Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy.

Neurodegenerative disorders with alpha-synuclein (α-syn) accumulation (synucleinopathies) include Parkinson's disease (PD), PD dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α-syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α-syn is a priority as a disease-modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α-syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α-syn synthesis, aggregation, clearance, and/or cell-to-cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery.

[Sildenafil and nitric oxide inhalation in neonatal pulmonary hypertension. Three case reports]. / Sildenafil ed ossido nitrico inalato nel trattamento dell'ipertensione polmonare neonatale. A proposito di tre casi.

INTRODUCTION: Neonatal persistent pulmonary hypertension (NPPH) is characterised by persistently high pulmonary vascular resistance (PVR). Sildenafil has recently been suggested as an alternative to or an associative therapy with inhaled nitric oxide (iNO) to reduce mortality (10-40%) and morbidity (major neurologic disabilities among surviving newborns remains approximately 15-60%). The objective is to report three cases of NPPH treated with sildenafil in association of iNO. CASE REPORTS: Echocardiography examination of three newborn babies with respiratory distress syndrome and a gestational age between 33 and 39 weeks revealed pulmonary hypertension following early onset sepsis. Synchronized intermittent mandatory ventilation (SIMV) and surfactant therapy had no effect on oxygen saturation (SatO2) and oxygen alveolar-arterial difference (AaDO2). High frequency oscillatory ventilation (HFOV) and iNO therapy proved to be equally ineffective. Oral sildenafil was administered at 2 mg/Kg/6 hs. A gradual but significant improvement in oxygenation was achieved and a reduction in AaDO2 along with oxygenation index (OI) and pulmonary arterial pressure (PAP) was observed in the first 6-10 hrs after administration of sildenafil. The therapy was maintained for 36-48 hrs with total success. CONCLUSIONS: A beneficial pulmonary vasodilator effect was obtained in treating NPPH with sildenafil where conventional methods had failed. Sildenafil used in association with iNO reduces the duration of treatment, the quantity of iNO normally required and the associated toxic effects. A multicentric, randomized trial could be useful in demonstrating the safety, efficacy, doses and forms of administration of sildenafil.

[Pompe's disease: the role for early diagnosis and treatment]. / Malattia di Pompe: efficacia di una diagnosi precoce.

Pompe's disease (PD) is a glycogen storage disease characterized by the deposition of glycogen within body cells. This may lead to severe cardiac hypertrophy, with heart failure. The authors describe a female infant with PD, who developed severe cardiac hypertrophy, and was treated with recombinant human enzyme replacement therapy. This approach led to a progressive reduction of the heart hypertrophy, with improvement of the clinical condition.

Impact of targeted-volume ventilation on lung inflammatory response in preterm infants with respiratory distress syndrome (RDS).

Volutrauma and pulmonary inflammation are thought to be the most important predisposing factors of chronic lung disease (CLD), a major complication of prematurity. A new option in patient-triggered ventilation (PTV), the volume guarantee (VG), a volume-targeted ventilation, seems to be a promising approach in reducing the risk of CLD, by limiting lung inflammatory injury and volutrauma. Our aim was to evaluate lung inflammatory response in preterm infants with respiratory distress syndrome (RDS), mechanically ventilated with and without VG, as measured by proinflammatory cytokines (IL-6, IL-8, and TNF-alpha) in tracheobronchial aspirate (TA) fluid. Fifty-three preterm infants (GA = 25-32 weeks) with RDS were randomized at birth to be ventilated using pressure support ventilation (PSV) with VG (Vt = 5 ml/kg) (n = 30) and without VG (n = 23) (Draeger Babylog 8000 Plus, 5.n). IL-6, IL-8, and TNF-alpha were determined by ELISA in TA samples on days 1, 3, and 7 of life. We observed a significant difference (ANOVA) in IL-8 and IL-6 levels on day 3 between the two groups (P < 0.05), and an increasing significative trend in IL-8 values in PSV group (P < 0.05). Mechanical ventilation lasted longer in the PSV group (12.3 +/- 3 vs. 8.8 +/- 3 days) (P = no significance). In conclusion, these preliminary data suggest a role for volume-targeted ventilatory strategy in reducing acute inflammatory response in preterm infants with RDS. Further studies are required in order to define whether this ventilatory strategy prevents lung injury.

Positive interaction between interferon and bleomycin in vitro and in animal experimental models.

Effect of combined bleomycin and interferon on cell growth was evaluated in vitro, on 2 leukemia cell lines, and on mice bearing a murine leukemia. Human alpha-A interferon or murine alpha-beta interferon were used. Synergism was observed in both models and the sequence of administration was decisive in this respect. The in vivo results were not completely comparable with those observed in vitro. This finding suggests that the in vitro results reflect the direct effects of the drugs on tumor cells, meanwhile the interaction between drugs in vivo are affected by pharmacokinetic characteristics and by host defense systems.

