Developing medical device software in compliance with regulations.

In the last decade, the use of information technology (IT) in healthcare has taken a growing role. In fact, the adoption of an increasing number of computer tools has led to several benefits related to the process of patient care and allowed easier access to social and health care resources. At the same time this trend gave rise to new challenges related to the implementation of these new technologies. Software used in healthcare can be classified as medical devices depending on the way they are used and on their functional characteristics. If they are classified as medical devices they must satisfy specific regulations. The aim of this work is to present a software development framework that can allow the production of safe and high quality medical device software and to highlight the correspondence between each software development phase and the appropriate standard and/or regulation.

CPDI: An Index for measuring deviations in Clinical Pathways.

Clinical Pathways (CPs) are evidence-based recommendation for treating a diagnosis and an effective instrument to decrease undesired practice variability and improve clinician performance. Deviations from CPs might just as well reduce quality of care. Moreover they can be associated to possible adverse events. In this perspective, we developed and tested a system for comparing a patient trajectory (PT) with the corresponding CP in order to recognize significant variations. To measure adherence, a Clinical Pathway Deviation Index (CPDI) was constructed as the weighted-sum of five indicators. To build the indicators three different tools for CPs modeling have been tested. Only two of them proved suitable for our system. A preliminary analysis has been carried out using data of 24 real PTs. The aim of this paper is to present the system and to characterize CPDI performances.

Electrochemical assembling/disassembling of helicates with hysteresis.

A series of eight tetradentate, ditopic, bisimino bisheterocyclic ligands (1-8), and their complexes with Cu(I) and Cu(II), have been studied in CH(3)CN solution, by means of (1)H NMR, mass, and UV/vis spectroscopy, while the crystal and molecular structure of the Cu(II) complexes [Cu(3)](CF(3)SO(3))(2) and [Cu(4)](CF(3)SO(3))(2) and of the Cu(I) complexes [Cu(2)(4)(2)](ClO(4))(2) and [Cu(2)(5)(2)](ClO(4))(2) have been determined by X-ray diffraction methods. The Cu(II) complexes are monomeric, almost square-planar structures, both in solution and in the solid state, while the Cu(I) complexes are two-metal, two-ligand dimers which can be both helical and "box-like" in the solid, while they adopt a simple helical configuration in acetonitrile solution. The systems made of ligands 1-8 and copper are bistable, as under the same conditions either the Cu(I) helical dimers or the Cu(II) monomers can be obtained and are stable. The electrochemical behavior of the 16 copper complexes has been studied in acetonitrile solutions by cyclic voltammetry. One reduction and one oxidation wave were found in all cases, which display no return wave and are separated by a 500-1000 mV interval. Irreversibility is due to the fast self-assembling process that follows the reduction of [Cu(II)(L)](2+) and to the fast disassembling process that follows the oxidation of [Cu(I)(2)(L)(2)](2+) (L = 1-8). However, the overall [oxidation+disassembling] or [reduction+self-assembling] processes, i.e., [Cu(I)(2)(L)(2)](2+) = 2[Cu(II)(L)](2+) + 2e(-), are fully reversible. Moreover, CV profiles show that solutions containing copper and L undergo hysteresis on changing the applied electrochemical potential: in the same potential interval, the systems can exist in solution as either [Cu(I)(2)(L)(2)](2+) or [Cu(II)(L)](2+), depending on the electrochemical history of the solution. Moreover, by changing the structural or donor features of the ligands it is possible to modulate the potentials at which the system undergoes a transition from one to the other of its two possible states, in the hysteresis cycle. In addition, the spectral properties of the Cu(I) and Cu(II) complexes of the considered ligands make these systems good candidates for storing information in solution, which can be electrochemically written or erased and spectroscopically read.

Effects of simvastatin treatment on sICAM-1 and sE-selectin levels in hypercholesterolemic subjects.

