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.     

Surgical treatment of acute dissection of the ascending aorta (20 years experience)

PURPOSE: In 1977, the use of gelatine-resorcine-formaline (GRF) biological glue during surgery of acute type A aortic dissection was proposed. The present study retrospectively analyses the late results obtained with this adjunct in an experience extending over a 20-year period. PATIENTS AND METHODS: From January 1977 to July 1997, 193 patients (139 males and 54 females) aged from 15 to 79 years (mean age: 53 +/- 14 years) underwent an emergency operation for type A aortic dissection in our institution. All patients suffering from acute type A dissection and 162 (84%) were operated on within 48 hours after the onset of symptoms. Twenty-eight patients (15.2%) had Marfan's syndrome. In all patients the ascending aorta was replaced and the aortic stumps were reinforced with the GRF glue. In 43 patients (22.2%), the aortic valve was replaced either independently (5 cases-2.5%) or by means of a composite graft (35 cases-19.5%). Recently three patients underwent a complete replacement of the ascending aorta and coronary reimplantation with preservation of the native aortic valve. Because of the location of the intimal tear, the aortic replacement was extended to the transverse arch in 58 patients (30%). RESULTS: Hospital mortality amounted to 21% (40 patients) (22.8% in patients with arch replacement and 20.3% in patients without arch replacement) (ns). The survivors were surveyed from 2 months to 20 years post-operatively (cumulative follow-up: 856 pt/years, mean follow-up: 85 +/- 66 months). During this period of time, 23 patients (15%) had to be reoperated on for a total of 29 procedures. Six of those patients (26%) died at reoperation. At univariate analysis, presence of Marfan's syndrome (P < 0.05) and absence of arch replacement (P < 0.02) were determinant risk factors for reoperation. Emergency (P < 0.01) and thoraco-abdominal replacement (P < 0.04) were determinant risk-factors of death at reoperation. The actuarial freedom from reoperation (Kaplan-Meier, CI: 95%) was: 96.5% (90.9-98.2), 87.6% (79.8-92.7), 80.9% (70.8-88.1), 66.4% (51.1-78.9) at one, 5, 10 and 15 years, respectively. A total of 36 patients (27.7%) died during follow-up. Presence of Marfan's syndrome (P < 0.01), reoperation (P < 0.02), stroke (P < 0.05), cardiac failure (P < 0.05) were determinant risk factors of late mortality. The actuarial late survival rate (Kaplan-Meier. CI: 95%), including hospital mortality, was: 71.5% (64.3-77.8), 66% (58.3-73), 56.4% (47.7-64.7), 46.3% (36.4-56.5) at one, 5, 10 and 15 years. CONCLUSION: The GRF glue has proved to be extremely useful during initial emergency surgery for acute type A dissection, making the procedure much easier and safer. Through this operative improvement, the use of the GRF glue seems to have a beneficial influence on the late results which, however, depend mainly on the patient's basic condition.     

Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes

OBJECTIVE: To demonstrate the efficacy, tolerability, and safety of acarbose compared with placebo in patients with type 2 diabetes inadequately controlled with diet and insulin. RESEARCH DESIGN AND METHODS: A multicenter randomized double-blind placebo-controlled parallel-group comparison study was conducted. The trial was 26 weeks with a 2-week screening period and a 24-week period of treatment with acarbose or placebo, with forced titration from 25 mg t.i.d. to 50 mg t.i.d. after 4 weeks, and titration of 50 mg t.i.d. to 100 mg t.i.d. after 12 weeks based on glucose control. The dosage of insulin was to remain stable. The primary efficacy variable was mean change from baseline in HbA1c, and secondary efficacy variables included mean changes in fasting and postprandial plasma glucose and triglyceride levels. RESULTS: The addition of acarbose to the treatment of patients receiving background insulin and diet therapy resulted in a statistically significant reduction in mean HbA1c of 0.69% compared with placebo. There were statistically significant reductions in postprandial plasma glucose and glucose area under the curve, and in postprandial serum triglyceride levels in the acarbose-treated patients. Gastrointestinal side effects were more frequently reported in the acarbose-treated patients. There were no significant differences in hypoglycemic events or liver transaminase elevations between groups. CONCLUSIONS: This study demonstrated that the addition of acarbose to patients with type 2 diabetes who are inadequately controlled with insulin and diet is safe and generally well tolerated and that it significantly lowers HbA1c and postprandial glucose levels.     

Methodology for the study and projection of surgical and anaesthetic workforce

The Australian Medical Workforce Advisory Committee has studied the specialties of anaesthesia, general surgery, orthopaedics, ophthalmology and urology in Australia. A methodology is presented for rationalizing various data sources to establish numbers and characteristics of the existing workforce, for applying a variety of information to establish opinion about current adequacy, to project future needs and to advise the mechanisms to ensure delivery of services. This study emphasizes the importance of the cooperative input of governments, health administrations and professional bodies, careful gathering of fundamental data, the studied application of uneven pieces of evidence, recognition of changes in needs and demands, the overlap of sectors of the medical workforce in service delivery, and the requirement for continued study and monitoring. The current size of the workforce in these surgical specialties is found to be satisfactory overall but with some uneven distribution. The anaesthetic workforce is found to be slightly deficient in number overall. The growth of future demand for these specialties was estimated between 1% and 3% per annum and requirements for increases in trainee numbers to meet these projected future demands are defined.     

Improving Predictive Accuracy with a Combination of Human Intuition and Mechanical Decision Aids

This study examines the intuitive combination of human judgment and mechanical prediction under varied information conditions. As expected, mechanical prediction outperformed human intuition when based on the same information, but a combined approach was best when judges had access to relevant information not captured by the model (information asymmetry). The model was useful for differentiating between the event outcomes (improved slope), while eliminating the bias caused by base-rate neglect. Human intuition was useful for incorporating relevant information outside the scope of the model, resulting in improved slope and reduced judgment scatter. The addition of irrelevant information was detrimental to judgment accuracy, causing an increase in bias and a reduction in slope. These results provide insight into how and when combining mechanical prediction and human intuition is likely to result in improved accuracy. Copyright 1998 Academic Press.     

Continuous spinal anaesthesia

CD59 is a cell membrane-bound complement regulatory protein on glomerular cells that inhibits C5b-9 assembly and insertion. This report describes a recently developed model of immune thrombotic microangiopathy (TMA) induced by the renal artery perfusion of anti-glomerular endothelial cell (anti-GEN) antibody. To examine the role of CD59 in protecting the GEN from immune-mediated injury, rats underwent selective renal artery perfusion with F(ab')2 fragments of anti-CD59 monoclonal antibody to block CD59 activity or control mouse IgG followed by anti-GEN antibody or control goat IgG. Neutralization of CD59 in normal rats did not result in any significant functional or histologic changes. Perfusion with anti-CD59 did not change deposition of the pathogenic anti-GEN IgG used to induce the TMA model. However, neutralization of CD59 in the TMA model resulted in more C5b-9 formation in glomeruli, accompanied by increased platelet and fibrin deposition, more severe endothelial injury, and reduced renal function compared with the animals perfused with control F(ab')2 fragments. These results demonstrate directly that CD59 serves a protective role for GEN in this TMA model of rats, and confirm that C5b-9 formation has a critical pathogenic role in the mediation of the disease. CD59 may play an important role in protecting glomerular endothelium from other complement-mediated types of injury.     

Calcium-sensitive calcium influx in photoreceptor inner segments

The effect of external calcium concentration ([Ca2+]o) on membrane potential-dependent calcium signals in isolated tiger salamander rod and cone photoreceptor inner segments was investigated with patch-clamp and calcium imaging techniques. Mild depolarizations led to increases in intracellular Ca2+ levels ([Ca2+]i) that were smaller when [Ca2+]o was elevated to 10 mM than when it was 3 mM, even though maximum Ca2+ conductance increased 30% with the increase in [Ca2+]o. When external calcium was lowered to 1 mM [Ca2+]o, maximum Ca2+ conductance was reduced, as expected, but the mild depolarization-induced increase in [Ca2+]i was larger than in 3 mM [Ca2+]o. In contrast, when photoreceptors were strongly depolarized, the increase in [Ca2+]i was less when [Ca2+]o was reduced. An explanation for these observations comes from an assessment of Ca2+ channel gating in voltage-clamped photoreceptors under changing conditions of [Ca2+]o. Although Ca2+ conductance increased with increasing [Ca2+]o, surface charge effects dictated large shifts in the voltage dependence of Ca2+ channel gating. Relative to the control condition (3 mM [Ca2+]o), 10 mM [Ca2+]o shifted Ca2+ channel activation 8 mV positive, reducing channel open probability over a broad range of potentials. Reducing [Ca2+]o to 1 mM reduced Ca2+ conductance but shifted Ca2+ channel activation negative by 6 mV. Thus the intracellular calcium signals reflect a balance between competing changes in gating and permeation of Ca2+ channels mediated by [Ca2+]o. In mildly depolarized cells, the [Ca2+]o-induced changes in Ca2+ channel activation proved stronger than the [Ca2+]o-induced changes in conductance. In response to the larger depolarizations caused by 80 mM [K+]o, the opposite is true, with conductance changes dominating the effects on channel activation.     

Resistance issues and treatment implications: pneumococcus, Staphylococcus aureus, and gram-negative rods

During the last decade there has been an unexpectedly rapid evolution of antimicrobial resistance in the respiratory pathogens for community- and hospital-acquired pneumonia. In order to choose the most optimal therapy for their patients, it is essential that physicians be aware of the prevalence and mechanisms of resistance and their implications on the effectiveness of the various antimicrobials.