Optic neuropathy diagnosis in the emergency room - retrospective observational study of the last 18 years.

INTRODUCTION: Optic neuropathies (ON), a broad spectrum of disorders of the optic nerve, are a frequent cause of visual loss, presenting either in isolation or associated to neurological or systemic disorders. They are often first evaluated in the Emergency Room (ER) and a rapid determination of the etiology is imperative for implementing timely and appropriate treatment. We aim to describe ER demographic data and clinical characteristics, as well as the performed imaging exams, of patients subsequently hospitalized and diagnosed with ON. Furthermore, we seek to explore the accuracy of ER discharge diagnosis and evaluate possible predictive factors that may influence it. METHODS: We retrospectively reviewed the medical records of 192 patients admitted to the ward of the Neurology Department of Centro Hospitalar Universitário São João (CHUSJ), with a discharge diagnosis of ON. Subsequently, we selected those admitted from the ER, with clinical, laboratory and imaging data, between January 2004 and December 2021. RESULTS: We included 171 patients. All participants were discharged from the ER and admitted in the ward with a main diagnostic suspicion of ON. Patients were stratified according to suspected etiology at the time of discharge: 99 inflammatory (57.9%), 38 ischemic (22.2%), 27 unspecified (15.8%) and 7 other (4.1%). By comparing with current follow-up diagnosis, 125 patients had an accurate ER diagnosis category (73.1%), 27 had an ON diagnosis of unspecified etiology that was defined only during follow-up (15.8%) and 19 had an inaccurate diagnosis category (11.1%). Diagnostic change was more common with ER ischemic diagnosis (21.1%) compared to inflammatory diagnosis (8.1%) (p = 0.034). CONCLUSIONS: Our study reveals that most patients with ON can be accurately diagnosed in the ER through clinical history neurological and ophthalmological evaluation.

Recurrent encephalopathy associated with pegylated beta-interferon treatment.

A 62-year-old woman with a history of multiple sclerosis (MS) presented with recurrent episodes of confusion, dysarthria and gait difficulties. These episodes occurred about 3 days after administration of pegylated interferon-beta-1a (Plegridy®) and resolved spontaneously in around 4 days. The brain MRI scan, laboratory findings and cerebrospinal fluid analysis during these episodes were negative for other causes of encephalopathy. She discontinued treatment with interferon and was started on teriflunomide, experiencing no recurrence of symptoms. We believe that interferon was responsible for this patient's recurrent encephalopathic syndrome, possibly due to its effects on inflammatory cytokines and endothelial dysfunction.

Metabolic syndrome parameters and multiple sclerosis disease outcomes: A Portuguese cross-sectional study.

BACKGROUND: Metabolic syndrome and multiple sclerosis [MS] share the presence of chronic inflammation in their pathogenic mechanisms. This study aimed to estimate the prevalence of metabolic syndrome parameters in MS and their association with disease disability, cognitive function, and Neurofilament Light chain [NfL] levels. METHODS: Clinical, analytical, and magnetic resonance imaging data were obtained through medical records. Disease disability was measured by the Expanded Disability Status Scale [EDSS], the MS Severity Scale [MSSS] along with cognitive impairment by the Brief International Cognitive Assessment for MS [BICAMS] and Word List Generation test [WLG]. Metabolic syndrome parameters were evaluated by fasting blood glucose, triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol, total cholesterol, blood pressure, and waist circumference [WC]. We also analysed serum leptin and ghrelin and cerebrospinal fluid NfL. RESULTS: Our sample included 51 people with MS, 34 (66.7%) females, mean age of 38.20±12.12 years and median disease duration of 3 years (P25=2.0, P75=5.0). Multivariate linear regression analysis confirmed that WC correlates with EDSS (ß=0.04, p=.001) and MSSS (ß=0.07, p=.002) as well as Brief Visuospatial Memory Test-Revised (ß=-0.29, p=.008), WLG (ß=-0.20, p=.039). NfL is also negatively associated with HDL-C (ß=-4.51, p=.038). CONCLUSIONS: Waist circumference is associated with disability and deficits in cognitive tests. A decrease in HDL-C is associated with an increase in NfL. This suggests metabolic syndrome might be an important factor in MS disease course.

A 6-month trial of memantine for nystagmus and associated phenomena in oculopalatal tremor.

