Postmenopausal estrogen use and Parkinson''s disease with and without dementia

Transmyocardial laser revascularization is an emerging technique for treatment of patients with coronary artery disease not amenable to standard revascularization by either percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. Transmyocardial laser revascularization is typically performed as an isolated procedure on the beating heart, although it has been performed as an adjunct to conventional coronary artery bypass grafting in nongraftable territories. We report the use of transmyocardial laser revascularization in combination with mitral valve replacement via a left lateral thoracotomy for treatment of ischemic mitral regurgitation.     

Functional analysis of the catalytic subunit of Dictyostelium PKA in vivo

Long-term amygdala kindling in rats produces increases in emotionality (Kalynchuk et al., Biol. Psychiatry, 41 (1997) 438-451). The present experiment was conducted to investigate whether this hyperemotionality is specific to amygdala kindling or whether it can be produced by kindling other structures. Rats received 99 convulsive or sham stimulations of either the amygdala, the hippocampus, or the caudate nucleus. One day after the stimulation phase, each rat's open-field activity and resistance to capture were assessed; the following day, each rat was tested on an elevated plus maze. The site of stimulation had a significant effect on the results of each of these tests. The amygdala-kindled and hippocampal-kindled rats explored less in the open field, were more resistant to capture from the open field, and engaged in a greater percentage of open-arm activity in the elevated plus maze than did the caudate-kindled rats or the sham-stimulated controls. The caudate-kindled rats were more active in the open field than their sham-stimulated controls, but they did not significantly differ from them in terms of the other measures. These results suggest that kindling-induced emotionality is produced by limbic kindling but not nonlimbic kindling.     

Prevalence of myopia between 3 months and 5 1/2 years in preterm infants with and without retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group

Familial hypertrophic cardiomyopathy can be caused by mutations in genes encoding sarcomeric proteins, including the cardiac isoform of myosin binding protein C (MyBP-C), and multiple mutations which cause truncated forms of the protein to be made are linked to the disease. We have created transgenic mice in which varying amounts of a mutated MyBP-C, lacking the myosin and titin binding domains, are expressed in the heart. The transgenically encoded, truncated protein is stable but is not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the pCa2+-force curve and, importantly, their power output was reduced. Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, resulting in a striking pattern of sarcomere disorganization and dysgenesis.     

Diffusible cytotoxic metabolites contribute to the in vitro bystander effect associated with the cyclophosphamide/cytochrome P450 2B1 cancer gene therapy paradigm

Tumor cells become sensitive to the inert prodrug cyclophosphamide (CPA) after transfer of the gene encoding cytochrome P450 2B1. This enzyme activates CPA into 4-hydroxycyclophosphamide, which ultimately degrades into acrolein and phosphoramide mustard, the anticancer and DNA-alkylating metabolite. It is imperative that any prodrug-activating gene therapy strategy against cancer possess the capacity to affect the proliferation of tumor cells even when they do not express the transgene (bystander effect), because current methodologies cannot achieve gene transduction in all tumor cells. Prodrug-activating gene therapy schemes described to date exhibit a bystander effect that is not mediated by conditioned medium in culture and may depend on cell contact. In contrast, we find that CPA-sensitized, P450-expressing C6 glioma cells (C6-P450) transfer cytotoxicity to nonexpressing cells by releasing diffusible metabolites through the medium. A 3-h exposure to the prodrug is necessary and sufficient to achieve killing of the transfected cells, and medium conditioned by these cells can kill untransfected cells with similar potency. This bystander effect occurs in the presence of CPA even when only 10% of cells in culture express the P450 2B1 gene, and it is not reproduced by cells that have been irradiated. In an animal model of intracerebral brain tumors, expression of the P450 2B1 gene within the neoplastic cells enhanced significantly the antitumor effect of CPA, even when it was administered systemically. This study shows that CPA/P450 2B1 gene therapy represents a novel tumor-killing strategy that displays an expanded range of cytotoxic action both spatially and temporally within tumor cells and significantly potentiates the anticancer action of CPA when administered i.v.     

Neutrophil collagenase in sputum from patients with cystic fibrosis

The potential role of neutrophil elastase in causing lung damage and exacerbating the inflammatory response in cystic fibrosis (CF) has received considerable attention. Although another potent neutrophil-derived enzyme, collagenase, is implicated in tissue destruction in several interstitial lung disorders, there has been no reference to this enzyme in CF. The objective of this study was to determine whether neutrophil collagenase is present in active form in CF sputum and, if so, whether it is related to disease severity. High levels of active collagenase were detected in sputum from patients with CF, and the majority of the enzyme present was of neutrophil origin. In a group of 16 patients with CF, negative relations between sputum collagenase activity and Shwachman score (r = -0.55, p < 0.05) and FEV1 (r = -0.59, p < 0.02) were noted, indicating an association between high collagenase activity and severity of disease. A positive correlation was observed between sputum collagenase and elastase activity (r = 0.62, p < 0.05). These results suggest that both neutrophil elastase and collagenase may play a significant role in lung destruction in CF.     

