylamine/nitric oxide exerts beta-independent positive inotropy/lusitropy in failing hearts
Authors: Tatsuo Katori, Carlo G Tocchetti, Katrina M Miranda, Hunter C Champion, Jon M Fukuto, David A Wink, David A Kass, Nazareno Paolocci
Journal: Journal of the American College of Cardiology (2004)
Immunogenetic Studies of Chronic Lymphocytic Leukemia: Revelations and Speculations about Ontogeny and Clinical Evolution
Authors: Anna Vardi, Andreas Agathangelidis, Lesley-Ann Sutton, Paolo Ghia, Richard Rosenquist, Kostas Stamatopoulos
Journal: Cancer Research (2014)

Abstract Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IG) has proved instrumental in dissecting chronic lymphocytic leukemia (CLL) pathogenesis. Initially, it was the finding that the level of somatic hypermutations in rearranged IG heavy-chain genes could define two CLL subtypes associated with a different clinical course that drew attention. As the years ensued, this not only continued to hold strong, but also revealed an unprecedented BcR restriction (aptly coined as “stereotypy”), thus cementing the idea that antigenic elements select the leukemic clones. With all this in mind, in the present review, we focus on the CLL BcR IG, a molecule that clearly lies at the heart of disease pathogenesis, and attempt to distil from past and emerging biologic knowledge the most relevant aspects in the context of the immunogenetics of CLL, while at the same time provoking questions that remain unanswered. We juxtapose CLL with mutated BcR IGs against CLL with unmutated BcR IGs due to their striking clinicobiologic differences; however, when considering ontogeny, common derivation of the two mutational subtypes cannot be excluded. The issue of stereotypy is intertwined throughout and we also raise the subject of isotype-switched CLL, which, despite its rarity, contributes intriguing ontogenetic hints. Cancer Res; 74(16); 4211–6. ©2014 AACR.
Hysterectomy and Sexual Functioning
Authors: Julia C. Rhodes, Kristen H. Kjerulff, Patricia W. Langenberg
Journal: JAMA (1999)

ContextWomen considering hysterectomy often are concerned about its potential effects on their sexual functioning but the effects of hysterectomy on sexual functioning remain unclear.ObjectiveTo examine changes in sexual functioning after hysterectomy.Design and SettingA 2-year prospective study (Maryland Women's Health Study) of hysterectomy, which included measures of sexual functioning prior to hysterectomy and at 6, 12, 18, and 24 months after hysterectomy, performed during 1992 and 1993.PatientsOf 1299 women interviewed prior to hysterectomy, 1101 (84.8%) completed the study and provided information about their sexual functioning. Most were between the ages of 35 and 49 years, white, married or living with a partner, and high school graduates.Main Outcome MeasuresFrequency of sexual relations, dyspareunia, orgasm, vaginal dryness, and sexual desire.ResultsThe percentage of women who engaged in sexual relations increased significantly from 70.5% before hysterectomy to 77.6% and 76.7% at 12 and 24 months after hysterectomy. The rate of frequent dyspareunia dropped significantly from 18.6% before hysterectomy to 4.3% and 3.6% at 12 and 24 months after hysterectomy. The rates of not experiencing orgasms dropped significantly from 7.6% before hysterectomy to 5.2% and 4.9% at 12 and 24 months after hysterectomy. Low libido rates also decreased significantly from 10.4% before hysterectomy to 6.3% and 6.2% at 12 and 24 months after hysterectomy. The distribution of women not reporting vaginal dryness in the past month improved significantly from 37.3% before hysterectomy to 46.8% and 46.7% at 12 and 24 months after hysterectomy. Prehysterectomy depression was associated with experiencing dyspareunia, vaginal dryness, low libido, and not experiencing orgasms after hysterectomy.ConclusionsSexual functioning improved overall after hysterectomy. The frequency of sexual activity increased and problems with sexual functioning decreased.
Portable Cholesterol Analyzers-Reply
Authors: Judith R. McNamara
Journal: JAMA (1990)

