Quantifying enamel demineralization from teeth with orthodontic brackets--a comparison of two methods. Part 1: repeatability and agreement

The aim of this investigation was to compare the repeatability of measuring enamel demineralization surrounding an orthodontic bracket using two techniques: computerized image analysis from digitally converted photographic slides and quantitative light-induced fluorescence (QLF). Fifteen human molars were halved and shaped to look like incisors. The teeth were individually numbered and orthodontic brackets bonded to the buccal surface. The crowns were covered with acid resistant varnish, except for windows approximately 1.5 x 3 mm adjacent to the gingival, occlusal, mesial, and distal edges of the bracket. The windows were variously exposed to a demineralizing gel for 0, 3, 7, or 14 days, and the acid resistant varnish was removed. Standardized photographic slides and QLF images of the teeth were taken. These were repeated after 1 week. The slides were converted to grey scale digital format and analysed using Image-Pro Plus 3.0. The QLF images were stored, processed, and analysed using customized software. All images were recoded for blind analysis. The four surfaces of the bracket were inspected and only areas of suspected demineralization were analysed. This was repeated after 1 week. The limits of agreement and mean difference between repeat readings of the area of demineralization were similar for both techniques (-0.04 +/- 0.43 for photographs and -0.10 +/- 0.63 for QLF). Mean grey level (photographs) and mean loss of fluorescence from that area (deltaF) (QLF) showed acceptable limits of agreement. The Intra Class Correlation (ICC) was below 0.81 for the measurement of area from QLF, suggesting that random error needs to be reduced. There was evidence of systematic bias for the repeat readings of the grey levels from the photographs (P < 0.001). Enamel demineralization surrounding an orthodontic bracket can be measured reproducibly using these two techniques.     

Radiotherapy for Non-Functioning Pituitary Tumors—When and Under What Circumstances?

The role of pituitary radiotherapy (RT) in the management of clinically non-functioning pituitary tumors (NFTs) remains controversial. Observational studies suggest that RT is effective in preventing the regrowth of NFT remnants following initial surgical debulking. However, not all tumor remnants will regrow in the absence of pituitary RT. Furthermore there are concerns relating to potential complications of pituitary RT, particularly hypopituitarism and its associated excess mortality. In the absence of any clear consensus guidelines relating to the application of pituitary RT in this setting, the following text sets out to review the evidence base for the efficacy of RT in preventing NFT regrowth and attempts to balance this against the potentially deleterious consequences of pituitary RT. A pragmatic approach is adopted with a view to offering clinically relevant guidance for managing patients with postoperative NFT remnants.     

Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis

Skeletal muscle is able to repair itself through regeneration. However, an injured muscle often does not fully recover its strength because complete muscle regeneration is hindered by the development of fibrosis. Biological approaches to improve muscle healing by enhancing muscle regeneration and reducing the formation of fibrosis are being investigated. Previously, we have determined that insulin-like growth factor-1 (IGF-1) can improve muscle regeneration in injured muscle. We also have investigated the use of an antifibrotic agent, decorin, to reduce muscle fibrosis following injury. The aim of this study was to combine these two therapeutic methods in an attempt to develop a new biological approach to promote efficient healing and recovery of strength after muscle injuries. Our findings indicate that further improvement in the healing of muscle lacerations is attained histologically by the combined administration of IGF-1 to enhance muscle regeneration and decorin to reduce the formation of fibrosis. This improvement was not associated with improved responses to physiological testing, at least at the time-points tested in this study.     

