Ends,Means and Innovation Management

The management of innovation inevitably implies the management of uncertainty. Research and practise clearly indicate that judgements about the size and the nature of this are often inaccurate. This can result in poor performance against expectations and in some cases in complete failure. In this paper it is argued that prior analysis of the type of uncertainty can help to improve the success rate and/or reduce the time to completion. Early signs that discontinuation, or a significant change in direction, might be called for are also highlighted by this analysis.     

Determinants of genital human papillomavirus infection among cytologically normal women attending the University of New Mexico student health center

OBJECTIVES: To confirm the risk factors for genital human papillomavirus (HPV) infection. GOAL OF THIS STUDY: To investigate risk factors for HPV detection apart from the correlated risk factors for cervical neoplasia. STUDY DESIGN: Cervical human papillomavirus (HPV) DNA was assessed in 357 cytologically normal women attending the University of New Mexico student health center. Cervical swab samples were obtained for HPV DNA detection and typing using a PCR-based DNA amplification system. Possible determinants of cervical HPV were examined including age, ethnicity, history of sexually transmitted disease, oral contraceptive use, smoking, age at first intercourse, lifetime number of sex partners, marital status, and history of pregnancy. RESULTS: A 44.3% overall prevalence of cervical HPV was observed. On univariate analysis, factors associated with increasing HPV prevalence included higher lifetime number of sex partners and single marital status. After adjustment for potential confounding variables, we found that HPV prevalence increased with higher lifetime number of sexual partners. CONCLUSION: These findings, along with those from the companion reports in this issue of the journal, support the sexual route of transmission of the virus.     

Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes

1. The synthesis and release of nitric oxide may play a role in the pathogenesis of peripheral vasodilatation and hyperdynamic circulation observed in liver cirrhosis. In this work, we analysed the synthesis of nitric oxide by the lympho-mononuclear cells of peripheral blood from patients with chronic alcoholic and non-alcoholic liver disease and we identified the isoform of nitric oxide synthase involved in the increased nitric oxide synthesis. 2. Patients were classified following clinical and histological criteria in non-alcoholic cirrhotic, alcoholic cirrhotic and non-cirrhotic chronic liver disease. We studied clinical and analytical characteristics, haemodynamic parameters and endotoxin levels in these patients. 3. Cirrhotic patients showed an increase of cardiac output and a decrease of peripheral vascular resistance. These patients had higher levels of plasma endotoxin than those observed in the control group. N omega-Nitro-L-arginine methyl ester (L-NAME)-inhibitable nitrite production from mononuclear lymphocyte cells was higher in patients than in the control group, the highest levels being in non-alcoholic cirrhotic patients, and the lowest levels in patients with non-cirrhotic alcoholic liver disease. 4. Immunocytochemistry studies revealed a positive immunoreactivity for the inducible isoform of nitric oxide synthase in lympho-mononuclear cells that was more evident in non-alcoholic than in alcoholic cirrhotic patients. By Northern blot, inducible nitric oxide synthase mRNA expression was observed only in lymphomononuclear cells from non-alcoholic cirrhotic patients. 5. Our patients show a correlation between nitric oxide synthesis, endotoxin levels and haemodynamic parameters. 6. These findings indicate that lympho-mononuclear cell stimulation may play a role in elevated nitric oxide production in hepatic cirrhosis. Thus, this increased nitric oxide synthesis could be implicated in the pathogenesis of the haemodynamic disturbances frequently found in cirrhotic patients. This increase seems to be induced, at least in part, by activation of an inducible isoform of nitric oxide synthase.     