<h3>In Reply.—</h3> Dr Massé makes a valid correction in the calculation of low-density lipoprotein cholesterol in SI units. In the study, we used conventional units and, for publication, converted all values to SI units. We did not report the correct calculation factor of low-density lipoprotein cholesterol in SI units, which is 2.18. Our results and discussion remain unaltered. Dr Massé's comment concerning the imprecision of the low-density lipoprotein calculation for specimens with triglyceride concentrations exceeding 4.52 mmol/L also is valid. Indeed, in our study we excluded all specimens with triglyceride concentrations equal to or exceeding 4.52 mmol/L, which is below the value generally associated with gross lipemia. We included in our evaluation only specimens within the range that is appropriate for low-density lipoprotein cholesterol calculation, according to the formula of Friedewald et al. Dr Nash's concern that cholesterol "screening programs" are simply for the separation of patients at low risk
Upregulation of Vascular Angiotensin II Receptor Gene Expression by Low-Density Lipoprotein in Vascular Smooth Muscle Cells
Authors: G. Nickenig, A. Sachinidis, F. Michaelsen, M. Bo¨hm, S. Seewald, H. Vetter
Journal: Circulation (1997)

Because LDL and the angiotensin II type 1 (AT1) receptor are thought to be involved in the pathogenesis of chronic vascular disease, we studied possible interactions between these two biological systems in cultured rat vascular smooth muscle cells.Incubation of vascular smooth muscle cells with 100 micrograms/mL LDL profoundly increased AT1 receptor mRNA to approximately 250% of control levels as assessed by Northern hybridization analysis. This effect is maximal 12 hours after addition of LDL to the culture medium and is sustained for up to 24 hours. The LDL-induced upregulation is dose dependent, with a maximal effect obtained with 100 micrograms/mL LDL. There is a correlative increase of cell surface-associated AT1 receptors as assessed by saturation radioligand binding assays. The half-life of AT1 receptor mRNA is increased substantially by LDL compared with that of cells treated only with 5,6-dichlorobenzimidazole to block transcription. Angiotensin II-induced elevation of cytosolic calcium concentration is significantly increased in vascular smooth muscle cells pretreated with LDL to 368 +/- 41 nmol/L compared with control cells pretreated with vehicle (248 +/- 33 nmol/L). Moreover, angiotensin II-induced DNA synthesis is markedly enhanced when cells are coincubated with 100 micrograms/mL LDL.These data reveal a significant upregulation of AT1 receptor gene expression by LDL in vascular smooth muscle cells through mechanisms that involve posttranscriptional mRNA stabilization. Ultimately, this AT1 receptor upregulation leads to an elevated functional response of vascular smooth muscle cells on angiotensin II stimulation.
Acetylcholine Receptor Antibodies in Myasthenia Gravis
Authors: Stanley H. Appel, Richard R. Almon, Nelson Levy
Journal: New England Journal of Medicine (1975)

RECENT studies suggest the involvement of the acetylcholine receptor and the immune system in the pathogenesis of the neuromuscular disorder, myasthenia gravis.1 2 3 4 5 Patrick and Lindstrom1 produced an experimental myasthenic-like syndrome in rabbits by inoculation of acetylcholine receptors purified from electric eel. Using the high affinity cholinergic antagonist, alpha-bungarotoxin, Fambrough et al.2 demonstrated an apparent reduction in the number of available acetylcholine receptors in muscle biopsies from myasthenic patients. Our own laboratory demonstrated the presence in myasthenic patients of a circulating globulin that blocked the binding of 125I-labeled alpha-bungarotoxin to the acetylcholine receptor extracted from denervated rat skeletal muscle.3 The globulin . . .
Treatment of Children With Nonmetastatic Paratesticular Rhabdomyosarcoma: Results of the Malignant Mesenchymal Tumors Studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology
Authors: Richard J. Stewart, Hélène Martelli, Odile Oberlin, Annie Rey, Nathalie Bouvet, Richard D. Spicer, Jan Godzinski, Michael C.G. Stevens
Journal: Journal of Clinical Oncology (2003)

