Substantia nigra hyperechogenicity in essential tremor and Parkinson's disease: a longitudinal study.

BACKGROUND AND PURPOSE: Essential tremor (ET) and Parkinson's disease (PD) sometimes overlap in their clinical expression with ET preceding PD onset, often leading to misdiagnosis. Transcranial sonography (TCS) has been shown to be a valid and non-invasive diagnostic tool to identify early idiopathic PD and to differentiate it from ET. The purpose of this study was to investigate the relevance of substantia nigra hyperechogenicity in patients with ET. METHODS: A total of 138 patients (79 with PD, 59 with ET) and 50 matched controls underwent TCS examination at baseline. All patients were followed in a 3-year longitudinal assessment. RESULTS: A total of 10 subjects were excluded from the analysis due to the bilateral absence of a temporal acoustic window. During the follow-up period, 11 of the patients with ET developed new-onset parkinsonian features, without fulfilling criteria for PD diagnosis (ET+). Nine patients developed clinical features meeting diagnostic criteria for probable PD (ET-PD). Patients with ET- did not develop parkinsonian features. For each group, the maximum size of the substantia nigra hyperechogenicity was as follows: 5.62 ± 5.40 mm2 in the control group, 19.02 ± 14.27 mm2 in patients with PD, 9.15 ± 11.26 mm2 in patients with ET-, 20.05 ± 13.78 mm2 in patients with ET+ and 20.13 ± 13.51 mm2 in patients with ET-PD. ET-PD maximum values were significantly different from controls. Maximum values in patients with ET+ were different from both controls and patients with ET-. CONCLUSION: Substantia nigra hyperechogenicity in ET seems to represent a risk marker for developing early parkinsonian symptoms or signs in the 3 years following TCS assessment.

Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.

BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

Heart rate reduction with ivabradine in the early phase of atherosclerosis is protective in the endothelium of ApoE-deficient mice.

Ivabradine, a heart rate reducing agent, protects the vascular system by unidentified mechanisms. We sought to determine the effects of the treatment with ivabradine, started before plaque formation, on early transcriptional changes and endothelium lesions in regions of aorta subjected to disturbed blood flow. Six week-old apolipoprotein E-deficient (ApoE-/-) mice, fed a low-fat diet, were treated with ivabradine to determine the effect on transcriptional changes (2-and 4-week treatment) and on lesions formation (19-week treatment) in the endothelium of the aortic arch. Microarrays analysis (60k probes) of endothelium-enriched RNA was carried out to detect changes in gene expression induced by treatment. Endothelium damage was assessed by en-face immunofluorescence staining for vascular endothelial (VE) cadherin. According to microarray analysis, 930 transcripts were affected by the treatment. We found downregulation of pro-apoptotic and pro-inflammatory genes, the majority of which are nuclear factor-κB (NF-κB)-and/or angiotensin II-regulated genes, and upregulation of anti-inflammatory genes. Many shear stress-responsive genes were affected by the treatment and the MAPK, Notch signalling and sterol metabolic processes were among the most significantly affected pathways. Consistently, we observed increased levels of Hes5, a Notch target gene, together with a reduction of endothelium damage, in the lower aortic arch of treated- compared with untreated- mice. We concluded that an early treatment with ivabradine protected the endothelium of the aortic arch of ApoE-/- mice. Activation of the Notch signalling could be part of the mechanism underlying this protection.

Long-acting insulin analog detemir displays reduced effects on adipocyte differentiation of human subcutaneous and visceral adipose stem cells.

