Trombopoietin: from molecule to medicine. Preface.
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Biomedical subjects
Publications and source records attributed to J Murphy.
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PURPOSE: To compare subcutaneous PCA tramadol with subcutaneous PCA morphine for postoperative pain relief after major orthopaedic surgery and for the incidence of side-effects. METHODS: In a double-blind randomised controlled study 40 patients (20 in each group) self-administered either tramadol or morphine for 72 hr after surgery via s.c. PCA. The following variables were recorded at various time intervals: (i) pain score by means of a visual analogue scale, (ii) drug consumption and total PCA demands, (iii) vital signs (blood pressure and heart rate), (iv) oxygen saturation and respiratory rate, and (v) side-effects (sedation, nausea/vomiting, pruritus, urinary retention and constipation). RESULTS: Both drugs provided effective analgesia. The mean consumption in the first 24 hr was 792 +/- 90 mg tramadol and 42 +/- 4 mg morphine. Thereafter, consumption of both drugs declined markedly. Moderate haemodynamic changes were observed in both the tramadol and morphine groups (with a maximum 20% decrease in mean blood pressure and a maximum 17% increase in heart rate) during the 72 hr period. Both tramadol and morphine were associated with a clinically and statistically significant (P < 0.001) decrease in oxygen saturation, but without changes in respiratory rates. Desaturation was less marked with tramadol. Tramadol appeared to cause more nausea and vomiting than morphine. Sedation was mild and only seen during the first few hours after surgery in both groups. CONCLUSION: Tramadol is an effective analgesic agent for the relief of acute postoperative pain when administered by PCA via the subcutaneous route. Under these conditions tramadol behaves much like morphine with a similar side-effect profile.
Idiopathic bronchiolitis obliterans organising pneumonia (BOOP) is an uncommon but well-recognised condition that usually presents radiologically as bilateral multifocal patchy areas of consolidation on the chest radiograph and on computed tomography (CT). Five cases are described in which the presenting feature was that of a solitary pulmonary nodule. Four of these nodules showed evidence of cavitation and three patients presented with haemoptysis. In all cases the appearances closely resembled bronchial carcinoma.
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A new instrument is presented which is capable of high resolution acoustic imaging at relatively low frequencies. This approach results in increased complexity of the signal processing required and reduced throughput of the instrument. However, these disadvantages are amply compensated by the ability to create velocity scan images of materials with either high attenuation or low material velocities. These measurements are not possible using traditional/acoustic microscopes. The initial performance of the new instrument is demonstrated using thin samples of shim materials to show that acceptable spatial resolution and highly accurate time delay measurements are possible. An application is then shown using the instrument to evaluate subchondral sclerosis in horse bones. It has been hypothesized that changes in the elastic modulus may be associated with fatigue-induced microdamage. The modulus change may further represent bone damage which precedes the development of microcracking. Thin samples are used to allow complementary microradiography to be performed on the bone slices. Because of the low material velocity, surface wave interference methods (so called V(z) curves) are not well suited for use in some bone samples. The thickness of the samples eliminates the potential for the samples to be evaluated using pulse-echo time delay measurements. The new instrument is thus unique in its ability to create velocity scans of these samples.
The product of a GFP-actin gene fusion, permanently or transiently transfected in diverse mammalian cell lines, was shown to be a suitable, intrinsic probe of both the organization and dynamics of the actin cytoskeleton. In live Swiss 3T3 and NIH 3T3 cells, the fusion protein was found to accumulate in lamellipodia, filopodia, focal contacts and stress fibers. Furthermore, comparisons of fluorescence images of GFP-actin and Cy3.5-phalloidin, an independent marker of F-actin, in permeabilized cells showed a complete overlap of the two fluorescence signals. In GFP-actin-transfected Hela cells that had been infected with Listeria monocytogenes, the fluorescence of the fusion protein was shown to dynamically associate in the F-actin rich comet tail that formed behind a motile bacterium. In stable transfectants of PC12 cells, GFP-actin constituted on the average 5% of the total actin - these cells exhibited normal growth behavior and responded to treatment with nerve growth factor by extending neurite-like extensions, the filopodia-like tips of which were densely packed with filamentous GFP-actin. Finally, the photobleaching decay time of GFP-actin in live cells of 63 seconds was much longer than that of fluorescein-labeled actin conjugates and little or no damage to the cytoskeleton was found during the photobleaching of GFP-actin. Having shown the suitability of GFP-actin as a probe of the cytoskeleton, its fluorescence was used in long-term imaging studies aimed at documenting changes in the cytoskeleton of rat bladder NBT-II carcinoma cells during the 24-hour growth factor-mediated epithelia to mesenchyme transformation. The intrinsic fluorescent probe was also used to investigate the organization of the actin cytoskeleton and behavior of individual mesenchyme NBT-II cells slowly migrating through a colony of epithelia cells.
