Lung cancer screening: a different paradigm

Thoracic computed tomography (CT) is a sensitive method for detecting early lung cancer but has a high false-positive rate and is not sensitive for detecting central preinvasive and microinvasive cancer. Our hypothesis was that automated quantitative image cytometry (AQC) of sputum cells as the first screening method may improve detection rate by identifying individuals at highest risk for lung cancer. A total of 561 volunteer current or former smokers 50 years of age or older, with a smoking history of more than or equal to 30 pack/years, were studied. Among these, 423 were found to have sputum atypia defined as five cells or more with abnormal DNA content using AQC. Noncalcified pulmonary nodules were found in 46% (259/561). Of the 14 detected cancers, 13 were detected in subjects with sputum atypia-nine by CT and four carcinoma in situ/microinvasive cancers by autofluorescence bronchoscopy. One cancer was detected by CT alone. AQC of sputum cells improved the detection rate of lung cancer from 1.8 to 3.1%. CT scan alone would have missed 29% of the cancers. This screening paradigm shift has the additional potential of reducing the number of initial CT scans by at least 25% with further savings in follow-up investigations and treatment.     

Brain death impairs coronary endothelial function

BACKGROUND: To characterize the impact of brain death (BD) on endothelial dysfunction after cardiac transplantation we investigated coronary circulation and vasomotor function in a canine model. METHODS: Left ventricular pressure-volume data (conductance catheter) and coronary blood flow (CBF) were monitored continuously. Endothelium-dependent vasodilatation after acetylcholine and endothelium-independent vasodilation after sodium nitroprusside were assessed before and 3 hr after BD induction (inflation of a subdural balloon). RESULTS: BD led to an initial hyperdynamic reaction with significant (P<0.05) increase of CBF. After 3 hr, CBF decreased significantly (P<0.05). Although before BD, application of acetylcholine led to a monophasic vasodilatative response, after BD a short mild vasodilatation was followed by a longer vasoconstriction. Endothelium-independent vasodilatation remained unchanged. CONCLUSIONS: BD affects coronary circulation by two means: (1) impairment of CBF to decrease in parallel in afterload with consecutive hemodynamic deterioration and (2) severe endothelial dysfunction that may be a contributing factor to posttransplant outcome.     

Analysis of the function of GABA(B) receptors on inhibitory afferent neurons of Purkinje cells in the cerebellar cortex of the rat

Purkinje cells, the output neurons of the cerebellar cortex, receive inhibitory input from basket, stellate and neighbouring Purkinje cells. The aim of the present study was to clarify the role of GABAB receptors on neurons giving inhibitory input to Purkinje cells. In sagittal slices prepared from the cerebellar vermis of the rat, the GABAB receptor agonist baclofen lowered the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) recorded in Purkinje cells. These effects were prevented by the GABAB receptor antagonist CGP 55845. Two mechanisms were involved in the depression of the inhibitory input to Purkinje cells. The first mechanism was suppression of the firing of basket, stellate and Purkinje cells. The second mechanism was presynaptic inhibition of GABA release from terminals of the afferent axons. This was indicated by the finding that baclofen decreased the amplitude of IPSCs occurring in Purkinje cells synchronously with action potentials recorded in basket cells. A further support for the presynaptic inhibition is the observation that baclofen decreased the amplitude of autoreceptor currents which are due to activation of GABAA autoreceptors at axon terminals of basket cells by synaptically released GABA. The presynaptic inhibition was partly due to direct inhibition of the vesicular release mechanism, because baclofen lowered the frequency of miniature IPSCs recorded in Purkinje cells in the presence of cadmium and in the presence of tetrodotoxin plus ionomycin. The results show that activation of GABAB receptors decreased GABAA receptor-mediated synaptic input to cerebellar Purkinje cells both by lowering the firing rate of the inhibitory input neurons and by inhibiting GABA release from their axon terminals with a presynaptic mechanism.     

Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone

Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and -glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.     

One-year outcomes after photodynamic therapy in patients with age-related macular degeneration with poor baseline visual acuity

Background Photodynamic therapy with verteporfin (PDT) has been demonstrated in randomized controlled trials to be a safe and effective therapy for choroidal neovascular membranes (CNV) secondary to age-related macular degeneration (AMD). Limited information is available on the prognosis with PDT for patients who fell outside the inclusion criteria for the clinical trials, however. The purpose of this study is to describe the clinical course of patients with CNV lesions in AMD treated with PDT, with baseline visual acuities sufficiently poor to warrant exclusion from previous randomized trials.Methods Retrospective case series. Ten consecutive patients with CNV secondary to exudative AMD treated with PDT with baseline visual acuity less than 34 ETDRS letters were followed for 1 year. The main outcome was median change in visual acuity on the ETDRS chart.Results The median change in acuity over 12 months was + 13 letters. All patients lost <3 lines of ETDRS acuity, and eight of ten patients (80%) gained at least one line of vision, over 12 months.Conclusions In our series, patients with low visual acuity at baseline appeared to respond to PDT on both visual acuity and fluorescein angiographic measurements. PDT treatment may be considered for selected patients with these baseline characteristics.Proprietary relationships: Dr. Potter has acted as a consultant to Novartis Ophthalmics and QLT Inc.; neither company provided funds or input to this report.This material was presented in part at the Annual Meeting of the Association for Research in Vision and Ophthalmology, 2003.     

Immunohistochemical localization of protein 3-nitrotyrosine and S-nitrosocysteine in a murine model of inhaled nitric oxide therapy

Inhaled nitric oxide (INO) therapy is currently used clinically to selectively dilate the pulmonary vasculature and to help treat persistent pulmonary hypertension and bronchopulmonary dysplasia in the neonate. However, in the presence of oxygen or superoxide, nitric oxide forms potentially harmful reactive nitrogen species. Using an experimental mice model, we examined the effects of concurrent hyperoxia and INO on protein tyrosine nitration and cysteine S-nitrosylation in pulmonary tissue. Data showed enhanced 3-nitrotyrosine staining within the airway epithelium and alveolar interstitium of mice lungs treated with hyperoxia, which did not increase significantly with INO administration. Within the alveolar interstitium, 3-nitrotyrosine staining was localized to macrophages. S-Nitrosocysteine staining in airway epithelium was significantly enhanced with INO administration regardless of oxygen content. These data suggest that the formation of protein S-nitrosocysteine is the major protein modification during administration of INO.     

Angle measurements of the distal radius: a cadaver study

The quality of reduction of distal radius fractures is assessed mainly by degree of restoration of radial angle and palmar tilt. This cadaver study investigates the effects of forearm rotation of these measurements. A 5° rotational change produces a 1.6° change in palmar tilt on the conventional lateral view and a 1.0° change on the 15° lateral view. Lateral radiographs could be rotated 15°–30° and still be considered acceptable. Therefore, rotation may produce up to a 4.0° (15° lateral view) or 6.4° (conventional lateral view) change in measured palmar tilt. To provide clearer measuring landmarks and minimize error due to rotation, we recommend obtaining the 15° lateral view routinely in fractures with significant dorsal angulation. We also studied the interobserver variability of different surgeons assessing radial angle and palmar tilt. The mean standard deviation between surgeons was 3.2° for radial angle, 3.6° for conventional lateral palmar tilt, and 2.1° for 15° lateral palmar tilt.