Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF). Methods and analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat. Ethics and dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences. Trial registration numbers: NCT05287503, EudraCT 2021-004565-13.

Parkinsonism in complex neurogenetic disorders: lessons from hereditary dementias, adult-onset ataxias and spastic paraplegias.

Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of Parkinson's disease, the most common cause of parkinsonism, and atypical parkinsonian disorders. However, parkinsonism can be a manifestation of complex neurological and neurodegenerative genetically determined disorders, which have a vast and heterogeneous motor and non-motor phenotypic features. Hereditary dementias, adult-onset ataxias and spastic paraplegias represent only few of this vast group of neurogenetic diseases. This review will provide an overview of parkinsonism's clinical features within adult-onset neurogenetic diseases which a neurologist could face with. Understanding parkinsonism and its characteristics in the context of the aforementioned neurological conditions may provide insights into pathophysiological mechanisms and have important clinical implications, including diagnostic and therapeutic aspects.

Dexmedetomidine as a sedative and analgesic adjuvant in spine surgery: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: This systematic review and meta-analysis appraise the clinical evidence on efficacy and safety of dexmedetomidine (DEX), as a sedative and analgesic adjunct in adult patients undergoing spine surgery. METHODS: A database search was conducted to identify randomized clinical trials (RCTs) pertinent to the perioperative use of DEX in spine surgery. Sedative and analgesic efficacy of DEX constituted the primary outcomes, whilst the incidence of hemodynamic changes, quality of recovery and occurrence of adverse events served as secondary ones. RESULTS: Fifteen studies enrolling a total of 913 patients were selected for qualitative analysis, among which eight RCTs incorporating a placebo comparison group were included in the meta-analysis. Most of the retrieved studies were of moderate to good quality and demonstrated an acceptable risk of bias. DEX-treated patients showed a significant reduction of both propofol [mean difference (MD), -214.47 mg; 95%CI, -253.16 to -175.78; P < 0.001] and morphine equivalents consumption both intraoperatively and postoperatively (MD, -2.69; 95% CI, -3.05 to -2.33; P < 0.001 and MD, -4.36 mg; 95%CI, -6.93 to -1.79; P < 0.001, respectively) compared to those assigned to placebo. Postoperative nausea and vomiting incidence were comparable between DEX and placebo groups, whilst other adverse events were not consistently reported. CONCLUSIONS: DEX emerges as an attractive alternative to standard sedative and analgesic modalities applied in spine surgery, by attaining a notable sedative and opioid-sparing effect, which goes with an enhanced safety profile. Yet, no definite conclusion can be drawn due to the considerable heterogeneity of available data. TRIAL REGISTRATION: PROSPERO CRD42015029537.

Effects of propofol or sevoflurane anesthesia induction on hemodynamics in patients undergoing fiberoptic intubation for cervical spine surgery: A randomized, controlled, clinical trial.

BACKGROUND AND AIMS: In patients undergoing surgery for cervical myelopathy, induction of general anesthesia can induce systemic arterial hypotension that may worsen spinal cord hypoperfusion and precipitate spinal injury. In this randomized, controlled, clinical trial study, we compared the hemodynamic changes related to anesthesia induction with intravenous (IV) propofol- and sevoflurane-based inhalational induction in patients undergoing fiberoptic intubation for cervical spine surgery. MATERIAL AND METHODS: A total of 72 patients were studied. Hemodynamic effects were assessed measuring mean arterial pressure (MAP), and the echocardiographic evaluation of the left ventricular function. A Student's t-test with Bonferroni correction or Chi-squared test was used, when appropriate, to assess differences in hemodynamic (extent of MAP drop and incidence of episodes of severe arterial hypotension) and other variables (occurrence and duration of episodes of apnea). RESULTS: Patients assigned to total IV anesthetic approach had a lower MAP, and more significant changes in cardiac function compared to those who received the inhalational approach (68.1 ± 9.3 mmHg vs. 75.5 ± 10.3 mmHg; 25% vs. 5.5%). CONCLUSION: Anesthesia induction with both propofol or sevoflurane is safe and effective. However, total IV anesthesia induction is associated with more pronounced MAP drop which can worsen spinal cord hypoperfusion.

Spine Surgery and Blood Loss: Systematic Review of Clinical Evidence.

Spine surgery has been growing rapidly as a neurosurgical operation, with an increase of 220% over a 15-year period. Intraoperative blood transfusion is a major outcome determinant of spine procedures. Various approaches, including pharmacologic and nonpharmacologic therapies, have been tested to decrease both intraoperative and postoperative blood loss. The aim of this systematic review is to report clinical evidence on the relationship between intraoperative blood loss (primary outcome) and on transfusion requirements and postoperative complications (secondary outcomes) in patients undergoing spine surgery. A literature search of PubMed database was performed using 5 key words: spine surgery and transfusion; spine surgery and blood loss; spine surgery and blood complications; spine surgery and deep vein thrombosis; and spine surgery and pulmonary embolism. Clinical reports (randomized controlled trials, prospective and retrospective studies, and case reports) were selected. A total of 473 articles were examined; 450 were excluded, and 24 were selected for this systematic review. Selected articles were categorized into 3 subchapters: (1) drugs active on coagulation (12 studies): tranexamic acid, aminocaproic acid, aprotinin, and recombinant activated factor VII; (2) drugs not active on coagulation (5 studies): ketorolac, epoetin alfa, magnesium sulfate, propofol/sevoflurane, and omega-3 and fish oil; (3) nonpharmacologic approaches (7 studies): surgical tips, patient positioning, and general or spinal anesthesia. Several studies have shown a significant reduction in intraoperative bleeding during spine surgery and in the requirement for blood transfusion.

Direct observation and reactions of Cl3 radical.

The broad absorption of Cl3 radical was observed between 1150 and 1350 nm using cavity ring-down spectroscopy at 213-265 K and 50-200 Torr with He, N2, Ar, or SF6 diluents. The absorption intensity of Cl3 increased at lower temperature and higher pressure. SF6 was the most efficient diluent gas. The temperature dependent equilibrium constants for Cl3 formation from Cl+Cl2 were theoretically calculated at the MP4SDQ6-311+G(d) level. Observed decay time profiles of Cl3 and the pressure dependence of Cl3 formation are explained by the equilibrium reaction and a decay reaction of Cl+Cl3.

Temperature and pressure dependence of the rate constants of the reaction of NO3 radical with CH3SCH3.

The reaction of nitrate radical with dimethyl sulfide was studied with cavity ring-down spectroscopy in 20-200 Torr of N2 diluent in the temperature range of 283-318 K. The rate constant for this reaction, k(1), is found to be temperature dependent and pressure independent: k1 = 4.5(-2.8)(+4.0) x 10(-13) exp[(310 +/- 220)/T] cm3 molecule(-1) s(-1). The uncertainties are two standard deviations from regression analyses. The present rate constants are in good agreement with those reported by Daykin and Wine (Int. J. Chem. Kinet. 1990, 22, 1083) and may be used in the atmospheric model calculation. Theoretical calculations were carried out to verify the existence of an intermediate complex.