Cryoballoon ablation for atrial fibrillation guided by real-time three-dimensional transoesophageal echocardiography: a feasibility study.

AIMS: Cryoballoon ablation (CBA; Arctic Front, Medtronic) has proven very effective in achieving pulmonary vein isolation. Real-time three-dimensional transoesophageal echocardiography (RT 3D TEE) is a novel technology, which permits detailed visualization of cardiac structures in a 3D perspective. The aim of the present study was to assess the feasibility, advantages, and safety of RT 3D TEE in guiding CBA in a series of patients affected by paroxysmal atrial fibrillation. METHODS AND RESULTS: Forty-five patients (34 males, mean age: 63 ± 12 years) underwent CBA guided by 3D TEE. A total of 190 veins could be documented by TEE. Real-time three-dimensional transoesophageal echocardiography successfully guided the operator to position the CB in the pulmonary vein (PV) ostium and obtain complete occlusion in all 190 (100%) veins. Transoesophageal echocardiography identified leakages in 25 (13%) veins led to successful elimination of PV-left atrium (LA) backflow by guiding correct balloon repositioning. In four (2%) veins, this imaging tool led to perform successful pull-down manoeuvres. After a mean 2.6 ± 1.4 applications, isolation could be documented in 190 (100%) PVs. Median procedural and fluoroscopy times were 145 and 24 min. During a median follow-up of 278 days, 37 (82%) patients did not experience atrial fibrillation recurrence following a 3-month blanking period. CONCLUSION: Cryoballoon ablation is safe and feasible under RT 3D TEE guidance. This imaging tool permits perfect visualization of all PV ostia and neighbouring LA structures. Most importantly, it proved very efficient in guiding the operator to achieve complete occlusion and successful isolation in all veins.

Monocyte activation in multiple sclerosis.

Monocytes, macrophages, and microglia have a central role in the CNS inflammation of MS. Monocytes are important in the earliest events in MS. Peripheral blood monocytes secrete prostaglandins before MS attacks. During clinical activity monocyte activation markers increase and IL-1 and TNF-alpha levels are elevated. Other monocyte products such as IL-10 reduce inflammation. IL-10 mRNA in MNC is increased during stable disease. Manipulation of monokine secretion and expression of monocyte surface proteins are reasonable approaches for immune therapy of MS.

Effects of an anti-IL-10 monoclonal antibody on rIFNbeta-1b-mediated immune modulation. Relevance to multiple sclerosis.

The mechanism of action of recombinant IFNbeta1b (IFNbeta-1b), as a therapy for multiple sclerosis (MS), is still unknown but may result from the enhancement of ConA-induced suppressor cell function and the inhibition of IFNgamma secretion by lymphocytes. We previously demonstrated that IFNbeta-1b stimulated modest amounts of IL-10 secretion by monocytes and IL-10 activity, as cytokine synthesis inhibitory factor, was normal in MS. To determine whether IL-10 plays a role in IFNbeta-1b modulation of immune function in MS, we studied ConA-induced suppressor cell function and IFNgamma production in presence of IFNbeta-1b and an anti-IL-10 monoclonal antibody (mAb). Anti-IL-10 mAb significantly reduced the effect of IFNbeta-1b on ConA-induced suppressor cell function and IFNgamma production in healthy subjects; MS patients showed a trend of inhibition. We hypothesized that IL-10 may play a role in mediating the effects of IFNbeta-1b on suppressor cell function and IFNgamma production but suppressor molecules other than IL-10 could be also involved.

Interferon effects on interleukin-10 secretion. Mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients.

The mechanism of action of recombinant interferon beta 1b (rIFN beta 1b/IFN beta-1b), the approved therapy for multiple sclerosis (MS), is still unclear. Here we present evidence that part of the therapeutic effects of rIFN beta 1b in MS might result from the induction of the secretion of interleukin (IL)-10, a cytokine previously designated cytokine synthesis inhibitory factor (CSIF). We observed that rIFN beta 1b stimulated significant IL-10 secretion by monocytes from MS patients after brief incubation (18 h), whereas rIFN gamma, an inducer of MS exacerbations, was unable to stimulate IL-10 production in similar conditions. To determine the role of IL-10 as CSIF in the disease, we have also investigated its effects on TNF alpha and IL-6 secretion by peripheral blood mononuclear cells from MS patients. Recombinant human IL-10 significantly inhibited tumor necrosis factor alpha and IL-6 secretion induced by rIFN gamma, lipopolysaccharide (LPS), and rIFN gamma + LPS in MS patients and in control subjects. The induction of IL-10 secretion by rIFN beta 1b and the IL-10 inhibitory activity on pro-inflammatory cytokine secretion induced by rIFN gamma in MS make this cytokine a potential candidate to treat the disease.

