Enteral Bioavailability of Human Granulocyte Colony Stimulating Factor Conjugated with Poly(ethylene glycol)

Purpose. The focus of this paper is to demonstrate that pegylation of a therapeutic protein, recombinant human granulocyte colony stimulating factor (PEG-G-CSF), results in an increase in stability and in retention of in vivo bioactivity when administered by the intraduodenal route and may, therefore, be a suitable form of the protein for inclusion in an oral delivery formulation. Methods. The ability of PEG-G-CSF to elicit a therapeutic response from the enteral route was investigated by two methods of intraduodenal dosing in an in vivo model to determine the optimal dosing method: by slow, constant infusion, or by a single bolus administration. Results. Circulating levels of the proteins confirmed that PEG-G-CSF was delivered into the systemic circulation from the enteral route and that biological activity was retained. Bioavailability from the enteral route by the constant infusion method was calculated from the intravenous administration of the proteins to be between 1.8 and 3.5% while un-modified G-CSF failed to elicit a quantifiable response by this method. Bolus administration of PEG-G-CSF also resulted in biological activity although responses were short lived and significantly lower than with the pegylated formulation. Conclusions. The possible mechanisms of enteral delivery of PEG-G-CSF are discussed. Our results indicate that oral delivery of pegylated G-CSF may be possible and in fact, preferable to using the un-modified form of the therapeutic.     

Simulation of blood flow in microgravity.

Knowledge of venous, capillary, and arterial blood flow in microgravity is required to modify hemostatic techniques for control of bleeding in traumatic injuries or surgical procedures in space. To simulate human arterial, venous, and capillary bleeding, fresh whole bovine blood was injected by two operators at calculated flow rates (3.5, 7, and 14 mL for venous and 14 and 28 mL for arterial) in 10 seconds with empirical controls in a lucent glove box during zero gravity parabolic flight on NASA's KC-135 aircraft. A pig's foot was used to mimic capillary bleeding. Hemostasis with sponges and laerdal suction was evaluated by video and still photography. Evaluations of the arterial and venous bleeding were conducted at 3 rates x 3 parabolas, and capillary bleeding was evaluated with 5 parabolas x 2 methods (pig's foot and sponge). Influenced by surface tension, the slow venous bleeding coated syringe surfaces and formed a dome over the skin laceration bleeding site. Arterial and venous bleeders broke into uniform spheres with low-velocity spheres bouncing off an absorbent pad and suction tip. Conventional dabbing with gauze fragmented blood into small spheres. Capillary oozing was better controlled by "wicking" up blood with gauze. Repeated arterial bleeding opacified the glove box wall. This stimulation demonstrated unique characteristics of extracorporeal blood flow and inadequacies of common methods of hemostasis in microgravity.     

The development of clinical indicators for a consultation-liaison service

OBJECTIVE: The aim of this paper is to describe the development and implementation of clinical indicators in the consultation-liaison service at Royal Melbourne Hospital (RMH). METHOD: A working party lead by the University of Melbourne was established in 1998 to develop clinical indicators and a database for the RMH consultation-liaison service. Core parameters for measuring service functioning and six clinical indicators were developed. The system was implemented using a data collection form and computerised database operating within a system of regular clinical reviews. RESULTS: The clinical indicators, database and review system were found to be a feasible, useful and efficient addition to a consultation-liaison service at a major general hospital. CONCLUSIONS: Clinical indicators may be used within specialist psychiatry services to enhance clinical care and aid in service development and teaching.     

Virtual lesions and the not-so-modular brain.

Because lesions usually affect contiguous areas of the brain, cognitive neuropsychology has generally posited modularity of brain function, assuming that specific regions of the brain have specific dedicated functions. However, a review of 36 published functional neuroimaging studies suggests that functions are distributed over multiple regions. Or, in other words, specific brain regions are usually multifunctional. By a technique of "virtual lesions," I measure the contribution that regions of the brain make to tasks imaged in 36 PET experiments, and propose a new and more detailed interlink between neuropsychology and functional neuroimaging.     

Early report: comparison of breath-hold MR excretory urography, Doppler ultrasound and isotope renography in evaluation of symptomatic hydronephrosis in pregnancy

AIM: To compare assessment by MR excretory urography (MREU), Doppler ultrasound and isotope renography of women with symptomatic hydronephrosis in pregnancy and to define its cause.MATERIALS AND METHODS: Eleven women at 19-34 weeks of gestation were studied prospectively with gadolinium-enhanced breath-hold gradient echo MREU and transabdominal Doppler ultrasound compared with a 'gold standard' of isotope renography employing frusemide challenge. All studies were performed within 24 h, were reported independently in a blinded fashion and employed clearly defined criteria. Obstetric and infant outcomes were obtained.RESULTS: There were no adverse reactions to gadolinium administration in pregnancy and no adverse obstetric or infant outcomes. Three of the 11 women were unable to tolerate the complete MREU protocol. Ultrasound indices could not be used to predict ureteric obstruction as shown by isotope renography. MREU agreed with renographic findings in five of the six cases with obstruction and in two without obstruction. MREU directly demonstrated hydronephrosis to result from extrinsic compression of the ureter between the gravid uterus and iliopsoas muscle. CONCLUSION: MR excretory urography is a promising technique which affords equivalent functional and additional anatomical information to isotope renography. It is more accurate than Doppler ultrasound in the assessment of ureteric obstruction in pregnancy.Spencer, J. A. (2000). Clinical Radiology55, 446-453.     

Creation, Evaluation, and Continuing Assurance of Excellence of the Certified Surgical Specialist

A position paper on the subject of certified surgical specialists was published in 1966 under the direction of Professor Charles Wells of Liverpool, England. President John Terblanche of the International Federation of Surgical Colleges brought together leaders in surgical education from four nations (Australia, Japan, South Africa, United States) to update current “state-of-the art” views. Presentations were made at the 38th Congress of the International Society of Surgery, August 18, 1999 in Vienna, Austria. After careful review of the four presentations, it was clear that surgeons all over the world have made great improvements in the many facets of surgical education. Yet the advances remain spotty, with gaps noted when viewed from an international perspective.     

Skp2 protein expression in soft tissue sarcomas.

BACKGROUND: p45 S phase kinase-associated protein-2 (p45(skp2)), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCF(skp2)). The latter has been implicated in the ubiquitination and degradation of p27(kip1) (p27) and G(1)-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated. METHODS: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. RESULTS: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (> or = 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P =.002) and Ki-67 proliferative index (r = 0.44; P <.0001), but not with p27 expression (r = -0.02; P =.80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival. CONCLUSION: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.