Liposomes containing lipid A serve as an adjuvant for induction of antibody and cytotoxic T-cell responses against RTS,S malaria antigen

Encapsulation of soluble protein antigens in liposomes was previously shown to result in processing of antigen via the major histocompatibility complex class I pathway, as evidenced by costaining of the trans-Golgi region of murine bone marrow-derived macrophages (BMs) by fluorophore-labeled liposomal antigen and by a trans-Golgi-specific fluorescent lipid. Evidence is presented here that free or liposome-encapsulated RTS,S, a particulate malaria antigen consisting of hepatitis B particles coexpressed with epitopes from the Plasmodium falciparum circumsporozoite protein, also was localized in the trans-Golgi after incubation with BMs, suggesting processing by the class I pathway. An in vivo cytotoxic T-lymphocyte (CTL) response was detected, however, only after immunization with RTS,S encapsulated in liposomes containing lipid A and not after immunization with free RTS,S or with RTS,S encapsulated in liposomes lacking lipid A. Therefore, intracellular delivery of antigen containing CTL epitopes to the Golgi of BMs does not necessarily result in a CTL response in vivo unless an additional adjuvant, such as liposomes containing lipid A, is utilized. Encapsulation of RTS,S in liposomes containing monophosphoryl lipid A (MPL) resulted in a dose-dependent enhancement of the NANP-specific immunoglobulin G (IgG) antibody response compared to that of free RTS,S. The IgG1 and IgG2a subclasses predominated after immunization with RTS,S encapsulated in liposomes containing MPL. These results demonstrate that encapsulation of a lipid-containing particulate antigen, such as RTS, S, in liposomes containing lipid A can enhance both humoral and cellular immune responses.     

Effect of pulmonary artery stenoses on the cardiopulmonary response to exercise following repair of tetralogy of Fallot

Data from exercise tests, echocardiograms, and lung perfusion scans were analyzed to determine whether the excessive minute ventilation (VE) often encountered among patients with tetralogy of Fallot is due to ventilation-perfusion mismatch secondary to branch pulmonary artery stenoses. Patients with branch PA stenoses had lower peak oxygen consumptions and higher VE during exercise than did patients without stenoses, and a strong correlation existed between the degree of pulmonary blood flow maldistribution on lung perfusion scan and the amount of excessive VE during exercise.     

Risk stratification using the Society of Thoracic Surgeons Program

In an era of progressive cost containment and public scrutiny, the wisdom of aggressive surgical therapy for high-risk candidates has been questioned. At our center in the previous 24 months, 728 patients with coronary artery disease were entered into The Society of Thoracic Surgeons national database, and the hospital outcomes plus length of stay were analyzed. Patients were separated according to the predicted mortality based on the groupings in The Society of Thoracic Surgeons database: 0 to 5% (453 patients); 5% to 10% (126 patients); 10% to 20% (96 patients); 20% to 30% (17 patients); and 30% and greater (36 patients). There was a close correlation with the predicted rates of mortality. Importantly, the preoperative risk stratification demonstrated a strong correlation with the significant morbidity and excessive length of stay in the highest-risk groups (predicted risk of 20% to > or = 30%). The incidences of the most common complications in the group with the highest predicted risk (> or = 30%) were 28%, renal failure; 33%, ventilator dependence; and 17%, cardiac arrest. In addition, at short-term follow-up (6 to 8 months), a 24.3% mortality was identified in patients with a predicted mortality that exceeded 20%. These data quantify the risks and morbidities associated with the care of seriously ill patients with coronary artery disease and demonstrate the need for professional and public discussions focusing on the association of a high preoperative risk status and the consumption of resources.     

Herniography in the investigation of groin pain in adults

Herniography is a useful investigation in adults with unexplained groin pain in whom there is no clinical evidence of a hernia, thus ensuring appropriate surgery. The technique is described, normal anatomy and different types of hernias illustrated.     

Ergonomics in rehabilitation: a comparison of two methods of moving an empty manual wheelchair short distances

Phthalimidomethyl derivatives 1, encompassing a wide range of leaving group abilities, are rapidly hydrolysed to the corresponding phthalamic acid via rate-determining attack at the phthalimide carbonyl group.     

