Cartesian genetic programming for diagnosis of Parkinson disease through handwriting analysis: Performance vs. interpretability issues.

In the last decades, early disease identification through non-invasive and automatic methodologies has gathered increasing interest from the scientific community. Among others, Parkinson's disease (PD) has received special attention in that it is a severe and progressive neuro-degenerative disease. As a consequence, early diagnosis would provide more effective and prompt care strategies, that cloud successfully influence patients' life expectancy. However, the most performing systems implement the so called black-box approach, which do not provide explicit rules to reach a decision. This lack of interpretability, has hampered the acceptance of those systems by clinicians and their deployment on the field. In this context, we perform a thorough comparison of different machine learning (ML) techniques, whose classification results are characterized by different levels of interpretability. Such techniques were applied for automatically identify PD patients through the analysis of handwriting and drawing samples. Results analysis shows that white-box approaches, such as Cartesian Genetic Programming and Decision Tree, allow to reach a twofold goal: support the diagnosis of PD and obtain explicit classification models, on which only a subset of features (related to specific tasks) were identified and exploited for classification. Obtained classification models provide important insights for the design of non-invasive, inexpensive and easy to administer diagnostic protocols. Comparison of different ML approaches (in terms of both accuracy and interpretability) has been performed on the features extracted from the handwriting and drawing samples included in the publicly available PaHaW and NewHandPD datasets. The experimental findings show that the Cartesian Genetic Programming outperforms the white-box methods in accuracy and the black-box ones in interpretability.

Excimer laser in acute myocardial infarction: single centre experience on 66 patients.

BACKGROUND: Pulsed-wave ultraviolet excimer laser light at 308 nm can vaporise thrombus, suppress platelet aggregation, and, unlike other thrombectomy devices, ablates the underlying plaque. AIM: To evaluate both safety and efficacy of laser ablation in patients presenting with Acute Myocardial Infarction (AMI) complicated by persistent thrombotic occlusion. METHODS: From May 2003 to October 2006, we enrolled 66 AMI patients (age 59+/-11 years; 57 men) presenting complete thrombotic occlusion of the infarct related vessel. All patients were treated with laser. Primary acute angiographic end-points was corrected TIMI frame count. Secondary echocardiographic end-point was left ventricular remodeling defined as an increase in end-diastolic volume >/=20% 6 months after infarction. Tertiary clinical endpoint was event-free survival at 6 months follow-up. RESULTS: There were no intra-procedural death or coronary perforation. One primary angiographic failure was observed during lasing. Major dissection occurred in 1 (1.5%) and distal embolization in 4 patients (6%). Corrected TIMI frame count was 100 at baseline, 29+/-0.6 after lasing and 22+/-3 after stenting. At 6-months follow-up, left ventricular remodeling occurred in 8% patients. Event-free survival was 95% at 6-months follow-up. CONCLUSION: Laser angioplasty is feasible, safe and effective for the challenging treatment of patients with AMI and thrombus-laden lesions. The acute effects on coronary epicardial and myocardial reperfusion are excellent.

Radiation dose exposure during cardiac and peripheral arteries catheterisation.