Drug sensitivity tests after cell separation on density gradients.

Cells from two leukaemic cell lines (K562 and L1210) were separated on a discontinuous Percoll gradient with densities from 1040 to 1090 by centrifugation. The cells recovered from gradient interfaces were checked for their DNA content and subjected to two different drug sensitivity tests using three cytostatic drugs. The purpose of the study was to compare the sensitivity of a sample of the whole population with that of the fractions thus obtained. Depending on the test used and the line tested, there was a 5.5 to 55.5% discordance between the results for the fractions and the non-separated cells.

A short-term chemosensitivity test with different labeled precursors of DNA or protein synthesis: correlation with clinical response.

Blood or bone marrow samples from 15 patients with newly diagnosed acute myeloblastic leukemia undergoing remission induction treatment with daunorubicin, cytosine-arabinoside and 6-thioguanine were tested in vitro. Leukemic cells were incubated for 24 h at 37 degrees C with or without the drugs alone or in combination. A 3-h pulse with labelled precursors of DNA synthesis (3H-thymidine) or protein synthesis (3H-leucine) was then given separately. In vitro growth, expressed as the percentage ratio between labeled precursor uptake in treated cells and in control cells, was compared with the clinical results obtained. Three patients were not considered evaluable (death occurred too early), 8 had a complete response (CR), and 4 were disease resistant to chemotherapy. Leukemic cells of resistant-disease patients showed a significantly lower growth inhibition than cells taken from CR patients, with each drug alone or in combination, when measured with thymidine. Inhibition of leucine uptake was not related to the clinical outcome.

[Lung injury and ventilatory strategies]. / Danno polmonare e strategie ventilatorie.

Premature lungs are highly susceptible to lung injury induced by chorioamionitis, mechanical ventilation or persistent exposure to high O2 concentrations. The Authors linger on the central role of atelectrauma and volutrauma (by inadequate tidal volume-Vt) in course of mechanical ventilation of preterm infants with RDS. In particular, they evaluate the efficacy and safety of the targeted volume ventilation with the option of the Volume Guarantee (VG). For this reason they present the results of randomized clinical trials in preterm infants (25-32 wks of gestational age) with severe RDS, in mechanical ventilation, without VG or with two different VG (Vt = 3 or 5 ml/Kg). Data collected demonstrate a significative difference (p < 0.05) in terms od reduction of mean airway pressure (PAW), peak inspiratory pressure (PIP) and cytokines production (IL6-IL8 and TNF alfa) in tracheal aspirate fluid in preterm infants in synchronized ventilation with VG set at 5 ml/Kg. These preliminary results seem to demonstrate the protective role of targeted volume ventilation with Vt = 5 ml/Kg (minimal volutrauma with less lung inflammatory response), but without significative reduction of chronic lung disease (CLD) in this group (probably due to multifactorial pathogenesis of CLD).

Correlations between volume delivery (VTHF) in course of high frequency oscillatory ventilation (HFOV) and severity of respiratory distress.

The treatment of severe respiratory distress in infants (e.g. respiratory distress syndrome--RDS, meconium aspiration syndrome--MAS and pulmonary haemorrage) with HFOV can cause sometimes a volume delivery (VTHF) exceeding the anatomical dead space, with the possibility of an increased risk of volutrauma, implicated in the pathogenesis of chronic lung disease (CLD). The authors examined the possible correlations between VTHF and the severity of respiratory distress in order to limit the risk of ventilator-induced lung injury (VILI). Thirty-five infants in HFOV because of respiratory distress were studied. The median VTHF registered was 2.25 ml/Kg (range: 1.3-3.4) with a significant correlation to some parameters espression of severity of the respiratory distress: arterial/Alveolar ratio (a/AO2) (r = 0.519), oxygen index (OI) (r = 0.512) and mean airway pressure (MAP) (r = 0.543).

[Umbilical cord IgE: a test for sensitivity, specificity and predictive value of atopy?]. / IgE cordonali: test di sensibilità, specificità e predittività di atopia?

Total IgE cord serum levels were measured in 200 newborns in the Hospital of Viadana-Bozzolo and familial allergic conditions were investigated in all the cases. In a 6 month follow up study attention was focused on the development of atopic symptoms. The sensibility, specificity and predictive value of the total IgE cord serum levels are discussed and the introducing of preventive measures in the at risk newborns is also questioned.

[Maxillary sinusitis in children: clinical and diagnostic aspects]. / Le sinusiti mascellari in età pediatrica: aspetti clinici e diagnostici.