Peptide growth factors in the prostate as mediators of stromal epithelial interaction

Peptide growth factors play a role in the maintenance of normal prostatic growth and differentiation (Fig. 2). It seems likely that the androgen sensitivity of human prostate is mediated by the production of peptide growth factors from stromal cells which act as the direct intermediate of androgen action on epithelial cells. TGF-beta 1 inhibition of epithelial cells is opposed by the stimulatory action of EGF, IGF and FGFs to maintain an equilibrium of epithelial cell numbers. The indirect mitogenic action of androgens appear to act by down-regulation of TGF-beta 1 and possibly EGF receptors. There is also interaction with the effects of IGF-II, produced by prostatic stromal cells and acting on epithelial cells to increase proliferation. The growth of normal prostatic fibroblasts is under the control of bFGF and TGF-beta 1. However, although our understanding of the actions of these growth factors in the normal prostate has improved over the last decade, their role in the development and maintenance of prostate cancer is less clearly defined. TGF-beta 1, classically considered to be inhibitory for epithelial cells, may be up-regulated in prostatic tumours, stimulating growth. Alternatively, autocrine production of such growth factors by tumour cells may lead to loss of inhibitory effects from exogenous TGF-beta 1, a mechanism also witnessed with TGF-alpha and bFGF. The role of EGF in the development of prostate cancer is confusing because results from the use of different cell types and experimental conditions is contradictory. It may be that a switch in the production of the predominant EGFr ligand from EGF to TGF-alpha is an important feature in the development and maintenance of the malignant phenotype. The presence of TGF-alpha autocrine loops has been shown clearly in some tumour cell lines. This switch in the production of a particular ligand may also be a feature of IGFs in prostate cancer. IGF-II may be replaced by IGF-I during malignant progression, both of which are able to act via the type 1 receptor. This change in IGF expression appears to be accompanied by altered expression of the IGF-BP2, with less detectable within prostatic tissues but elevated serum levels [58]. Basic FGF is normally produced by prostatic fibroblasts but is also produced by some prostatic cancer cell lines [64]. However, as with all growth factors, the expression of the bFGF protein and its receptor is dependent on the cell line examined. The autocrine and paracrine control of normal and abnormal prostatic growth by growth factors is important in determining their role in the development and maintenance of prostate cancer. Better understanding of such mechanisms is essential for the development of novel therapeutic strategies in the control and treatment of prostate cancer.     

Electromyographic and neuromuscular variables in post-polio subjects

OBJECTIVE: Post-polio subjects experience functional deterioration many years after developing acute poliomyelitis and have been shown previously to have a deficit in strength recovery after isometric activity. This study characterized the size and stability of the motor units in a group of post-polio subjects with macro and single fiber electromyography (EMG) and correlated these variables with isometric strength, endurance, "work capacity," and strength recovery after fatiguing isometric exercise. DESIGN: A cohort of 12 post-polio subjects was tested for neuromuscular function. Electromyographic variables were determined on a separate day. SETTING: Volunteers were recruited from the community and tested in our neuromuscular research laboratory. SUBJECTS: A volunteer sample was obtained from advertisements. All subjects acknowledged post-polio syndrome symptoms. MAIN OUTCOME MEASURES: Neuromuscular variables were isometric knee extension peak torque, endurance (time to exhaustion) at 40% of maximal torque, tension time index, and recovery of torque at 10 minutes. Electromyographic variables were macro EMG and single fiber EMG (percent blocking and jitter). RESULTS: Macro EMG amplitude was ninefold the control value, and both jitter and blocking were greatly increased in comparison to control values. Isometric strength significantly (p < .05) correlated negatively with macro EMG amplitude. CONCLUSIONS: The weakest subjects had the greatest number of muscle fibers within the motor unit (as measured by macro EMG amplitude). Jitter and blocking did not correlate with neuromuscular function.     

Addressing a state''s physician workforce priorities through the funding of graduate medical education: the TennCare model

OBJECTIVE: To investigate differences in second-, third-, and fourth-year medical students' knowledge of bloodborne pathogen exposure risks, as well as their attitudes toward, and intentions to comply with, Universal Precautions (UP). DESIGN: Cross-sectional survey. PARTICIPANTS AND SETTING: Surveys about students' knowledge, attitudes, and intentions to comply with UP were completed by 111 second-year (preclinical), 80 third-year, and 60 fourth-year medical students at Washington University School of Medicine in the spring of 1996. RESULTS: Preclinical students knew more than clinical students about the efficacy of hepatitis B vaccine, use of antiretroviral therapy after occupational exposure to human immunodeficiency virus, and nonvaccinated healthcare workers' risk of infection from needlestick injuries (P<.001). Students' perceived risk of occupational exposure to bloodborne pathogens and attitudes toward hepatitis B vaccine did not differ, but preclinical students agreed more strongly that they should double glove for all invasive procedures with sharps (P<.001). Clinical students agreed more strongly with reporting only high-risk needlestick injuries (P=.057) and with rationalizations against using UP (P=.008). Preclinical students more frequently reported contemplating or preparing to comply with double gloving, wearing protective eyewear, reporting all exposures, and safely disposing of sharps, whereas students with clinical experience were more likely to report compliance. Clinical students also were more likely to report having "no plans" to practice the first three of these precautions (P<.001). CONCLUSIONS: Differences in knowledge, attitudes, and intentions to comply with UP between students with and without clinical experience may have important implications for the timing and content of interventions designed to improve compliance with UP.