BACKGROUND AND AIMS: Since treatment with insulin detemir results in a lower weight gain compared to human insulin, we investigated whether detemir is associated with lower ability to promote adipogenesis and/or lipogenesis in human adipose stem cells (ASC). METHODS AND RESULTS: Human ASC isolated from both the subcutaneous and visceral adipose tissues were differentiated for 30 days in the presence of human insulin or insulin detemir. Nile Red and Oil-Red-O staining were used to quantify the rate of ASC conversion to adipocytes and lipid accumulation, respectively. mRNA expression levels of early genes, including Fos and Cebpb, as well as of lipogenic and adipogenic genes, were measured at various phases of differentiation by qRT-PCR. Activation of insulin signaling was assessed by immunoblotting. ASC isolated from subcutaneous and visceral adipose tissue were less differentiated when exposed to insulin detemir compared to human insulin, showing lower rates of adipocyte conversion, reduced triglyceride accumulation, and impaired expression of late-phase adipocyte marker genes, such as Pparg2, Slc2a4, Adipoq, and Cidec. However, no differences in activation of insulin receptor, Akt and Erk and induction of the early genes Fos and Cebpb were observed between insulin detemir and human insulin. CONCLUSION: Insulin detemir displays reduced induction of the Pparg2 adipocyte master gene and diminished effects on adipocyte differentiation and lipogenesis in human subcutaneous and visceral ASC, in spite of normal activation of proximal insulin signaling reactions. These characteristics of insulin detemir may be of potential relevance to its weight-sparing effects observed in the clinical setting.

ROS, Notch, and Wnt signaling pathways: crosstalk between three major regulators of cardiovascular biology.

Reactive oxygen species (ROS), traditionally viewed as toxic by-products that cause damage to biomolecules, now are clearly recognized as key modulators in a variety of biological processes and pathological states. The development and regulation of the cardiovascular system require orchestrated activities; Notch and Wnt/ß -catenin signaling pathways are implicated in many aspects of them, including cardiomyocytes and smooth muscle cells survival, angiogenesis, progenitor cells recruitment and differentiation, arteriovenous specification, vascular cell migration, and cardiac remodelling. Several novel findings regarding the role of ROS in Notch and Wnt/ß-catenin modulation prompted us to review their emerging function in the cardiovascular system during embryogenesis and postnatally.

Cyclophilin A: a key player for human disease.

Cyclophilin A (CyPA) is a ubiquitously distributed protein belonging to the immunophilin family. CyPA has peptidyl prolyl cis-trans isomerase (PPIase) activity, which regulates protein folding and trafficking. Although CyPA was initially believed to function primarily as an intracellular protein, recent studies have revealed that it can be secreted by cells in response to inflammatory stimuli. Current research in animal models and humans has provided compelling evidences supporting the critical function of CyPA in several human diseases. This review discusses recently available data about CyPA in cardiovascular diseases, viral infections, neurodegeneration, cancer, rheumatoid arthritis, sepsis, asthma, periodontitis and aging. It is believed that further elucidations of the role of CyPA will provide a better understanding of the molecular mechanisms underlying these diseases and will help develop novel pharmacological therapies.

Antiproliferative and pro-apoptotic activity of novel phenolic derivatives of resveratrol.

Gloriosaols A-C, isolated from Yucca gloriosa (Agavaceae), are novel phenolic compounds structurally related to resveratrol. In the present study, we show that gloriosaols possess antiproliferative and pro-apoptotic activity on tumor cells of different histogenetic origin and that their cell growth inhibition potential is higher than that of resveratrol. Despite the close similarities in their structure, gloriosaols A-C exhibited different antiproliferative potency, as the EC(50) ascending order is: gloriosaol C, gloriosaol A, gloriosaol B. Further mechanisms of gloriosaol C cytotoxicity were elucidated in detail in U937 cells, the most sensitive of the cell lines tested. The effect of gloriosaol C on cell growth turned out to be strongly dependent upon the concentration. Gloriosaol C doses lower than the EC(50) value (8 mu-icroM) blocked the cell cycle in G(0)/G(1), with a concurrent decrease in the number of cells in the G(2)/M phases of the cell cycle. At higher doses, this arrest overlaps with the occurrence of apoptosis and necrosis. In the 10-25 microM range of doses, gloriosaol C caused cell death mainly by apoptosis, as measured by hypodiploidia induction, phosphatidyl serine externalization and disruption of mitochondrial transmembrane potential. A switch in the mode of death from apoptosis to necrosis occurred at doses of gloriosaol C higher than 30 microM. Gloriosaol C was found to induce production of reactive species dose-dependently, but also to counteract their elevation in stressed cells. Thus, the different fate of cells, that is cell cycle arrest or cell death, in response to different doses of gloriosaol C might be related to the extent of induced oxidative stress.