To report the results of the Malignant Mesenchymal Tumors studies (MMT 84 and 89) of the International Society of Pediatric Oncology (SIOP) in males with nonmetastatic paratesticular rhabdomyosarcoma.From 1984 to 1994, 96 males were treated in SIOP protocols. Radical inguinal orchidectomy was recommended, but initial retroperitoneal lymph node dissection was not performed. Disease was staged according to the SIOP tumor-node-metastasis staging system. Treatment was stratified by stage. In the MMT 89 study, males with completely resected tumors at diagnosis received less chemotherapy (vincristine and dactinomycin) than patients in the MMT 84 study (ifosfamide, vincristine, and dactinomycin).Median age at diagnosis was 65 months. Thirty-one tumors were larger than 5 cm, and 13 males were older than 10 years with a tumor larger than 5 cm. At a median follow-up of 7 years, 87 patients were alive; 79 were in first complete remission and eight were in second complete remission. Relapse occurred in 16 patients (17%). At 5 years, the overall survival (OS) rate was 92%, with an event-free survival (EFS) rate of 82%. OS and EFS were significantly worse for males with tumors greater than 5 cm and for males older than 10 years at diagnosis.Males with paratesticular RMS have an excellent prognosis except for a selected group of patients older than 10 years or with tumor greater than 5 cm. Intensified chemotherapy incorporating alkylating agents for this subgroup may be preferred to the use of systematic lymphadenectomy to improve survival while minimizing the burden of therapy.
Ian Duthie Adams
Authors: J. Piggott
Journal: BMJ (2014)

Ian Duthie Adams completed military service as M O Captain in 2nd Battalion, Parachute Regiment, and then joined his father as a GP in Beeston, Leeds, where he stayed for 13 years.

Medical officer to Leeds United Football Club for 13 years, he completed his MD, on osteoarthritis of the knee joint in sportsmen, while working in general practice. The sports medicine clinic …
Unrecognised depression in general practice.
Authors: P Freeling, B M Rao, E S Paykel, L I Sireling, R H Burton
Journal: BMJ (1985)

Patients attending their general practitioner were screened and a group with unrecognised major depressive disorder identified. This group was interviewed and the findings compared with those in a group of patients recognised correctly as depressed by their general practitioners. Half of the patients with severe depression screened in their doctors' waiting rooms went unrecognised, and they differed in few ways from those who were recognised. The differences found were that the patients with unrecognised depression were less obviously depressed and their illness had lasted longer. Physical illness was present in nearly 30% of patients in the unrecognised group, and the depression seemed related to it. Patients with unrecognised depression were more likely to have feelings other than those of normal sadness and more likely to respond with change of mood to intercurrent events. These data suggest that patients might benefit if general practitioners were better trained to recognise depression, although it is not known whether treatment would be effective.
An Investigation of Factors Influencing the General Health of Presumably "Normal" Women.
Authors: L. E. Hinkle
Journal: Annals of Internal Medicine (1961)

s1 May 1961An Investigation of Factors Influencing the General Health of Presumably "Normal" Women.L. E. Hinkle Jr., M.D., F.A.C.P., W. N. Christenson, M.D., B. Benjamin, M.D., (Assoc.), F. D. Kane, M.D., H. G. Wolff, M.D., F.A.C.P.L. E. Hinkle Jr., M.D., F.A.C.P.Search for more papers by this author, W. N. Christenson, M.D.Search for more papers by this author, B. Benjamin, M.D., (Assoc.)Search for more papers by this author, F. D. Kane, M.D.Search for more papers by this author, H. G. Wolff, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-54-5-1065_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo study the factors influencing the health of presumably "normal" people, 24 women, aged 22 to 39, were selected at random from 727 persons engaged in office work in two large rooms of a building in Manhattan and were studied weekly for six months by examinations, interviews, diagnostic tests, cultures, throat washings, serum samples, and photographs of the nose and throat. All recognizable episodes of illness were described and classified. Data on diseases present in the larger group, in the city and in families of participants; data on daily weather; data on general events affecting the whole population; data on... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1961Volume 54, Issue 5Page: 1065-1065KeywordsPharynx ePublished: 1 December 2008 Issue Published: 1 May 1961 PDF downloadLoading ...
Antibodies to Aquaporin 4, Myelin-Oligodendrocyte Glycoprotein, and the Glycine Receptor α1 Subunit in Patients With Isolated Optic Neuritis
Authors: Eugenia Martinez-Hernandez, Maria Sepulveda, Kevin Rostásy, Romana Höftberger, Francesc Graus, Robert J. Harvey, Albert Saiz, Josep Dalmau
Journal: JAMA Neurology (2014)