IFN-gamma, IFN-beta, and PGE1 affect monokine secretion: relevance to monocyte activation in multiple sclerosis.

Activated antigen-presenting cells and central nervous system microglia produce IL-1 beta, TNF-alpha, IL-6, and PGE-1. These monokines participate in the lymphocyte activation, demyelination, and intrathecal immunoglobulin synthesis seen in multiple sclerosis (MS). Exacerbations of MS are ameliorated by IFN-beta, but provoked by IFN-gamma, possibly through an effect on monocytes (Mo). We studied the effects of IFNs and PG on monokine secretion under stringent low-endotoxin conditions. Spontaneous and IFN-gamma-induced IL-1 beta secretion was greater in MS than in NL Mo. IFN-beta did not inhibit IFN-gamma-induced secretion of monokines, which contrasts with IFN-beta's inhibitory effect on IFN-gamma-induced MHC class II expression. PGE1, a cAMP agonist, caused a 30-fold induction of IL-6 secretion. Indomethacin directly inhibited this induction. Low-dose IFN-beta, through effects on T cells, and cAMP agonists, through effects in T cells and Mo, may ameliorate inflammatory diseases characterized by excessive monokine secretion.

Memory and naive CD4+ lymphocytes in multiple sclerosis.

Helper-inducer (CD29+CD4+) and suppressor-inducer (CD45RACD4+) T-cells have been recently renamed as memory and naive T-cells, respectively. We measured cells expressing these phenotypes in peripheral blood of 46 definite multiple sclerosis (MS) patients [32 relapsing-remitting (RR-MS), 14 secondary progressive (P-MS)] and controls. CD25+ (interleukin-2-receptor-positive) cells were also evaluated in the same groups of patients. RR-MS patients showed increased levels of CD29+CD4+ and CD25+ cells compared with controls. This finding was more evident in RR-MS patients during the attack than during the stable phase of the disease. In P-MS patients we found a reduction of CD45+CD4+ cells compared with either RR-MS patients or control subjects. Our results show that RR-MS and P-MS are characterized by two different T-cell subpopulations. This finding supports the hypothesis that during the evolution from RR-MS and P-MS changes occur in the immunological status of the patients.

Inhibition of interleukin-1 (alpha and beta), interleukin-2 secretion and surface expression of interleukin-2 receptor (IL-2R) by a novel cytokine interleukin-1 receptor antagonist (IL-1ra).

IL-1 is a mediator of the acute inflammatory response and plays a key role in influencing growth and differentiation of immunocompetent lymphocytes. It can enhance transcription and secretion of the T-cell growth factor interleukin-2 (IL-2) and can stimulate the expression of membrane receptors for IL-2. However, the regulation and control of IL-1 activities are poorly understood. Recently an IL-1 inhibitor, interleukin-1 receptor antagonist (IL-1ra), has been described and cloned. This protein is a monokine originally found in the urine of febrile patients and in supernatants of human monocytes adhering to an IgG-coated surface, with an approximate molecular weight of 17 kDa, which is similar to IL-1 beta but having no IL-1-like activity and antagonizing IL-1 by binding to its cell surface receptor. These studies have examined some biological properties of hrIL-1ra, such as its effects on the secretion of IL-1 alpha or IL-1 beta and IL-2, the surface expression of IL-2R and DNA synthesis by peripheral blood mononuclear cells (PBMC). PBMC from normal volunteers were separated and used at a concentration of 2.5 x 10(6) cells/ml. The cells were pretreated for 2 h with hrIL-1ra (0.025-250 ng/ml), treated with LPS (10 ng/ml), and IL-1 alpha and IL-1 beta secretion were determined by an ELISA method. In addition the influence of hrIL-1ra (25 ng/ml) on IL-2 generation was determined. In another set of experiments, flow cytometric analysis with an anti-CD25 monoclonal antibody was determined on PHA-stimulated PBMC pretreated with hrIL-1ra (2 h) and cultured for 48 h. The inhibition by hrIL-1ra of IL-2R expression was dose-dependent and when hrIL-1ra was used at 250 ng/ml the IL-2R was completely abolished. Lymphocyte DNA synthesis calculated from the net uptake of [3H]-thymidine (3H-TdR) was also inhibited by hrIL-1ra (0.025-25 ng/ml). In this report we found that hrIL-1ra inhibits, in a dose-dependent manner, the secretion of IL-1 alpha, IL-1 beta, IL-2, the surface expression of IL-2R and 3H-TdR incorporation in PBMC in vitro. These data suggest a new biological activity of hrIL-1ra and further extend the immunomodulatory potential and significance of this new cytokine. The action of IL-1ra on modulating the synthesis of IL-1 may be of paramount importance in the regulation of these effects.