Application of a new image analysis technique to study brain asymmetry in schizophrenia

The hypothesis that normal brain torque (i.e. rightward frontal and leftward occipital asymmetry) is anomalous in schizophrenia (Crow, 1997. Trends in Neuroscience, 20, 339-343) was tested by application of a novel image analysis technique on three-dimensional magnetic resonance images obtained in 26 adult patients with chronic schizophrenia (18 males, 8 females) and 24 controls (14 males, 10 females). Right and left cerebral hemisphere tissue was extracted via non-linear co-registration with a mask image, and maps were computed of inter-hemispheric differences in tissue volume in an array of columns of voxels orthogonal to the mid-plane (2D), and profiles of coronal slice volumes (1D). Furthermore, integration of two-dimensional column maps gave approximate lobar asymmetries, and occipital and frontal asymmetries were combined to give a volumetric measure of brain torque. Significant brain torque was revealed in male and female control and patient groups, and did not correlate with brain size. Frontal and occipital asymmetries were significantly correlated in all groups. Both frontal and occipital components of torque were significantly increased in males than females. Patients tended to have reduced torque, particularly the leftward occipital component. Furthermore, 3/26 patients (but no controls) had reversed torque (leftward frontal and rightward occipital asymmetry). Contrary to Crow's hypothesis, brain torque was not significantly reduced in patients with schizophrenia relative to controls, although reversal of torque was found in three cases. Future studies with larger sample sizes should consider sexual dimorphism and specific symptoms in relation to asymmetry.     

Novel cardioprotective effects of tetrahydrobiopterin after anoxia and reoxygenation: Identifying cellular targets for pharmacologic manipulation

OBJECTIVES: Contemporary cardioprotective strategies to prevent perioperative ischemia-reperfusion injury have focused on the l-arginine nitric oxide pathway. Tetrahydrobiopterin is an absolute cofactor required for the enzyme nitric oxide synthase and is thus a critical determinant of nitric oxide production. We hypothesized that ischemia-reperfusion results in diminished levels of tetrahydrobiopterin, which might represent a key cellular defect underlying endothelial and myocyte dysfunction after ischemia-reperfusion. To this aim, we examined the effects of tetrahydrobiopterin supplementation in (1) an in vivo experimental model of global ischemia-reperfusion and (2) an in vitro human ventricular heart cell model of simulated ischemia-reperfusion. Measures of endothelial function, oxidant production, cell survival, and cardiac function were used to assess outcome. METHODS: In study 1 Wistar rats were divided into one of 2 groups (n = 10 per group). One group received tetrahydrobiopterin (25 mg x kg(-1) x d(-1) for 7 days), and the other group served as the control group. Hearts were subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion, and left ventricular developed pressure, left ventricular systolic pressure, and left ventricular end-diastolic pressure were determined by using the modified Langendorff technique. In study 2 we quantitated myocardial malondialdehyde, a marker of lipid peroxidation, in ventricular tissues from both groups of animals using butanol phase extraction and spectrophotometric analysis. In study 3 coronary vascular responses were determined in vascular segments of the left coronary artery in both groups of animals after ischemia-reperfusion. Endothelium-dependent and endothelium-independent vasodilatation to acetylcholine and sodium nitroprusside, respectively, were compared between groups. In study 4, using a human ventricular heart cell model of simulated ischemia-reperfusion, we studied the effects of tetrahydrobiopterin (20 micromol/L) on cellular injury (as assessed by means of trypan blue uptake). RESULTS: After ischemia-reperfusion, myocardial dysfunction was evidenced by a decrease in left ventricular developed pressure and an increase in left ventricular end-diastolic pressure (P =.01 compared with baseline). Hearts from tetrahydrobiopterin-treated rats exhibited protection against ischemia-reperfusion injury (left ventricular developed pressure: 74 +/- 4 vs control 42 +/- 8 mm Hg, P =.01; left ventricular end-diastolic pressure: 12 +/- 3 vs 34 +/- 7 mm Hg, P =.01). Furthermore, tetrahydrobiopterin treatment attenuated the rise in malondialdehyde levels after ischemia-reperfusion (P =.01). After reperfusion, coronary endothelial function to acetylcholine was attenuated (P =.003 vs sham-treated mice), whereas responses to sodium nitroprusside remained unchanged. Tetrahydrobiopterin-treated rats exhibited an improvement in acetylcholine-mediated vasorelaxation (P =.01 vs ischemia-reperfusion group). Cellular injury, as assessed by means of trypan blue uptake, was higher in human ventricular heart cells subjected to simulated ischemia-reperfusion; this effect was prevented with tetrahydrobiopterin treatment (P =.001). CONCLUSIONS: Supplemental tetrahydrobiopterin provides a novel cardioprotective effect on left ventricular function, endothelial-vascular reactivity, oxidative damage, and cardiomyocyte injury after ischemia-reperfusion injury and might represent an important cellular target for future operative myocardial protection strategies.     

Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: reversal with endothelin antagonism

OBJECTIVES: We have previously demonstrated an importance of endothelin-1 in diabetic patients undergoing bypass surgery. Recent evidence suggests that cardiomyocytes might also produce endothelin-1, which might directly impair myocyte contractility by increasing intracellular calcium levels. Because hyperglycemia is a potent stimulus of endothelin-1 production, we hypothesized that increased production, action, or both of endothelin-1 might be a mediator of direct cardiomyocyte injury in diabetes. Therefore we studied the effects of endothelin receptor blockers (BQ-123 and bosentan) on hyperglycemia-induced endothelin-1 production and cellular injury after ischemia-reperfusion. METHODS: Using a human ventricular heart cell model of simulated ischemia-reperfusion, we studied the effects of normoglycemia (5 mmol/L, 48 hours) and hyperglycemia (25 mmol/L, 48 hours) on cellular injury and endothelin-1 production. Furthermore, the effects of selective endothelin-A and mixed endothelin-A/B receptor antagonism (with BQ-123 and bosentan, respectively) were evaluated. RESULTS: Cellular injury, as assessed by means of trypan blue uptake, was higher in human ventricular heart cells subjected to hyperglycemia and simulated ischemia-reperfusion injury (P =.01); this effect was prevented with both BQ-123 and bosentan (P =.01). In addition, heart cells from the hyperglycemic group elaborated more endothelin-1 after ischemia-reperfusion (P =.02). CONCLUSIONS: Endothelin-1 production and cellular injury were greater in human ventricular heart cells subjected to hyperglycemic conditions and simulated ischemia-reperfusion. These effects are mediated by endothelin-A receptors because both BQ-123 and bosentan exerted similar degrees of protection. Endothelin receptor blockade is a novel strategy to improve the resistance of the diabetic heart to cardioplegic arrest and reperfusion.     

Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression

PURPOSE: We assessed the feasibility of a watchful waiting protocol with selective delayed intervention using clinical, prostate specific antigen (PSA) or histological progression as treatment indications for clinically localized prostate cancer. MATERIALS AND METHODS: In this prospective, single arm cohort study patients with favorable clinical parameters (stage T1b to T2b N0M0, Gleason score 7 or less and PSA 15 ng./ml. or less) are conservatively treated with watchful waiting. When a patient meets disease progression criteria, arbitrarily defined by the 3 parameters of the rate of PSA increase, clinical progression or histological upgrade on repeat prostate biopsy, appropriate treatment is implemented. Patients are followed every 3 months for the first 2 years and every 6 months thereafter. Serum PSA measurement and digital rectal examination are done at each visit and repeat prostate biopsy is performed 18 months after study enrollment. RESULTS: Since November 1995, the study has accrued 206 patients with a median followup of 29 months (range 2 to 66). Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons. There was clinical, PSA and histological progression in 16, 15 and 5 cases, respectively. The estimated actuarial probability of remaining on the surveillance protocol was 67% at 2 years and 48% at 4. The probability of remaining progression-free was 81% and 67% at 2 and 4 years, respectively. CONCLUSIONS: A policy of watchful waiting with selectively delayed intervention based on predefined criteria of disease progression is feasible. This strategy offers the benefit of an individualized approach based on the demonstrated risk of clinical or biochemical progression with time and, thus, it may decrease the burden of therapy in patients with indolent disease, while providing definitive therapy for those with biologically active disease.