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Biomedical subjects

R Furlan

Publications and source records attributed to R Furlan.

At least 55 records · Page 3Linked to original sources
PubMed1999

Method for intracellular magnetic labeling of human mononuclear cells using approved iron contrast agents.

A method for intracellular iron labeling of human mononuclear cells (lymphocytes and monocytes) for magnetic resonance imaging (MRI) using simple incubation of cells with approved MRI iron contrast agents is presented. Labeled cells can be detected by MRI in vitro, and this suggests the possibility that the technique could become a marker for in vivo lymphocyte and monocyte trafficking studies in acute inflammatory lesions such as those in Multiple Sclerosis.

Cell Survival↗
PubMed1999

Neurally mediated syncope: pathophysiology and implications for treatment.

Neurally mediated syncope may occur in patients whose hemodynamic picture does not fit the characteristics of orthostatic intolerance as described elsewhere in this issue. Nonetheless, patients who suffer from neurocardiogenic or vasovagal syncope may be seriously incapacitated by their episodes of syncope or presyncope. Although it has been assumed that vagal activation as a result of stimulation of ventricular mechanoreceptors is essential to the production of these episodes, several critical observations are presented that suggest that other mechanisms may also be operative in some patient subsets. In addition, evidence is presented that the sympathetic responses of many of these patients may be reduced rather than increased and that abnormal baroreflex responsiveness may also play an causative role. These findings suggest new avenues for therapy in this field in which carefully controlled, randomized, double-blind trials are scarce.

Autonomic Nervous System↗
PubMed1999

Peripheral levels of caspase-1 mRNA correlate with disease activity in patients with multiple sclerosis; a preliminary study.

The cysteine protease caspase-1 plays a crucial part in the inflammatory process due to its ability to proteolitically activate proinflammatory cytokine precursors, such as interleukin (IL)-1beta and IL-18. Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS in which the pathogenic process is mainly orchestrated by proinflammatory cytokines. The role of caspase-1 in multiple sclerosis was evaluated by measuring its mRNA levels in peripheral blood mononuclear cells (PBMCs) from seven patients with relapsing-remitting multiple sclerosis every 15 days over a 1 year period. The recorded levels were compared with clinical and MRI evidence of disease activity. Brain MRI was performed monthly in each patient. Caspase-1 mRNA levels were significantly increased in PBMCs from patients with multiple sclerosis compared with healthy controls (p<0.001). In patients with multiple sclerosis, a twofold to threefold increase of caspase-1 mRNA mean level was found in the week preceding an acute attack (p<0. 05). The magnitude of caspase-1 mRNA increase correlated with the number of new (p=0.01) but not persisting gadolinium enhancing brain MRI lesions. In conclusion, caspase-1 might be involved in the immune mediated process underlying CNS inflammation and might represent a suitable peripheral immunological marker of disease activity in multiple sclerosis.

Adult↗
PubMed1998

Central nervous system delivery of interleukin 4 by a nonreplicative herpes simplex type 1 viral vector ameliorates autoimmune demyelination.