This study was performed to determine whether the levels of soluble intercellular adhesion molecule-1 (sICAM-l) and soluble endothelial molecule-1 (sE-selectin) were elevated in subjects with hypercholesterolemia who presented with no other risk factors or evidence of atherosclerosis. The effects of administration of an HMG-CoA reductase inhibitor on the serum levels of these molecules were also examined. Forty hypercholesterolemic subjects (HCh) (19 males and 21 females), without hypertension or cardiovascular disease, received placebo for 4 weeks. The patients were then randomized in two groups; 20 of them (simvastatin group) were treated with simvastatin (20 mg/day) and the other 20 (placebo group) continued placebo administration. After 12 and 24 weeks of either simvastatin or placebo treatment, sICAM-1 and sE-selectin levels were measured. The same parameters were measured in 20 control subjects (C) with normal cholesterol levels, matched for sex and age. HCh had sICAM-1 basal values higher than C (352.4+/-57.9 ng/ml versus 114.9+/-89.6 ng/ml; P<0.001); however, sE-selectin basal values were not different in the two groups. No correlation was observed between HCh sICAM-1 levels and cholesterol levels (total and low-density lipoprotein). Furthermore, cholesterol-lowering treatment with simvastatin did not significantly diminish sICAM-1 levels. Our findings would support the hypothesis that patients with isolated hypercholesterolemia and without clinical atherosclerosis may be silent carriers of arterial subendothelial inflammation, expressed as an increase of sICAM-1.

Gemfibrozil, nicotinic acid and combination therapy in patients with isolated hypoalphalipoproteinemia: a randomized, open-label, crossover study.

OBJECTIVES: To assess the effects of nicotinic acid (NA), gemfibrozil and combination therapy on the lipid profile of patients with clinical atherosclerotic disease and isolated hypoalphalipoproteinemia. BACKGROUND: Isolated hypoalphalipoproteinemia (low high density lipoprotein cholesterol [HDL-C] alone) accounts for a significant percentage of patients with premature atherosclerosis. However, it remains unclear whether currently available pharmacotherapy has the ability to favorably affect the lipid profile and therefore potentially reduce clinical events. METHODS: Twenty-three patients with clinically well-defined atherosclerosis and isolated hypoalphalipoproteinemia were prospectively randomized to receive gemfibrozil, NA or combination therapy in an open-label, crossover design trial to assess the effects on serum lipids. Lipid profiles and other relevant laboratory variables were monitored while the patients were on and off pharmacologic lipid-modulating therapy. RESULTS: In those 14 patients able to tolerate all forms of pharmacotherapy, HDL-C of 0.89 +/- 0.17 mmol/liter (34.5 +/- 6.5 mg/dl) increased by 15%, to 1.02 +/- 0.18 mmol/liter (39.7 +/- 7.1 mg/dl), while taking gemfibrozil (1,200 mg/day); by 35%, to 1.20 +/- 0.21 mmol/liter (46.5 +/- 8.1 mg/dl), while taking NA (mean dose 2,250 mg/day); and by 45%, to 1.29 +/- 0.19 mmol/liter (50.0 +/- 7.5 mg/dl), while taking combination therapy of gemfibrozil plus NA (p < 0.001 for all interventions as compared with baseline/washout; p < 0.005 NA vs. gemfibrozil; p < 0.001 combination therapy vs. gemfibrozil alone; p = 0.088 combination therapy vs. NA alone). Statistically significant favorable alterations were also observed with low density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C, non-HDL-C/HDL-C, apolipoprotein (Apo) B and Apo B/Apo A1. CONCLUSIONS: In the majority of patients with clinical atherosclerotic disease and isolated hypoalphalipoproteinemia, pharmacologic therapy to raise HDL-C is not only feasible but is also effective with currently available agents, particularly when used in combination.

Effects of fluvastatin treatment on red blood cell Na+ transport systems in hypercholesterolemic subjects.

This study was performed to ascertain the effects of short-term cholesterol-lowering therapy with fluvastatin on red blood cells Na+ transport systems. Forty familial hypercholesterolemic subjects (FH; 19 men and 21 women) without hypertension or cardiovascular disease were given a placebo for 4 weeks, and then randomized in two groups. Twenty (fluvastatin group) were given fluvastatin (40 mg/day), and the other 20 (placebo group) continued placebo administration. After the placebo period and after 4 and 12 weeks of placebo or fluvastatin treatment, we measured Na+/K+ pump activity, Na+/K+ cotransport (Na+/K+ Ct), Na+/Li+ countertransport (Na+/Li+ Cnt), passive Na+ permeability (Na+PP), and internal Na+ content (Na+i). The same parameters were measured in 23 control subjects (C) with normal cholesterolemic values, who were matched for sex and age. FH had higher Na+/Li+ Cnt values than C (193.2 +/- 59.4 vs. 139.8 +/- 48.7 microM cells/h; p < 0.01), an increase in Na(+)PP (0.034 +/- 0.012/h vs. 0.018 +/- 0.004/h; p < 0.001), and higher Na(+)i (7.5 +/- 1.5 vs. 6.2 +/- 0.9 mM cells; p < 0.001). In hypercholesterolemic subjects, Na(+)i values were correlated with cholesterol (total and LDL) and apo B levels, whereas an inverse correlation was found for HDL-c and apo AI levels. Reduced total and LDL cholesterol and apo B levels after fluvastatin treatment caused a decrease in both Na(+)/Li(+) Cnt (from 186.1 +/- 60.5 to 125.1 +/- 34.0 microM cells/h; p < 0.001) and Na(+) PP (from 0.035 +/- 0.013/h to 0.02 +/- 0.016/h; p < 0.01), and an increase in Na+/K+ pump activity (from 1,549.0 +/- 507.7 to 1,894.2 +/- 536.2 microM cells/h; p < 0.04), with a significant reduction in the internal Na+ content (from 7.5 +/- 1.6 to 5.8 +/- 2.4 mM cells; p < 0.001). Our findings show that hypercholesterolemia affects red blood cell Na+ transport systems, with an increase in Na+/Li+Cnt, Na+PP, and the internal Na+ content. Cholesterol-lowering treatment with fluvastatin influences Na+ transport systems and reduces the internal Na+ content. This might also be responsible for the greater vascular reactivity observed in hypercholesterolemic patients, and its amelioration after a reduction in cholesterol levels.