Multiple sclerosis: an immune system activation disease.

Two-color flow-cytometric analysis on peripheral blood lymphocytes of 46 untreated multiple sclerosis patients (MS), 36 other medical disease patients (OMD) and 19 healthy control subjects (HC) was performed to know the relationships between T and B cell subpopulations. In MS patients we observed an increase of total lymphocyte count and an increase of CD4+CD29+ cells, which are adjuvant to B cell in antibody production. We hypothesized this change is related to the reduction of CD21+ cells, expressing B2 antigen which disappears after B cell activation. The unperfect balance of immune system in MS was also demonstrated by the increased level of CD25+ cells in relapsing-remitting patients and by the decreased level of CD4+ CD45RA+ (suppressor inducer) cells in progressive patients.

CNS involvement in chronic inflammatory demyelinating polyneuropathy: an electrophysiological and MRI study.

Eight consecutive patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were investigated by visual evoked potential (VEP), brainstem auditory evoked response (BAER) and magnetic resonance imaging (MRI) to assess central nervous system (CNS) involvement. VEPs were abnormal in 6 patients and BAERs in 2. MRI showed changes suggestive of CNS demyelination in 2 cases. Our findings suggest the existence of a combined central and peripheral demyelinating syndrome and emphasize the possibility of a common pathogenetic mechanism for both.

HTLV-1-associated myeloneuropathy in an Italian.

A 58-year old man presented with slowly progressive spastic paraparesis, ataxia, absent ankle jerks, bladder disturbances, impairment of vibration sense and mental deterioration. Electrophysiological studies documented axonal sensory neuropathy, posterior column and optic nerve involvement. Serum tests for anti-HTLV-1 antibodies were negative but HTLV-1 proviral sequences were consistently demonstrated in white blood cell genomic DNA using the polymerase chain reaction technique. Western blot and polymerase chain reaction assays of sera and DNA from family members were negative for HTLV-1. The most likely cause of infection in this patient was a blood transfusion received 2 years before onset of symptoms. This is the second Italian case of HTLV-1 associated myelopathy and the fourth reported in white subjects living in Europe.

CD21+ (B2 antigen+) cell decrement and CD4+CD29+ (helper-inducer) cell increment suggest an activation of cell immune reactivity in multiple sclerosis.

Two-color flow cytometric analysis on peripheral blood lymphocytes of 35 untreated multiple sclerosis (MS) patients, 17 other medical disease (OMD) patients and 14 healthy control (HC) subjects was performed to evaluate the levels of different T and B cell subpopulations. In MS patients we observed an increase in CD4+CD29+ helper-inducer cells but this increase was not related to the different phases of the disease. We hypothesize that this change is related to the reduction of CD21+ cells expressing B2 antigen, a 140 kDa molecule disappearing after B cell activation. An increased level of CD4+CD45RA- (helper-inducer-like cells) and a reduction of CD4+CD29- (suppressor-inducer-like cells) were also present in our patients. These findings demonstrate an immune 'disequilibrium' in MS, which is linked with an increased level of CD25+ cells expressing the interleukin-2 (IL-2) receptor. IL-2, besides being a T cell growth factor, is also a B cell growth factor. These data let us hypothesize that an activation of the immune response is present in MS.