Multiple sclerosis (MS) is a T cell-mediated organ-specific inflammatory disease leading to central nervous system (CNS) demyelination. On the basis of results obtained in experimental autoimmune encephalomyelitis (EAE) models, MS treatment by administration of antiinflammatory cytokines such as interleukin 4 (IL-4) is promising but is hampered by the limited access of the cytokines to the CNS and by the pleiotropic effects of systemically administered cytokines. We established a cytokine delivery system within the CNS using non-replicative herpes simplex type 1 (HSV-1) viral vectors engineered with cytokine genes. These vectors injected into the cisterna magna (i.c.) of mice diffuse in all ventricular and subarachnoid spaces and infect with high efficiency the ependymal and leptomeningeal cell layers surrounding these areas, without obvious toxic effects. Heterologous genes contained in the vectors are efficiently transcribed in infected ependymal cells, leading to the production of high amounts of the coded proteins. For example, 4.5 ng of interferon gamma (IFN-gamma) per milliliter is secreted into the cerebrospinal fluid (CSF) up to day 28 postinjection (p.i.) and reaches the CNS parenchyma in bioactive form, as demonstrated by upregulation of MHC class I expression on CNS-resident cells. We then exploited the therapeutic potential of the vectors in EAE mice. An HSV-1-derived vector containing the IL-4 gene was injected i.c. in Biozzi AB/H mice at the time of EAE induction. We found the following in treated mice: (1) delayed EAE onset, (2) a significant decrease in clinical score, (3) a significant decrease in perivascular inflammatory infiltrates and in the number of macrophages infiltrating the CNS parenchyma and the submeningeal spaces, and (4) a reduction in demyelinated areas and axonal loss. Peripheral T cells from IL-4-treated mice were not affected either in their antigen-specific proliferative response or in cytokine secretion pattern. Our results indicate that CNS cytokine delivery with HSV-1 vectors is feasible and might represent an approach for the treatment of demyelinating diseases. Advantages of this approach over systemic cytokine administration are the high cytokine level reached in the CNS, the absence of effects on the peripheral immune system, and the long-lasting cytokine production in the CNS after a single vector administration.

Animals↗
PubMed1998

Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control.

BACKGROUND: Chronic orthostatic intolerance (COI) is a debilitating autonomic condition in young adults. Its neurohumoral and hemodynamic profiles suggest possible alterations of postural sympathetic function and of baroreflex control of heart rate (HR). METHODS AND RESULTS: In 16 COI patients and 16 healthy volunteers, intra-arterial blood pressure (BP), ECG, central venous pressure (CVP), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during 75 degrees tilt. Spectral analysis of RR interval and systolic arterial pressure (SAP) variabilities provided indices of sympathovagal modulation of the sinoatrial node (ratio of low-frequency to high-frequency components, LF/HF) and of sympathetic vasomotor control (LFSAP). Baroreflex mechanisms were assessed (1) by the slope of the regression line obtained from changes of RR interval and MSNA evoked by pharmacologically induced alterations in BP and (2) by the index alpha, obtained from cross-spectral analysis of RR and SAP variabilities. At rest, HR, MSNA, LF/HF, and LFSAP were higher in COI patients, whereas BP and CVP were similar in the two groups. During tilt, BP did not change and CVP fell by the same extent in the 2 groups; the increase of HR and LF/HF was more pronounced in COI patients. Conversely, the increase of MSNA was lower in COI than in control subjects. Baroreflex sensitivity was similar in COI and control subjects at rest; tilt reduced alpha similarly in both groups. CONCLUSIONS: COI is characterized by an overall enhancement of noradrenergic tone at rest and by a blunted postganglionic sympathetic response to standing, with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These data suggest that in COI, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.

Adult↗
PubMed1998

Yohimbine in neurally mediated syncope. Pathophysiological implications.

In this study, we evaluated if increased sympathetic stimulation is an essential requirement for the development of neurally mediated syncope (NMS) by manipulating overall sympathetic outflow in subjects susceptible to tilt-induced syncope. Eight previously characterized patients with recurrent NMS (five females and three males; 34+/-2 yr) were recruited from the Vanderbilt Syncope Unit and eight age-matched controls underwent initial administration of clonidine (CLO) or yohimbine (YHO). This was done, prospectively, to determine doses of these agents that would increase or decrease plasma norepinephrine levels by >/= 30%. On a different day, in all subjects we determined intraarterial blood pressure, EKG and muscle sympathetic nerve activity (MSNA) both supine and during upright tilt. After this, subjects randomly received either CLO or YHO, and 3 h later another tilt was performed. After 1 wk, a similar procedure with the other drug was performed. During the two basal tilts, all the control subjects completed the study, whereas all the NMS patients developed syncope. Reduction in sympathetic tone by CLO resulted in a decreased tolerance to tilt in three out of eight controls and in all the NMS patients. In contrast, YHO not only increased basal plasma NorEpi levels and MSNA, but also prevented syncope in seven out of eight patients. In a selected population of patients, increased sympathetic activity is not a prerequisite for the development of syncope. Yohimbine-induced enhancement of sympathetic tone in patients with NMS improves orthostatic tolerance and raises the possibility that this drug may be a useful agent in the treatment of NMS.

