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.

CoQ10 plasmatic levels in breast-fed infants compared to formula-fed infants.

BACKGROUND: Coenzyme Q10 has been recognized as an important antioxidant factor besides its main role in bioenergetic metabolism. CoQ10 tissue levels depend both on exogenous dietetic intake and on endogenous biosynthesis, as this compound can be partly synthesized in human cells. Q10 plasma levels reflect the tissue content of the coenzyme and can be used to evaluate the presence of this compound in the human organism. DESIGN/METHODS: Aim of the study was to measure CoQ10 plasmatic levels in a newborn breast-fed population and to compare them to CoQ10 levels in a newborn formula-fed population in order to verify whether changes in CoQ10 plasmatic contents could be related to a different dietetic intakes. We measured CoQ10 plasmatic levels in 25 healthy term neonates with different dietetic intakes: 15 breast-fed and 10 bottle-fed with a common infant formula. These infants were evaluated prospectively during the first month of life. The analyses were performed on the mothers' blood samples and cord blood samples at the time of delivery, then on infants at 4 and 28 days of age. RESULTS: Our results showed markedly reduced Q10 levels in cord blood samples compared to maternal Q10 plasmatic levels at the time of delivery, suggesting placental impermeability towards this molecule or increased fetal utilization during labor and delivery. At 4 days of age Q10 levels had increased in both groups of neonates, but significantly more in breast-fed infants compared to formula-fed babies (p <0.05). At 4 weeks of age no significant changes occurred in breast-fed infants, while values increased significantly in formula-fed infants (p <0.05). The content of Q10 in breast milk samples was lower than in infant formula. CONCLUSIONS: The results of this study show that CoQ10 plasmatic levels are at least partly influenced by the exogenous dietetic supply.

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.

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.

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).

[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).

Hypothermia reduces neurological damage in asphyxiated newborn infants.

BACKGROUND: Perinatal asphyxia remains one of the most devastating neurologic processes. There is experimental and clinical evidence that cerebral cooling may suppress the biochemical cascades leading to delayed cerebral damage. OBJECTIVE: To determine if hypothermia started soon after delivery reduces cerebral damage in term infants. DESIGN/METHODS: Retrospective chart analysis with historical controls. Ten asphyxiated newborns treated with hypothermia between October 1998 and October 1999 were compared to 11 asphyxiated newborns admitted from September 1997 to September 1998. Characteristics at birth of infants of the two groups (control and hypothermia) were comparable. After obtaining parental consent, whole-body hypothermia was induced before the 6th hour of life by placing a cold blanket (Polar Air, Augustine Medical Inc., model 600) around the body of the patients. Rectal temperature was maintained between 32 and 34 degrees C for 72 h. Outcome was assessed by neurological evaluation at birth and every 3 months up to the 12th month. Brain MRI was performed in the 2nd month. We had no evidence of severe adverse events related to hypothermia. In the hypothermic group there was a significant (p < 0.05) reduction of major neurologic abnormalities at follow-up and abnormal MRI findings. CONCLUSIONS: Hypothermia appears to be safe. Our results on morphological damage evaluated by brain MRI and neurological outcome are encouraging: randomized controlled trials are needed to confirm this experience.

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.

[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.

[The "guaranteed volume" in pressure support ventilation reduces the risk of barotrauma in premature children with severe respiratory syndrome]. / Il "volume garantito" (VG) in corso di pressure support ventilation (PSV) riduce il rischio di barotrauma in pretermine con sindrome respiratoria grave (RDS).

Chronic Lung Disease (CLD) remains a major complication of prematurity, and barovolutrauma is thought to be one of the most important predisposing factors. In view of reducing the damage due to variability of tidal volume (Vt), we studied the application of the new option of volume guarantee (VG). We analyzed ventilatory data of 25 preterm infants with respiratory distress syndrome (RDS) in two situations: pressure support ventilation (PSV) + VG vs PSV alone. Data collected showed application of significantly lower peak inspiratory pressure (p < 0.001) and mean airway pressure (p < 0.001) with the constant Vt. We conclude that this ventilatory strategy, by reducing the barotrauma, could be considered a protective ventilation.

[QTc interval in newborns with gastroesophageal reflux treated with cisapride and ranitidine]. / Intervallo QTc in neonati con reflusso gastroesofageo (RGE) in terapia con cisapride e ranitidina.

Gastroesophageal reflux (GER) is very common in infants, especially in prematures and may be cause of gastrointestinal and cardiorespiratory symptoms. Cisapride, a prokinetic agent, is used in order to avoid the transient esophageal sphincter relaxation, but it is sometimes associated to transient prolongation of QT interval on EKG, especially with high dosage. The authors report the effects of cisapride therapy (0.8 mg/Kg/day) on QTc interval (QTc = QT interval corrected on heart frequency) in a pediatric population (50 infants) with GER. Results demonstrate the relatively safety of cisapride therapy at low dose also in the pediatric period.

Cerebral vasoreactivity to arterial carbon dioxide tension in preterm infants: the effect of ibuprofen.

Cerebral vasoreactivity to CO(2), calculated by linear regression of total cerebral hemoglobin, measured by near infrared spectroscopy, and corresponding PaCO(2), in infants <32 weeks' gestation, was found to be unaffected by the administration of ibuprofen, which was given on the first postnatal day as prophylaxis against patent ductus arteriosus.

[Endotracheal tube cuff pressure. Monitoring during general anesthesia]. / Pressione della cuffia del tubo endotracheale. Monitoraggio durante anestesia generale.

BACKGROUND: To value changes of endotracheal tube cuff pressure during anaesthesia with N2O, using standard tubes or Brandt-system tubes. METHODS: Endotracheal cuff pressure during anaesthesia in three groups of patients has been monitored: Group 1 (n. 41): endotracheal tube with low-pressure cuff using N2O/O2 (2:1 or 1:1); Group 2 (n. 55): Brandt's double cuff-tubes using N2O/O2 (2:1 or 1:1); Group 3 (n. 20-control group): tubes with low-pressure cuff using O2/air. Values of pressure (M +/- DS: p < 0.05) have been compared with ANOVA, Bonferroni's method (p < 0.017). RESULTS AND CONCLUSIONS: Brandt's double cuff-tubes (G2) succeed in avoiding uncontrolled increase of cuff-pressure during anaesthesia with N2O. Standard low-pressure tubes (G1) shown increase of cuff pressure during anaesthesia with N2O which is absent using no N2O (G3).

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.