Introduction: Oculopalatal tremor (OPT) is a late manifestation of a Guillain-Mollaret triangle lesion. Memantine has been shown to improve nystagmus in OPT, but its long-term efficacy and putative distinct effects on each plane of nystagmus and on associated phenomena (e.g., gravity perception) are largely unknown. Methods: We conducted a 6-month open-label study to evaluate the effect of memantine in OPT patients. Baseline (visit 1), 2 (visit 2), and 6 months (visit 3) assessments included video-oculography, best corrected visual acuity (BCVA), visual function questionnaire (VFQ25), palatal tremor frequency, and subjective visual vertical (SVV). Memantine was titrated to 20 mg per day and stopped after 6 months. Results: We included six patients (5 females; mean age 68.5+/-9.7). At visit 2, nystagmus improved >50% only along the horizontal plane in two patients, while worsening >50% along the vertical and horizontal planes in 4 and 1 patients, respectively. At visit 3, previous improvement of nystagmus along the horizontal plane in two patients was not sustained, and it further worsened >50% along the vertical plane in 4. The mean vertical velocity and amplitude of nystagmus in the left eye significantly worsened from visit 2 to visit 3 (p = 0.028). Throughout the study, nystagmus frequency remained unchanged (p = 0.074), BCVA improved in both eyes (p = 0.047, p = 0.017), SVV progression was unpredictable (p = 0.513), and the mean VFQ-25 score (p = 0.223) and mean palatal frequency remained unchanged. Conclusion: The long-term use of memantine 20 mg per day in OPT produced a modest and only transient improvement in nystagmus, predominantly along the horizontal plane. Visual acuity improved, albeit without relevant changes in vision-related quality of life.

Multiple Sclerosis, Disease-Modifying Therapies and COVID-19: A Systematic Review on Immune Response and Vaccination Recommendations.

Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As for the general population, advanced age, comorbidities, and higher disability significantly impact COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination implications. Clinical evidence does not support an increased risk of MS relapse or vaccination failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it is recommended to wait 3-6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at least 4-6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols.

Cerebral Venous Thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine.

The development of SARS-CoV-2 vaccines has raised several concerns regarding venous thromboembolism, namely cerebral venous thrombosis. Although cerebral venous thrombosis has been reported after administration of a viral vector vaccine, due to a possible auto-immune mechanism inducing thrombocytopenia, the same has not happened in mRNA vaccines. We report two cases of cerebral venous thrombosis, shortly after administration of mRNA vaccine. In both patients, there was no evidence of thrombocytopenia or antiplatelet antibodies, and alternative causes for cerebral venous thrombosis were found. As such, despite the temporal relation of both cases to vaccine administration, these types of cerebral venous thrombosis do not seem to be pathophysiological different from cerebral venous thrombosis not associated to SARS-CoV-2 vaccination. Continuous pharmacovigilance is necessary to monitor possible new events and clarify this association.

Asian and African/Caribbean AQP4-NMOSD patient outcomes according to self-identified race and place of residence.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy characterized by aquaporin-4 antibodies, whose prognosis is influenced by onset age, race, environmental exposures and immunosuppression. Distinguishing the contribution of environment from genetics is challenging. We aimed to compare neuromyelitis optica spectrum disorder (NMOSD) patient outcomes according to self-identified racial group and place of residence. METHODS: This retrospective analysis of prospectively collected data included non-white anti-aquaporin-4 antibody positive NMOSD patients under follow-up from 15 centers [United Kingdom, France, Germany, Denmark, Martinique, United States of America, Japan, South Korea, Singapore, Thailand, China (including Hong Kong) and India]. Racial groups were designated: African/Caribbean; South Asian; East Asian (including Southeast Asia). Patients from these racial groups residing outside Africa/Caribbean or Asia were compared with those living in the Caribbean or the Asian areas. Kaplan-Meier survival curves and Cox models were generated using time to sustained Expanded Disability Status Scale≥6.0 or death; time to sustained Kurtzke Visual Function Score≥3.0 or a composite endpoint of all three. RESULTS: Among 821 patients, African/Caribbean patients (n = 206) had the shortest time to immunosuppression and higher visual disability at onset. South Asian patients (n = 65) were younger, had lower visual disability at onset and higher mortality rate. East Asians (n = 550) had the lowest relapse rate and lowest accrued motor disability. Survival analysis of African/Caribbean outside Africa/Caribbean vs those in the Caribbean showed a significant difference in the composite endpoint (p = 0.024,log-rank test), not apparently related to treatment differences. No significant differences between native and those residing outside Asia were found for other racial groups. CONCLUSION: This NMOSD study reports the effects of place of residence on the outcomes in different races. Place of residence may not be a significant driver of disability among Asian patients, while it may influence African/Caribbean patient outcomes. Validating these findings could help distinguish between genetic causes and potentially modifiable environmental factors.