BACKGROUND: Ionising radiation carries an oncogenic risk which is linearly related to the dose. An estimation of the effective dose can be obtained from the measurements of the dose-area product (DAP), which is a measure of stochastic risk and a potential quality indicator. AIM: To assess radiation exposure of patients in a large volume cardiac cath-lab. METHODS: A retrospective analysis of adult cardiac and peripheral percutaneous procedures (April to December 2004) was carried out to determine the DAP and estimated risk of malignancy. We identified 6 groups: Group 1 (n=100, coronary angiography and ventriculography); Group 2 (n=50, carotid stenting); Group 3 (n=50, aortography+coronary angiography+ventriculography); Group 4 (n=100, inferior extremities angiography+predilatation and stenting); Group 5 (n=100, coronary angiography+ventriculography+direct coronary stenting); Group 6 (n=100, coronary angiography+ventriculography+coronary predilation and stenting). Dose-area product meter attached on the X-ray unit was used for the estimation of the radiation dose received by the patient during the procedures. RESULTS: DAP values (mean+/-S.D.) ranged from 41+/-30 Gy cm2 in Group 1 (lowest) to 118+/-89 Gy cm2 in Group 6 (highest). Within each group, individual radiation exposure varies substantially: from 11 to 200 Gy cm2 in Group 1, and from 30 to 733 Gy cm2 in Group 6 patients. Average exposure in a Group 6 patient corresponds to a risk of mortality from a malignancy of about 1 in 1000. CONCLUSION: The radiation dose varies substantially across different types of procedures and up to tenfold within the same procedure. The enhanced knowledge of radiation dose might help the cardiologist to implement radiation sparing procedures eventually minimizing patient and operator radiation hazards in invasive cardiology.

Direct coronary stenting: effect on coronary blood flow, immediate and late clinical results.

Direct stenting (DS) was attempted in 99 coronary lesions in 94 patients while standard stenting (SS) was attempted in 113 lesions in 103 patients matched for clinical characteristics, stenosis type, and location and stent type. The angiographic result was also evaluated according to TIMI frame count method (TFC) before and after procedure. A clinical follow-up was performed 1 year after the procedure. Before the procedure, TIMI grade 3 flow was detected in 42 cases (42.4%), grade 2 in 40 cases (40.4%), grade 1 in 5 cases (5.1%), and grade 0 in 12 cases (12.1%) in the DS group; these data were similar in SS group. After the procedure, TIMI grade flow was 3 in 90 cases (92.8%) in DS group and in 87 (77.0%) in SS group (P < 0.005); grade 2 was observed in 7 case (7.2%) in DS group and in 25 (22.1%) in SS group (P < 0.005). Major adverse cardiac events during hospitalization and at follow-up were similar in two groups. Radiation exposure time and procedure costs per lesion were significantly reduced in DS group compared to SS group (10.1 +/- 8 min vs. 13.9 +/- 4.7 min, P < 0.001; and 1901 +/- 687 Euro vs. 2352 +/- 743 Euro, P < 0.001, respectively). This study confirms that, in selected patients, direct stenting is a safe and successful procedure, allowing a significant reduction in radiation exposure time and procedural costs compared to standard stenting technique. The angiographic success is confirmed by the improvement in TFC in all cases.

Exercise training restores ischemic preconditioning in the aging heart.

OBJECTIVES: To investigate the effects of ischemic preconditioning in hearts from adult and both sedentary and trained senescent rats. BACKGROUND: Ischemic preconditioning does not prevent postischemic dysfunction in the aging heart, probably because of reduction of cardiac norepinephrine release. Exercise training can reverse the age-related decrease of norepinephrine production. METHODS: We investigated the effects on mechanical parameters of ischemic preconditioning against 20 min of global ischemia followed by 40 min of reperfusion in isolated perfused hearts from adult (six months) and sedentary or trained (six weeks of graduated swim training) senescent (24 months) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. RESULTS: Final recovery of percent-developed pressure was significantly improved after preconditioning in adult hearts (91.6+/-9.6%) versus unconditioned controls (54.2+/-5.1%, p<0.01). The effect of preconditioning on developed pressure recovery was absent in sedentary but present in trained senescent hearts (39.6+/-4.1% vs. 64.3+/-7.1%, p<0.05). Norepinephrine release significantly increased after preconditioning in adult and in trained but not in sedentary senescent hearts. The depletion of myocardial norepinephrine stores by reserpine abolished preconditioning effects in adult and trained senescent hearts. CONCLUSIONS: In adult and trained but not in sedentary senescent hearts, preconditioning reduces postischemic dysfunction and is associated with an increase in norepinephrine release. Preconditioning was blocked by reserpine in both adult and trained senescent hearts. Thus, exercise training may restore preconditioning in the senescent heart through an increase of norepinephrine release.

Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury.

OBJECTIVES: We sought to evaluate the effects of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on vascular smooth muscle cell (VSMC) proliferation in vitro and neointimal formation in vivo after vascular injury. BACKGROUND: Neointimal hyperplasia after vascular injury is responsible for restenosis after arterial stenting, whereas arterial remodeling and neointimal formation are the causes of restenosis after percutaneous transluminal coronary angioplasty. METHODS: We assessed the effect of simvastatin on in vitro VSMC proliferation. To study the effects of simvastatin in vivo, balloon injury and stent deployment were performed in the common carotid artery of rats. Neointimal area was measured two weeks later in the balloon injury model and three weeks after stent deployment. RESULTS: Simvastatin markedly inhibits VSMC proliferation in vitro. In vivo, simvastatin reduced, in a dose-dependent manner, the neointimal area and the neointima-media ratio after balloon injury from 0.266 +/- 0.015 mm2 to 0.080 +/- 0.026 mm2 and from 1.271 +/- 0.074 to 0.436 +/- 0.158 (p < 0.001 vs. control rats) at the highest dose. Simvastatin also significantly reduced the neointimal formation and the neointima-media ratio after stenting from 0.508 +/- 0.035 mm2 to 0.362 +/- 0.047 mm2 (p < 0.05 vs. control rats) and from 2.000 +/- 0.136 to 1.374 +/- 0.180 (p < 0.05 vs. control rats). The vessel thrombosis rate after stent deployment was 30% in the control group and 11.1% in the treated group (p = NS). Moreover, the systemic administration of simvastatin did not affect hepatic and renal functions, blood pressure or heart rate. CONCLUSIONS: Simvastatin potently inhibits VSMC proliferation in vitro and reduces neointimal formation in a rat model of vascular injury.

Multicenter evaluation of the XT modular coronary stent: clinical and angiographic results.

BACKGROUND: In the past few years, the indications for stent implantation have broadened, along with a larger number of available designs. The Bard XT stent is a new modular stent with an original structure and design. METHODS: To evaluate the new Bard XT stent, we studied its use in a multicenter experience in 163 patients, with a total of 168 lesions and 180 implanted units. RESULTS: Despite the predominance of complex lesions, the procedural success rate was 98%, with only a 2% failure of stent implantation. There was only one death (no-reflow phenomenon in a rescue primary PTCA in a patient in cardiogenic shock) without other major periprocedural complications. Centralized QCA showed a statistically significant increase of MLD (from 0.73 +/- 0.43 mm to 2.71 +/- 0.40 mm, p < 0.0001) and DS reduction (from 73.8 +/- 15.1% pre-treatment to 7.8 +/- 0.4% after stent implantation; p < 0.0001). Aspirin and ticlopidine were routinely administered after the procedure. Thirty-day follow-up reported only one case of subacute stent thrombosis (in the first day), treated with re-PTCA. CONCLUSIONS: In a group of patients with complex lesions, we obtained a high rate of success with a low incidence of complications. The Bard XT stent had a high-performance profile with normalization of vessel diameter and angiographic results similar to the ones obtained with the "slotted tube" stents.

Ischemic threshold and myocardial stunning in the aging heart.