Adult↗
PubMed1998

Cardiac autonomic patterns preceding occasional vasovagal reactions in healthy humans.

BACKGROUND: The wide range of clinical presentation of orthostatic vasovagal syncope suggests different underlying changes in the cardiac autonomic modulation. METHODS AND RESULTS: To evaluate the beat-by-beat modifications in the neural control of heart period preceding a syncopal event, we studied RR interval variability in 22 healthy subjects who experienced fainting for the first time during a 90 degrees head-up tilt and in 22 control subjects by means of time-variant power spectral analysis. Sympathetic and vagal modulations to the sinoatrial node were assessed by the normalized power of the low-frequency (LF, approximately 0.1-Hz) and high-frequency (HF, approximately 0.25-Hz) oscillatory components of RR variability. When the patients were supine, no differences were observed in the hemodynamic and spectral parameters of the 2 groups. During the tilt procedure, RR, LFNU, and HFNU (NU=normalized units) values were relatively stable in control subjects. During early tilt (T1), subjects with syncope had reduced RR intervals compared with control subjects. In 13 subjects with syncope, RR decreased while LFNU and LF/HF increased in the last minute of tilt before syncope (T2). Conversely, in the remaining 9 fainters, LFNU and LF/HF decreased from T1 to T2 and HFNU increased slightly. CONCLUSIONS: Two different patterns may be recognized in the cardiac autonomic changes preceding an occasional vasovagal event, namely, one characterized by a progressive increase of the marker of cardiac sympathetic modulation up to the onset of syncope, the other by a sympathetic inhibition with an impending vagal predominance. The recognition of different pathophysiological mechanisms in fainters may have important therapeutic implications.

Adolescent↗
PubMed1998

Effect of standing on neurohumoral responses and plasma volume in healthy subjects.

Upright posture leads to rapid pooling of blood in the lower extremities and shifts plasma fluid into surrounding tissues. This results in a decrease in plasma volume (PV) and in hemoconcentration. There has been no integrative evaluation of concomitant neurohumoral and PV shifts with upright posture in normal subjects. We studied 10 healthy subjects after 3 days of stable Na+ and K+ intake. PV was assessed by the Evans blue dye method and by changes in hematocrit. Norepinephrine (NE), NE spillover, epinephrine (Epi), vasopressin, plasma renin activity, aldosterone, osmolarity, and kidney response expressed by urine osmolality and by Na+ and K+ excretion of the subjects in the supine and standing postures were all measured. We found that PV fell by 13% (375 +/- 35 ml plasma) over approximately 14 min, after which time it remained relatively stable. There was a concomitant decrease in systolic blood pressure and an increase in heart rate that peaked at the time of maximal decrease in PV. Plasma Epi and NE increased rapidly to this point. Epi approached baseline by 20 min of standing. NE spillover increased 80% and clearance decreased 30% with 30 min of standing. The increase in plasma renin activity correlated with an increase in aldosterone. Vasopressin increased progressively, but there was no change in plasma osmolarity. The kidney response showed a significant decrease in Na+ and an increase in K+ excretion with upright posture. We conclude that a cascade of neurohumoral events occurs with upright posture, some of which particularly coincide with the decrease in PV. Plasma Epi levels may contribute to the increment in heart rate with maintained upright posture.

Adult↗
PubMed1998

A gene therapy approach to treat demyelinating diseases using non-replicative herpetic vectors engineered to produce cytokines.