The usefulness of clinical indexes in the evaluation of cardiovascular risk in non cardiac surgery.

AIM: The preoperative cardiac evaluation of a patient who undergoes noncardiac surgery is a very important problem, particularly for diagnostic tools used. Aim of this study is to test the usefulness of 4 most used clinical indexes for the evaluation of cardiovascular risk in the management of patients who undergo noncardiac surgery. METHODS: The study is based on a retrospective analysis of a group of 45 patients, who underwent extracardiac surgery in biennium 2002-2004. The cardiovascular risk scores of Goldman, Detsky, Lee and Eagle were used; a comparison among the different scores was done. RESULTS: Six out of our 45 patients had perioperative cardiovascular complications, and 4 of them died. The Eagle and Lee scores were more predictive than Goldman and Detsky ones. About the 13 echocardiographic tests recorded, no one of them modified the patient preoperative risk. CONCLUSIONS: In the preoperative assessment of risk, the Eagle score was more useful than the others ones and improved the negative predictive value of the Goldman and Detsky scores. The preventive application of the clinical indexes allows optimizing the preoperative stratification of the risk, limiting the request of useless examinations and offering to the patient a well appropriated preoperative management, reducing the incidence of complications.

Ventricular arrhythmias in hypertensive patients with mild metabolic alterations.

BACKGROUND: Ventricular arrhythmias (VA) are prevalent in hypertensives, as well as in diabetics and dyslipidemics. The aim of our study is to evaluate if alterations in glucose or lipid metabolism increase the risk of VA in hypertensive patients. METHODS: Sixty-eight patients (24 males, 44 females, aged 45-78), with mild-moderate hypertension, were divided into 2 groups: group A (n=24) normoglycemic and normolipemic, and group B (n=44) with serum cholesterol >220 mg% and/or triglycerides >165 mg% and/or glucose >110 mg%. Patients with clinical or ECG signs of ischemia or kaliemia <3.5 mEq/l, were not admitted to the study. After a 15-days pharmacological wash-out, 24-hour Holter ECG and echocardiography were performed on all patients. RESULTS: Ventricular ectopic beats (VEB) were found in 66% of group A and 100% of group B (difference =34%, 95% C.I. =18-50%). VEB were less severe in group A (Lown's class 1-2), while group B had VEB ranging from class 1 to 5. Left ventricular hypertrophy (LVH) was found in 33% of group A and in 72.7% of group B, and was not closely correlated to VA. Group B patients with LVH had more severe VA (4 A, 4 B and 5 Lown's class). CONCLUSIONS: Hyperglycemia and/or dyslipidemia, even mild, seem to increase the risk of VA in the hypertensive patient with or without LVH. It suggests that 24 hour Holter ECG may be useful to select, among patients with metabolic alterations, those at high risk for VA.

Antiarrhythmic benefits of dual chamber stimulation with rate-response in patients with paroxysmal atrial fibrillation and chronotropic incompetence: a prospective, multicentre study.

BACKGROUND: While the haemodynamic benefits of DDDR pacing compared with DDD pacing in patients with brady-tachy syndrome and chronotropic incompetence (CI) are well demonstrated, the antiarrhythmic advantage is controversial and so far not clearly demonstrated. AIM: We have performed a prospective, randomized, multicentre study to evaluate the efficacy of DDDR and DDD pacing modes in preventing paroxysmal atrial fibrillation (PAF) episodes in patients with brady-tachy syndrome and CI. METHODS AND RESULTS: Seventy-eight patients were included in the study. All patients had a dual chamber pacemaker implanted and were randomly programmed to DDD or DDDR with a cross over (DDD --> DDDR or vice versa) at 3 months. The final evaluation was performed at 6 months by means of two self-administered symptom questionnaires to evaluate activity. Symptoms of palpitations were analysed and scored. The patients were less symptomatic with the DDDR mode. The number of mode-switch activations compared with symptomatic episodes of PAF confirmed the high rate of asymptomatic PAF episodes in patients with brady-tachy syndrome. We conclude that in a small but well defined population of patients affected by sick sinus syndrome with CI and severely symptomatic PAF, DDDR pacing compared with DDD pacing may offer an additional antiarrhythmic benefit and should be considered the primary mode of pacing.

