Autoimmune maintenance and neuroprotection of the central nervous system

The genesis of immune privilege high in the evolutionary tree suggests that immune privilege is necessary, if not advantageous for the progressive development of the CNS. Upon reaching a certain degree of complexity, it seems as if the CNS was obliged to restrain the immune system from penetrating the blood-brain barrier. CNS autoimmunity against myelin proteins is known to be a contributory factor in the pathophysiology of multiple sclerosis and in the animal model of experimental autoimmune encephalomyelitis (EAE) (Wekerle, 1993). Such autoimmunity has therefore been regarded as detrimental and hence obviously undesirable. However, recent findings in our laboratory suggest that T-cell autoimmunity to CNS self-antigens (Moalem et al., 1999), if expressed at the right time and the right place, can do much good in the CNS. We shall review the experiments briefly, and then discuss their implications for our understanding of immune privilege and CNS maintenance after injury.     

Dendritic cells in experimental allergic encephalomyelitis and multiple sclerosis

The mechanisms by which autoimmune diseases are triggered and by which the activation of autoreactive T cells is initiated and maintained are not yet fully understood. As the most potent antigen presenting cells (APC), and also being responsible for antigen transport as well as primary sensitisation of T cells, dendritic cells (DC) are capable of breaking the state of self-ignorance and inducing aggressive autoreactive T cells. In the development of autoimmune diseases, different types of DC exhibit distinct properties for inducing Th1/Th2 cell responses. Appropriate cytokines can convert immunogenic DC to tolerogenic DC. Utilizing the possibility to promote the tolerogenic effects of DC, a new therapeutic tool might soon become available to treat multiple sclerosis and other autoimmune diseases.     

Effects of local MAO inhibition in the locus coeruleus on extracellular serotonin and 5-HIAA during exposure to sensory and cardiovascular stimuli

Previously, we have shown that in the presence of pargyline the release of serotonin (5-HT) in the locus coeruleus is modulated by various sensory stimuli and blood pressure fluctuations. The aim of the present study was to investigate whether local inhibition of monoamine oxidase (MAO) influences basal and stimulus-induced release of 5-HT in the locus coeruleus. For this purpose, the locus coeruleus was superfused in the absence and in the presence of the MAO inhibitor pargyline. Additionally, we examined whether the release of the 5-HT metabolite 5-hydroxy-indole acetic acid (5-HIAA) in the locus coeruleus is altered in response to stimuli. The locus coeruleus of the conscious rat was superfused through a push-pull cannula with artificial cerebrospinal fluid (CSF). 5-HT and 5-HIAA were determined in the superfusate. The basal release rate of 5-HT and the basal outflow of 5-HIAA averaged 2.0 fmol/min and 69 fmol/min, respectively. The basal release rate of 5-HT and the 5-HIAA outflow were tetrodotoxin (TTX)-sensitive. In the absence of pargyline, the sensory stimuli noise stress or tail pinch, applied for 10 min, increased 5-HT and 5-HIAA outflow by 50–70%. In contrast, an experimentally induced rise in blood pressure for 10 min enhanced 5-HT release by 50%, but had no effect on 5-HIAA outflow. The release of 5-HT and/or 5-HIAA elicited by sensory stimuli or a blood pressure rise was abolished by TTX. Addition of pargyline to the CSF enhanced 5-HT release fourfold and slightly decreased 5-HIAA outflow. These levels remained stable throughout the entire observation period of 8 h. In the presence of pargyline, 5-HT release elicited by noise, tail pinch and increase in blood pressure was enhanced. It is concluded that superfusion with pargyline enhances 5-HT release and reduces 5-HIAA outflow in the locus coeruleus. Furthermore, the ability of sensory stimuli and baroreceptor activation to enhance 5-HT release is preserved during a prolonged pargyline-induced increase in extracellular 5-HT. Since sensory stimuli enhanced, while baroreceptor activation did not influence 5-HIAA outflow, 5-HIAA is not a reliable index for short-term changes in the activity of serotonergic neurons in the locus coeruleus. Received: 13 July 1998 / Accepted: 10 December 1998     

Radiofrequency ablation in children

Radiofrequency (RF) catheter ablation has ushered in a new era in the management of patients with symptomatic tachyarrhythmias. By providing the ability to cure the underlying arrhythmic substrate, RF catheter ablation obviates the need for life-long antiarrhythmic drugs. In the reported series, the success has been high and the complications have been infrequent and relatively minor. Not unexpectedly, RF catheter ablation has become the treatment of choice for patients with symptomatic paroxysmal tachyarrhythmias. The role of radiofrequency catheter ablation in infants and small children remains controversial, and awaits a larger experience and longer follow-up data.     