The aging heart appears to be more susceptible to ischemia-reperfusion injury than the adult heart. There is no evidence of an age-related difference in the threshold of myocardial ischemia and myocardial stunning. We studied the effects on mechanical, hemodynamic, and metabolic parameters of graded reduction of coronary perfusion pressure from 66 to 29 mmHg in isolated and perfused hearts from adult and senescent rats. Cardiac function was also assessed during recovery following ischemic period. In both adult and senescent hearts developed pressure and +dP/dt linearly decreased and end-diastolic pressure linearly increased with decreasing perfusion pressure. However, all mechanical parameters were more severely impaired in senescent than in adult hearts at 37 mmHg and 29 mmHg perfusion pressure, respectively (p < 0.01 vs. adult). At 29 mmHg, in both adult and senescent hearts lactate production similarly increased whereas creatine kinase leakage did not differ from controls. Developed pressure recovered more slowly in senescent than in adult hearts (p < 0.001) in the absence of cellular damage and in the presence of restoration of coronary flow. Lactate production observed at the same step of coronary perfusion pressure suggests that the ischemic threshold is similar in adult and senescent hearts. The slow recovery of myocardial contractility after the ischemic period observed in senescent hearts suggests an age-related increase in myocardial stunning.

Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart?

OBJECTIVES: The present study examined whether angina 48 h before myocardial infarction provides protection in adult and elderly patients. BACKGROUND: The mortality rate for coronary artery disease is greater in elderly than in young patients. In experimental studies, ischemic preconditioning affords an endogenous form of protection against ischemia-reperfusion injury in adult but not in senescent hearts. Angina before myocardial infarction, a clinical equivalent of experimental ischemic preconditioning, has a protective effect in adult patients. It is not known whether angina before myocardial infarction is also protective in aged patients. METHODS: We retrospectively verified whether antecedent angina within 48 h of myocardial infarction exerts a beneficial effect on in-hospital outcomes in adult (< 65 years old, n = 293) and elderly (> or = 65 years old, n = 210) patients. RESULTS: In-hospital death was more frequent in adult patients without than in those with previous angina (10% vs. 2.6%, p < 0.01), as were congestive heart failure or shock (10.7% vs. 3.3%, p < 0.02) and the combined end points (in-hospital death and congestive heart failure or shock) (20.7% vs. 5.9%, p < 0.0003). In contrast, the presence or absence of previous angina before acute myocardial infarction in elderly patients seems not to influence the incidence of in-hospital death (14.4% vs. 15.2%, p = 0.97), congestive heart failure or shock (11.0% vs. 11.9%, p = 0.99) and the combined end points (25.4% vs. 27.1%, p = 0.89). Logistic regression analysis models for in-hospital end points show that previous angina is a positive predictor in adult but not in elderly patients. CONCLUSIONS: The presence of angina before acute myocardial infarction seems to confer protection against in-hospital outcomes in adults; this effect seemed to be less obvious in elderly patients. This study suggests that the protection afforded by angina in adult patients may involve the occurrence of ischemic preconditioning, which seems to be lost in senescent patients.

The role of aging on the control of contractile force by Na(+)-Ca2+ exchange in rat papillary muscle.