M and P double helical complexes of copper(I) with bis-imino bis-quinoline enantiomerically pure chiral ligands.

The enantiomerically pure bis-imino bis-quinoline ligands R,R-ImQ and S,S-ImQ have been prepared by Schiff condensation of 2-quinoline carboxyaldehyde with the pure R,R and S,S enantiomers of trans-1,2-diaminocyclohexane. Both ligands form 2:2 helical complexes with CuI perchlorate, and the crystal and molecular structure of [Cu2(R,R-ImQ)2]ClO4.H2O have been determined by X-ray diffraction methods: the [Cu2(R,R-ImQ)2]2+ molecular cation is a chiral double helix of M handedness, in which the two ligands are entertwined in such an arrangement that half of each ligand is not equivalent to the other half of the same ligand. Coupled circular dichroism and 1H NMR studies reveal that in CH3CN solution a rearrangement takes place toward a more symmetric helical structure (in which the two halves of the same ligand become equivalent), which maintains the same handedness found in the solid state and is a pure M isomer. Solid state and CH3CN solution CD experiments confirm that [Cu2(S,S-ImQ)2]ClO4.H2O, both in solution and in the solid state, is a pure double helix of P handedness, i.e., the enantiomer of the species containing the R,R ligand.

[Elevated levels of lipoprotein(a) are present in subjects with early ischemic cardiopathy and with a familial history of ischemic cardiopathy]. / Più elevati livelli di lipoproteina(a) sono presenti in soggetti con cardiopatia ischemica precoce e con storia familiare di cardiopatia ischemica.

BACKGROUND: Elevated levels of lipoprotein(a) are associated with a greater risk of atherothrombotic cardiovascular diseases. Since the Lp(a) levels are genetically determined and fairly stable in the course of life and a family history appears to be an independent risk factor of cardiovascular diseases, we evaluated the behavior of Lp(a) levels in patients with early events of coronary heart disease (CHD) and also in subjects with positive family history of ischemic heart diseases. METHODS: The levels of lipoprotein (a) [Lp(a)] were measured in 254 subjects, 138 males and 116 females with an average age of 48.6 +/- 13.8 years (range 20-76 years). Diabetic subjects, females submitted to oestrogen treatment and those already in treatment with hypolipidaemic drugs were excluded from the study. Forty of the 254 patients (15.7%), 27 males and 13 females, had CHD (29 a previous myocardial infarction and 11 a stable angina). A positive family history for CHD was considered present (102 of the 254 patients) if one or more first degree relatives had angina or myocardial infarction before the age of 60 years in men and 65 in women. RESULTS: The levels of Lp(a) were higher (p < 0.01) in women (25.1 +/- 28.3 mg/dl) compared to men (17.6 +/- 18.4 mg/dl), without differences in relation to age. The Lp(a) plasmatic levels were not correlated with age, body mass index, total cholesterol, LDL and HDL, triglycerides, apo B, apo AI, fibrinogen and there were no differences in Lp(a) levels in presence or absence of other known cardiovascular risk factors such as hypertension and smoking. The Lp(a) levels were not different between subjects with CHD (28.15 +/- 31.7 mg/dl) and controls (20.3 +/- 22.8 mg/dl). The subjects with CHD were older and had higher levels of fibrinogen and a significantly greater prevalence of hypertension and family history of CHD. Fifteen of the 40 subjects with CHD had an early onset of CHD (before 50 years of age) and only in such patients the Lp(a) levels were significantly greater compared to controls (35.8 +/- 33.2 mg/dl vs 20.3 +/- 22.8 of the controls, p < 0.01), independently of other variables (age, BMI, smoking, hypertension, cholesterol, triglycerides, HDL-c, LDL-c, fibrinogen). Furthermore the Lp(a) plasmatic levels were higher in subjects with a family history of CHD (28.3 +/- 27.6 mg/dl vs 16.3 +/- 18.6 mg/dl of the subjects without a family history of CHD, p < 0.01) even if they had or not had a previous coronary ischemic event. CONCLUSIONS: Such data confirm the importance of high levels of Lp(a) above all for the early events of CHD and for the subjects with a family history of CHD, which could be expression of a greater predisposition for cardiovascular events.

