Caveolins as tumour markers in lung cancer detected by combined use of cDNA and tissue microarrays

To identify new potential diagnostic markers for lung cancer, the expression profiles of 37 lung tumours were analysed using cDNA arrays. Seven samples were from small-cell lung cancer (SCLC), two from large-cell neuroendocrine tumours (LCNEC), and 28 from other non-small-cell lung cancers (mainly squamous cell cancer and adenocarcinoma). Principal component analysis and the permutation test were used to detect differences in the gene expression profiles and a set of genes was found that distinguished high-grade neuroendocrine carcinomas (SCLC and LCNEC) from other lung cancers. In addition, several genes, such as caveolin-1 (CAV1) and caveolin-2 (CAV2), were constantly deregulated in all types of tumour sample, compared with normal tissue. The expression of these two genes was investigated further at the protein level on a tissue microarray containing tumours from 161 patients and normal tissues. Immunostaining for CAV1 was negative in 48% of tumours, whereas 28% of the tumours did not express CAV2. Lack of CAV1 protein expression was not caused by methylation or mutation. In stage I adenocarcinomas, CAV2 protein expression correlated with shorter survival. In conclusion, the present study was able to identify genes that have not previously been implicated in lung cancer by the combined use of two different array techniques. Some of these genes may provide novel diagnostic markers for lung cancer.     

Ultrasonographic and power Doppler evaluation of the patellar tendon ten years after harvesting its central third for reconstruction of the anterior cruciate ligament: comparison of patients without or with anterior knee pain

BACKGROUND: The long-term morphologic changes in the patellar tendon after harvesting its central third for the reconstruction of the anterior cruciate ligament have not been reported. HYPOTHESIS: Sonographic morphologic changes in the harvested patellar tendon are common 10 years after the harvesting procedure. STUDY DESIGN: Retrospective cohort study. METHODS: Thirty-one patients who had undergone an anterior cruciate ligament reconstruction using central-third bone-patellar tendon-bone autograft with a closure of the patellar tendon defect were included in this study. An ultrasonographic and Power Doppler examination was performed at a mean follow-up of 10 years. RESULTS: Ultrasonography of the harvested patellar tendon showed intratendinous calcification in 9 patients, hypoechoic lesion in 20 patients, hyperechoic lesion in 1 patient, and peritendinous changes in 1 patient. Only 3 (9.7%) of the 31 patients had no changes in the harvested patellar tendon. No abnormality was visible in the contralateral (normal) patellar tendons of the 31 patients. The harvested patellar tendon was significantly thicker than the contralateral patellar tendon (P < 0.05). CONCLUSIONS: Sonographic morphologic changes of the patellar tendon were common 10 years after the harvesting procedure, although no evidence of inflammatory process, as could be seen in Power Doppler flow, was found inside of any patellar tendon.     

Anterior knee pain and thigh muscle strength after intramedullary nailing of tibial shaft fractures: a report of 40 consecutive cases

OBJECTIVES: Chronic anterior knee pain is a common complication following intramedullary nailing of a tibial shaft fracture. The source of pain is often not known nor is the reason for a simultaneous decrease in thigh muscle strength. Anterior knee pain has also been reported following an anterior cruciate ligament rupture. No previous investigation has assessed whether weakness of the thigh muscles is associated with anterior knee pain following intramedullary nailing of tibial shaft fractures. DESIGN: Prospective study. SETTING: University Hospital of Tampere, University of Tampere. PATIENTS: Fifty consecutive patients with a nailed tibial shaft fracture were initially included in the study. Ten patients did not have isokinetic strength testing for various reasons and were eliminated from the study. MAIN OUTCOME MEASUREMENTS: Isokinetic muscle strength measurements were done in 40 patients at an average 3.2 +/- 0.4 (SD) years after nail insertion (1.7 +/- 0.3 years after the nail extraction). RESULTS: Twelve (30%) patients were painless and 28 (70%) patients had anterior knee pain at follow-up. With reference to the hamstrings muscles, the mean peak torque deficit of the injured limb (as compared with the uninjured limb) was 2 +/- 11% in the painless group and 11 +/- 17% in the pain group at a speed of 60 degrees /s (P = 0.09, [95% CI for the group difference = -18% to 0%]). At a speed of 180 degrees /s, the corresponding deficits were -3 +/- 13% and 10 +/- 21% (P = 0.03, [95% CI for the group difference = -4% to -2%]). With reference to the quadriceps muscles, the mean peak torque deficit of the injured limb was 14 +/- 15% in the painless group and 15 +/- 15% in the pain group at speed of 60 degrees /s (P = 0.71, [95% CI for the group difference = -11% to 10%]). At a speed of 180 degrees /s, the corresponding deficits were 9 +/- 11% and 14 +/- 17% (P = 0.46, [95% CI for the group difference = -14% to 5%]). CONCLUSION: Based on this prospective study, we conclude that anterior knee pain after intramedullary nailing of a tibial shaft fracture, although of multifactorial origin, may be related to deficiency in the flexion strength of the thigh muscles.     