Acute or chronic sinusitis is often overlooked and poorly understood in the pediatric population as many children have frequent episodes of upper respiratory infections that confuse accurate diagnosis. The authors present a prospective study in 89 children with clinical and radiographic presence of maxillary sinusitis in order to underline the most frequent clinical symptoms and signs and the most significant diagnostic procedures that help confirm precise definition of this common disease. The authors also discuss the relationship with allergic factors, clinical causes of poor sinus drainage, and environmental factors that may increase the possibility of sinus infection.

Successful use of tissue plasminogen activator (t-PA) in catheter-related intracardiac thrombi of two premature infants.

We describe the cases of two premature infants carrying a central venous line who developed on the fourth day of life a catheter related intracardiac thrombus. Although they were clinically asymptomatic we opted for thrombolytic treatment considering the potential risks of this situation. Treatment with recombinant tissue plasminogen activator (rt-PA) was performed for one day in the first case and for three days in the second one, in association with fresh frozen plasma. Thrombus dissolution occurred in both patients and no adverse effects were noted. In our experience tissue plasminogen activator was a therapy acceptably safe and effective inducing clot lysis in very low birthweight neonates into critical situations.

[Bronchoalveolar lavage with diluted porcine surfactant for alveolar debris removal in newborns treated with mechanical ventilation]. / Lavaggio broncoalveolare (BAL) con surfattante suino diluito per l'eliminazione dei detriti alveolari in neonati in ventilazione meccanica.

Lung debris in respiratory distress syndrome (RDS) and meconium aspiration syndrome (MAS) contribute to deteriorate pulmonary function. Surfactant lavage, also with minimal quantity of diluted surfactant, is an effective method for treatment of severe MAS and seems to be useful also in course of RDS evolving to chronic lung disease (CLD), by improving lung mechanics. Authors report a clinical study in which tracheobronchial lavage with surfactant (15 ml/Kg of diluted porcine surfactant) improved significantly lung function in 3 patients with RDS in prolonged mechanical ventilation and in 2 patients with MAS.

Esophageal leiomyomatosis in a woman with a history of vulvar leiomyoma and Barrett's esophagus: a case report and review of the literature.

BACKGROUND: The diagnosis and treatment of esophageal pathology remains a challenge despite advances in preoperative endoscopy, radiographic staging, and perioperative care. CASE REPORT: In this article, we present an interesting case of esophageal leiomyomatosis in a woman with a history of vulvar leiomyoma and Barrett's esophagus. This paper represents the first reported simultaneous occurrence of these three pathologic entities in the English literature. CONCLUSIONS: The clinical presentation and characteristic pathologic findings in patients with esophageal leiomyomatosis are reviewed. Diagnostic and therapeutic approaches to esophageal masses are discussed including the indications for esophageal resection.

Sarcoma arising from an abdominal aortic aneurysm.

A rare case of retroperitoneal sarcoma arising from an aneurysm sac is diagnosed in a patient following tube graft repair of the abdominal aortic aneurysm. The radiographic studies illustrate the characteristics of malignancy which are distinguishable from more common vascular complications. Malignancy should be considered in the differential diagnosis of retroperitoneal masses during radiographic follow-up of patients after aortic surgery. Sarcoma is optimally treated with complete excision, sometimes requiring concomitant vascular reconstruction. Radical en bloc resection was not attempted in this case due to extensive involvement of the aorta and inferior vena cava.

Coenzyme Q10 levels in maternal plasma and cord blood:correlations with mode of delivery.

BACKGROUND: Oxygen (O2) plays a critical role in the O2-reduction reactions indispensable for life, but can produce free radicals that are involved in many diseases. Coenzyme Q10 (CoQ10), acting as a redox carrier in the respiratory chain, occupies a central position in the energy metabolism and oxidative defence. Neonates seem to be very subjected to oxidative stress because of their deficient antioxidant systems. DESIGN/METHODS: The aim of the study was to verify whether the mode of delivery may affect CoQ10 levels in the mother and neonate, and thus influence the risk of oxidative damage in the newborn. We measured CoQ10 levels in maternal plasma and cord blood at birth after three different modes of delivery (45 term healthy pregnancies): (1) vaginal in room air (VD) (n = 15); (2) elective caesarean section with general anaesthesia (50% O2 and 50% N2O) (CSg) (n = 15), and (3) elective caesarean section with spinal anaesthesia without O2 (CSs) (n = 15). Our results showed higher levels of Q10 in mothers and neonates with VD (1.29 +/- 0.43 and 0.15 +/- 0.06 microg/ml, respectively) or CSs (1.15 +/- 0.28 and 0.24 +/- 0.06 microg/ml, respectively) when compared to CSg (0.74 +/- 0.28 and 0.07 +/- 0.03 microg/ml, respectively) (p < 0.01). CONCLUSIONS: These data demonstrate that the mode of delivery may affect CoQ(10) levels in mothers and neonates, and thus influence the risk of oxidative damage in the newborn.