Assessment of fitness in patients with cystic fibrosis and mild lung disease

The purpose of this investigation was to examine if exercise-induced arterial oxyhemoglobin desaturation selectively observed in highly trained endurance athletes could be related to differences in the pulmonary diffusing capacity (DL) measured during exercise. The DL of 24 male endurance athletes was measured using a 3-s breath-hold carbon monoxide procedure (to give DLCO) at rest as well as during cycling at 60% and 90% of these previously determined VO2max. Oxyhemoglobin saturation (SaO2%) was monitored throughout both exercise protocols using an Ohmeda Biox II oximeter. Exercise-induced oxyhemoglobin desaturation (DS) (SaO2% < 91% at VO2max) was observed in 13 subjects [88.2 (0.6)%] but not in the other 11 nondesaturation subjects [NDS: 92.9 (0.4)%] (P < or = 0.05), although VO2max was not significantly different between the groups [DS: 4.34 (0.65) l/min vs NDS: 4.1 (0.49) l/min]. At rest, no differences in either DLCO [ml CO.mmHg-1.min-1: 41.7 (1.7) (DS) vs 41.1 (1.8) (NDS)], DLCO/VA [8.2 (0.4) (DS) vs 7.3 (0.9) (NDS)], MVV [l/min: 196.0 (10.4) (DS) vs 182.0 (9.9) (NDS)] or FEV1/FVC [86.3 (2.2) (DS) vs 82.9 (4.7) (NDS)] were found between groups (P > or = 0.05). However, VE/VO2 at VO2max was lower in the DS group [33.0 (1.1)] compared to the NDS group [36.8 (1.5)] (P < or = 0.05). Exercise DLCO (ml CO.mmHg-1.min-1) was not different between groups at either 60% VO2max [DS: 55.1 (1.4) vs NDS: 57.2 (2.1)] or at 90% VO2max [DS: 61.0 (1.8) vs NDS: 61.4 (2.9)]. A significant relationship (r = 0.698) was calculated to occur between SaO2% and VE/VO2 during maximal exercise. The present findings indicate that the exercise-induced oxyhemoglobin desaturation seen during submaximal and near-maximal exercise is not related to differences in DL, although during maximal exercise SaO2 may be limited by a relatively lower exercise ventilation.     

Early treatment of posterior retinopathy of prematurity: a controlled trial

OBJECTIVE: The purpose of the study is to assess the possible benefits of early laser treatment for posterior retinopathy of prematurity (ROP) and to provide data concerning the natural history of posterior ROP. DESIGN: The study design was a prospective, multicenter, randomized trial. PARTICIPANTS: A total of 19 infants with prethreshold posterior ROP were studied. INTERVENTION: Randomization to immediate indirect laser photocoagulation or observation, with application of laser photocoagulation for those control eyes reaching threshold disease, was performed. MAIN OUTCOME MEASURES: Patients were assessed at 3 months and the anatomic outcome recorded along with any adverse treatment effects. RESULTS: An unfavorable structural outcome developed in 3 (16%) of 19 early treatment eyes compared with 3 (18%) of 17 for those treated only if threshold disease was reached. Of the 17 control eyes, 15 (88%) reached threshold disease. Progression to threshold occurred within 1 week in all but two eyes. All 12 control eyes with posterior ROP and any amount of extraretinal fibrovascular proliferation progressed to threshold disease. CONCLUSIONS: Although the number of patients studied is too small to reach statistical significance, the likelihood of a favorable outcome for eyes with prethreshold posterior ROP treated immediately with laser photocoagulation is comparable to that obtained by withholding treatment until threshold disease is reached. There is a high probability of progression from prethreshold to threshold disease, usually within 1 week or less.     

Retrospect of a pharmacologist''s life]

Two fluorescent probes were used for the measurement of membrane fluidity in patients on haemodialysis and continuous ambulatory peritoneal dialysis. 1,6-Diphenyl-1,3,5-hexatriene (DPH) anisotropy gives an indication of lipid order and pyrene measures lateral diffusion through the membrane. Pyrene dimer/monomer ratio was significantly lower than controls in both pre-dialysis and post-dialysis samples but DPH anisotropy was unchanged. Both methods showed an increase in membrane fluidity across a 4 hour haemodialysis session. There was an increase in membrane fluidity in CAPD patient samples which was more marked using DPH than pyrene. These results suggest that the two probes give different but complementary information about changes in membrane fluidity and may be more informative when used together rather than singly.