BACKGROUND: Sarcolemmal Na(+)-Ca2+ exchange system is believed to be fundamental to the control of cardiac contractility. However, the relation between Na(+)-Ca2+ exchange and the control of contractile force has not been studied in senescent myocardium. METHODS: The role of Na(+)-Ca2+ exchange in the regulation of the cardiac muscle's contractile force was studied in adult and senescent papillary muscles by simultaneously measuring intracellular sodium activity (aNai), action potential, and contractile force while varying extracellular concentration of sodium and/or calcium. RESULTS: Reduction of [Na+]o decreased aNai from 8.0 +/- 1.8 to 4.1 +/- 0.8 in adult (-3.9 mM) and from 8.7 +/- 1.9 to 4.7 +/- 0.9 in senescent (-4.0 mM) papillary muscles, while developed tension (DT) increased by 80.2% in adult and by 135.6% in senescent papillary muscles (p < .01 vs adult). During low [Ca2+]o and high [Na+]o, aNai and DT modifications were similar both in adult and senescent papillary muscles. During high [Ca2+]o, aNai decreased to a similar extent in both adult and senescent papillary muscles, while DT increased by 37.8% in adult and by 67.8% in senescent (p < .05 vs adult). Simultaneous reduction of [Na+]o and [Ca2+]o decreased aNai from 8.1 +/- 1.2 to 6.8 +/- 1.1 mM in adult (-1.3 mM), and from 8.4 +/- 1.0 to 7.2 +/- 1.0 mM in senescent (-1.2 mM) papillary muscles while DT decreased by 22.1% in adult and by only 12.0% in senescent (p < .01 vs adult) papillary muscles. Simultaneous increase of [Na+]o and [Ca2+]o similarly increased aNai in both adult senescent papillary muscles, but decreased DT by 28.5% in adult and by 11.7% in senescent (p < .01 vs adult). After [Na+]o modifications, the equilibration time for the ratio of external and internal sodium ion activities was slowed in senescent papillary muscles (i.e., in low [Na+]o solution the equilibration time was 4.6 +/- 0.9 min in adult and 6.3 +/- 1.2 min in senescent papillary muscles, p < .001). CONCLUSIONS: Similar changes of aNai during transmembrane Na+ and Ca2+ gradients modifications associated to changes in contractile force seem to demonstrate that Na(+)-Ca2+ exchange is probably not modified by the aging process. However, the slow equilibration time for the ratio of Na+ activities might reflect an age-related reduction of the Na(+)-K+ pump activity.

Preconditioning does not prevent postischemic dysfunction in aging heart.

OBJECTIVES: This study was performed to investigate the effect of single or multiple brief periods of ischemia and the administration of exogenous norepinephrine before a more prolonged ischemic period and after reperfusion in adult and senescent isolated and perfused rat hearts. BACKGROUND: The mortality rate for coronary artery disease is greater in the elderly. Ischemic preconditioning has been proposed as an endogenous form of protection against ischemia-reperfusion injury. However, the role of preconditioning in aging heart is unknown. METHODS: We compared the protective effect of preconditioning transient ischemic and norepinephrine stimuli against 20 min of global normothermic ischemia and 40 min of reperfusion in isolated perfused hearts of adult (6 months old) and senescent (24 months old) rats. Norepinephrine release in coronary effluent was determined by high performance liquid chromatography. RESULTS: Final recovery of percent developed pressure was improved after single preconditioning transient ischemic and norepinephrine stimuli in adult hearts (87.7 +/- 9% and 82.3 +/- 8.7%) versus unconditioned control hearts (50.6 +/- 4.8%, p < 0.01 [mean +/-SD]). The effect of preconditioning on developed pressure recovery was not present in senescent hearts after transient ischemic stimulus (39.8 +/- 4.9% vs. 41.6 +/- 5.8%, p = NS) but was present after norepinephrine stimulus (74.3 +/- 10.5, p < 0.01). Norepinephrine release significantly increased after preconditioning transient ischemic stimulus in adult but not in senescent hearts (p < 0.01 vs. adult). Transient ischemic- and norepinephrine-induced preconditioning was blocked by alpha-adrenergic receptor antagonists in both adult and senescent hearts. Multiple transient ischemic stimuli were able to reduce postischemic dysfunction in adult but not in senescent hearts. CONCLUSIONS: Preconditioning transient ischemic stimulus significantly reduces postischemic dysfunction in adult but not in senescent hearts, whereas exogenous norepinephrine is able to mimic preconditioning in both adult and senescent hearts. Ischemic preconditioning induces an increase in norepinephrine release in adult but not in senescent hearts. Preconditioning induced by transient ischemic stimulus and norepinephrine was abolished by alpha-adrenergic receptor blockade in both adult and senescent hearts. Thus, our data demonstrate that preconditioning is absent in aging heart and is probably related to the reduction of norepinephrine release and alpha-adrenergic receptor stimulation in response to ischemic preconditioning.

Safety of echo-dipyridamole test in elderly patients with coronary artery disease.