[Manufacture and in vitro characterization of a new fluid theophylline sustained-release form. Sachets with microcapsules for administration in a drinkable sustained-release suspension]. / Herstellung und In-vitro-Charakterisierung einer neuen flüssigen Theophyllin-Retardarzneiform. Sachets mit Mikrokapseln zur Bereitung einer trinkfertigen Retardsuspension.

The administration of currently available theophylline (CAS 58-55-9) sustained release preparations with high drug doses (hard capsules, tablets) presents difficulties for certain patient groups as children and elderly, due to the large geometry of these dosage forms. Therefore, a suspension for easy administration based on the novel Liquitard technology was developed using theophylline microcapsules. This paper describes the manufacturing procedure of the new dosage form and its in vitro release characteristics as a function of various parameters. During manufacturing, the suspension-forming excipients are first granulated and then filled into sachets together with the microcapsules. The sustained release suspension is prepared by the patient himself immediately before administration. The in vitro release of theophylline from the dosage form is neither affected by the suspension-forming excipients nor by the drug amount. This allows for the manufacture of sachets with different drug strength maintaining the same qualitative composition. Furthermore, the in vitro release is independent of pH, osmolality, agitation and of the addition of surfactants and native bile to the dissolution medium. The new dosage form thus meets the current EC-guidelines for oral sustained release dosage forms. The in vitro limits of the dissolution testing were verified on the basis of the bioequivalence of the batches at the upper and lower specification limits.

Transabdominal preperitoneal laparoscopic inguinal herniorrhaphy (TPLIH) under regional anaesthesia.

BACKGROUND: In an attempt to investigate whether laparoscopy really is a major advance in the treatment of inguinal hernia, the authors performed laparoscopic transabdominal preperitoneal inguinal herniorrhaphy under regional anaesthesia in 15 consecutive patients, 7 of whom with severe medical conditions contraindicating general anaesthesia. METHODS: In the first 5 patients (Group 1) an epidural anaesthesia was performed, whereas in the following 10 patients (Group 2), fentanyl was added to the epidural anaesthesia, and bupivacaine was administered into the subarachnoid space. RESULTS: Results from Group 1 were poorer than those obtained in Group 2. All patients complained of shoulder pain and discomfort which required the intraoperative administration of analgesics in 7 patients and conversion to open repair in one patient. CONCLUSIONS: Although laparoscopy is a feasible and effective procedure in repairing inguinal hernias, it is not indicated in high-risk patients who can be safely, effectively, and less expensively treated with open tension-free repair techniques under local anaesthesia.

[Effects of betamethasone on neuromuscular blockade induced by vecuronium in continuous infusion]. / Effetti del betametasone sul blocco neuromuscolare indotto con vecuronium in infusione continua.

The aim of the study was to determine a possible interaction between a corticosteroid (betamethasone) and vecuronium, a nondepolarizing muscle relaxant. The authors studied 20 patients, ASA I-II, aged 20-54, both sexes, scheduled for abdominal surgery. Mechanomyographic and clinical evaluation by single twitch and TOF stimulation of the ulnar nerve at the wrist and measurement of the concomitant abductor pollicis muscle was applied. The onset time of vecuronium after a single bolus dose of 0.08 mg/kg, duration of action to 10% single twitch recovery, duration of continuous infusion of 0.4-0.5 micrograms/kg/min of vecuronium started at 10% single twitch recovery, and the effects of 0.1 mg/kg betamethasone administration 10 min after continuous infusion were evaluated. The recovery rate of vecuronium after stopping infusion at 10% recovery was also evaluated. Corticosteroids may interact with non-depolarizing muscle relaxants both in prejunctional and postjunctional acetylcholine receptors by several mechanisms of action.