A successful gene therapy approach in organ-specific autoimmune diseases, such as multiple sclerosis (MS), encompasses the inhibition of the autoreactive T cells or the modification of the target organ cells by the introduction of exogenous 'protective' genes. In MS, an autoimmune disease of the central nervous system (CNS), the inciting autoantigen is still unknown and therefore the isolation of autoreactive T cells may only be inferential. At present, gene therapy approaches in MS should therefore aim to the modification of the target organ. Possible candidate genes to be transferred within the CNS of MS patients are those coding for anti-inflammatory cytokines (i.e. interleukin-4, interleukin-10, transforming growth factor beta) which have been shown to ameliorate demyelinating diseases at least in experimental models. However, a limiting factor for this therapy is the difficulty to reach the CNS. A gene therapy approach using viral vectors able to infect post-mitotic cells, such as those present within the CNS, without inducing toxic reactions, may overcome this limitation. We propose to use non-replicative herpetic vectors, which represent a viable gene-transfer alternative to the classical retroviral and adenoviral vectors. Key advantages are their size, able to accommodate multiple foreign genes, and their ability to infect post-mitotic cells such as those present within the CNS. We first transferred a gene coding for interleukin-4 within the CNS of mice undergoing experimental allergic encephalomyelitis, an animal model for MS, using non-replicative Herpes Simplex Virus type 1-derived vectors. We found that this approach ameliorates the disease course and delays the disease onset. The establishment of this technique to deliver anti-inflammatory cytokines within the CNS using herpetic vectors should clarify the role of individual cytokines in the demyelinating process and allow assessment of whether gene therapy using herpetic vectors is a feasible and safe approach to treat human demyelinating disorders.

Animals↗
PubMed1997

Individual recognition by heart rate variability of two different autonomic profiles related to posture.

BACKGROUND: Power spectrum analysis of heart rate variability (HRV) can estimate the state of sympathovagal balance modulating sinus node activity. In view of the large distribution of spectral variables, a recognition of well-defined physiological conditions has never been attempted on an individual basis. METHODS AND RESULTS: We considered 10 spectral variables extracted from short segments (200 to 500 cardiac cycles) of 350 ECG tracings recorded in normal subjects in both supine and upright positions (700 patterns). The tracings were first ordered consecutively and subsequently assigned alternatively to a training or to a test set (each consisting of 175 cases, providing 350 patterns considered to be independent). A forecasting linear method estimated a normalized activation index (ranging from -1 for supine to +1 for upright) that concentrated the information derived from spectral variables and that identified, in the test set, individual by individual, approximately 84% of corresponding body postures. CONCLUSIONS: The combined use of spectral methodology and forecasting analysis has revealed an information content embedded, per se, in a short series of RR intervals capable of recognizing, individual by individual, two different autonomic profiles related to posture.

Adolescent↗
PubMed1997

Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt.

The pathophysiology of neurally mediated syncope is poorly understood. It has been widely assumed that excessive sympathetic activation in a setting of left ventricular hypovolemia stimulates ventricular afferents that trigger hypotension and bradycardia. We tested this hypothesis by determining if excessive sympathetic activation precedes development of neurally mediated syncope, and if this correlates with alterations in baroreflex function. We studied the changes in intraarterial blood pressure (BP), heart rate (HR), central venous pressure (CVP), muscle sympathetic nerve activity (MSNA), and plasma catecholamines evoked by upright tilt in recurrent neurally mediated syncope patients (SYN, 5+/-1 episodes/mo, n = 14), age- and sex-matched controls (CON, n = 23), and in healthy subjects who consistently experienced syncope during tilt (FS+, n = 20). Baroreflex responses were evaluated from changes in HR, BP, and MSNA that were obtained after infusions of phenylephrine and sodium nitroprusside. Compared to CON, patients with SYN had blunted increases in MSNA at low tilt levels, followed by a progressive decrease and ultimately complete disappearance of MSNA with syncope. SYN patients also had attenuation of norepinephrine increases and lower baroreflex slope sensitivity, both during tilt and after pharmacologic testing. FS+ subjects had the largest decrease in CVP with tilt and had significant increases in MSNA and heart rate baroreflex slopes. These data challenge the view that excessive generalized sympathetic activation is the precursor of the hemodynamic abnormality underlying recurrent neurally mediated syncope.

Adult↗
PubMed1997

Multivariate time-variant identification of cardiovascular variability signals: a beat-to-beat spectral parameter estimation in vasovagal syncope.