Amplifications of multiple regions of the HTLV-I genome from DNA of an Italian spastic paraparesis patient but not from DNA of multiple sclerosis patients.

We searched for evidence of infection by the human T-cell lymphoma/leukemia virus type I (HTLV-I) in patients with multiple sclerosis (40 cases); brainstem encephalitis (1 case); Friedreich's ataxia (1 case); spastic paraparesis of unknown etiology (1 case). All patients were from the region of Abruzzo, Italy. Sera were all negative for anti-HTLV-I reactivity by the Western blotting (WB) analysis. DNAs from peripheral blood mononuclear cells were amplified using the polymerase chain reaction (PCR) technique with primers specific for the HTLV-I gag, pol, and env proviral regions. HTLV-I sequences were amplified only in the patient with spastic paraparesis of unknown etiology. In this case, HTLV-I infection might have been related to blood transfusions received 2 years prior to the onset of the neurologic symptoms. Members of the patient's family were negative for HTLV-I by PCR and WB. These data indicate that HTLV-I associated myelopathy is present also in Italy, but fail to substantiate an association of HTLV-I with multiple sclerosis.

Aneurysm of an aberrant right subclavian artery. Report of a surgically treated case.

A 53-year-old man was admitted for treatment of an aberrant right subclavian artery aneurysm that had been diagnosed 5 years earlier and had recently begun to enlarge. The aneurysm, which involved the right subclavian artery from its origin, measured 47 mm in diameter and about 10 cm in length. Because of the lesion's size and friability, a 2-stage operation was performed. In the 1st stage, the right subclavian and right vertebral arteries were revascularized with double bypass grafts via a right cervical approach. In the 2nd stage, the patient was repositioned and a left thoracotomy incision was made. With the aid of left-heart bypass, the aorta was cross-clamped proximal and distal to the lesion, and the aneurysmal orifice was closed with a Dacron patch. The patient was discharged from the hospital on the 17th postoperative day and remains asymptomatic 24 months later. We recommend the 2-stage technique for similar cases because it prevents limb ischemia and reduces the risk of hemorrhagic and embolic complications.

Recurrent cranial nerve palsies, midbrain infarction and hydrocephalus due to megadolichobasilar artery.

A 67-year-old man presented four recurrent, alternating facial palsies, two right abducens palsies and eventually a right extrinsic third nerve palsy due to brain-stem infarction in a 37-year time-span. Neuroradiological examinations showed hydrocephalus and an elongated, tortuous, ectasic basilar artery. This patient presented in his lifetime the whole clinical spectrum of the dolichoectasic basilar artery complications.

Coexistence of diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis.

To the best of our knowledge, only two patients with concurrent diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) have been reported so far. Here we present 3 patients in whom clinical and radiological findings indicative of DISH and AS coexisted. Two of these cases exhibited HLA B27. Although the presence of sacroiliitis would appear to exclude DISH, calcification and ossification of the anterior common vertebral ligament (ACVL) confirmed diagnosis of the latter disease.

Spinal artery steal syndrome in Paget's disease of bone.

We report a case of vertebral Paget's disease with paraplegia and no evidence of spinal cord compression, in which the neurological condition improved dramatically after treatment with calcitonin. Spinal cord vascular steal syndrome is suggested as another mechanism responsible for this neurologic complication.

Aneurysms involving the aortic arch. Report on thirteen surgically treated patients.

Since the beginning of 1980, 13 patients with aneurysms of the aortic arch have been operated in our department. In 4 cases the aneurysm was limited to the aortic arch, while in 10 patients the ascending aorta was involved. In 7 patients an emergency procedure was required. Eleven patients were operated using deep hypothermia and circulatory arrest, in 2 right axillary and femoral artery cannulation with moderate hypothermia was used. In 5 patients a concomitant aortic insufficiency was corrected with a mechanical valve. Three patients died in the hospital. Transient cerebral dysfunctions occurred in 4 patients. Deep hypothermia and circulatory arrest provided a convenient method especially in older patients. Bleeding due to generalized coagulopathy and bleeding diathesis was one of the major problems. The methods adopted to avoid these complications are reported and discussed in detail.