Innovative oral spray-dried Idebenone systems to improve patient compliance.

Idebenone is a high permeable drug with very slight water solubility that affects the dissolution rate in the biological fluids, causing an irregular and limited in vivo absorption after oral administration. Moreover, it is marketed in Europe as tablets equivalent to 150 mg, with the consequent administration of multiple dose of solid unit to obtain the correct dose, a deterrent for the patients' compliance. According to these considerations, our goal was to develop spray-dried microparticles using a soluble ß-cyclodextrin (CD) polymer and an enhancer of dissolution rate, such as carboxymethyl cellulose, to obtain a formulation easily dosable and soluble in water. The complex in solution was evaluated by phase solubility studies and the Idebenone/CD molar ratio selected was 1:1. According to Higuchi and Connors, adding carboxymethyl cellulose, a Bs-type profile was obtained. This result was due to the presence of carboxymethyl cellulose that competes with the CD in forming Idebenone microsystems, reducing of 10-fold the formulation bulk. UV-Vis absorption, (1)H nuclear magnetic resonance and circular dichroism showed the formation of the CD/Idebenone inclusion complex confirmed also by differential scanning calorimetry, Fourier transform infrared spectroscopy and fluorescence microscope (FM). The water solubility data and the in vitro dissolution tests performed in simulated gastric fluid, showed an increase of the drug water interaction due to the presence of the CD and carboxymethyl cellulose, both able to improve drug wettability, water solubility and dissolution rate. This approach seems to be suitable to produce microsystems which are able to enhance the in vivo absorption of Idebenone after oral administration and to increase the patient compliance.

Huge ascending aorta and aortic arch aneurysm in ultra octogenarian.

Giant ascending aorta aneurysms (AAA), which are larger than 10 cm, are rarely been reported (1-7). We hereby present the case of a giant AAA of about 11 cm in a very old women who was successfully operated on for ascending aorta and aortic arch replacement under deep hypothermic circulatory arrest.

Additional applications of the Foley catheter in cardiac surgery.

We describe an additional use of the Foley catheter for preoperative and postoperative evaluation of the regurgitant mitral valve.

Incorporation of a calixarene-based glucose functionalised bolaamphiphile into lipid bilayers for multivalent lectin recognition.

The synthesis, characterization and inclusion in liposomes of a glucosylated bolaamphiphile built on a calix[4]arene scaffold are described. The new glucocalixarene bolaamphiphile destabilizes bilayers of saturated lipids whereas it rigidifies those of unsaturated lipids, thus reducing leakage of calcein from the liposome internal aqueous compartment. Moreover, from fluorescence and turbidimetry experiments it was found that the glucose units of bolaamphiphile 1 functionalised liposomes allow a specific multivalent interaction with the tetrameric glucose binding protein Concanavalin A. These results therefore represent a novel strategy to functionalise liposomes with saccharides, exploiting multivalent glycosylated ligands to be used in the preparation of drug delivery systems potentially able to target specific lectins.

Two cases of right atrial myxoma in redo patients. A mere coincidence?

We describe two cases of right atrial myxoma in redo patients who had previously undergone to coronary artery by-pass grafting (CABGs) and mitral valve replacement respectively. Both of patients experienced effort dyspnea and were assessed by trans-thoracic echocardiography, revealing the right atrial masses. They were operated on for myxoma resection and postoperative course was uneventful. Our report deals with the interesting topic of the location of benign masses that are usually more common in the left atrium. Should we hypothesize that the right atrial manipulation during the previous surgery induces the onset of the right atrial mass? It is an interesting matter to debate.

Transcutaneous insertion of the Chitwood® clamp in case of minimally invasive cardiac surgery. Personal experience.

We describe a simple trick consisting of an insertion of a trans-thoracic Chitwood® clamp (Scanlan International, Inc, St Paul, MN, USA) through a small skin incision (<1cm), via the second intercostal space along the anterior axillary line, in case of minimally invasive mitral surgery, through right thoracotomy. This trick has been used in more than 100 patients and no complication or discomfort have been reported so far.

Aortic valve replacement through the upper ministernotomy: preliminary experience with modified technique.

Minimally invasive approach for aortic valve surgery has been developed since 1995, reducing the complications related to the full sternotomy. We have introduced a new method for central cannulation that reduces the length of surgical incision for the aortic valve replacement through upper mini-sternotomy. To improve the surgical view without enlargement of the incision, two small additional incisions are performed for both arterial and atrial cannulation. We have used the modified technique in 60 patients without sternal infection or other surgical complications and with good cosmetic results.

The Actis-gouge: a simple cutting tool for proper muscular resection in hypertrophic cardiomyopathy.

