Understanding and optimising patient and public involvement in trial oversight: an ethnographic study of eight clinical trials.

BACKGROUND: Trial oversight is important for trial governance and conduct. Patients and/or lay members of the public are increasingly included in trial oversight committees, influenced by international patient and public involvement (PPI) initiatives to improve the quality and relevance of research. However, there is a lack of guidance on how to undertake PPI in trial oversight and tokenistic PPI remains an issue. This paper explores how PPI functions in existing trial oversight committees and provides recommendations to optimise PPI in future trials. This was part of a larger study investigating the role and function of oversight committees in trials facing challenges. METHODS: Using an ethnographic study design, we observed oversight meetings of eight UK trials and conducted semi-structured interviews with members of their trial steering committees (TSCs) and trial management groups (TMGs) including public contributors, trial sponsors and funders. Thematic analysis of data was undertaken, with findings integrated to provide a multi-perspective account of how PPI functions in trial oversight. RESULTS: Eight TSC and six TMG meetings from eight trials were observed, and 66 semi-structured interviews conducted with 52 purposively sampled oversight group members, including three public contributors. PPI was reported as beneficial in trial oversight, with public members contributing a patient voice and fulfilling a patient advocacy role. However, public contributors were not always active at oversight meetings and were sometimes felt to have a tokenistic role, with trialists reporting a lack of understanding of how to undertake PPI in trial oversight. To optimise PPI in trial oversight, the following areas were highlighted: the importance of planning effective strategies to recruit public contributors; considering the level of oversight and stage(s) of trial to include PPI; support for public contributors by the trial team between and during oversight meetings. CONCLUSIONS: We present evidence-based recommendations to inform future PPI in trial oversight. Consideration should be given at trial design stage on how to recruit and involve public contributors within trial oversight, as well as support and mentorship for both public contributors and trialists (in how to undertake PPI effectively). Findings from this study further strengthen the evidence base on facilitating meaningful PPI within clinical trials.

The hot plasma environment at jupiter: ulysses results.

Measurements of the hot plasma environment during the Ulysses flyby of Jupiter have revealed several new discoveries related to this large rotating astrophysical system. The Jovian magnetosphere was found by Ulysses to be very extended, with the day-side magnetopause located at approximately 105 Jupiter radii. The heavy ion (sulfur, oxygen, and sodium) population in the day-side magnetosphere increased sharply at approximately 86 Jupiter radii. This is somewhat more extended than the "inner" magnetosphere boundary region identified by the Voyager hot plasma measurements. In the day-side magnetosphere, the ion fluxes have the anisotropy direction expected for corotation with the planet, with the magnitude of the anisotropy increasing when the spacecraft becomes more immersed in the hot plasma sheet. The relative abundances of sulfur, oxygen, and sodium to helium decreased somewhat with decreasing radial distance from the planet on the day-side, which suggests that the abundances of the Jupiter-derived species are dependent on latitude. In the dusk-side, high-latitude region, intense fluxes of counter-streaming ions and electrons were discovered from the edge of the plasma sheet to the dusk-side magnetopause. These beams of electrons and ions were found to be very tightly aligned with the magnetic field and to be superimposed on a time- and space-variable isotropic hot plasma background. The currents carried by the measured hot plasma particles are typically approximately 1.6 x 10(-4) microamperes per square meter or approximately 8 x 10(5) amperes per squared Jupiter radius throughout the high-latitude magnetosphere volume. It is likely that the intense particle beams discovered at high Jovian latitudes produce auroras in the polar caps of the planet.

Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia.

Hematological changes induced by various stress stimuli are accompanied by replacement of the primary acetylcholinesterase (AChE) 3' splice variant acetylcholinesterase-S (AChE-S) with the myelopoietic acetylcholinesterase-R (AChE-R) variant. To search for putative acetylcholinesterase-S interactions with hematopoietic pathways, we employed a yeast two-hybrid screen. The transcriptional co-repressor C-terminal binding protein (CtBP) was identified as a protein partner of the AChE-S C terminus. In erythroleukemic K562 cells, AChE-S displayed nuclear colocalization and physical interaction with CtBP. Furthermore, co-transfected AChE-S reduced the co-repressive effect of CtBP over the hematopoietic transcription factor, Ikaros. In transgenic mice, overexpressed human (h) AChE-S mRNA induced selective bone marrow upregulation of Ikaros while suppressing FOG, another transcriptional partner of CtBP. Transgenic bone marrow cells showed a correspondingly elevated potential for producing progenitor colonies, compared with controls, while peripheral blood showed increased erythrocyte counts as opposed to reduced platelets, granulocytes and T lymphocytes. AChE's 3' alternative splicing, and the corresponding changes in AChE-S/CtBP interactions, thus emerge as being actively involved in controlling hematopoiesis and the potential for modulating immune functions, supporting reports on malfunctioning immune reactions under impaired splice site selection.

Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients.

We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.

Simple immuno bead labeling of leukemic cell clusters cultured in methylcellulose.

In studies of in vitro leukemic clonogenic cells it is of importance to determine the cell lineage of individual clusters grown in culture. A method is described for the in-situ identification of leukemic cell clusters in methylcellulose cultures. Whole cultures are dried and incubated with various monoclonal antibodies, followed by incubation with beads coated with secondary antibody. Clusters containing antibody-positive cells are heavily labeled with beads which simplifies the recognition and scoring of clusters using normal light microscopy. This method has general applications and can also be used to identify normal myeloid and lymphoid clusters depending on the availability of lineage specific monoclonal antibodies.

Recombinant human interleukin-6 accelerates in-vitro megakaryocytopoiesis and platelet recovery post autologous peripheral blood stem cell transplantation.

Prolonged thrombocytopenia complicated by bleeding episodes represent a major problem following autologous bone marrow transplantation (ABMT). Recombinant human interleukin-6 (rhIL-6) has been shown to be a maturation factor for both mouse and human megakaryocytes. We administered rhIL-6 to a 43 year old woman who developed marked resistant and prolonged thrombocytopenia with bleeding episodes following autologous peripheral blood stem cell transplantation (APBSCT). Twenty days after the initiation of rhIL-6 therapy, the number of megakaryocyte (MK) progenitors (CFU-MK and BFU-MK) cultured from the peripheral blood increased followed by a moderate increase in the number of bone marrow megakaryocytes. The platelet count increased and the bleeding episodes disappeared. Although spontaneous platelet recovery cannot be ruled out in this case it seems that rhIL-6 may be an important thrombopoietic factor for severe thrombocytopenia following APBSCT.

Oat bran concentrate bread products improve long-term control of diabetes: a pilot study.

OBJECTIVE: To evaluate the long-term effects oat bran concentrate bread products in the diet of free-living subjects with non-insulin-dependent diabetes (NIDDM) via dietary, clinical, and biochemical methods. DESIGN: A 24-week crossover study consisting of two 12-week periods. SUBJECTS/SETTING: Eight men with NIDDM (mean age = 45 years) who lived in the community. Glucose and insulin profiles were conducted in a clinical investigation unit. INTERVENTION: Palatable, high-fiber, oat bran concentrate (soluble fiber [beta-glucan] content = 22.8%) bread products were developed. Four randomly chosen subjects ate oat bran concentrate breads first; the other subjects ate control white bread first. MAIN OUTCOME MEASURES: Dietary intake (four 48-hour dietary recalls per period) was assessed. Blood glucose and insulin (8-hour profiles) and lipid parameters after fasting were measured (at 0, 12, and 24 weeks). STATISTICAL ANALYSES PERFORMED: Analysis of variance and repeated-measures analysis of variance. RESULTS: Total energy and macronutrient intakes were similar in both periods. Mean total dietary fiber intake was 19 g/day in the white bread period and 34 g/day (9 g soluble fiber per day from oat bran concentrate) in the oat bran concentrate period. Body weight remained stable. Mean glycemic and insulin response areas (area under the curve) were lower (P < or = .05 and not significant, respectively) for the oat bran concentrate period than the white bread period. After breakfast, area under the curve for the oat bran concentrate period was lower for glucose (P < or = .01) and insulin (P < or = .05); insulin peak was reached earlier (P < or = .05) than in the white bread period. Dietary fiber intake was correlated negatively with insulin area under the curve (P < or = .05). Mean total plasma cholesterol and low-density lipoprotein cholesterol levels were lower (P < or = .01) in the oat bran concentrate period than in the white bread period. In the oat bran concentrate period, the mean ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol was reduced by 24% (P < or = .05). CONCLUSIONS: The well-accepted oat bran concentrate bread products improved glycemic, insulinemic, and lipidemic responses.