Biotransformation and toxicity of the lipoxygenase inhibitor 2-hydroxy-5-methyllaurophenone oxime (FLM 5011) on Hep G2 cells

2-Hydroxy-5-methyllaurophenone oxime (FLM 5011) is an inhibitor of lipoxygenase with antiinflammatory and antiallergic actions. We incubated FLM 5011 on the human immortal cell line Hep G2 and found a similar metabolite spectrum as in rat urine and faeces. We also measured the cytotoxicity of FLM 5011 on Hep G2 monolayers by the amido black assay and found that the influence of cell proliferation is partly due to apoptotic activities. Although the metabolic activity of Hep G2 cells is lower compared to rat hepatocyte cultures they are a suitable test system for biotransformation studies. Their higher proliferation rate allows toxicity to be characterised more exactly.     

Anti-inflammatory activity of myricetin-3-O-beta-D-glucuronide and related compounds

OBJECTIVE AND DESIGN: The anti-inflammatory effect of myricetinglucuronide (MGL) was investigated and structurally-related compounds were compared to examine the structure/activity-relationship in carrageenan-induced rat paw edema. MATERIALS AND SUBJECTS: In vitro studies were performed using rat basophilic leukemia (RBL-1) cells, human polymorphonuclear leukocytes (PMNL), COX-1 from ram seminal vesicle, COX-2 from sheep placenta and human venous blood. For the in vivo tests male Wistar rats were used, for the ex vivo test perfused rabbit ears. TREATMENT: 1-300 microg/kg MGL or myricetinmethylglucuronate and 0.1-5 mg/kg other related compounds administered p.o. (carrageenan edema). 5, 50 and 150 microg/kg MGL p.o. for 14 days (Freund's adjuvant arthritis), 5 and 50 microg/kg p.o. for 6 days (ulceration). METHODS: Anti-inflammatory effects were measured in carrageenan edema and in adjuvant arthritis. Incidence of gastric lesions was tested in an ulcerogenicity model in vivo. Influence on COX was determined in the perfused rabbit ear, in PMNL and in a test assay using COX-1 and COX-2. 5-LOX activity was studied using PMNL and RBL-1. The influence on platelet aggregation was evaluated measuring light transmission. RESULTS: MGL exerted a marked and dose-dependent anti-inflammatory effect in acute (carrageenan edema, ED50 15 microg/kg, indomethacin ED50 10 mg/kg) and chronic (adjuvant arthritis, inhibition at 150 microg/kg 18.1 % left paw, 20.6% right paw, indomethacin 3 mg/kg 18.0% and 19.4%)) models of inflammation. In the perfused rabbit ear 1 microg MGL inhibited the release of PGI2, PGD2 and PGE2 to the same extent as 1 microg indomethacin. The inhibition of COX-1 in the intact cell system was IC50 = 0.5 microM, that of indomethacin 0.0038 microM. In the isolated enzyme preparations of COX-1 and COX-2 the IC50 was 10 microM and 8 microM, that of indomethacin 9.2 mM and 2.4 microM. In the RBL-1 and PMNL test assay the inhibition of 5-LOX was 0.1 microM and 2.2 microM. An orally administered dose of 50 microg/kg/day induced no gastric ulcers in rats treated for 6 days. The investigations on carrageenan edema showed a close relationship between the structure of MGL and the anti-inflammatory effect. CONCLUSIONS: MGL is a COX-1, COX-2 and 5-LOX inhibitor. In view of the moderate in vitro activity and the very potent in vivo activity an additive mechanism must be involved. Small changes in the molecular structure lead to the loss or reduction of the anti-inflammatory activity.     

Familial idiopathic intracranial hypertension with spinal and radicular pain

OBJECTIVE: To describe a mother and her 2 sons affected by idiopathic intracranial hypertension (IIH), associated in the sons with root irritation symptom. Unlike the other 4 families reported previously, obesity was not present in our patients. DESIGN: Case reports. SETTING: Department of pediatrics in a university school of Medicine, Naples, Italy. PATIENTS: A mother (aged 36 years) and her 2 sons (aged 14 and 9 years) developed IIH at different times. Neuroimaging showed an empty sella in the mother, while IIH was associated with spinal and radicular pain in her 2 sons. The mother and the younger son developed permanent visual loss. CONCLUSIONS: Ophthalmologic follow-up in our patients indicates that IIH is a chronic disease. Surgical treatment should be considered an option.     