In patients with isolated optic neuritis (ON), the presence of antibodies to aquaporin 4 (AQP4) has diagnostic and prognostic value. In the same clinical setting, the significance of antibodies to myelin-oligodendrocyte glycoprotein (MOG) or the glycine receptor α1 subunit (GlyR) is unclear.To investigate the frequency of antibodies to AQP4, MOG, and GlyR in patients with unilateral or bilateral, severe, or recurrent isolated ON and to determine their clinical and prognostic correlates.Retrospective case-control study from November 1, 2005, through May 30, 2014 with the detection of autoantibodies in a neuroimmunology referral center. We included 51 patients with ON but without clinical and magnetic resonance imaging findings outside the optic nerves and 142 controls (30 healthy individuals, 48 patients with neuromyelitis optica, and 64 patients with multiple sclerosis).Clinicoimmunologic analysis. We determined the presence of antibodies to AQP4, MOG, and GlyR using cell-based assays.The median age of the patients at the onset of ON symptoms was 28 (range, 5-65) years; 36 patients (71%) were female. Antibodies were identified in 23 patients (45%), including MOG in 10 patients, AQP4 in 6 patients, and GlyR in 7 patients (concurrent with MOG in 3 and concurrent with AQP4 in 1). Patients with AQP4 antibodies (median visual score, 3.5 [range, 1-9]) had a worse visual outcome than patients with MOG antibodies alone (median visual score, 0 [range, 0-5]; P = .007), patients with seronegative findings (n = 28) (median visual score, 1.0 [range, 0-14]; P = .08), and patients with GlyR antibodies alone (n = 3) (median visual score, 0 [range, 0-2]; P = .10).The median age of the 7 patients with GlyR antibodies was 27 (range, 11-38) years; 5 (71%) of these were female. Among the 3 patients with GlyR antibodies alone, 1 patient had monophasic ON, 1 had recurrent isolated ON, and 1 had conversion to multiple sclerosis. The 3 patients with GlyR antibodies concurrent with MOG antibodies had recurrent isolated ON, and the patient with concurrent AQP4 antibodies had conversion to neuromyelitis optica. Of the 48 controls with neuromyelitis optica, 37 (77%) had AQP4 antibodies, 4 (8%) had MOG antibodies, 2 (4%) had AQP4 antibodies concurrent with MOG antibodies, and 5 (10%) were seronegative. Of the 64 controls with multiple sclerosis, 5 (8%) had GlyR antibodies.Forty-five percent of patients with unilateral or bilateral, severe, or recurrent isolated ON had antibodies to MOG, AQP4, or GlyR. Patients with AQP4 antibodies had the poorest visual outcomes, whereas patients with MOG antibodies had a better outcome that was similar to that of patients with seronegative findings. The significance of GlyR antibodies in the setting of ON is unclear and deserves further study.
Intratumoral characteristics of tumor and immune cells at baseline and on-treatment correlated with clinical responses to MPDL3280A, an engineered antibody against PD-L1
Authors: Holbrook Kohrt, Marcin Kowanetz, Scott Gettinger, John Powderly, Hartmut Koeppen, Jeffrey A Sosman, Cristina Cruz, Yuanyuan Xiao, Ahmad Mokatrin, Gregg Fine, Daniel S Chen, F Stephen Hodi
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts PD-L1, PD-L2 and other immune-related molecules regulate Th1 and Th2 immune responses. Tumor-expressed PD-L1, when bound to PD-1 or B7.1 on activated T cells, can mediate cancer immune evasion. While inhibiting PD-L1 receptor binding represents an attractive strategy to restore