tbuckley/cabot-search huggingface dataset:
A mixed methods study to compare models of spirometry delivery in primary care for patients at risk of COPD
Authors: J A Walters, E C Hansen, D P Johns, E L Blizzard, E H Walters, R Wood-Baker
Journal: Thorax (2007)

To increase recognition of airflow obstruction in primary care, we compared two models of spirometry delivery in a target group at risk of chronic obstructive pulmonary disease (COPD).A 6 month qualitative/quantitative cluster randomised study in eight practices compared opportunistic spirometry by "visiting trained nurses" (TN) with optimised "usual care" (UC) from general practitioners (GPs) for smokers and ex-smokers, aged over 35 years. Outcomes were: spirometry uptake and quality, new diagnoses of COPD and GPs' experiences of spirometry.In the eligible target population, 531/904 (59%) patients underwent spirometry in the TN model and 87/1130 (8%) patients in the UC model (p < 0.0001). ATS spirometry standards for acceptability and reproducibility were met by 76% and 44% of tests in the TN and UC models, respectively (p < 0.0001). 125 (24%) patients tested with the TN model and 38 (44%) with the UC model reported a pre-existing respiratory diagnosis (p < 0.0001). Three months after spirometry, when the ratio of forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) was < 0.7 and no prior COPD diagnosis was reported, nine (8%) participants had a new doctor recorded COPD diagnosis in practices with the TN model and two (8%) participants in practices with the UC model. Mislabelling of participants with a diagnosis of COPD when FEV(1)/FVC was > or = 0.7 was present in both models prior to and after spirometry. GPs valued high quality spirometry and increased testing of patients at risk of COPD in the TN model. They identified limitations, including the need for better systematic follow-up of abnormal spirometry and support with interpretation, which may explain persisting underdiagnosis of COPD in practice records.Although opportunistic testing by visiting trained nurses substantially increased and improved spirometry performance compared with usual care, translating increased detection of airflow obstruction into diagnosis of COPD requires further development of the model.Australian Clinical Trials Registry: registration No 12605000019606.
Linear morphoea follows Blaschko’s lines
Authors: L. Weibel, J.I. Harper
Journal: British Journal of Dermatology (2008)

The aetiology of morphoea (or localized scleroderma) remains unknown. It has previously been suggested that lesions of linear morphoea may follow Blaschko's lines and thus reflect an embryological development. However, the distribution of linear morphoea has never been accurately evaluated.We aimed to identify common patterns of clinical presentation in children with linear morphoea and to establish whether linear morphoea follows the lines of Blaschko.A retrospective chart review of 65 children with linear morphoea was performed. According to clinical photographs the skin lesions of these patients were plotted on to standardized head and body charts. With the aid of Adobe Illustrator a final figure was produced including an overlay of all individual lesions which was used for comparison with the published lines of Blaschko.Thirty-four (53%) patients had the en coup de sabre subtype, 27 (41%) presented with linear morphoea on the trunk and/or limbs and four (6%) children had a combination of the two. In 55 (85%) children the skin lesions were confined to one side of the body, showing no preference for either left or right side. On comparing the overlays of all body and head lesions with the original lines of Blaschko there was an excellent correlation.Our data indicate that linear morphoea follows the lines of Blaschko. We hypothesize that in patients with linear morphoea susceptible cells are present in a mosaic state and that exposure to some trigger factor may result in the development of this condition.
SALT AND WATER LOSSES IN DIURETIN DIURESIS AND THEIR RELATION TO SERUM NON-PROTEIN NITROGEN AND ELECTROLYTE CONCENTRATIONS
Authors: Edmond Kerpel-Fronius, Allan M. Butler
Journal: The Journal of Experimental Medicine (1935)

The losses of sodium, potassium, chloride, nitrogen, and water following the administration of diuretin to rabbits over 5 to 9 day periods together with the changes in serum concentrations of sodium, chloride, N. P. N., and total protein occurring simultaneously with these losses are described. The circumstances responsible for the presence of azotemia in the animals were investigated in particular and the dependence of nitrogen retention upon dehydration and the modification of this dependence by variation in urine volume were demonstrated. It was clearly shown that no direct relationship exists between the azotemia and the coincident hypochloremia. It was found that nitrogen retention can be removed by the administration of water without salt, and the extent to which serum electrolyte and protein concentrations can be lowered by this procedure was also observed. The withdrawal from the body of large amounts of potassium as well as of sodium and chloride following the administration of diuretin, and also the inefficacy of sodium chloride solution in preventing the potassium loss was demonstrated.
Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth
Authors: Soraya Zorro Manrique, Maria Adelaida Duque Correa, Dominique B. Hoelzinger, Ana Lucia Dominguez, Noweeda Mirza, Hsi-Hsien Lin, Joan Stein-Streilein, Siamon Gordon, Joseph Lustgarten
Journal: The Journal of Experimental Medicine (2011)

Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b(+)F4/80(+)CD68(+), indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b(+)F4/80(+)Foxp3(+) macrophages using Foxp3-GFP mice. Analysis of CD11b(+)F4/80(+)Foxp3(+) macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3(-) macrophages did not. Suppression of T cell proliferation was mediated through soluble factors. Foxp3(-) macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3(+) macrophages. The cytokine and transcriptional profiles of Foxp3(+) macrophages were distinct from those of Foxp3(-) macrophages, indicating that these cells have different biological functions. Functional in vivo analyses indicated that CD11b(+)F4/80(+)Foxp3(+) macrophages are important in tumor promotion and the induction of T reg cell conversion. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells in which expression of Foxp3 correlates with suppressive function.
Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses
Authors: Bertrand Coiffier, Barbara Pro, H Miles Prince, Francine Foss, Lubomir Sokol, Matthew Greenwood, Dolores Caballero, Franck Morschhauser, Martin Wilhelm, Lauren Pinter-Brown, Swaminathan Padmanabhan Iyer, Andrei Shustov, Tina Nielsen, Jean Nichols, Julie Wolfson, Barbara Balser, Steven Horwitz
Journal: Journal of Hematology & Oncology (2014)

Romidepsin is a structurally unique, potent, bicyclic class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received ≥ 1 prior systemic therapy and patients with peripheral T-cell lymphoma (PTCL) who have received ≥ 1 prior therapy. Approval for PTCL was based on results (n = 130; median follow-up, 13.4 months) from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL. The objective is to present updated data (median follow-up, 22.3 months) and to characterize patients who achieved long-term responses (≥ 12 months) to romidepsin. Patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; patients with response or stable disease could continue romidepsin beyond 6 cycles. The primary endpoint was rate of confirmed/unconfirmed complete response (CR/CRu) determined by an Independent Review Committee. Secondary endpoints included objective response rate (ORR) and duration of response (DOR). For patients who achieved CR/CRu, baseline characteristics by DOR (≥ 12 vs < 12 months) were examined. The ORR to romidepsin was 25%, including 15% with CR/CRu. The median DOR for all responders was 28 months (range, < 1-48+) and was not reached for those who achieved CR/CRu. Patients with lack of response or transient response to prior therapy achieved durable responses with romidepsin. Of the 19 patients who achieved CR/CRu, 10 had long-term (≥ 12 months) responses; none of the baseline characteristics examined—including heavy pretreatment, response to prior therapy, or advanced disease—precluded long-term responses to romidepsin. With a median progression-free survival of 29 months, patients who achieved CR/CRu for ≥ 12 months had significantly longer survival vs those with CR/CRu for < 12 months or < CR/CRu. Extended treatment and longer follow-up did not affect the reported safety profile of romidepsin. Treatment with romidepsin leads to highly durable responses in a subset of patients with relapsed/refractory PTCL, with responses ongoing as long as 48 months. NCT00426764
Pharmacological Activation of Normal and Arrhythmia-Associated Mutant KCNQ1 Potassium Channels
Authors: Guiscard Seebohm, Michael Pusch, Jun Chen, Michael C. Sanguinetti
Journal: Circulation Research (2003)

KCNQ1 alpha-subunits coassemble with KCNE1 beta-subunits to form channels that conduct the slow delayed rectifier K+ current (IKs) important for repolarization of the cardiac action potential. Mutations in KCNQ1 reduce IKs and cause long-QT syndrome, a disorder of ventricular repolarization that predisposes affected individuals to arrhythmia and sudden death. Current therapy for long-QT syndrome is inadequate. R-L3 is a benzodiazepine that activates IKs and has the potential to provide gene-specific therapy. In the present study, we characterize the molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, and determine its effect on several long-QT syndrome-associated mutant KCNQ1 channels heterologously expressed in Xenopus oocytes. Scanning mutagenesis combined with voltage-clamp analysis indicated that R-L3 interacts with specific residues located in the 5th and 6th transmembrane domains of KCNQ1 subunits. Most KCNQ1 mutant channels responded to R-L3 similarly to wild-type channels, but one mutant channel (G306R) was insensitive to R-L3 possibly because it disrupted a key component of the drug-binding site.
John Ruddock Solari
Authors: Edmund Dunstan
Journal: BMJ (2005)

​FormerFormer general practitioner Birmingham (b Blackpool 1937; q Birmingham 1961; BSc), died from bowel cancer on 16 May 2005.




