Gene Replacement Strategies for Lung Cancer

Advances in our understanding of the molecular genetics of cancer present an opportunity to develop prevention and treatment strategies based on the reversal of specific genetic lesions. This strategy is analogous to the classic concept of gene therapy for replacement of defective or nonfunctioning genes. The gene families implicated in carcinogenesis include dominant oncogenes and tumor suppressor genes. Regional administration of viral vectors expressing wildtype p53 and antisense K-ras prevents tumor growth for tumors with the specific genetic lesions in orthotopic tumor models and mediates regression of large established tumors. These studies provide a rationale for a new clinical protocol recently approved by the National Institutes of Health Recombinant DNA Advisory Committee and Food and Drug Administration to replace a defective p53 gene with intratumor injection of recombinant retrovirus expressing wild-type p53 or elimination of activated K-ras by expression of antisense K-ras messenger RNA. If these agents are efficacious, their lack of toxicity may provide a sufficiently high therapeutic index such that they could be used as an adjuvant to surgery to treat patients with earlier stages of cancer or as prevention for second primary cancers for individuals with genetic abnormalities in premalignant lesions. Although much research needs to be done, the possibility of specific gene targeting with a high therapeutic index makes this a promising area of investigation.     

Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia

In this prospective study, the postoperative analgesic effects of intraoperative iv clonidine were evaluated. Two hundred consecutive patients undergoing major abdominal surgery were randomly assigned to either balanced anaesthesia with iv clonidine (Group 1) or balanced anaesthesia alone (Group 2). A PCA infuser was connected immediately after tracheal extubation. It was programmed to deliver morphine "on demand" iv boluses at doses of 1 mg for patients greater than 65 yr and 1.5 mg for women or 2 mg for men less than 65 yr old. A blinded observer assessed postoperative analgesia by recording the analgesic demands (both met and unmet), patient pain scores, sedation scores, and any side effects during the first 36 hr after surgery. Intraoperative clonidine reduced the number of analgesic demands during the observation period (45 +/- 27 demands in Group 1 vs 81 +/- 60 in Group 2, P = 0.0001). This resulted in a reduction in morphine delivered (55.4 +/- 30.6 mg vs 67.1 +/- 45.1 mg, P less than 0.05), mainly during the first 12 hr (19.7 +/- 11.1 mg vs 27.6 +/- 18.1, mg P less than 0.001) and the unmet demand rate was also reduced at all time intervals (P less than 0.01). Clonidine did not exacerbate sedation or side effects. However, clonidine provided better analgesia in men and in patients less than 65 yr of age. Intraoperative iv clonidine enhances morphine analgesia after abdominal surgery.     

Laser angioplasty in peripheral arterial disease

Laser angioplasty was performed in 66 patients with total occlusion of the ilio-femoral artery. The system used consisted of a pulsed dye laser operating at 480 nm, 50 mJ pulse^–1, 2s pulse^–1 and 5 Hz. The treatment laser was coupled into a 200m optical fibre wrapped around a coil for improved flexibility and radiopacity. The treatment laser was connected with a diagnostic laser consisting of a continuous wave helium-cadmium laser operating at 325 nm, 50 ms and 3 mW for tissue detection using fluorescence spectroscopy. The primary success rate was 82%, the complication rate was 15% without any clinical sequelae and the 18 month follow-up patency rate was 64%. Due to the narrow pilot channel created by laser angioplasty, in each case a complementary balloon angioplasty was required to restore the arterial lumen. The success rate did not depend upon the length of occlusion but was rather related to the extent of calcification. Laser angioplasty guided by spectroscopy is effective and safe in patients with totally occluded peripheral arteries in whom mechanical devices failed to cross the obstruction.     

Mapping of c-fos gene expression in the brain during morphine dependence and precipitated withdrawal, and phenotypic identification of the striatal neurons involved

The c-fos gene is expressed in the central nervous system in response to various neuronal stimuli. Using in situ hybridization, we examined the effects of chronic morphine treatment and withdrawal on c-fos mRNA in the rat brain, and particularly within identified striatal neurons. Morphine dependence was induced by subcutaneous implantation of two pellets of morphine for 6 days and withdrawal was precipitated by administration of naltrexone. Placebo animals and morphine-dependent rats showed a very weak c-fos mRNA expression in all the structures studied. Our study emphasized the spatial variations in c-fos mRNA expression, and also revealed a peak expression of c-fos mRNA at 1 h after naltrexone-precipitated withdrawal in the projection areas of dopaminergic neurons, noradrenergic neurons and in several regions expressing opiate receptors. Interestingly, morphine withdrawal induces c-fos mRNA expression in the two efferent populations of the striatum (i.e. striatonigral and striatopallidal neurons) both in the caudate putamen and nucleus accumbens. Moreover, the proportions of activated neurons during morphine withdrawal are different in the caudate putamen (mostly in striatopallidal neurons) and in the shell and core parts of the nucleus accumbens (mostly in striatonigral neurons). The activation of striatopallidal neurons suggests a predominant dopaminergic regulation on c-fos gene expression in the striatum during withdrawal. On the contrary, c-fos induction in striatonigral neurons during withdrawal seems to involve a more complex regulation like opioid-dopamine interactions via the mu opioid receptor and the D1 dopamine receptor coexpressed on this neuronal population or the implication of other neurotransmitter systems.     

Duration of antibiotic treatment in intensive care: current data

OBJECTIVE: To review the current data on the duration of an antibiotic treatment. METHODS: Analysis of recent and older articles on criteria of discontinuation of an antibiotic treatment in intensive care patients. SYNTHESIS: In intensive care patients the initiation of an antibiotic therapy is more or less codified, in spite of numerous existing problems. The duration of its maintenance, although based on scientific data depends mainly on a multitude of variables. The first step is to assess the therapeutic efficiency in considering the regression of clinical manifestations, the normalization of the acute phase reactants, the sterility of bacteriological samples and the absence of relapse at therapy discontinuation. An assessment after 48 hours is essential, in order to decide the maintenance or the modification of therapy. Finally the indication of bitherapy is considered. The theoretical duration of antibiotic therapy is determined in taking into account the involved microbial agent(s), the centre of infection, the bacterial inoculum, the patient, the presence of foreign material, and the administered antibiotic.     

Prevalence of methicillin-resistant Staphylococcus aureus nasal carriage among patients with femoral neck fractures: implication for antibiotic prophylaxis.

Fifteen (8.4%) of 179 patients admitted with femoral neck fractures carried MRSA. Among 96 patients admitted from their homes, only 2 (2%) were carriers, whereas 13 (15.6%) of 83 patients from nursing or residential homes or long-term-care facilities were colonized (P = .001). Routine prophylaxis with vancomycin is recommended in the latter group.