Quantification of Mitral and Tricuspid Regurgitation Using Jet Centerline Velocities: An In Vitro Study of Jets in an Ambient Counterflow

A method for quantifying mitral and tricuspid regurgitant volume that utilizes a measure of jet orifice velocity U(0) - m/sec), a distal centerline velocity (U(m) - m/sec), and the intervening distance (X - cm) was recently developed; where jet flow rate (Q(cal) - L/min) is calculated as Q(cal) = (U(m)X)(2)/(26.46U(o)). This method, however, modeled the regurgitant jet as a free jet, whereas many atrial jets are counterflowing jets because of jet opposing intra-atrial flow fields (counterflows). This study concentrated on the feasibility of using the free jet quantification equation in the atrium where ambient flow fields may alter jet centerline velocities and reduce the accuracy of jet flow rate calculations. A 4-cm wide chamber was used to pump counterflows of 0, 4, and 22 cm/sec against jets of 2.3, 4.8, and 6.4 m/sec originating from a 2-mm diameter orifice. For each counterflow-jet combination, jet centerline velocities were measured using laser Doppler anemometry. For free jets (no counterflow), flow rate was calculated with 98% mean accuracy. For all jets in counterflow, the calculation was less accurate as: (i) the ratio of jet orifice velocity to counterflow velocity decreased (U(o)/U(c), where U(c) is counterflow velocity), i.e., the counterflow was relatively more intense, and (ii) centerline measurements were made further from the orifice. But although counterflow lowered jet centerline velocities beneath free jet values, it did so only significantly in the jet's distal portion (X/D > 16, i.e., >16 orifice diameters from the origin of the jet). Thus, the initial portion (X/D < 16) of a jet in counterflow behaved essentially as a free jet. As a result, even in significant counterflow, jet flow rate was calculated with >93% accuracy and >85% for jets typical of mitral and tricuspid regurgitation, respectively. Counterflow lowers jet centerline velocities beneath equivalent free jet values. This effect, however, is most significant in the distal portion of the jet. Therefore, regurgitant jets, although not classically free because of systolic atrial inflow or jet-induced intra-atrial swirling flows, will decay in their initial portions as free jets and thus are candidates for quantification with the centerline technique. (ECHOCARDIOGRAPHY, Volume 13, July 1996)     

Dopamine,dopexamine and dobutamine in liver transplant recipients: a comparison of their effects on hemodynamics,oxygen transport and hepatic venous oxygen saturation

The purpose of this study was to determine the effects of vasoactive treatment with dopamine (DO), dopexamine (DX), and dobutamine (DOB) on hemodynamics, oxygen transport and hepatic venous oxygen saturation (SvhO₂) after orthotopic liver transplantation (OLT). A pulmonary artery catheter was inserted into the right hepatic vein of 17 OLT patients. Timed infusion of DO, DX, and DOB was performed at the following rates: DO at 4 and 8 g/kg per minute, and DOB at 5 and 10 g/kg per minute. Hemodynamics, oxygen transport variables, and SvhO₂ were assessed. Each catecholamine induced a significant increase in cardiac index, oxygen delivery, and SvhO₂. Mean arterial pressure was increased during DO and DOB, but significantly reduced during DX. Each inotrope increased oxygen delivery in parallel with SvhO₂, suggesting a corresponding increase in hepatic oxygen supply. Therefore, it appears that each vasoactive drug may be utilized in OLT patients to provide oxgen delivery without impairment of splanchnic oxygenation.     