DdLim, a multi-domain member of the cysteine-rich family of LIM domain proteins, was isolated from Dictyostelium cells where it localizes in lamellipodia and at sites of membrane ruffling. The transcription and expression of DdLim are developmentally regulated, and the timing of its increased association with the actin cytoskeleton coincides with the acquisition in starved cells of a motile, chemotactic behavior. Vegetative cells that overexpress DdLim contain large lamella and exhibit ruffling at the cortex. The high frequency of large, multinucleated mutant cells found in suspension culture suggests that excess DdLim interferes with cytokinesis. DdLim was also identified as a protein in a Dictyostelium cell lysate that associated indirectly, but in a guanosine triphosphate-dependent manner, with a GST-rac1 fusion protein. The data presented suggest that DdLim acts as an adapter protein at the cytoskeleton-membrane interface where it is involved in a receptor-mediated rac1-signaling pathway that leads to actin polymerization in lamellipodia and ultimately cell motility.
OBJECTIVE: To evaluate the effectiveness and safety of a single-dose treatment for acute repetitive seizure (ARS) episodes (e.g., clusters) administered in a nonmedical setting by caregivers. BACKGROUND: Patients with epilepsy may experience ARS episodes despite optimal anticonvulsant treatment. Such episodes require rapid treatment as medical emergencies. Typically, the patient is treated in an emergency medical setting with i.v. medication by trained medical personnel. METHODS: The authors undertook a multicenter, randomized, parallel, double-blind study of a single administration of Diastat (diazepam rectal gel) for treating episodes of ARS. ARS episodes and treatment criteria were defined for each patient at the start of the study. Caregivers were taught to determine ARS episode onset, administer a predetermined dose of study medication, monitor outcome, count respirations, and record seizures and adverse events. RESULTS: A total of 29 centers enrolled 158 patients, of whom 114 patients had a treated ARS episode (Diastat, n = 56; placebo, n = 58). Diastat treatment reduced median seizure frequency (p = 0.029). More Diastat patients were seizure free post-treatment (Diastat, 55%; placebo, 34%; p = 0.031). Kaplan-Meier analysis of the time to the next seizure favored Diastat treatment (p < 0.007). The most common adverse event was somnolence. CONCLUSION: Administration of a single rectal dose of Diastat was significantly more effective than placebo in reducing the number of seizures following an episode of ARS. Caregivers could administer treatment safely and effectively in a nonmedical setting.
DGAP1 of Dictyostelium discoideum is a cell cortex associated 95 kDa protein that shows homology to both RasGTPase-activating proteins (RasGAPs) and RasGAP-related proteins. When tested for RasGAP activity, recombinant DGAP1 protein did not promote the GTPase activity of human H-Ras or of Dictyostelium RasG in vitro. Instead, DGAP1 bound to Dictyostelium Rac1A and human Rac1, but not to human Cdc42. DGAP1 preferentially interacted with the activated GTP-bound forms of Rac1 and Rac1A, but did not affect the GTPase activities. Since Rho-type GTPases are implicated in the formation of specific F-actin structures and in the control of cell morphology, the microfilament system of mutants that either lack or overexpress DGAP1 has been analysed. DGAP1-null mutants showed elevated levels of F-actin that was organised in large leading edges, membrane ruffles or numerous large filopods. Expression of actin fused to green fluorescent protein (GFP) was used to monitor the actin dynamics in these cells, and revealed that the F-actin cytoskeleton of DGAP1-null cells was rapidly re-arranged to form ruffles and filopods. Conversely, in DGAP1-overexpressing cells, the formation of cellular projections containing F-actin was largely suppressed. Measurement of cell migration demonstrated that DGAP1 expression is inversely correlated with the speed of cell motility.
The CT findings in a fatal case of aorto-oesophageal fistula secondary to an atheromatous plaque in the thoracic aorta are described. These features are correlated with findings on endoscopy and barium studies.
We analysed in-vivo migration and wear over a long period of all-polyethylene acetabular cups which had not been affected by mechanical loosening. The selection criteria of regular radiological follow-up, good clinical outcome (Charnley score of 5 or 6), continued walking without crutches and no radiological signs of loosening of the acetabular cups were fulfilled by 25 Charnley total hip arthroplasties. Mean migration, measured by the Nunn method, was 0.6 mm in the medial and 0.2 mm in the cranial direction. The mean yearly rate of wear was 0.05 mm and 0.04 mm, with six and two cups having no detectable wear, as measured by the Livermore and Charnley-Cupic methods, respectively. The maximal detected wear was 3.7 mm. There were no changes in the rate of wear with time. Computerised Ein Bild Röntgen Analyse (single-image radiological analysis) measurements of 20 hips indicated plastic deformation of the cups. We conclude that long-term successful cups do not migrate and have a very low rate of wear which was not affected by ageing of the polyethylene. There was no evidence that polyethylene wear alone caused mechanical loosening of the cup but high rates of wear seem to have an adverse prognostic value in terms of the long-term survival of the prosthesis.
