Netrin-1 dampens pulmonary inflammation during acute lung injury.

RATIONALE: Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential. OBJECTIVES: To test the role of pulmonary netrin-1 during ALI. METHODS: Pulmonary netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1(+/-), and A2BAR(-/-) animals. Exogenous netrin-1 was used to evaluate its impact on pulmonary inflammation. MEASUREMENTS AND MAIN RESULTS: Wild-type animals demonstrated repression of pulmonary netrin-1 after LPS inhalation. In vitro studies confirmed the repression of netrin-1. Studies in the putative netrin-1 promoter identified a nuclear factor-kappaB-dependent mechanism to be involved in this repression. Ntn1(+/-) animals demonstrated increased inflammatory changes after LPS inhalation compared with Ntn1(+/+) animals. Reconstitution with netrin-1 dampened the infiltration of neutrophils and cytokine production in the alveolar space. This effect was dependent on the adenosine 2b receptor. The importance of netrin-1 for the control of pulmonary inflammation could be corroborated in a model of ventilator-induced lung injury. CONCLUSIONS: Pulmonary netrin-1 levels are repressed during ALI. This results in pronounced pulmonary damage, an increased infiltration of neutrophils, and increased pulmonary inflammation. Exogenous netrin-1 significantly dampens the extent of ALI through the adenosine 2B receptor.

Neuromuscular correlates of subthalamic stimulation and upper limb freezing in Parkinson's disease.

OBJECTIVE: The pathophysiology of deep brain stimulation mechanisms and resistant freezing phenomena in idiopathic Parkinson's disease (iPD) remains incompletely understood. Further studies on the neuromuscular substrates are needed. METHODS: We analyzed 16 patients with advanced iPD and bilateral subthalamic nucleus stimulation, and 13 age- and gender-matched healthy controls. Patients were tested after overnight withdrawal of medication with 'stimulation off' (StimOff) and 'stimulation on' (StimOn). Subjects performed continuous tapping of the right index finger with simultaneous recordings of biomechanical registration, EMG of finger flexors and extensors, and EEG. First, we analyzed EEG and EMG spectral measures comparing StimOff with healthy controls and StimOff with StimOn (irrespective of freezing). Second, we contrasted 'regular (unimpaired) tapping' and 'freezing' resistant to subthalamic neurostimulation as obtained in StimOn. RESULTS: iPD showed increased intermuscular coherence around 8Hz in StimOff that was reduced in StimOn. This 8Hz muscular activity was not coherent to cortical activity. 'Freezing' episodes showed increased muscle activity of finger flexors and extensors at 6-9Hz, and increased cortical activity at 7-11Hz. During transition from regular tapping to 'freezing' the cortical activity first increased over the left sensorimotor area followed by a spread to the left frontal and right parietal areas. CONCLUSIONS: We identified neuromuscular motor network features of subthalamic neurostimulation therapy and resistant upper limb freezing that point to increased low-frequency muscular and cortical activity. SIGNIFICANCE: Together, our findings demonstrate several motor network abnormalities associated with upper limb freezing that may translate into future research on freezing of gait in iPD.

Long-term outcome of deep brain stimulation in fragile X-associated tremor/ataxia syndrome.

INTRODUCTION: Fragile X-associated tremor/ataxia syndrome (FXTAS) presents as complex movement disorder including tremor and cerebellar ataxia. The efficacy and safety of deep brain stimulation of the nucleus ventralis intermedius of the thalamus in atypical tremor syndromes like FXTAS remains to be determined. METHODS: Here, we report the long-term outcome of three male genetically confirmed FXTAS patients treated with bilateral neurostimulation of the nucleus ventralis intermedius for up to four years. RESULTS: All patients demonstrated sustained improvement of both tremor and ataxia - the latter included improvement of intention tremor and axial tremor. Kinematic gait analyses further demonstrated a regularization of the gait cycle. Initial improvements of hand functional disability were not sustained and reached the preoperative level of impairment within one to two years from surgery. CONCLUSION: Our data on patients with a genetic cause of tremor show favorable outcome and may contribute to improved patient stratification for neurostimulation therapy in the future.

TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. METHODS: This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. RESULTS: There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. CONCLUSIONS: These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed.