Adenovirus-mediated Bak gene transfer induces apoptosis in mesothelioma cell lines

OBJECTIVE: Conventional treatment for mesothelioma is largely ineffective. We therefore evaluated the novel approach of adenoviral gene transfer of the proapoptotic Bcl-2 family member Bak in mesothelioma cancer cell lines, which are sensitive and resistant to adenoviral p53. METHODS: Binary adenoviral Bak (Ad/GT-Bak and Ad/GV16) and LacZ (Ad/GT-LacZ and Ad/GV16) vectors were used for transduction of the mesothelioma cell lines I-45 (p53 resistant) and REN (p53 sensitive). Protein levels were determined by Western blotting. Apoptosis was assessed by morphologic changes, caspase-3 cleavage, and fluorescence-activated cell sorter analysis of subdiploid populations. Cell viability was determined with the XTT assay. Statistical analysis was performed with analysis of variance and the Student t test. RESULTS: High levels of Bak gene transfer were seen after coadministration of Ad/GT-Bak and Ad/GV16 in both mesothelioma cell lines. Apoptosis was induced 24 hours after Bak but not LacZ gene transfer ([Bak: I-45, 36%; REN, 25%] vs [LacZ: I-45, 1%; REN, 3%], P <.05]) in p53-sensitive (REN) and p53-resistant (I-45) cell lines. Cellular viability was significantly decreased 48 to 72 hours after Bak gene transfer compared with control vector in both cell lines (72 hours: Bak I-45, 1.4% +/- 1.0%, and Bak REN, 4.7% +/- 1%, vs Lac-Z I-45, 83% +/- 3%, and Lac-Z REN, 100% +/- 1%; P <.05). CONCLUSIONS: Adenovirus-mediated overexpression of the Bak gene induces apoptosis and decreased cellular viability in p53-sensitive and p53-resistant mesothelioma cells. These data suggest that the gene transfer of proapoptotic Bcl-2 family members may represent a novel gene therapy strategy to treat mesothelioma.     

Effect of multimodality therapy on circulating vascular endothelial growth factor levels in patients with oesophageal cancer

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. The switch to the angiogenic phenotype depends on the net balance between positive and negative angiogenic factors released by the tumour. It was hypothesized that patients with oesophageal cancer would express raised serum levels of vascular endothelial growth factor (VEGF) which would return to normal values with neoadjuvant chemoradiotherapy. METHODS: Forty-four patients with oesophageal cancer who were selected for treatment with neoadjuvant chemoradiotherapy had blood samples taken before treatment, during chemoradiotherapy, before operation, on days 1, 3 and 5 after surgery, and 3 months after resection. Serum levels of VEGF were measured. Values were correlated with response to treatment. Controls were patients who were undergoing surgery for non-malignant conditions. RESULTS: Serum VEGF levels were raised in patients with oesophageal cancer compared with age-matched controls (mean 247 versus 1157 pg/ml; P < 0.01). VEGF levels were unaffected by neoadjuvant treatment but fell significantly on the first day after operation (652 versus 1057 pg/ml before operation; P < 0.05). No decrease occurred in control patients. VEGF levels had returned to preoperative levels by day 5. A similar postoperative rise in VEGF levels was seen in the control subjects (1194 pg/ml on day 5 versus 71 pg/ml before operation; P = 0.001). There was no correlation between VEGF level and response to treatment or tumour stage. VEGF levels had decreased significantly at 3 months following tumour resection (594 versus 1558 pg/ml on day 5; P = 0.03). CONCLUSION: VEGF levels are raised in patients with oesophageal cancer and are unaltered by neoadjuvant treatment, suggesting an additional source other than tumour cells for this proangiogenic agent.     