OBJECTIVE: Our aim was to obtain mental health patients' views on psychiatrists' and case managers' attire. METHODS: Eighty-six patients treated at a community mental health service were surveyed. Various types of commonly worn attire were listed. Respondents were asked to choose what they thought was most appropriate for their psychiatrist and case manager to wear. RESULTS: Over 50% of respondents felt that psychiatrist or case manager dress was not an important issue. However, those who felt that it was preferred less formal attire. CONCLUSIONS: Psychiatrists and case managers in a community mental health team could consider adopting less formal attire. This conclusion is limited by the small sample and may be relevant to rural areas only. Further research is needed in urban centres. Implications of these findings are discussed.
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A 22-year-old man was admitted to a district general hospital with chest injuries, a ruptured spleen and limb fractures, sustained in a road traffic accident. After an emergency splenectomy, the patient developed unilateral pulmonary oedema with hypoxaemia which was resistant to both conventional controlled mechanical ventilation (CMV) and independent lung ventilation (ILV). He was transferred to a specialist cardiothoracic unit where high frequency jet ventilation (HFJV) also failed to achieve adequate oxygenation. Combined high frequency ventilation (CHFV), using high frequency pulses from a Bromsgrove Penlon Jet ventilator superimposed onto small tidal volumes from an Engstrom Erica improved oxygenation rapidly to allow decreases in inspired oxygen fraction (FiO2), peak airway pressure (PAWP) and positive end expiratory pressure (PEEP). Progressive weaning from ventilatory support was then possible over five days. CHFV is a valuable technique in the treatment of acute catastrophic lung injury and needs wider recognition.
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Cells of the unicellular eukaryote Dictyostelium discoideum take up all their nutrients by endocytosis. Both particle- and fluid-containing vacuoles are transiently surrounded by a cytoskeletal coat [1] [2]. When this coat has dissociated, acidification and digestion of the vesicle contents occur, followed by exocytosis of the indigestible remnants after 60-90 minutes. At least nine compartments are needed for mathematical modelling of endocytic transit [3], suggesting that markers associate for only a few minutes with a specific endocytic compartment. Among the proteins that have been identified as components of endocytic vesicles are actin, subunits of the V-H+ ATPase and small GTP-binding proteins of the Rab family [4] [5] [6] [7]. Using a monoclonal antibody produced against Dictyostelium endocytic vesicles, we have isolated a cDNA corresponding to a novel protein that we have named vacuolin. In order to determine the precise step along the endocytic pathway that involves vacuolin, we generated a fusion protein of the green fluorescent protein (GFP) and vacuolin. GFP-vacuolin-decorated vesicles were identified as a post-lysosomal compartment that acquires endocytic markers shortly before exocytosis. At earlier stages, this post-lysosomal compartment was identified by the binding of a tagged cytoskeletal protein, coronin-GFP. Vacuoles were coated with filamentous actin along the entire post-lysosomal pathway, and the integrity of the actin coat was required for exocytosis.
PURPOSE: Previous phase I and II studies of intraperitoneal recombinant human tumor necrosis factor-alpha (rhTNF-alpha) suggested a high degree of efficacy in reducing or eliminating ascitic fluid. To more accurately determine the efficacy of this agent, the role of paracentesis versus paracentesis plus intraperitoneal rhTNF-alpha was studied in a randomized trial. PATIENTS AND METHODS: Thirty-nine patients with symptomatic ascites with a volume of > 1000 ml from recurrent epithelial ovarian carcinoma or primary peritoneal carcinoma, which was refractory to standard therapy, were randomized either to receive 0.06 mg/m2 rhTNF-alpha (Knoll, Canada) (the dose determined optimal from phase I and II studies) intraperitoneally after drainage of fluid or to receive drainage alone. A maximum of three treatments were given at weekly intervals. Eighteen patients were randomized to receive rhTNF-alpha. RESULTS: None of 18 evaluable rhTNF-alpha patients had either a complete response (CR) (no clinical evidence of ascites and < 400 ml of fluid on ultrasound) or a partial response (PR) (asymptomatic ascites and < or = 1000 ml of fluid ultrasound). There were no CRs or PRs in the 17 evaluable patients who received drainage alone. The intraperitoneal infusion of rhTNF-alpha was generally well tolerated. Moderate to severe toxicity consisted of pain/discomfort in 42.1%, fever/chills in 36.9%, nausea/vomiting in 10.5%, edema in 10.5%, and hypotension in 5.3% of patients receiving rhTNF-alpha. CONCLUSION: rhTNF-alpha, as given in this study, was not effective in preventing recurrence of ascites in this patient population.