Stem cell factor (SCF) synergizes with megakaryocyte colony stimulating activity in post-irradiated aplastic plasma in stimulating human megakaryocytopoiesis.

Plasma obtained from lethally irradiated animals contains a megakaryocyte (MK) growth factor which has recently been identified as the ligand for the c-mpl receptor and has been named thrombopoietin (TPO). We demonstrate that post-irradiation aplastic canine plasma (PICS-J) and plasma from a human subject (ML) who was accidentally exposed to lethal irradiation, contain high levels of this activity, which support both MK proliferation and maturation in a dose-dependent manner. These plasma were far more active in stimulating human MK colony formation than other types of thrombocytopenic plasma or a number of exogenously added human recombinant cytokines and their combinations. The addition of stem cell factor (SCF), which alone has a minimal stimulatory affect, to post lethal-irradiation plasma provided a synergistic stimulation of megakaryocytopoiesis both in colony assays and liquid cultures. In colony assays, the combination of SCF with PICS-J or ML almost doubled the number of burst forming units (BFU-MK) and provided a 1.5-fold increase in colony forming units (CFU-MK). A 1.6-fold increase in the number of CD34+ BM cell-derived MK colonies was also elicited. In liquid cultures, the presence of both SCF and PICS-J or ML induced the appearance of a high proportion of CD34+ (6.56% vs 0.6% control) and CD41+ (3.5% vs 1.2% control) cells after 3 days in culture. By day 10, 66.8 x 10(4) CD41+ cells and 29.8 x 10(4) CD34+ cells were derived from 2 x 10(6) BMMC originally seeded. We propose that these unique plasma, which do not contain elevated level of IL-6, IL-3, GM-CSF, IL-1 beta, erythropoietin or SCF, probably contain high levels of TPO. The addition of SCF to the post-irradiation plasma provides a synergistic stimulation of megakaryocytopoiesis which may become relevant for future clinical application.

[Horse racing and animal welfare]. / Pferderennen und Tierschutz.

Intensive strain of racing-horses during training and race is not an end in itself but should be understood from the social task to create exceptionally efficient horses. This roughness in sports obliges the responsible associations to issue rigorous regulations for the protection of horses. In this paper, some physical and psychical disorders of racing-horses are described. Improved keeping conditions as well as performance-adapted training methods will help to avoid defects. The aids being used during training and races are critically investigated on their effects according to the regulations on animal protection.

[Equipment, methods of constraint and other aids in horse racing]. / Ausrüstungen, Zwangsmassnahmen und sonstige Hilfsmittel im Galopprennsport.

After a brief introduction to the most important aspects of the current sport of horse-racing the equipment and tack will be described with respect to the horses wellbeing: bridles, tonguestrap, blinkers, saddle and girth. With reference to incorrect equipment for the rider, the wip and its misuse will be discussed. Problems with saddling and at the starting gate are often indicators of the incorrect application of aids. Then the misuse of the automatic horse trainer, treadmills and swimmingpools will be explained. Finally, the three most important requirements for improving the protection of racehorse are summarized: the racing regulations should conform to animal welfare laws and the application of these laws should be in the hands of an independent veterinary surgeon, who has the authority to enforce its requirement.

Differential regulation of the apoptotic machinery during megakaryocyte differentiation and platelet production by inhibitor of apoptosis protein Livin.

Livin is a member of the inhibitor of apoptosis proteins (IAP) family of intracellular antiapoptotic proteins that act by binding and inhibiting caspases. Upon strong apoptotic stimuli, it is then specifically cleaved by caspases to produce a truncated protein (tLivin) with a paradoxical proapoptotic activity. Intriguingly, we have detected robust protein levels of Livin in normal mature bone marrow megakaryocyte (MK) and platelets. To evaluate the potential role of Livin in thrombopoiesis, we used the human BCR-ABL+ cell line, LAMA-84, and cord blood CD34+ cells to induce differentiation toward MKs. Upon differentiation, induced by phorbol myristate acetate and concurrent with increase in Livin protein expression, LAMA-84 cells formed functional platelet-like particles. Livin overexpression in CD34+ progenitor cells induced higher endoreplication in the MKs generated. Furthermore, overexpression of Livin increased the ability of both primary MKs and differentiated LAMA-84 cells to produce functional platelets. In the differentiated LAMA-84 cells, we observed accumulation of proapoptotic tLivin concomitant with increased caspase-3 activity. Downregulation of Livin with small interfering RNA in both leukemic and primary MK cells decreased their ability to produce functional platelets. We suggest that Livin has a role in thrombopoiesis by regulating the apoptotic and antiapoptotic balance in MK endoreplication and platelet production.