State of the Art and Future Challenges in Multiple Sclerosis Research and Medical Management: An Insight into the 5th International Porto Congress of Multiple Sclerosis.

The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes-including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)-led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools.

Automated and objective measures of gait dynamics in camptocormia Parkinson's Disease subthalamic deep brain stimulation.

OBJECTIVE: Axial motor features are common in Parkinson's disease (PD). These include gait impairment and postural abnormalities, such as camptocormia. The response of these symptoms to deep brain stimulation (DBS) is variable and difficult to assess objectively. For the first time, this study analyzes the treatment outcomes of two PD patients with camptocormia that underwent bilateral subthalamic nucleus (STN)-DBS evaluated with disruptive technologies. PATIENTS AND METHODS: Two patients with PD and camptocormia who underwent STN-DBS were included. Gait parameters were quantitatively assessed before and after surgery by using the NeuroKinect system and the camptocormia angle was measured using the camptoapp. RESULTS: After surgery, patient 1 improved 29 points in the UPDRS-III. His camptocormia angle was 68° before and 38° after surgery. Arm and knee angular amplitudes (117.32 ±â€¯7.47 vs 134.77 ±â€¯2.70°; 144.51 ±â€¯7.47 vs 169.08 ±â€¯3.27°) and arm swing (3.59 ±â€¯2.66 vs 5.40 ±â€¯1.76 cm) improved when compared with his preoperative measurements. Patient 2 improved 22 points in the UPDRS-III after surgery. Her camptocormia mostly resolved (47° before to 9° after surgery). Gait analysis revealed improvement of stride length (0.29 ±â€¯0.03 vs 0.35 ±â€¯0.03 m), stride width (18.25 ±â€¯1.16 vs 17.9 ±â€¯0.84 cm), step velocity (0.91 ±â€¯0.57 vs 1.33 ±â€¯0.48 m/s), arm swing (4.51 ±â€¯1.01 vs 7.38 ±â€¯2.71 cm) and arm and hip angular amplitudes (131.57 ±â€¯2.45° vs 137.75 ±â€¯3.18; 100.51 ±â€¯1.56 vs 102.18 ±â€¯1.77°) compared with her preoperative results. CONCLUSION: The gait parameters and camptocormia of both patients objectively improved after surgery, as assessed by the two quantitative measurement systems. STN-DBS might have a beneficial effect on controlling axial posturing and gait, being a potential surgical treatment for camptocormia in patients with PD. However, further studies are needed to derive adequate selection criteria for this patient population.

Intensive Blood Pressure Treatment Reduced Stroke Risk in Patients With Albuminuria in the SPRINT Trial.

Background and Purpose- Albuminuria is associated with stroke risk among individuals with diabetes. However, the association of albuminuria with incident stroke among nondiabetic patients is less clear. Methods- We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial), which examined the effect of higher versus lower intensity blood pressure management on mortality in 8913 participants without diabetes. We fit unadjusted and adjusted Cox proportional hazards models to estimate the association of baseline albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g versus<30 mg/g) with stroke risk. We also assessed effect modification according to treatment arms. Results- Mean age was 68±9 years, 35% were female, and 30% were black. Median follow-up was 3.2 years, and 19% patients had baseline albuminuria. Incident stroke occurred in 129 individuals during follow-up. Albuminuria was associated with increased stroke risk (unadjusted hazard ratio, 2.24; 95% CI, 1.55-3.23; adjusted hazard ratio 1.73; 95% CI, 1.17-2.56). The association of albuminuria with incident stroke differed according to the randomized treatment arm (P interaction=0.03). In the intensive treatment arm, the association of albuminuria and stroke was nonsignificant (unadjusted hazard ratio, 1.25; 95% CI, 0.69-2.28), whereas, in the standard treatment arm, it was significant (unadjusted hazard ratio, 3.44; 95% CI, 2.11-5.61). Conclusions- In a post hoc analysis of SPRINT, baseline albuminuria (versus not) was associated with a higher risk of incident stroke, but this relationship appeared to be restricted to those in the standard treatment arm. Further studies are required to conclusively determine if reduction of albuminuria in itself is beneficial in reducing stroke risk. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Intraoperative microelectrode recording in Parkinson's disease subthalamic deep brain stimulation: Analysis of clinical utility.