Increase of striatal dopamine release by cadmium in nursing rats and its prevention by dexamethasone-induced metallothionein

Repeated daily intraperitoneal (i.p.) administrations of cadmium (CdCl2, 1 mg/kg per day for 5 days) increased striatal dopamine (DA) release (180% of controls) and turnover (150% of controls) in 13-day-old rats. Cd treatment also increased striatal metallothionein (MT) content (161%), Cd (127%) and lipid peroxidation (LPO, 190%). In addition, Cd treatment decreased striatal tyrosine hydroxylase (TH) activity (-28%), and such an effect may result from D-2 receptor blockade as a consequence of excessive dopamine release, since sulpiride (a specific D-2 receptor antagonist) administration to Cd-treated rats abolished the effect of Cd on TH. No effect was observed on striatal monoamine oxidase (MAO) activity. Dexamethasone (Dx) treatment increased striatal MT content and caused no effect on either DA release or turnover. However, Dx administration prevented the effects caused by Cd, including the increased DA release and enhanced striatal lipid peroxidation. These results indicate that toxic effects on the brain are to be expected as a result of Cd exposure and that Dx administration can attenuate them.     

Effects of gemfibrozil (Lopid) on hyperlipidemia in acitretin-treated patients. Results of a double-blind cross-over study

Retrospectively 78 patients with uni- or bilateral acute acoustic trauma (AAT) were evaluated to assess the therapeutic effect of hyperbaric oxygenation (HBO). All subjects received saline or dextran (Rheomacodrex) infusions with Ginkgo extracts (Tebonin) and prednisone. Thirty six patients underwent additional hyperbaric oxygenation at a pressure of 2 atmospheres absolute for 60 minutes once daily. Both treatment groups were comparable as far as age, gender, initial hearing loss and prednisone dose are concerned. The delay of therapy onset was 15 hours in both groups and treatment was started within 72 hours in all cases. Control audiometry was performed after 6.5 days, when the HBO group had had 5 exposures to hyperbaric oxygenation. The average hearing gain in the group without HBO was 74.3 dB and in the group treated additionally with HBO 121.3 dB (P < 0.004). It is concluded, that hyperbaric oxygenation significantly improves hearing recovery after AAT. Therefore acute acoustic trauma with significant hearing threshold depression remains an otological emergency. Minimal therapy involving waiting for spontaneous recovery, which is mostly incomplete leaving a residual C5 or C6 and handicapping tinnitus, is not the treatment of choice. Randomized prospective clinical trials with a larger patient series are needed and further experimental studies are required to understand the physiological mechanisms of HBO responsible for the clinical success in AAT.     

Heterogeneity in susceptibility to metronidazole among Helicobacter pylori isolates from patients with gastritis or peptic ulcer disease

Combination therapies that include metronidazole (MTZ) are the most successful therapies used in eradicating Helicobacter pylori. In this study, the prevalence and the relevance of heterogeneity in susceptibility to MTZ among H. pylori populations of 156 patients were evaluated. The results of this study show that 37 patients (24%) were infected with MTZ-resistant H. pylori (MIC > or = 8 micrograms/ml). Furthermore, 33% (52 of 156) of the patients were found to be infected with H. pylori populations heterogeneous for their susceptibility to MTZ. The reassessment of the MICs of MTZ for these 52 H. pylori populations revealed MTZ resistance in 28 of them, increasing the number of MTZ-resistant H. pylori populations among the 156 patients to 65 (42%). Out of 20 isolates, 2 (10%) heterogeneous in their susceptibility to MTZ also appeared to be heterogeneous at the genome level as determined by randomly amplified polymorphic DNA fingerprinting. In conclusion, the results show the limitations and risk of possible misinterpretations when only a single colony, picked from the primary H. pylori populations isolated from patients, is analyzed for its susceptibility to MTZ.