BACKGROUND: Surgical treatment of hypertrophic cardiomyopathy (HC) may be challenging for the risk of surgical complications or insufficient resection. We present our cutting tool to perform proper muscular resection in HC. MATERIAL AND METHODS: Ten patients (5 males, mean age 43,1 +/- 19,6 years, range 9-70 years) were operated on for HC using this semicircular cutting device. Combined procedures were : mitral valve repair (n = 1), mitral valve replacement (n = 2), right ventricular myectomy (n = 1), aortic valve replacement (n = 1), mitral and aortic replacement (n = 1). RESULTS: There was one early death. All the surviving patients are alive over a variable follow up from 2 to 8 years, with consistent reduction of symptoms: in fact, no patient had residual angina with significant reduction of the NYHA class from 3,2 +/- 0,6 to 1,3 +/- 0,5 postoperatively (p < 0,05). Muscular resection was effective with significant reduction of sub-valvular gradient from 84.5 + 33,4 mmHg to 14,1 +/- 17,6 mmHg (p < 0,05) without complications such as complete atrio-ventricular block or ventricular septal defects. CONCLUSION: Our semicircular myotome is an effective tool to perform a safe myectomy and it avoids surgical complications such as atrio-ventricular blocks or sub-valvular injuries. Our experience suggests that this cutting tool offers a reproducible method for muscular resection and it shows appreciable effects in the reduction of sub-valvular gradient with promising results in terms of morbidity and mortality.

Transmyocardial laser revascularization. Personal experience.

BACKGROUND: Indirect revascularization is a therapeutic approach in case of severe angina not suitable for percutaneous or surgical revascularization. Transmyocardial revascularization (TMR) is one of the techniques used for indirect revascularization and it allows to create transmyocardial channels by a laser energy bundle delivered on left ventricular epicardial surface. Benefits of the procedure are related mainly to the angiogenesis caused by inflammation and secondly to the destruction of the nervous fibers of the heart. PATIENTS AND METHOD: From September 1996 up to July 1997, 14 patients (9 males - 66.7%, mean age 64.8±7.9 years) underwent TMR. All patients referred angina at rest; Canadian Angina Class was IV in 7 patients (58.3%), III in 5 (41.7%). Before the enrollment, coronarography was routinely performed to find out the feasibility of Coronary Artery Bypass Graft (CABG): 13 patients (91,6%) had coronary arteries lesions not suitable for direct revascularization; this condition was limited only to postero-lateral area in one patient submitted to combined TMR + CABG procedures. RESULTS: Mean discharge time was 3,2±1,3 days after surgery. All patients were discharged in good clinical conditions. Perfusion thallium scintigraphy was performed in 7 patients at a mean follow-up of 4±2 months, showing in all but one an improvement of perfusion defects. Moreover an exercise treadmill improvement was observed in the same patients and all of them are in good clinical conditions, with significantly reduced use of active drugs. CONCLUSION; Our experience confirms that TMR is a safe and feasible procedure and it offers a therapeutic solution in case of untreatable angina. Moreover, it could be a hybrid approach for patients undergoing CABGs in case of absence of vessels suitable for surgical approach in limited areas of the heart.

Results with cyclosporine monotherapy in long-term cardiac transplant recipients.

BACKGROUND: Triple therapy is the gold standard after heart transplantation while few reports have described experiences with cyclosporine monotherapy (CM). We have analyzed our experience with CM in long-term heart transplant recipients, surviving >5 years. METHODS: Of the 219 patients transplanted between January 1990 and December 1998, 143 survived >5 years (mean age, 49.6 +/- 10.4). There were 124 (86.7%) male subjects. Matching patients respect to follow-up length, we obtained 2 groups: group A of 41 patients on double therapy (DT; cyclosporine plus Azathioprine) and group B of 41 patients on CM. RESULTS: After a mean follow-up of 119.8 +/- 32.2 months, we did not observe a significant difference in terms of survival and major events: heart failure, malignancy, dialysis, infections, and CAV. CONCLUSION: We strongly support the use of triple therapy in cardiac transplant recipients because of its known safety and efficacy. However, our experience with CM suggests the utility of this approach.

Does everolimus associated with a low dose of cyclosporine in long-term cardiac transplant recipients improve renal function? Initial experience.