This retrospective study aims to explore the clinical utility of microelectrode recording (MER) during subthalamic deep brain stimulation (DBS) surgery in patients with Parkinson's disease (PD). We analyzed the data from 103 PD patients, who consecutively received bilateral subthalamic nucleus (STN) DBS at an experienced academic medical center. We collected demographic, clinical, and DBS related data, including intraoperative microelectrode recording data, electrode positioning, and clinical effects provided by intraoperative microstimulation. The 2 brain sides were independently analyzed and are described as first and second side (to be operated on); the first side is contralateral to motor symptoms onset. Patients were mostly men (64.1%). In both sides of the brain, percentage of agreement with the electrode final position was higher with clinical results than with intraoperative microelectrode recordings (98% vs 57% on the first implantation side, and 97% vs 58% on the second implantation side, respectively). Regarding electrode final implantation depth, 86% of electrodes were implanted between 0 mm and +2 mm in relation to anatomical target, and 95% of electrodes were implanted from -2 mm to +2 mm. Our study suggests that MER might not be necessary to achieve good clinical outcomes in PD patients undergoing STN DBS. These results support and inform the design of future prospective controlled research studies.

Electrochemical Immunosensor for TNFα-Mediated Inflammatory Disease Screening.

Inflammation associated with cancer, neurodegenerative, ocular, and autoimmune diseases has a considerable impact on public health. Tumor necrosis factor alpha (TNFα) is a key mediator of inflammatory responses, responsible for many of the systemic manifestations during the inflammatory process. Thus, inhibition of TNFα is a commonplace practice in the treatment of these disorders. Successful therapy requires the ability to determine the appropriate dose of anti-TNFα drugs to be administered in a timely manner, based on circulating TNFα levels. In this Letter, we report the development of an immunosensor technology able to quantify TNFα at the picogram level in relevant human body fluids, holding the potential to early detect inflammation  and monitor TNFα levels during treatment, enabling TNFα-targeted treatments to be tailored according to the immune status of an individual patient. This immunosensor technology is significantly more rapid and sensitive than conventional enzyme linked immunosorbent assays, maintaining high specificity and requiring small sample volumes. These features might also be advantageous in the context of personalized medicine, as this analytical platform can deliver advanced diagnostics and reduce clinical burden.

Brody disease: when myotonia is not myotonia.

A 56-year-old man presented with painless impairment of muscle relaxation on vigorous contraction (eg, eyelid closure, hand grip, running). There were no episodes of paralysis, symptom progression, weakness or extramuscular symptoms. Five of his fifteen siblings had similar complaints. His serum creatine kinase was normal. Electromyography showed electrical silence on muscle relaxation, without myotonic discharges. DMPK, ClCN1 and SCN4A genetic testing was normal, but he had a homozygous pathogenic variant of ATP2A1 (c.1315G>A; pGlu439Lys). Brody disease is a rare autosomal recessive myopathy due to ATP2A1 mutations that reduce sarcoplasmic reticulum calcium-ATPase1 activity, hence delaying muscle relaxation.

MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock.

OBJECTIVES: Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155-dependent mechanisms of myocardial and vascular dysfunction in septic shock. DESIGN: Prospective, randomized controlled experimental murine study and clinical cohort analysis. SETTING: University research laboratory and ICU at a tertiary-care center. PATIENTS: Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting. SUBJECTS: C57Bl/6J and genetic background-matched microRNA-155 knockout mice. INTERVENTIONS: Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings. MEASUREMENTS AND MAIN RESULTS: We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1-mediated inhibition of nitric oxide production and nitric oxide-mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings. CONCLUSIONS: Our study demonstrates multiple new microRNA-155-mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.

Emerging Biosensing Technologies for Neuroinflammatory and Neurodegenerative Disease Diagnostics.