Alpha-motoneuron excitability at high altitude

Summary It has been hypothesized that chronic hypobaric hypoxia could lead to inhibition of the-motoneuron pool, thus limiting the maximal activation of working skeletal muscles. To test this hypothesis six subjects [32 (SEM 2) years] were evaluated in resting conditions, at sea level and after acclimatization at 5,050 m. The recruitment curves of the Hofmann-reflex (H-) and the direct muscle-response (M-) of the right soleus muscle were obtained by stimulating the posterior tibeal nerve with different intensities while recording the electromyogram of the soleus muscle. From the recorded data the net-motoneuron excitability (ratio of maximal H-reflex to M-response H_max : M_max ratio), the threshold and gain for both responses, obtained from linear regressions through the rising phase of the recruitment curves of both responses, as well as the latency times of both responses were determined. The latency times and the H_max :M_max ratio were unchanged at altitude. The thresholds of both responses and the gain of the M-response were unaltered. The gain of the H-response was significantly higher at altitude when compared to sea level. It is concluded that in the acclimatized subjects at rest the signal conduction velocity through the different parts of both pathways was unaltered and therefore nerve and muscle conduction velocity as well as synaptic and muscle end-plate transmission were unchanged, that the recruitment of the H-reflex was slightly facilitated after acclimatization to high altitude suggesting increased excitability of the-motoneurons, through either postsynaptic facilitatory changes in the soma or a different descending drive, and that the unchanged H_max:M_max ratio indicated no change in the net excitatory and inhibitory influences on the-motoneuron pool. The above hypothesis is thus not strengthened by the results that were, however, obtained in resting conditions.     

Type I familial amyloid polyneuropathy and pontine haemorrhage

A Portuguese female, aged 47 years, who had emigrated to Spain, was admitted to the hospital in 1991 for pontine haematoma. The patient, four siblings and her father were affected by a peripheral neuropathy, indicating autosomal dominant inheritance. The patient presented in the 2nd decade with sensory and motor neuropathy beginning in the lower extremities. Alternating constipation and diarrhoea, and urinary incontinence became uncontrollable. She had to be colostomised, and, eventually, confined to a wheelchair from the age of 43. Neurological examination showed bilateral facial involvement, and severe signs of sensory and motor peripheral neuropathy, and later right hemiplegia. There were abnormalities of atrial rhythm and left bundle branch block. Computerised axial tomography and magnetic resonance images demonstrated left-sided pontine haemorrhage. Nerve conduction studies revealed severe diminution of motor conduction velocity and absence or reduction of amplitude of sensory and motor action potentials. Inanition and a respiratory infection led to her death. Clinical diagnosis was type I familial amyloid polyneuropathy (FAP). Postmortem examination demonstrated amyloid deposits in peripheral nerves, including spinal roots and cranial nerves, leptomeninges, thyroid, breasts, heart, adrenal glands, kidneys, intestines, pancreas, and meningeal and some pontine vascular structures. Advanced pontine haematoma was verified. Cerebral haemorrhage usually occurs with cerebrovascular amyloidosis, but exceptionally with FAP. A minority of patients presenting with CNS haemorrhage showed arteriovenous malformation or embolism [Da Silva Horta and Dias Coelho (1960) Arch de Vecchi Anal Patol Med Clin 31=163–172]. However, amyloid deposition in some small pontine vessels could have played a role in the pathogenesis of haemorrhage in the present case.     

Hexachlorophene and the central nervous system

Summary A study on hexachlorophene encephalopathy in mice and baboons is reported. By light microscopy, a severe spongiform lesion of the central nervous system (CNS) was localized in the white matter, without myelin breakdown or cellular reaction. By electron microscopy, the myelin alteration was characterized by wide intralamellar spaces or splitting developed in the intraperiod line of compact sheaths. The acute changes described were induced by administration of the drug by the digestive or cutancous routes at various dosage levels in an aqueous solution or in talcum powder. The toxic effects depended on the age of the animals, the survival times and the concentrations of hexachlorophene, i.e., 6%, 3%, and 0.5%. The findings are compared with previous reports on the neurotoxicity of hexachlorophene and other chemicals in humans and experimental animals. Hexachlorophene cannot be recommended for use in young infants because of its neurotoxicity in very low doses as demonstrated in the present report.     

Echocardiographic and color flow Doppler assessment of systemic and pulmonary venous connection and drainage in the neonate with congenital heart disease

Systemic and pulmonary venous anomalies are frequently encountered either as isolated lesions or as a significant component of a more complex lesion in the newborn infant with congenital heart disease. Two-dimensional echocardiography and Doppler techniques (conventional and color flow) have become the primary diagnostic imaging modality in this setting. Precise pre-operative definition of these variable venous connection and drainage patterns is critical as the required surgical procedure may solely be based on exact understanding of the veins' anatomy and physiology. On the systemic venous site, anomalies of superior and inferior venae cavae, innominate vein, and coronary sinus can be equally well imaged with either echocardiography or angiography. However, on the pulmonary venous site, echocardiography and Doppler techniques including color flow mapping are superior to angiography for precise definition of the connection and drainage sites of the individual pulmonary veins.