In this paper a bivariate, time-variant model able to continuously measure the mutual interactions between heart rate and systolic blood pressure variability signals is presented. A recursive identification of the model parameters makes it possible to estimate, on a beat-to-beat basis, spectral low-frequency (LF) and high-frequency (HF) power, (LF/HF ratio) and cross-spectral (coherence and phase relationships between spectral peaks) indexes during nonstationary events. These indexes can be helpful in: 1) physiological study of autonomic nervous system mechanisms of cardiovascular control and 2) quantification and clinical evaluation of the neural and mechanical links between the two signals. In addition, an estimate of baroreceptive activation (alpha-gain) is continuously extracted. Before applying the model to cardiovascular signals, the reliability of the estimated parameters was tested on simulated signals. Subsequently, the model was applied to investigating vasovagal syncope episodes, aiming at the assessment of autonomic nervous system status and autonomic role in the dynamic phenomena which lead to syncope. The proposed model, which provides noninvasive beat-to-beat evaluation of the autonomic events, may be useful in the description of the syncopal episodes and in the comprehension of the complex physiological mechanisms of syncope.

Algorithms↗
PubMed1997

Malignant vagotonia due to selective baroreflex failure.

Baroreflex failure is characterized by dramatic fluctuations of sympathetic activity and paroxysms of hypertension and tachycardia. In contrast, unopposed parasympathetic activity has not been described in patients with baroreflex failure because of concurrent parasympathetic denervation of the heart. We describe the unusual case of a patient with baroreflex failure in a setting of preserved parasympathetic control of HR manifesting episodes of severe bradycardia and asystole. Thus, parasympathetic control of the HR may be intact in occasional patients with baroreflex failure. Patients with this selective baroreflex failure require a unique therapeutic strategy for the control of disease manifestations.

Baroreflex↗
PubMed1996

Human T-cell lymphotropic virus type-I infection in the severe combined immunodeficiency mouse.

Human T-cell lymphotropic virus type-I (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). HAM/TSP and ATL occur infrequently among HTLV-I-infected individuals, and rarely develop in the same individual. To study host and viral factors involved in the induction, tissue tropism, as well as pathogenesis of HAM/TSP, peripheral blood lymphocytes (PBL) from 14 patients with HAM/TSP and from 9 controls were introduced into severe combined immunodeficiency (SCID) mice by intraperitoneal injection. Mice were followed for up to 26 weeks. Human IgG was produced from 2 to 14 weeks after reconstitution in all animals. Thirty-two of 44 mice (72%) showed circulating human antibody against the major viral protein products of HTLV-I. Analysis of viral sequences by polymerase chain reaction (PCR) demonstrated HTLV-I sequences in 21/38 (55%) brains and in 7/17 (41%) spinal cords from HTLV-I-hu SCID mice. No animal had clinical evidence of neurological impairment or pathological findings similar to those seen in HAM/TSP. Seven mice who received PBL from Epstein Barr virus (EBV)-seropositive patients developed an intraperitoneal lymphoma. In 2 mice an infiltration of brain by a lymphoblastic tumor of B/T cell type was observed. By PCR, all the tumors were EBV-positive; HTLV-I sequences were detected in 5 of them. Our study suggests that the HTLV-I-hu-SCID mouse provides a potentially valuable system for studying the production, kinetics, and pathogenicity of anti-HTLV-I antibody, and may help clarify the interaction of EBV and retroviruses in the development of disease.

Adult↗
PubMed1996

An immunovirological study of central nervous system involvement during HIV-1 infection of chimpanzees.