Alveolar capillary dysplasia. Report of a case of prolonged life without extracorporeal membrane oxygenation (ECMO) and review of the literature

We describe an unusual infant with the diagnosis of alveolar capillary dysplasia who had a relatively prolonged life without extracorporeal membrane oxygenation (ECMO). We have used this case as a springboard for a thorough review of the literature. This was a full-term female infant who presented with a picture of persistent pulmonary hypertension of the newborn. She was treated as such, with various ventilatory modes, alkalinizing agents, surfactant therapy, tolazoline, prostacyclin and nitric oxide. Because of the prolonged clinical course the possibility of alveolar capillary dysplasia was raised. The parents refused ECMO. Despite all efforts she progressively deteriorated and died at 22 days of age. Macro- and microscopic examination of the lung at autopsy were diagnostic of alveolar capillary dysplasia. A detailed review of 39 cases published in the literature with comments regarding incidence, etiology, pathophysiology, clinical picture, diagnosis and treatment is presented.     

Corneal topographic changes following strabismus surgery in Grave's disease.

A computerized topographic analysis system was used to evaluate corneal changes after strabismus surgery in eight eyes of five patients with Graves' disease. All patients underwent inferior rectus muscle recession; three eyes also had medial rectus recession. Corneal topographic analysis revealed that, postoperatively, corneas steepened inferiorly and inferotemporally at 1.5 mm from corneal apex (p less than 0.05). The opposite effect was observed in the superior quadrant (average flattening of 1.20 +/- 0.32 D at 1.5 mm from corneal apex, and 1.08 +/- 0.39 D at 3.0 mm from corneal apex; p less than 0.05). Superotemporally, the cornea flattened by an average of 0.65 +/- 0.26 D at 3.0 mm from corneal apex, and superonasally 0.72 +/- 0.19 D at 3.0 mm from corneal apex (p less than 0.05). Central, nasal, and temporal cornea did not show statistically significant changes. Spherical equivalent did not change significantly after surgery. The amount of restriction and upgaze measured preoperatively was correlated weakly with inferior corneal steepening (r2 = 0.44; p = 0.046). These results are indicative that corneal topography may be influenced by strabismus surgery for Graves' disease through alteration of extraocular muscle tension or intraocular pressure.     

Electroretinographic findings in macular dystrophy

The flash and pattern electroretinogram were investigated in a group of families with rare forms of inherited macular dystrophy, which included Sorsby's fundus dystrophy, X-linked retinoschisis and macular dystrophy of uncertain classification and variable expression. Flash electroretinograms, under both photopic and scotopic conditions, were attenuated in both Sorsby's fundus dystrophy and X-linked retinoschisis—with some effect on implicit time being noted in the latter condition—but in the unknown group the effect was less demonstrable, only 50% having attenuated flash electroretinograms. Pattern electroretinograms were reduced in all three conditions and in almost all cases. The study demonstrates that some so-called macular dystrophies also have widespread abnormalities affecting the peripheral retina. These findings may contribute to a better understanding of the underlying pathophysiologic mechanisms in these rare forms of retinal dysfunction.     

Efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting

Objectives : To determine the efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. Methods : In this double-blind field trial, 156 children aged 4 36 months with persistent diarrhoea not associated with Giardia lamblia infestation seeking treatment in a community outpatient clinic, were randomized to receive a combination of nalidixic acid and metronidazole, metronidazole alone, or placebo for 7 days. Results : In comparison with placebo, metronidazole treatment did not result in a significant reduction in the mean post-enrolment diarrhoeal duration and stool frequency, increase in the proportion of patients recovered by days 3, 5 and 7 of treatment, and increase in weight gain at days 7 and 14. Comparing the combination of nalidixic acid and metronidazole with metronidazole alone, 17.5% more children treated with the combination recovered by day 3 of treatment ( p = 0.08) and the mean stool frequency ascertained on day 7 for the previous 24 h was 26.8% less in them ( p = 0.05). The weight gains at days 7 and 14 were similar in the two groups. Conclusions : These findings indicate that metronidazole offers no therapeutic benefit in persistent diarrhoea not associated with Giardia lamblia and nalidixic acid has only a modest clinical benefit, which is not substantial enough to warrant its routine use.