Acetylcholinesterase-R increases germ cell apoptosis but enhances sperm motility.

Changes in protein subdomains through alternative splicing often modify protein-protein interactions, altering biological processes. A relevant example is that of the stress-induced up-regulation of the acetylcholinesterase (AChE-R) splice variant, a common response in various tissues. In germ cells of male transgenic TgR mice, AChE-R excess associates with reduced sperm differentiation and sperm counts. To explore the mechanism(s) by which AChE-R up-regulation affects spermatogenesis, we identified AChE-R's protein partners through a yeast two-hybrid screen. In meiotic spermatocytes from TgR mice, we detected AChE-R interaction with the scaffold protein RACK1 and elevated apoptosis. This correlated with reduced scavenging by RACK1 of the pro-apoptotic TAp73, an outcome compatible with the increased apoptosis. In contrast, at later stages in sperm development, AChE-R's interaction with the glycolytic enzyme enolase-alpha elevates enolase activity. In transfected cells, enforced AChE-R excess increased glucose uptake and adenosine tri-phosphate (ATP) levels. Correspondingly, TgR sperm cells display elevated ATP levels, mitochondrial hyperactivity and increased motility. In human donors' sperm, we found direct association of sperm motility with AChE-R expression. Interchanging interactions with RACK1 and enolase-alpha may hence enable AChE-R to affect both sperm differentiation and function by participating in independent cellular pathways.

A preliminary single case magnetic resonance imaging investigation into maxillary frontal-parietal manipulation and its short-term effect upon the intercranial structures of an adult human brain.

OBJECTIVE: To investigate the hypothesis that external cranial manipulation can cause change within the structures of the human brain. DESIGN: Single subject. SETTING: Private office. PARTICIPANT: A 42-yr-old man. INTERVENTION: MRI scan was administered without manipulative pressure but with the investigator's contacts on the test subjects maxillary palate and frontal/parietal region surrounding the bregma. OUTCOMES: Measurements were taken along the superior border of the corpus callosum, the width of the fornix column, the exposed anterior/superior wall of the lateral ventricle posterior to the fornix, the angular surface of the cerebellar central lobule and the posterior surface of the inferior colliculi. RESULTS: Results from the second MRI (administered during the application of external cranial pressure) demonstrated elimination of a 5-mm peak along the superior border of the corpus callosum and a 4-mm reduction in the width of the fornix column. The exposed anterior/superior wall of the lateral ventricle posterior to the fornix column increased 51 degrees cephalad with manipulative application. The angular surface of the central lobule altered by minus 26 degrees, and the posterior surface of the inferior colliculi varied by minus 7 degrees. The subject experienced no change in his asymptomatic condition as a result of this study. CONCLUSION: The present study supports the theory that external cranial manipulation affects the structure of the brain. It also suggests support for the theory regarding suture mobility.

Anaesthesia for carotid artery surgery.

Twenty-one carotid endarterectomies were performed on 18 patients anaesthetised during droperidol, fentanyl and a cervical plexus block. This technique permitted testing for motor function during carotid clamping, and allowed the operation to proceed safely without a shunt in the majority of patients.

The effect of positive end expiratory pressure on lung mechanics and arterial oxygenation after open heart surgery in young children.

The effect of positive end expiratory pressure (PEEP) during mechanical ventilation of the lungs was measured in 10 young children, aged 3 weeks to 30 months, who were being ventilated artificially after cardiopulmonary bypass surgery. Changes in the end-tidal lung volume were measured directly using a jacket plethysmograph, and were assumed to indicate change in functional residual capacity (FRC). Simultaneous changes in compliance and blood-gases were measured also. FRC was increased in all subjects, and in most this increase was accompanied by an increase in arterial oxygenation. There was no significant alteration in the mean values of dynamic or static compliance in the group, although dynamic compliance increased during PEEP in six patients. PEEP may be of value after cardiopulmonary bypass in young children when oxygenation is poor despite high inspired oxygen fractions. The possible mechanisms by which it increases PaO2 are discussed.