Pulmonary artery blood temperature at admission to the intensive care unit is predictive of outcome after on-pump coronary artery bypass surgery

OBJECTIVE: To evaluate whether pulmonary artery blood (PA) temperature on admission to the intensive care unit (ICU) is predictive of postoperative outcome after isolated on-pump coronary artery bypass grafting (CABG). DESIGN: A retrospective study on 1639 patients who underwent isolated on-pump CABG in whom PA temperature at admission to the ICU was available for review. RESULTS: Thirty-three patients (2.0%) died during the in-hospital stay and 87 patients (5.3%) developed low cardiac output syndrome. PA temperature at admission to the ICU was significantly associated with an increased risk of overall postoperative death (p = 0.002), cardiac death (p = 0.03), and low cardiac output syndrome (p < 0.0001), and was significantly correlated with prolonged length of ICU stay (p < 0.0001) and postoperative bleeding (p = 0.001). Patients with high PA temperature had significantly more severe comorbidities, and longer aortic cross-clamping and cardiopulmonary bypass time. The receiver operating characteristic curve showed that PA temperature at admission to the ICU in predicting postoperative death had an area under the curve of 0.660 (p = 0.002) and its best cut-off value was 36.4 degrees C (sensitivity: 63.6%, specificity: 65.2%). When the PA temperature at admission to the ICU was > or = 36.4 degrees C, the postoperative mortality and low cardiac output syndrome rates were 3.6 and 8.3%, whereas they were 1.1 and 3.7% when the PA temperature at admission to the ICU was < 36.4 degrees C (p = 0.001, p < 0.0001), respectively. CONCLUSION: Patients having a PA temperature > or =36.4 degrees C at admission to the ICU after CABG seem to be at higher risk of poor postoperative outcome.     

Striatal dopamine D2 receptors in modulation of pain in humans: a review

We review evidence indicating that the striatum and striatal dopamine D2 receptors are involved in the regulation of pain in humans. Painful stimulation produces an increase in regional cerebral blood flow in the human striatum. Pain is a common symptom in patients with nigrostriatal dopaminergic hypofunction. Positron emission tomography findings show that a low dopamine D2 receptor availability in the striatum of healthy subjects (indicating either a low density of dopamine D2 receptors or a high synaptic concentration of dopamine) is associated with a high cold pain threshold and a low capacity to recruit central pain inhibition by conditioning stimulation. Patients with chronic orofacial pain have higher dopamine D2 receptor availability than their age-matched controls. We propose that the striatal dopamine D2 receptor may be an important target for the diagnosis and treatment of chronic pain.     

Concomitant vinorelbine and radiation in head and neck squamous cell carcinoma in vitro

Concomitant chemoradiotherapy has been used for locally advanced head and neck squamous cell carcinoma (HNSCC) particularily with cisplatin, 5-FU, methotrexate, bleomycin and taxanes. Vinorelbine is a semisynthetic vinca alcaloid, which causes a block in the G2/M phase of the cell cycle. HNSCC cell lines have previously been reported to be sensitive to vinorelbine in nanomolar concentrations. In the current study the effect of vinorelbine as a radiosensitizer in vitro was studied and eight recently established head and neck SCC cell lines of the UT-SCC-series were tested. Vinorelbine concentrations of 0.4-1.6 nM were used, corresponding to the IC70, IC50 and IC30 values of each cell line, resulting in 30%, 50% and 70% inhibition in clonogenic survival. The desired concentrations of vinorelbine were added to the medium and the cells were plated in 96-well culture plates in this solution. The plated cells were irradiated 24 h later with 4MeV photons generated by a linear accelerator and incubated at 37 degrees C with 5% CO2 for 4 weeks. Thereafter, the number of wells containing coherent, living colonies, consisting of 32 cells or more, was counted. The plating efficiency was calculated and the fraction survival data were fitted to the linear quadratic model [F = exp[-(alphaD + betaD2)]]. An additive effect of combining vinorelbine and irradiation could be demonstrated. The dose-dependent decrease in survival was seen at vinorelbine doses of 0.4-1.6 nM in all cell lines tested.     

Flavonol and Flavone Intake and the Risk of Intermittent Claudication in Male Smokers

The objective of this study was to investigate the association between flavonol and flavone intake and the risk of intermittent claudication in male smokers. The study population consisted of participants of the Finnish alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) Study, who were free of intermittent claudication at study entry. These 25,041 male smokers were 50-69 years old at baseline. Participants completed a validated dietary questionnaire at baseline. The occurrence of intermittent claudication was assessed by annual administration of the Rose questionnaire. During the median follow-up of 4.1 years, 2412 new cases of intermittent claudication were observed. Dietary intake of flavonols and flavones was inversely associated with the risk of intermittent claudication when adjusted for cardiovascular risk factors (relative risk, RR in the highest vs. lowest quintile of intake 0.86, 95% confidence interval, CI: 0.75-0.98, p for trend 0.007). However, after further adjustment for intakes of vitamins C and E and total carotenoids, the association was attenuated (RR: 0.93, 95% CI: 0.81-1.08, p for trend 0.12). The risk of intermittent claudication was lower among men in the highest quintile of vegetable consumption (RR: 0.78, 95% CI: 0.69-0.89, p for trend 0.0001) and among wine drinkers (RR: 0.63, 95% CI: 0.41-0.98). Adjustment for flavonol and flavone intake only marginally changed these associations. In conclusion, flavonol and flavone intake was not independently associated with the risk of intermittent claudication.     

Cancer cells as targets for lentivirus-mediated gene transfer and gene therapy

Lentiviruses have been used as gene transfer vectors for almost 10 years and their utility has been demonstrated in a variety of different applications. However, their value in cancer gene therapy has not been studied thoroughly. Here we show that VSV-G pseudotyped HIV-1-based lentiviruses are efficient vectors for human tumor cells in vitro and in vivo. Lentiviral gene transfer efficiency was demonstrated by transducing 42 different cell lines, representing 10 different human tumor types. It was shown that most of the cell lines were good or excellent targets for lentiviral transduction, allowing 50-95% gene transfer efficiency. These results were comparable to those obtained with an E1/E3 deleted, serotype 5 adenovirus vector. Analysis of lentivirus vector structure revealed that virus particles devoid of HIV-1 accessory proteins appeared to be more efficient, but the presence of enhancing elements cPPT and WPRE did not play a major role in transduction efficiency to four different human tumor cell lines. However, their effect on the gene expression level in these cells was apparent. To examine the impact of lentiviral gene expression level on suicide gene therapy approach, human osteosarcoma cells were transduced with lentivirus- or adenovirus vectors carrying the fusion gene HSV-TK-GFP and exposed to ganciclovir. Cell viability analysis after the treatment revealed that both vector types induced similar level of cytotoxicity, suggesting that lentiviral expression of a suicide gene is adequate for tumor cell destruction. Finally, in vivo transduction studies with subcutaneous tumors showed that lentivirus vectors can yield similar gene transfer efficiency than adenovirus vector, despite three orders of magnitude lower titer of the lentiviral preparation. In conclusion, these data show that lentiviruses are efficient gene transfer vehicles for human tumor cells and justify their use in further preclinical cancer gene therapy studies.     

Asphyxia aggravates systemic hypotension but not pulmonary hypertension in piglets with meconium aspiration

Meconium aspiration and birth asphyxia are both separately connected to significant pulmonary and systemic hemodynamic changes in newborns, but, although these insults frequently coexist, their combined effects on the neonatal circulation are still controversial. To determine the pulmonary and systemic circulatory changes induced by pulmonary meconium contamination with concurrent asphyxia, 41 anesthetized and ventilated newborn piglets (10-12 d) were studied for 6 h. Eleven piglets were instilled with a bolus of human meconium intratracheally, and 10 piglets had meconium instillation with immediate induction of an asphyxic insult. Eight piglets had only asphyxia and 12 ventilated piglets served as controls. Meconium instillation (with and without asphyxia) resulted in a sustained decrease in the oxygenation, which remained, however, on the control level in the asphyxic group. Although meconium insufflation (with and without asphyxia) increased pulmonary artery pressure and vascular resistance progressively during the study period, the meconium-induced hypertensive effect was actually diminished by additional asphyxia. Asphyxia alone did not have any effect on these pulmonary hemodynamic parameters. On the other hand, whereas systemic arterial pressure and vascular resistance remained on the control level after meconium instillation alone, asphyxia (with and without pulmonary meconium insult) resulted in a sustained fall in systemic pressure already by 4 h. Our data thus indicate that although the coexisting asphyxia seems to moderate the meconium aspiration-induced pulmonary hypertensive response, this additional asphyxic insult does not affect the associated hypoxemia, but rather significantly exacerbates systemic hypotension.