BACKGROUND: Cyclosporine (CsA) renal toxicity is a well-known side effect. Various immunosuppressive strategies have been developed to minimize renal insufficiency. The use of everolimus associated with low levels of CsA can be an alternative strategy. METHODS: From October 2007 to April 2008, everolimus was started with a lower dose of cyclosporine (trough levels from 109.3 +/- 27.5 to 93.7 +/- 30.1 ng/mL after 45 days) in 21 cardiac transplant recipients (18 male and 3 female patients, mean age 56.4 +/- 10.7 years). Pre-everolimus therapy creatinine levels, creatinine clearances, and glomerular filtration rates were 1.9 +/- 0.9 mg/dL, 54.2 +/- 18.1 mL/mins and 44.3 +/- 16.5 mL/min/m(2), respectively. RESULTS: We observed a significant reduction in creatinine levels (from 1.9 +/- 0.9 to 1.4 +/- 0.3 mg/dL, P = .022) as well as a significant improvement in creatinine clearances (from 54.2 +/- 18.1 to 69.0 +/- 19.0 mL/min, P = .020) and glomerular filtration rates (from 44.3 +/- 16.5 to 57.1 +/- 16.3 mL/min/m(2), P = .010) after 7 days of everolimus therapy. Upon univariate analysis patient age, pretransplantation creatinine clearance, creatinine clearance after everolimus introduction, glomerular filtration rate at 45 days, and time from transplantation were associated with renal improvement. Upon multivariate analysis, only creatinine clearance at 7 days was related to the renal improvement. CONCLUSIONS: These preliminary data suggested that everolimus with a low dose of CsA may be safe and effective to reduce CsA-related renal insufficiency among selected, heart transplant patients.

Role of oral sildenafil in the treatment of right ventricular dysfunction after heart transplantation.

OBJECTIVE: Right ventricular dysfunction (RVD) after heart transplantation is a major complication, especially in patients with pulmonary hypertension (PH). Herein we have presented our initial experience with oral sildenafil for RVD following heart transplantation. MATERIALS AND METHODS: From February 2006 to February 2008, 10 patients (7 males and 3 females) of overall mean age of 56.7 +/- 9.5 years suffered from acute RVD immediately after heart transplantation. Preoperative hemodynamic data before and after a vasodilatation test (sodium nitroprusside; NTP) showed: systolic pulmonary arterial pressure (SPAP) 59.5 +/- 12.9 and 44.2 +/- 12.4 mm Hg; cardiac output (CO) 3.3 +/- 0.9 and 3.7 +/- 0.8 L/min; transpulmonary gradient (TPG) 11.7 +/- 3.9 and 8.7 +/- 3.6 mm Hg; and pulmonary vascular resistance (PVR) 3.9 +/- 2.1 and 2.4 +/- 1.3 wood units (WU), respectively. All patients required inotropes and inhaled nitric oxide (iNO) to be weaned from cardiopulmonary bypass (CPB). RESULTS: Intravenous (IV) or inhaled vasodilators could be weaned using oral sildenafil in all patients. The hemodynamic data obtained during IV or inhaled drugs (between postoperative days 5 and 10) compared with those obtained on sildenafil therapy alone (about 1 month after transplantation) showed a significant decrease in SPAP (39.0 +/- 8.2 vs 32.0 +/- 6.5 mm Hg; P = .049). CONCLUSION: These data suggested that oral sildenafil may have a role in the treatment of RVD after heart transplantation.

Physical characteristics and aerosol performance of naringin dry powders for pulmonary delivery prepared by spray-drying.

The aim of the present work was to develop dry powders containing naringin for a direct administration to the lung to combat oxidative stress. Naringin microparticles were prepared by spray-drying the neat flavonoid (2-5% w/v) from different water/ethanol co-solvents. The spray-dried powders were characterised for morphology, density, particle size distribution, residual humidity, crystallinity, solubility, thermal behaviour and respirable fraction. The fine fraction of the powders was measured by single-stage glass impinger and Andersen cascade impactor, using the Turbospin device for the deposition tests, wherein the dose to be aerosolised was premetered in a gelatine capsule. By increasing the ethanol content, the feed liquid turned from a suspension into a solution: the spray of flavonoid suspensions led to powders with high crystallinity degree, low water solubility and high bulk density, while the spray of drug solutions led to more amorphous particles, with higher solubility, lower density and improved aerodynamic behaviour. The optimisation of the operative parameters produced enhanced aerosol performance of the flavonoid powders containing only the active compound.

Single versus double lung transplantation in pulmonary fibrosis: a debated topic.