Figure 1




After a short time in obstetrics, John settled into general practice in Kings Norton and Alvechurch, Worcestershire. In addition to his busy practice, he was active in the Birmingham Medical Institute and the local medical committee, was medical director of a deputising service, and served in the St John Ambulance aeromedical evacuation service. For most of his career he also worked in the local geriatric service, and after retirement from general practice continued to do so, principally in palliative care, until his own illness. Outside medicine, he had a passion for railways. He leaves a wife, Jill, and three children.
Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans
Authors: Rajeev Aurora, Maureen J. Donlin, Nathan A. Cannon, John E. Tavis
Journal: Journal of Clinical Investigation (2008)

Hepatitis C virus (HCV) is a common RNA virus that causes hepatitis and liver cancer. Infection is treated with IFN-α and ribavirin, but this expensive and physically demanding therapy fails in half of patients. The genomic sequences of independent HCV isolates differ by approximately 10%, but the effects of this variation on the response to therapy are unknown. To address this question, we analyzed amino acid covariance within the full viral coding region of pretherapy HCV sequences from 94 participants in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) clinical study. Covarying positions were common and linked together into networks that differed by response to therapy. There were 3-fold more hydrophobic amino acid pairs in HCV from nonresponding patients, and these hydrophobic interactions were predicted to contribute to failure of therapy by stabilizing viral protein complexes. Using our analysis to detect patterns within the networks, we could predict the outcome of therapy with greater than 95% coverage and 100% accuracy, raising the possibility of a prognostic test to reduce therapeutic failures. Furthermore, the hub positions in the networks are attractive antiviral targets because of their genetic linkage with many other positions that we predict would suppress evolution of resistant variants. Finally, covariance network analysis could be applicable to any virus with sufficient genetic variation, including most human RNA viruses.
Phase III double-blind comparison of dolasetron mesylate and ondansetron and an evaluation of the additive role of dexamethasone in the prevention of acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy.
Authors: W S Lofters, J L Pater, B Zee, E Dempsey, D Walde, J P Moquin, K Wilson, P Hoskins, R M Guevin, S Verma, R Navari, J E Krook, J Hainsworth, M Palmer, C Chin
Journal: Journal of Clinical Oncology (1997)

PURPOSE To compare the efficacy of dolasetron and ondansetron in controlling nausea and vomiting in the first 24 hours; to evaluate the efficacy when dexamethasone is added to either drug in the first 24 hours; and to extend these comparisons over 7 days in patients receiving moderately emetogenic chemotherapy. PATIENTS AND METHODS This was a multicenter, double-blind, randomized study with six parallel arms that used a 2 x 2 factorial design in chemotherapy-naive patients. In arm 1, dolasetron (2.4 mg/kg) was given intravenously (I.V.) prechemotherapy, followed 24 hours later by oral dolasetron (200 mg once daily) for 6 days. Arms 2 and 3 consisted of dolasetron and dexamethasone 8 mg I.V., followed 24 hours later by oral dexamethasone (8 mg once daily) in one arm, and oral dexamethasone and dolasetron in the other, also for 6 days. In arms 4, 5, and 6, ondansetron (32 mg I.V. or 8 mg orally twice daily) was administered in a similar manner to arms 1, 2, and 3 before and 24 hours after chemotherapy. Mean nausea severity (MNS) was assessed on a visual analog scale (VAS) in a daily diary. RESULTS Of 703 patients enrolled, 696 were eligible. There were 343 dolasetron- and 353 ondansetron-treated patients; 57% of dolasetron-treated patients had complete protection in the first 24 hours versus 67% of patients who received ondansetron (P = .013). MNS was also more pronounced on the dolasetron arm (P = .051). Sixty-seven percent of patients who received added dexamethasone in the first 24 hours had complete protection, compared with 55% without dexamethasone (P &lt; .001). MNS was significantly reduced with the addition of dexamethasone (P &lt; .001). At 7 days, dolasetron and ondansetron had equivalent complete protection rates (36% and 39%, respectively). With the addition of dexamethasone, 48% of patients compared with 28% had complete protection (P &lt; .001). MNS was significantly improved with added dexamethasone (P &lt; .001). CONCLUSION At the doses used, dolasetron was significantly less effective than ondansetron at controlling nausea and vomiting in the first 24 hours in patients receiving moderately emetogenic chemotherapy, but there was no demonstrable difference between both drugs over 7 days. The addition of dexamethasone significantly improved the efficacy of both drugs in the first 24 hours and over 7 days.
Trans-saccadic representation makes your Porsche go places
Authors: Peter De Graef, Karl Verfaillie, Filip Germeys, Veerle Gysen, Caroline Van Eccelpoel
Journal: Behavioral and Brain Sciences (2001)

