The effects of carbenoxolone on human myocardial conduction: a tool to investigate the role of gap junctional uncoupling in human arrhythmogenesis.

OBJECTIVES: This study assessed the effects of carbenoxolone on human myocardial conduction and refractoriness. BACKGROUND: Carbenoxolone, an antipeptic ulcer drug, has been shown to reduce gap junctional coupling without affecting cellular ion channels. Gap junctions (GJ) are considered to be determinants of cardiac action potential propagation. The effects of GJ uncoupling in the human heart are unknown. METHODS: Right atrial (RA) and ventricular (RV) activation mapping (Carto, Biosense Webster Inc., Diamond Bar, California) was performed during sinus rhythm. Right atrial and RV wavefront propagation velocity (WPV), specifically in the direction of propagation, was determined from these maps using a triangulation method. Refractoriness at multiple RA and RV sites, sinus rhythm cycle length, and AH, PR, QRS, and QT intervals were measured. The protocol was repeated 1 h after oral administration of 100 mg of carbenoxolone. RESULTS: In 11 patients, WPV was reduced from 79.6 +/- 13.3 cm/s to 57.2 +/- 9.1 cm/s (-27.1 +/- 12.8%, p < 0.001) in RA and from 98.7 +/- 19.8 cm/s to 76.5 +/- 21.7 cm/s (-22.7 +/- 14.1%, p < 0.01) in RV after carbenoxolone. Conduction slowing was more marked in 6 older patients with ischemic heart disease compared with younger subjects with normal hearts (RA -35.1 +/- 5.5% vs. -17.5 +/- 12.7%, p = 0.03; RV -33.8 +/- 5.1% vs. -9.3 +/- 7.7%, p < 0.001). Refractoriness and electrocardiogram parameters remained unchanged. CONCLUSIONS: Carbenoxolone causes a 27% reduction in human RA WPV and 23% in the RV without affecting refractoriness. The slowing of myocardial conduction by carbenoxolone demonstrates the significance of GJ in regulating human myocardial conduction and provides a tool for investigating the effects of GJ uncoupling on human arrhythmogenesis.     

The contribution of the ossific nucleus to the structural stiffness of the capital femoral epiphysis: a porcine model for DDH.

The preosseous femoral head is thought to be vulnerable to compressive ischemic injury during the treatment of developmental dysplasia of the hip. The ossific nucleus has been proposed to increase the mechanical strength of the capital femoral epiphysis (CFE) and to decrease the risk of avascular necrosis. Sixty mixed-breed fetal and postgestational femoral head specimens were evaluated for structural stiffness in relation to the size of the ossific nucleus within the CFE. The structural stiffness of the CFE in the porcine model was found to increase exponentially with the size of the ossific nucleus. A finite-element model revealed that the presence of an ossific nucleus occupying 40% of the epiphyseal volume reduced the compressive strain in the region of the posterior-superior branch of the medial circumflex artery by an average of 54%. The results of this study support the hypothesis that the presence of the ossific nucleus may protect the CFE from compressive ischemic injury in the treatment of DDH.     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D1 and D2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D₁ and D₂ dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D₁ and D₂ dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (‘priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D₁ and D₂ receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D₁/D₂ agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D₁ and D₂ dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.     

The unreamed tibial nail in the treatment of distal metaphyseal fractures.

In recent years biological surgical solutions have been recommended in cases of distal tibial fractures, with the aim of reducing damage to soft tissues and to bone vascular supply. Between the years 1991-1995, 52 patients suffering from fractures of the distal tibial metaphysis were treated in our department with an unreamed tibial nail (UTN). Fractures were categorized in accordance with the AO Classification. 32 fractures had no articular involvement (43A1, 43A2, 43A3) and 20 included intra-articular extension (43C1, 43C2). 32 fractures had significant metaphyseal comminution (43A2, 43A3, 43C2). 12 were open fractures. All the fractures were treated by means of UTN using distal locking. In 13 patients an additional percutaneous interfragmentary fixation was also applied. 22 patients underwent an additional operation in order to facilitate bone union (dynamization, bone grafting and/or fibulectomy). In 50 of the 52 patients the fracture united with a very good range of knee and ankle motion. In 2 patients non-union with breakage of the UTN occurred and in two open fractures post-operative infections were observed. Our experience with the treatment of fractures of the distal tibia, including intra-articular fractures with no comminution, points at an excellent functional outcome with a low incidence of complications.     

Case control study of environmental factors in the etiology of the first attack of acute pancreatitis

Summary The aim of this case control study was to assess environmental factors in the etiology of the first attack of acute pancreatitis (AP) in Soweto, South Africa, in the light of modern developments. The study group consisted of 30 patients presenting with a first attack of AP, and 30 healthy age- and gender-matched controls. Fruit intake was found to be a protective factor (odds ratio [OR] 5.3). Crude ORs, although of marginal importance, showed that daily alcohol intake and years of exposure to occupational chemicals may be of significance but would require a much larger study to test these factors. This would be necessary in order to explain the rapid increase in pancreatitis coincident with urbanization and industrialization in the community.     

Axonal proliferation following lesions of cerebellar peduncles. A combined fluorescence microscopic and radioautographic study

The hippocampus and the cerebellar cortex, two terminal fields of N. locus coeruleus (LC), contain increased adrenergic innervation 30 days after partial lesions of the superior cerebellar peduncle (SP). The qualitative observation of enhanced terminal fluorescence after lesioning was confirmed by counting terminals in the hippocampus and cerebellum labeled by radioautography after injection of ³H-proline into LC of the rat. Use of the Vibratome method for catecholamine-fluorescence permitted the observation of both fluorescence and labeled terminals in sections from the same animal. The increased terminal density in the hippocampus following partial SP lesions suggests that this growth may be initiated by retrograde changes within LC neurons or collaterals of the cut axons and does not require a prior denervation of the post synaptic cells.     

The behavior of sonicated albumin microbubbles within the microcirculation: a basis for their use during myocardial contrast echocardiography

The purpose of this study was to determine whether the behavior of sonicated albumin microbubbles accurately mimics red blood cell flow in the microcirculation and is thus consistent with their use as in vivo tracers of red blood cell flow during myocardial contrast echocardiography. Accordingly, microbubbles prepared from fluorescein-conjugated albumin and fluorescently labeled red blood cells were injected intravascularly in eight golden hamsters. Their intravascular distribution, velocities, arteriolar-to-venular transit and flux ratios at branch points were determined in the microcirculation of the cheek pouch. Albumin microbubbles (mean diameter, 4.9 +/- 3.6 microns) and red blood cells displayed a similar frequency of distribution across the arteriolar lumen (33% in the central 20% of the arterioles), and their arteriolar velocities were also similar (2.5 +/- 0.7 mm/sec and 2.3 +/- 0.7 mm/sec,p = NS). The mean velocities of microbubbles correlated well with those of red blood cells at baseline and after adenosine application (r = 0.97 and r = 0.89, respectively), as did the calculated maximum velocity (r = 0.98 and r = 0.80, baseline and adenosine, respectively). The velocity profiles across the lumen of the vessels for albumin microbubbles and red blood cells were similar at baseline and after adenosine-induced velocity changes. The flux ratios at branch points also correlated well (r = 0.92, p less than 0.001). Arteriolar-to-venular transit times of albumin microbubbles were similar to those of red blood cells in vessels ranging in size from 22 microns to 45 microns. We conclude that the behavior of albumin microbubbles in the microcirculation mimics that of red blood cells and supports their use as intravascular tracers of red blood cell flow during myocardial contrast echocardiography.