Steroid-eluting electrodes prevent chronic pacing threshold rise in the atrial chamber after oral propafenone administration.

The aim of the study was to evaluate chronic atrial pacing threshold increase after oral propafenone therapy. Fifty patients affected by advanced AV block and sick sinus syndrome were studied at least 6 months after pacemaker implantation, before and after oral propafenone therapy (450-900 mg/day based on body weight). The patients were subdivided into three groups as to the type of electrode implanted, all three unipolar: group I (20 patients) Medtronic CapSure 4003, group II (13 patients) Medtronic Target Tip 4011, group III (17 patients) Medtronic 4057 screw-in leads. In all cases, Medtronic unipolar pacemakers were implanted with the same noninvasive autothreshold measurement method. Propafenone and 5-OH-propafenone blood levels were measured 3-5 hours after drug administration. The packing autothreshold was measured at 0.8, 1.6, and 2.5 V by reducing the pulse width. After propafenone, groups II and III showed a statistically significant threshold rise (P ranging from < 0.01 to 0.05), whereas no significant difference was found in group I. Propafenone and 5-OH-propafenone blood vessels did not show any significant difference among the three groups. Strength-duration curves were drawn for the three groups before and after propafenone: at baseline the curves shifted to the left with the steep part above the knee, clearly favoring CapSure over the other two groups. After propafenone, the curves shifted to the right, with the flat par progressively more evident in groups II and III. In the atrial chamber, steroid-eluting leads prevented threshold increase after propafenone therapy, in contrast with a significant threshold rise with conventional porous and screw-in leads.

Effect of steroid eluting versus conventional electrodes on propafenone induced rise in chronic ventricular pacing threshold.

The aim of this study was to evaluate chronic ventricular pacing threshold increase after oral propafenone therapy. Eighty-three patients affected by advanced atrioventricular block and sick sinus syndrome were studied at least 3 months after pacemaker implantation, before and after oral propafenone therapy (450-900 mg/day based on body weight). The patients were subdivided into three groups according to the type of unipolar electrode that was implanted: group I (41 patients) Medtronic CapSure 4003, group II (30 patients) Medtronic Target Tip 4011, and group III (12 patients) Osypka Vy screw-in lead. In all cases a Medtronic unipolar pacemaker was implanted: 30 Minix, 23 Activitrax, 14 Elite, 12 Legend, and 4 Pasys. Propafenone blood level was measured in 75 patients 3-5 hours after propafenone administration. The pacing autothreshold was measured at 0.8 V, 1.6 V, and 2.5 V by reducing pulse width. At the three different outputs before and after propafenone, threshold increments were significantly lower in group I in comparison with group II and group III (propafenone ranging from < 0.001 to < 0.05). No significant difference was found in pacing impedance or in propafenone plasma concentration in the three groups. Strength-duration curves were drawn for each group at baseline and after propafenone administration. Before propafenone, in group I, the knee was markedly shifted to the left and downward as compared to the classic curve, so that the steep part was predominant; in group II and group III this shift was progressively less evident.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of cloridarol in coronary insufficiency]. / Impiego del cloridarol nell'insufficienza coronarica

The therapeutical activity of a new oral drug with a coronaric and myocardiotrophic action of choice, 2-benzofuryl-p-chlorophenyl-carbinol (Menacor, Menarini) in 20 patients with chronic coronary insufficiency was studied by administering 750 mg/day for at least 20 days. General and gastroenteric tolerance was excellent, while good or fair therapeutic results were obtained in 16 cases (80%). It is felt that the drug can be usefully employed in the management of coronary insufficiency.