Idiopathic pulmonary fibrosis (IPF) represents the second most frequent indication for lung transplantation after chronic obstructive pulmonary disease. Survival rate after transplantation is poorer compared with other lung diseases for reasons that are not completely clear. Medical therapy with anti-inflammatory drugs may improve symptoms and quality of life, but it does not influence the survival rate. Lung transplantation is the best therapy for end-stage IPF. The debate regarding the superiority of double lung transplantation (DLT) compared with single lung transplantation (SLT) is still ongoing. Until some years ago, SLT was almost uniformly utilized for this indication. In the most recent years, a larger application of DLT has been observed worldwide, probably related to higher 1-year and 5-year survivals. The unanswered question is whether it is ethical to use two lungs for the same patient, considering the donor shortage, when a single lung would suffice. Many reports have demonstrated that SLT offers acceptable pulmonary function and satisfactory early and intermediate survival. Probably DLT should be reserved for younger recipients, for those with concomitant or possible chronic infection of the contralateral lung, or cases of marginal donors. Further studies will be needed to formulate recommendations regarding the preferred surgical approach in IPF.

A prospective study of prevalence of 60-days postoperative wound infections after cardiac surgery. An updated risk factor analysis.

AIM: Postoperative wound infections generally cause considerable extra morbidity, mortality and costs. The prevalence of total wound infections after cardiac surgery, including both sternal wound and donor site infections, ranges from 1.3 to 12.8%. The present study was conducted to identify the incidence of wound infections following cardiac surgery, to identify the risk factors and evaluate the efficacy of present modes of management. METHODS: From September 2004 to May 2005, 493 consecutive patients undergoing cardiac surgery were included in the study and were followed for the prevalence of surgical site infection (SSI) up to 60 days postoperatively. The wound infections were defined according to the Centers for Disease Control and Prevention (CDC) and U.S. National Nosocomial Infections Surveillance (NNIS) system criteria. RESULTS: The total incidence of SSI was 3.9%. Sternal wound infection (SWI) occurred in 17 patients (3.4%). Superficial wound infection was diagnosed in 10 patients (2%) and deep wound infection in 7 patients (1.4%). Donor site infection (DSI) occurred in 2 patients (0.4%). Early reoperation for bleeding, postoperative dialysis and the use of one internal mammary artery were independently associated with an increased risk of SWI. CONCLUSION: Preventing SSI in the operating room is the primary goal of the surgical team. Attention should be paid to antibiotic prophylaxis and Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage treatment. The identification of risk factors will help to further reduce the incidence of wound infection.

Calixarene-based multivalent ligands.

Multivalency is a powerful concept which explains the strong binding observed in biological systems and guides the design and synthesis of ligands for self-assembly and molecular recognition in Chemistry. The phenol-formaldehyde cyclic oligomers, called calixarenes, have been used as scaffolds for the synthesis of multivalent ligands thanks to the fact that they have a variable number of reactive positions for attaching the ligating functions, well defined conformational properties and, in some cases, cavities of molecular dimensions eventually able to encapsulate guest species. This tutorial review illustrates the fundamental aspects of multivalency and the properties of calixarene-based multivalent ligands in lectin binding and inhibition, DNA condensation and cell transfection, protein surface recognition, self-assembly, crystal engineering, and nanofabrication.

[Check-list for inspection in banks]. / Check list per il sopralluogo nel comparto bancario.

We suggest a checklist for inspection in banks. The checklist is composed of 14 schedules where information on bank clerks and buildings is collected. Principle risk factors are analysed (workplaces, lighting and noise, air quality, emergency management). The critical points are observed and the times of intervention are established. Then follows data processing and the reports are transmitted to the employer. The checklist, tested on 250 workplaces, allows us to identify the interventions having priority to be realized through appropriate planning. A quantitative evaluation of the risk is matched with immediate and brief operative indications. The situations to improve are: cleanliness of workplaces, thermal comfort, electricity/telephone wires. The checklist seems to be a valid instrument for the evaluation of risk factors, their management and times of intervention. Such instrument simplifies, moreover, the employer choices of intervention.

The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein.

The INK4a gene, one of the most often disrupted loci in human cancer, encodes two unrelated proteins, p16(INK4a) and p14(ARF) (ARF) both capable of inducing cell cycle arrest. Although it has been clearly demonstrated that ARF inhibits cell cycle via p53 stabilization, very little is known about the involvement of ARF in other cell cycle regulatory pathways, as well as on the mechanisms responsible for activating ARF following oncoproliferative stimuli. In search of factors that might associate with ARF to control its activity or its specificity, we performed a yeast two-hybrid screen. We report here that the human homologue of spinophilin/neurabin II, a regulatory subunit of protein phosphatase 1 catalytic subunit specifically interacts with ARF, both in yeast and in mammalian cells. We also show that ectopic expression of spinophilin/neurabin II inhibits the formation of G418-resistant colonies when transfected into human and mouse cell lines, regardless of p53 and ARF status. Moreover, spinophilin/ARF coexpression in Saos-2 cells, where ARF ectopic expression is ineffective, somehow results in a synergic effect. These data demonstrate a role for spinophilin in cell growth and suggest that ARF and spinophilin could act in partially overlapping pathways.