Chimpanzees infected with human immunodeficiency virus type 1 (HIV-1) are used to model acquired immunodeficiency syndrome (AIDS). Since the central nervous system (CNS) is involved in AIDS, we performed an immunovirological study in 18 chimpanzees inoculated up to 87 months prior to the study (mean, 45 months) with HIV-1 and 8 uninfected controls. Serum and cerebrospinal fluid (CSF) IgG and albumin levels of infected chimpanzees never exceeded those of controls. The CSF/serum albumin ratio was elevated in 1 of 18 infected chimpanzees compared to controls; however, all animals had an elevated ratio indicating a more open blood-brain barrier relative to humans. The intrathecal IgG production index was elevated in only 1 of 18 infected chimpanzees compared to controls. Identical serum and CSF IgG bands were found by isoelectric focusing in 2 of 8 controls and in 1 of 18 infected chimpanzees. None of these bands reacted with recombinant HIV-1 p24gag or gp 120env. HIV-1 was isolated from the peripheral blood of 4 of 18 infected chimpanzees but never from the paired CSF samples. Anti-HIV-1 antibody was detected by a enzyme-linked immunosorbent assay in 18 of 18 paired serum and CSF samples and by Western blot in 18 of 18 serum and 13 of 18 CSF samples from infected chimpanzees without a difference in pattern. Polymerase chain reaction analysis on brain tissue of one animal was negative for HIV-1 sequences. Our results demonstrate that, unlike human infection, chimpanzees inoculated with HIV-1 show no evidence of isolatable virus in the CSF and no evidence of intrathecal anti-HIV-1 antibody synthesis up to several years after experimental infection. The lack of CNS involvement may contribute to the delay or suppression of clinical disease in infected chimpanzees.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Atrial natriuretic peptide in multiple system atrophy.

Central nervous system feedback loops centered on hypothalamic neurons control atrial natriuretic peptide (ANP). We evaluated the ANP response to arterial hypotension, isotonic blood volume expansion, and increase in plasma osmolality in 14 patients with multiple system atrophy (MSA). Seven of the patients were characterized by a lack of vasopressin response to hypotension (MSA type B), suggesting chronic sinoaortic denervation, and seven by a preserved response (MSA type A). Orthostatic hypotension decreased ANP in controls and type A patients, whereas ANP in type B was not affected. Isotonic saline infusion increased ANP and diuresis in controls and type A patients, whereas it did not affect ANP in type B. Osmotic load increased plasma osmolality and vasopressin in controls and MSA patients and ANP in controls and type A but not in type B patients. In MSA patients with altered afferent control of vasopressin, ANP secretion is not stimulated by blood volume expansion, osmotic load, or blood pressure, suggesting that afferent excitatory control plays a role in the release of ANP.

Atrial Natriuretic Factor↗
PubMed1995

Pure Autonomic Failure: complex abnormalities in the neural mechanisms regulating the cardiovascular system.

The aim of this study was to evaluate the sympatho-vagal interaction modulating cardiovascular function and the possible impairment of baroreceptor sensitivity in patients affected by Pure Autonomic Failure (PAF). We studied 4 patients affected by PAF and 7 controls at rest and during different levels (45 degrees, 60 degrees, 90 degrees) of head-up tilt. On a different day all subjects underwent i.v. administration of phenylephrine at dosages adequate to enhance systolic blood pressure by about 20 mmHg both at rest and during 45 degrees head-up tilt. Finally, 1.5 mg atropine was infused intravenously only in the patients. Spectral analysis of RR interval and systolic arterial pressure (SAP) variabilities provided markers of sympathetic (low-frequency oscillations, about 0.1 Hz, LFRR) and vagal (high-frequency oscillations, about 0.25 Hz, HFRR) modulations of heart period and of sympathetic vasomotor activity (low-frequency oscillations of SAP variability, LFSAP). Baroreceptor mechanisms were quantified by means of the index alpha (calculated from the square root of the ratio between the powers of HF components of RR interval and SAP variabilities) and of the phenylephrine RR-SAP slope. Patients affected by PAF were characterized by a drastic decrease in total power of RR variability and by the absence of LFRR and LFSAP components. Moreover, HFRR, although largely predominant in its relative value, was also markedly reduced in its absolute value. Finally, the baroreceptive mechanisms appeared to be heavily impaired. In conclusion, PAF patients seem to be characterized by a complex alteration of neural mechanisms, which in addition to the signs of a sympathetic denervation include an impairment, at least functional, of the vagal modulation of heart rate.

Atropine↗