Electrocardiographic tall R waves in the right precordial leads. Comparison of recently proposed ECG and VCG criteria for distinguishing posterolateral myocardial infarction from prominent anterior forces in normal subjects.

Electrocardiographic tall R waves in the right precordial leads may be present in patients with posterior myocardial infarction, right ventricular hypertrophy, various conduction disturbances, and some forms of cardiomyopathy and in clinically otherwise normal subjects with prominent anterior electromotive forces. Clinical uncertainty most often arises in distinguishing possible prior posterolateral myocardial infarction (PMI) from the unusual normal variant (PAF). The ECGs and VCGs of 15 subjects with posterolateral infarction were compared with tracings from 12 subjects with no evidence of cardiac disease, all individuals demonstrating tall R waves (R/S greater than 1.0 in V1 and/or V2) in the right precordial leads on surface ECG. By standard ECG, the infarction group was characterized by taller T waves in leads V1 and V2, shorter T waves in V6, greater T2-T6 index, and a more negative two variable function as described by Nestico. By VCG, the infarction group was characterized by a more anteriorly oriented T loop, more leftward maximal frontal plane QRS vector and a lower calculated -45 degrees/ab, as described by Suzuki. An algorithm was proposed that permitted proper classification (PAF vs. PMI) based on ECG criteria in 75% of subjects with 90% accuracy. This compared favorably with performance of the Frank vectorcardiogram, including using more recently proposed criteria. Routine use of the VCG, therefore, in this clinical setting may no longer be justified.

Diltiazem treatment for the management of ischaemia in patients with poor left ventricular function: safety of long term administration.

The tendency of oral diltiazem (a calcium entry blocking agent and a negative inotrope) to induce or exacerbate congestive heart failure when used for the long term management of myocardial ischaemia in patients with poor left ventricular function has not been investigated before. Twenty two patients (aged 42-73 years) with pretreatment left ventricular ejection fraction ranging from 0.11 to 0.39 were given open label oral diltiazem (120-360 mg/24 h (mean 254 mg)) for two weeks to 16 months (mean 7.5 months, median 6.2 months). There was a weight change of greater than 3 lb (1.35 kg) in nine patients--five gained weight and four lost it. Diltiazem treatment did not alter the mean (SD) cardiothoracic ratio on chest x ray (0.47 (0.06) before vs 0.48 (0.05) after) or the left ventricular ejection fraction at rest (0.28 (0.09) before vs 0.26 (0.08) after). Diltiazem was discontinued in one patient because of symptoms indicative of worsening congestive heart failure. No patient required admission to hospital for treatment of symptoms resulting from further left ventricular decompensation. Diltiazem was discontinued in six other patients for other reasons. Long term administration of oral diltiazem was not regularly associated with a deterioration in clinical, radiographic, or radionuclide ventriculographic estimates of left ventricular function, even in patients with poor baseline left ventricular systolic performance.

Q wave, S-T segment, and T wave myocardial infarction. Useful clinical distinction.

Abundant experimental and clinical evidence now suggests that the presence or absence of Q waves on surface electrocardiography does not permit distinction between pathologic transmural and subendocardial myocardial infarction. It has been recommended, therefore, that use of certain electrocardiographic descriptors of myocardial infarction be avoided. One hundred fourteen consecutive patients with first myocardial infarction were studied. The lack of development of Q waves accompanying acute myocardial infarction delineated a group of patients with low in-hospital mortality. Left ventricular ejection fraction was less after Q wave (0.48 +/- 0.16) than after non-Q wave (0.67 +/- 0.10) infarction (p less than 0.0001). Left ventricular end-diastolic pressure was greater after Q wave (16.1 +/- 5.9 mm Hg) than after non-Q wave (11.7 +/- 2.7 mm Hg) infarction (p less than 0.02). Fixed thallium perfusion scintigraphic defects were more common in survivors of Q wave (98 percent [41 of 42]) than in survivors of non-Q wave (64 percent [seven of 11]) infarction (p less than 0.002). Objectively demonstrable myocardial ischemia was more common after non-Q wave (68 percent [13 of 19]) than after Q wave (32 percent [16 of 50]) infarction (p less than 0.01). The incidence of late cardiac events (sudden death plus reinfarction) did not differ after Q wave or non-Q wave infarction. Q wave, S-T segment, and T wave myocardial infarctions differ physiologically, clinically, and prognostically. It is of little consequence to the clinician managing patients whether such useful electrocardiographic descriptors also accurately define groups that differ anatomically with regard to the thickness of the injured myocardial wall.