The authors prospectively studied the feasibility and safety of high-dose dipyridamole echocardiography in 166 patients (77 younger and 89 elderly patients) referred for clinical evaluation of coronary artery disease. Echocardiographic examinations were adequate for analysis of parameters considered in 135 of the 166 patients (81.3%; 73 elderly, 62 younger patients). The feasibility of dipyridamole echocardiography test was 80.5% in young and 82% in elderly patients (P = ns). The incidence of side effects during dipyridamole echocardiography was similar in the two groups, except for dyspnea, which was observed in 20.5% of older and 3.2% of younger patients (p < 0.05). These data demonstrate that the dipyridamole test combined with echocardiographic monitoring of regional myocardial contractility may be considered a valid noninvasive method of evaluating coronary artery disease in the elderly.

Reduced aerobic metabolic efficiency in postischemic myocardium dysfunction in rats: role of aging.

It has been suggested that aging may enhance the deleterious effects of myocardial ischemia-reperfusion. This study evaluates the relationship between oxygen consumption and functional impairment during reperfusion following myocardial ischemia in adult and senescent rat hearts. Global ischemia induced a marked impairment of contractile function which was significantly higher in senescent than in adult hearts. During reperfusion postischemic dysfunction was more evident in senescent hearts: at the 10th minute, the developed pressure recovered less (p < 0.05) and end-diastolic pressure increased more (p < 0.05) in senescent than in adult hearts. However, oxygen consumption per unit of work was significantly higher throughout 60 min of reperfusion when compared to controls with no significant difference between adult and senescent hearts. This study demonstrates that following ischemia and reperfusion depression of function and inappropriately high oxygen consumption were observed in both adult and senescent hearts. However, aging was associated with greater contractile impairment, which occurred in the absence of further deterioration of metabolic efficiency of contraction.

Role of aging on electrical, mechanical, and coronary modification induced by ouabain and epinine in isolated rat heart.

OBJECTIVE: The contractile response to digitalis and beta adrenoceptor agonists is lower in the senescent than in the adult myocardium, while the development of ventricular arrhythmias is increased. The aim of this study was to examine the effects of aging on cardiac response to digitalis and an adrenergic agonist used clinically. METHODS: The electrical and mechanical responses were tested in isolated and perfused hearts from 3-24 month old rats receiving 15 min infusion of digitalis drug (ouabain, 6 x 10(-5) M) alone, and after 5 min of beta adrenoceptor agonist drug (epinine, 1.5 x 10(-7) M). RESULTS: Ouabain action was associated with a rise in left ventricular end diastolic pressure (p < 0.01) which increased progressively with aging, and with an elevation of left ventricular developed pressure (p < 0.01) which decreased progressively with aging. Epinine induced a reduction of left ventricular end diastolic pressure (p < 0.01) and a rise in left ventricular developed pressure (p < 0.01) but both effects decreased progressively with aging. Ouabain reduced coronary flow and this decrease was more pronounced with aging (p < 0.01), while epinine caused an increase (p < 0.01) that diminished in older hearts. Ouabain given after epinine resulted in a greater increase in left ventricular end diastolic pressure than epinine (p < 0.01) but lower than that caused by ouabain alone (p < 0.01), a greater increase in left ventricular developed pressure than epinine and ouabain (p < 0.01), and a smaller reduction of coronary flow rate than ouabain alone (p < 0.01). All these effects, however, diminished progressively with aging. Arrhythmia scores were higher during ouabain than in control (p < 0.01) and in epinine treated hearts (p < 0.01); pretreatment with epinine did not modify arrhythmia score during ouabain administration. The number and severity of arrhythmias, however, increased with aging in all groups. CONCLUSIONS: Aging has a negative effect on both the positive inotropic and the arrhythmogenic effects of ouabain and epinine, although these phenomena are more pronounced during ouabain administration. However, when the two drugs are given simultaneously, epinine does not modify the arrhythmogenic effect of ouabain but reduces some of its deleterious haemodynamic effects.