Neuroinflammation plays a critical role in the onset and progression of many neurological disorders, including Multiple Sclerosis, Alzheimer's and Parkinson's diseases. In these clinical conditions the underlying neuroinflammatory processes are significantly heterogeneous. Nevertheless, a common link is the chronic activation of innate immune responses and imbalanced secretion of pro and anti-inflammatory mediators. In light of this, the discovery of robust biomarkers is crucial for screening, early diagnosis, and monitoring of neurological diseases. However, the difficulty to investigate biochemical processes directly in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory responses have been identified in different body fluids, such as blood, cerebrospinal fluid, and tears. In addition, progress in micro and nanotechnology has enabled the development of biosensing platforms capable of detecting in real-time, multiple biomarkers in clinically relevant samples. Biosensing technologies are approaching maturity where they will become deployed in community settings, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight both clinical and recent technological advances toward the development of multiplex-based solutions for effective neuroinflammatory and neurodegenerative disease diagnostics and monitoring.

Ocular neuromyotonia.

Ocular neuromyotonia is a rare, albeit treatable, ocular motor disorder, characterised by recurrent brief episodes of diplopia due to tonic extraocular muscle contraction. Ephaptic transmission in a chronically damaged ocular motor nerve is the possible underlying mechanism. It usually improves with carbamazepine. A 53-year-old woman presented with a 4-month history of recurrent episodes of binocular vertical diplopia (up to 40/day), either spontaneously or after sustained downward gaze. Between episodes she had a mild left fourth nerve palsy. Sustained downward gaze consistently triggered downward left eye tonic deviation, lasting around 1 min. MR scan of the brain was normal. She improved on starting carbamazepine but developed a rash that necessitated stopping the drug. Switching to lacosamide controlled her symptoms.

A role for prolyl isomerase PIN1 in the phosphorylation-dependent modulation of PRRXL1 function.

Prrxl1 encodes for a paired-like homeodomain transcription factor essential for the correct establishment of the dorsal root ganglion - spinal cord nociceptive circuitry during development. Prrxl1-null mice display gross anatomical disruption of this circuitry, which translates to a markedly diminished sensitivity to noxious stimuli. Here, by the use of an immunoprecipitation and mass spectrometry approach, we identify five highly conserved phosphorylation sites (T110, S119, S231, S233 and S251) in PRRXL1 primary structure. Four are phospho-S/T-P sites, which suggest a role for the prolyl isomerase PIN1 in regulating PRRXL1. Accordingly, PRRXL1 physically interacts with PIN1 and displays diminished transcriptional activity in a Pin1-null cell line. Additionally, these S/T-P sites seem to be important for PRRXL1 conformation, and their point mutation to alanine or aspartate down-regulates PRRXL1 transcriptional activity. Altogether, our findings provide evidence for a putative novel role of PIN1 in the development of the nociceptive system and indicate phosphorylation-mediated conformational changes as a mechanism for regulating the PRRXL1 role in the process.

Dual role of Tlx3 as modulator of Prrxl1 transcription and phosphorylation.

The proper establishment of the dorsal root ganglion/spinal cord nociceptive circuitry depends on a group of homeodomain transcription factors that includes Prrxl1, Brn3a and Tlx3. By the use of epistatic analysis, it was suggested that Tlx3 and Brn3a, which highly co-localize with Prrxl1 in these tissues, are required to maintain Prrxl1 expression. Here, we report two Tlx3-dependent transcriptional mechanisms acting on Prrxl1 alternative promoters, referred to as P3 and P1/P2 promoters. We demonstrate that (i) Tlx3 induces the transcriptional activity of the TATA-containing promoter P3 by directly binding to a bipartite DNA motif and (ii) it synergistically interacts with Prrxl1 by indirectly activating the Prrxl1 TATA-less promoters P1/P2 via the action of Brn3a. The Tlx3 N-terminal domain 1-38 was shown to have a major role on the overall Tlx3 transcriptional activity and the C-terminus domain (amino acids 256-291) to mediate the Tlx3 effect on promoters P1/P2. On the other hand, the 76-111 domain was shown to decrease Tlx3 activity on the TATA-promoter P3. In addition to its action on Prrxl1 alternative promoters, Tlx3 proved to have the ability to induce Prrxl1 phosphorylation. The Tlx3 domain responsible for Prrxl1 hyperphosphorylation was mapped and encompasses amino acid residues 76 to 111. Altogether, our results suggest that Tlx3 uses distinct mechanisms to tightly modulate Prrxl1 activity, either by controlling its transcriptional levels or by increasing Prrxl1 phosphorylation state.