Receptor tyrosine kinases expressed in metastatic colon cancer

Using a PCR-based cloning technique, we have isolated a series of DNA fragments coding for tyrosine kinases that are expressed in a metastatic human colon tumor, and have subsequently analyzed their expression pattern at the protein level in human tumors. We identified both the α and the β forms of the platelet-derived growth factor receptor (PDGFR), axl and 8 other genes, including 3 cytoplasmic tyrosine kinases. To study their expression in human colon cancer, we performed Western blots of matched sets of normal tissues and of carcinomas from the same patient. These revealed that the α-PDGFR migrates predominantly as a 200-kDa band in 8/8 normal tissues, and as a 170-kDa band in 17/17 malignant tissues, as well as in colonic polyps, suggesting that expression of an isoform of this receptor may be a marker for the progression of colon cancer. Additional studies showed that the Axl receptor tyrosine kinase was expressed at 10-fold higher levels in a peritoneal metastatic nodule than in other normal and malignant tissues. Immunohistochemistry revealed Axl over-expression specifically in the malignant cells of the tumor. This indicates that over-expression and possibly a differential processing event of tyrosine kinase receptors may be involved in colon cancer, and that they are potential markers for the progression of this disease. © 1995 Wiley-Liss. Inc.     

Cerebral palsy and juvenile-onset bipolar disorder. A preliminary report

Cerebral palsy refers to a heterogeneous group of congenital and early acquired brain disorders. Children with cerebral palsy and other brain disorders have an increased rate of psychiatric disorder. The pattern of disorder is not particularly distinctive and no specific association has been found. We report two cases of spastic diplegia of prematurity comorbid with juvenile onset bipolar disorder, which highlight some of the diagnostic difficulties in these cases. An interesting association between the periventricular leucomalacia as an aetiological factor in cerebral palsy and the white matter lesions seen on magnetic resonance imaging in cases of bipolar disorder is noted.     

5-HT1A and 5-HT2 receptors differentially regulate the excitability of 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro

We have used intracellular recording techniques to examine the effects of 5-hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30-300 microM) had two opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previously in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neurones, which appeared to involve the activation of an inwardly rectifying K(+) conductance. This hyperpolarizing response was blocked by the 5-HT(1A) receptor-selective antagonist WAY-100635 (30-100 nM). In the presence of WAY-100635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparent input resistance of the neurone, likely due to the suppression of a K(+) conductance. Like the hyperpolarizing response to 5-HT, this depolarization could be recorded in the presence of the Na(+) channel blocker tetrodotoxin. In addition, the response was not significantly attenuated by the alpha(1)-adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of alpha(1)-adrenoceptors by 5-HT. The 5-HT(3) receptor antagonist granisetron (1 microM) and the 5-HT(4) receptor antagonist SB 204070 (100 nM) failed to reduce the depolarizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 microM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT(2) receptors.     

Sample size calculation for clinical trials: the impact of clinician beliefs

The UK Medical Research Council (MRC) randomized trial of gastric surgery, ST01, compared conventional (D1) with radical (D2) surgery. Sample size estimation was based upon the consensus opinion of the surgical members of the design team, which suggested that a change in 5-year survival from 20% (D1) to 34% (D2) could be realistic and medically important. On the basis of these survival rates, the sample size for the trial was 400 patients. However, this trial was exceptional in the way that a survey of surgeons' opinions was made at the start of the trial, in 1986, and again before results were analysed but after termination of the trial in 1994. At the initial survey, the three surgeons from the trial steering committee and 23 other surgeons experienced in treating gastric carcinoma were given detailed questionnaires. They were asked about the expected survival rate in the D1 group, anticipated difference in survival from D2 surgery, and what difference would be medically important and influence future treatment of patients. The consensus opinion of those surveyed was that there might be a survival improvement of 9.4%. In 1994, prior to closure of the trial, and before any survival information was disclosed, the survey was repeated with 21 of the original 26 surgeons. At this second survey, the opinion of the trial steering committee was that 9.5% difference was more realistic. This was in accord with the opinion of the larger group, which remained little changed since 1986. The baseline 5-year D1 survival was thought likely to be about 32%, which corresponded closely to the actual survival of recruited patients. Revised sample size calculations suggested that, on the basis of these more recent opinions, between 800 and 1200 patients would have been required. Both surveys assessed the level of treatment benefit that was deemed to be sufficient for causing surgeons to change their practice. This showed that the 13% difference in survival used as the study target was clinically relevant, but also indicated that many clinicians would remain unwilling to change their practice if the difference is only 9.5%. The experience of this carefully designed trial illustrates the problems of designing long-term, randomized trials. It raises interesting questions about the common practice of basing sample size estimates upon the beliefs of a trial design committee that may include a number of enthusiasts for the trial treatment. If their opinion of anticipated effect sizes drives the design of the trial, rather than the opinion of a larger community of experts that includes sceptics as well as enthusiasts, there is likely to be a serious miscalculation of sample size requirements.     