To eliminate the leap of faith required to explain how visual consciousness arises from visual representation, O'Regan &amp; Noë focus on the sensorimotor interaction with the outside world and ban internal representations from their account of vision. We argue that evidence for transsaccadic representations necessitates a central position for an internal, on-line stimulus rendition in any adequate theory of vision.
REGULATION OF PHOSPHORUS HOMEOSTASIS BY THE TYPE IIA NA/PHOSPHATE COTRANSPORTER
Authors: Harriet S. Tenenhouse
Journal: Annual Review of Nutrition (2005)

▪ Abstract The type IIa Na/phosphate (Pi) cotransporter (Npt2a) is expressed in the brush border membrane (BBM) of renal proximal tubular cells where the bulk of filtered Pi is reabsorbed. Disruption of the Npt2a gene in mice elicits hypophosphatemia, renal Pi wasting, and an 80% decrease in renal BBM Na/Pi cotransport, and led to the demonstration that Npt2a is the target for hormonal and dietary regulation of renal Pi reabsorption. Regulation is achieved by changes in BBM abundance of Npt2a protein and requires the interaction of Npt2a with various scaffolding and regulatory proteins. Molecular studies in patients with renal Pi wasting resulted in the identification of novel regulators of Pi homeostasis: fibroblast growth factor-23 (FGF-23) and a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). In mouse models, increased FGF-23 production or loss of Phex function causes hypophosphatemia and decreased renal Pi reabsorption, secondary to decreased BBM Npt2a protein abundance. Thus, Npt2a plays a major role in the maintenance of Pi homeostasis in both health and disease.
Decreased Cardiac Expression of Vascular Endothelial Growth Factor and Its Receptors in Insulin-Resistant and Diabetic States
Authors: Eva Chou, Izumi Suzuma, Kerrie J. Way, Darren Opland, Allen C. Clermont, Keiko Naruse, Kiyoshi Suzuma, Nancy L. Bowling, Chris J. Vlahos, Lloyd Paul Aiello, George L. King
Journal: Circulation (2002)

Background — Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states. Methods and Results — The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes. Conclusions — The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients.
Expression of transglutaminase activity in developing human epidermis
Authors: M. Akiyama, L.T. Smith, H. Shimizu
Journal: British Journal of Dermatology (2000)

Epidermal transglutaminase (TGase) is known to catalyse cross‐linking of several precursor proteins in the formation of cornified cell envelope at the terminal differentiation of keratinocytes. Expression of TGase activity was studied using an in situ TGase activity assay in human fetal skin samples of 49–163 days estimated gestational age (EGA). In the early two‐layered epidermis (49–56 days EGA), in situ TGase activity was not observed in the periderm cells or the basal cells. In the late two‐layered epidermis (57–65 days EGA), in situ TGase activity became weakly positive in the periderm cells, but not in the basal cells. In the three‐layered (66–95 days EGA) and in four‐ or more layered (96–135 days EGA) stratified epidermis, in situ TGase activity was still restricted only to the periderm cells. After keratinization occurred in the interfollicular epidermis (163 days EGA), in situ TGase activity was expressed in the granular and cornified layers. This unique localization of TGase activity further support the hypothesis that periderm cells form cornified cell envelope during their regression process in human fetal skin development.
THE FATE OF VACCINIA VIRUS ON CULTIVATION IN VITRO WITH KUPFFER CELLS (RETICULO-ENDOTHELIAL CELLS)
Authors: Joseph W. Beard, Peyton Rous
Journal: The Journal of Experimental Medicine (1938)

The pathogenic activity of vaccinia virus is in large part suppressed when it is mixed with living Kupffer cells or clasmatocytes in the test-tube and injected intradermally. Vaccinia increases in quantity when introduced into cultures of Kupffer cells in vitro, and survives in immediate association with these elements. No antiviral principle is elaborated by them under such conditions.
Efficacy of granulocyte/monocyte apheresis for moderate to severe Crohn's disease
Authors: James A Eaden, Alexander Charles Ford
Journal: Gut (2012)

We read the article by Sands et al 1 with interest. The efficacy of granulocyte/monocyte apheresis (GMA) in inflammatory bowel disease (IBD) is controversial, with previous studies mainly conducted in Japan, involving small numbers of patients, often without sham controls.2–4 The authors should, therefore, be congratulated for performing a large, randomised, double-blind, sham-controlled study of GMA in moderate to severely active Crohn's disease in a Western population.

The …