The Cost-effectiveness of Preventing AIDS-Related Opportunistic Infections

Context.— Multiple options are now available for prophylaxis of opportunistic infections related to the acquired immunodeficiency syndrome (AIDS). However, because of differences in incidence rates as well as drug efficacy, toxicity, and costs, the role of different types of prophylaxis remains uncertain. Objective.— To determine the clinical impact, cost, and cost-effectiveness of strategies for preventing opportunistic infections in patients with advanced human immunodeficiency virus (HIV) disease. Design.— We developed a Markov simulation model to compare different strategies for prophylaxis of Pneumocystis carinii pneumonia (PCP), toxoplasmosis, Mycobacterium avium complex (MAC) infection, fungal infections, and cytomegalovirus (CMV) disease in HIV-infected patients. Data for the model were derived from the Multicenter AIDS Cohort Study, randomized controlled trials, and the national AIDS Cost and Services Utilization Survey. Main Outcome Measures.— Projected life expectancy, quality-adjusted life expectancy, total lifetime direct medical costs, and cost-effectiveness in dollars per quality-adjusted life-year (QALY) saved. Results.— For patients with CD4 cell counts of 0.200 to 0.300x10⁹/L (200-300/µL) who receive no prophylaxis, we projected a quality-adjusted life expectancy of 39.08 months and average total lifetime costs of $40288. Prophylaxis for PCP and toxoplasmosis with trimethoprim-sulfamethoxazole for patients with CD4 cell counts of 0.200x10⁹/L (200/µL) or less increased quality-adjusted life expectancy to 42.56 months, implying an incremental cost of $16000 per QALY saved. Prophylaxis for MAC for patients with CD4 cell counts of 0.050x10⁹/L (50/µL) or less produced smaller gains in quality-adjusted life expectancy; incremental cost-effectiveness ratios were $35000 per QALY saved for azithromycin and $74000 per QALY saved for rifabutin. Oral ganciclovir for the prevention of CMV infection was the least cost-effective prophylaxis ($314000 per QALY saved). Results were most sensitive to the risk of developing an opportunistic infection, the impact of opportunistic infection history on long-term survival, and the cost of prophylaxis. Conclusions.— The cost-effectiveness of prophylaxis against HIV-related opportunistic infections varies widely, but prophylaxis against PCP or toxoplasmosis and against MAC delivers the greatest comparative value. In an era of limited resources, these results can be used to set priorities and explore new alternatives for improving HIV patient care.      

Hepatitis B exposure in emergency medical personnel: Prevalence of serologic markers and need for immunization

To assess the occupational risk of hepatitis B infection in emergency medical personnel, a seroepidemiologic survey of 87 emergency medical technicians and paramedics was conducted. Serologic markers indicating exposure to hepatitis B virus were detected in 18 percent. The prevalence of markers was associated with race (p = 0.006), with a relative risk of 3.5 (95 percent confidence interval 1.42 to 8.63) for nonwhites. Seropositivity was not associated with age, sex, previous clinical hepatitis, or blood transfusion. There was a suggestion that duration of employment as an emergency medical technician was related to the prevalence of hepatitis B markers (p = 0.11). Efforts to control the risk of hepatitis B infection in this profession are complicated by unique problems with postexposure prophylaxis and uncontrolled exposure to blood. Immunization with hepatitis B vaccine would be the optimal strategy to reduce infection in this high-risk occupation.     

A prospective study of plasma angiotensin-converting enzyme in normotensive primigravidae and their infants

Plasma angiotensin-converting enzyme (ACE) has been measured prospectively throughout pregnancy, at delivery and in the puerperium in 18 normotensive primigravidae and their infants. Plasma ACE was consistently lower during pregnancy than in comparable, non-pregnant controls, but rose progressively from about 30 weeks to term. At vaginal delivery maternal and fetal ACE levels did not differ significantly. There was a steady increase in maternal ACE activity up to 6 weeks post partum, when the levels were not significantly different from non-pregnant controls. No correlation could be found between plasma ACE and plasma renin activity or concentration, or plasma AII. Plasma aldosterone increased in parallel with ACE during the last ten weeks of pregnancy.