Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study.

BACKGROUND: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. METHODS: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. FINDINGS: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. INTERPRETATION: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. FUNDING: Janssen Research & Development.

Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal.

An innovative lab-based training program to help patient groups understand their disease and the research process.

Genuine partnership between patient groups and medical experts is important but challenging. Our training program meets this challenge by organizing hands-on, lab-based training sessions for members of patient groups. These sessions allow "trainees" to better understand their disease and the biomedical research process, and strengthen links between patients and local researchers. Over the past decade, we and our partner institutes have received more than 900 French patients, with the participation of over 60 researchers and clinicians.

Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.

BACKGROUND: Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. METHODS: In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3.2 and ≤5.1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15-25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. FINDINGS: 604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5-49.1%; p<0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0-44.8%; p<0.0001). INTERPRETATION: Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. FUNDING: Pfizer.

Basal Forebrain Cholinergic Neurons Have Specific Characteristics during the Perinatal Period.

Cholinergic neurons of the basal forebrain represent the main source of cholinergic innervation of large parts of the neocortex and are involved in adults in the modulation of attention, memory, and arousal. During the first postnatal days, they play a crucial role in the development of cortical neurons and cortical cytoarchitecture. However, their characteristics, during this period have not been studied. To understand how they can fulfill this role, we investigated the morphological and electrophysiological maturation of cholinergic neurons of the substantia innominata-nucleus basalis of Meynert (SI/NBM) complex in the perinatal period in mice. We show that cholinergic neurons, whether or not they express gamma-aminobutyric acid (GABA) as a cotransmitter, are already functional at Embryonic Day 18. Until the end of the first postnatal week, they constitute a single population of neurons with a well developed dendritic tree, a spontaneous activity including bursting periods, and a short-latency response to depolarizations (early-firing). They are excited by both their GABAergic and glutamatergic afferents. During the second postnatal week, a second, less excitable, neuronal population emerges, with a longer delay response to depolarizations (late-firing), together with the hyperpolarizing action of GABAA receptor-mediated currents. This classification into early-firing (40%) and late-firing (60%) neurons is again independent of the coexpression of GABAergic markers. These results strongly suggest that during the first postnatal week, the specific properties of developing SI/NBM cholinergic neurons allow them to spontaneously release acetylcholine (ACh), or ACh and GABA, into the developing cortex.

Subthalamic lesion or levodopa treatment rescues giant GABAergic currents of PINK1-deficient striatum.

Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons. We investigated whether similar signatures are present in Pink1(-/-) mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1(-/-) mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan. We show that 75% of the MSNs of 5- to 7-month-old Pink1(-/-) mice exhibit giant GABAergic currents, occurring either singly or in bursts (at 40 Hz), rather than the low-frequency (2 Hz), low-amplitude, tonic GABAergic drive common to wild-type MSNs of the same age. STN neurons from 5- to 7-month-old Pink1(-/-) mice spontaneously generated bursts of spikes instead of the control tonic drive. Chronic kainic acid lesion of the STN or chronic levodopa treatment reliably suppressed the giant GABAergic currents of MSNs after 1 month and replaced them with the control tonic activity. The similarity between the in vitro resting states of Pink1 MSNs and those of fully dopamine (DA)-depleted MSNs of 6-OHDA-treated mice, together with the beneficial effect of levodopa treatment, strongly suggest that dysfunction of mesencephalic dopaminergic neurons in Pink1(-/-) mice is more severe than expected. The beneficial effect of the STN lesion also suggests that pathological STN activity strongly influences striatal networks in Pink1(-/-) mice.

Creative research science experiences for high school students.

A French research institute raises the bar for public outreach with an educational laboratory that engages 1,000 high school students per year in mini research projects.

The early excitatory action of striatal cholinergic-GABAergic microcircuits conditions the subsequent GABA inhibitory shift.

Cholinergic interneurons of the striatum play a role in action selection and associative learning by activating local GABAergic inhibitory microcircuits. We investigated whether cholinergic-GABAergic microcircuits function differently and fulfill a different role during early postnatal development, when GABAA actions are not inhibitory and mice pups do not walk. We focused our study mainly on dual cholinergic/GABAergic interneurons (CGINs). We report that morphological and intrinsic electrophysiological properties of CGINs rapidly develop during the first post-natal week. At this stage, CGINs are excited by the activation of GABAA receptors or GABAergic synaptic inputs, respond to cortical stimulation by a long excitation and are linked by polysynaptic excitations. All these excitations are replaced by inhibitions at P12-P15. Early chronic treatment with the NKCC1 antagonist bumetanide to evoke premature GABAergic inhibitions from P4 to P8, prevented the GABA polarity shift and corticostriatal pause response at control postnatal days. We propose that early excitatory cholinergic-GABAergic microcircuits are instrumental in the maturation of GABAergic inhibition.

Dopamine-deprived striatal GABAergic interneurons burst and generate repetitive gigantic IPSCs in medium spiny neurons.

Striatal GABAergic microcircuits modulate cortical responses and movement execution in part by controlling the activity of medium spiny neurons (MSNs). How this is altered by chronic dopamine depletion, such as in Parkinson's disease, is not presently understood. We now report that, in dopamine-depleted slices of the striatum, MSNs generate giant spontaneous postsynaptic GABAergic currents (single or in bursts at 60 Hz) interspersed with silent episodes, rather than the continuous, low-frequency GABAergic drive (5 Hz) observed in control MSNs. This shift was observed in one-half of the MSN population, including both "D(1)-negative" and "D(1)-positive" MSNs. Single GABA and NMDA channel recordings revealed that the resting membrane potential and reversal potential of GABA were similar in control and dopamine-depleted MSNs, and depolarizing, but not excitatory, actions of GABA were observed. Glutamatergic and cholinergic antagonists did not block the GABAergic oscillations, suggesting that they were generated by GABAergic neurons. In support of this, cell-attached recordings revealed that a subpopulation of intrastriatal GABAergic interneurons generated bursts of spikes in dopamine-deprived conditions. This subpopulation included low-threshold spike interneurons but not fast-spiking interneurons, cholinergic interneurons, or MSNs. Therefore, a population of local GABAergic interneurons shifts from tonic to oscillatory mode when dopamine deprived and gives rise to spontaneous repetitive giant GABAergic currents in one-half the MSNs. We suggest that this may in turn alter integration of cortical signals by MSNs.

Pathological synchronization in Parkinson's disease: networks, models and treatments.

Parkinson's disease is a common and disabling disorder of movement owing to dopaminergic denervation of the striatum. However, it is still unclear how this denervation perverts normal functioning to cause slowing of voluntary movements. Recent work using tissue slice preparations, animal models and in humans with Parkinson's disease has demonstrated abnormally synchronized oscillatory activity at multiple levels of the basal ganglia-cortical loop. This excessive synchronization correlates with motor deficit, and its suppression by dopaminergic therapies, ablative surgery or deep-brain stimulation might provide the basic mechanism whereby diverse therapeutic strategies ameliorate motor impairment in patients with Parkinson's disease. This review is part of the INMED/TINS special issue, Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Latest view on the mechanism of action of deep brain stimulation.

How does deep brain stimulation (DBS) applied at high frequency (100 Hz and above, HFS) in diverse points of cortico-basal ganglia thalamo-cortical loops alleviate symptoms of neurological disorders such as Parkinson's disease, dystonia, and obsessive compulsive disorders? Do the effects of HFS stem solely or even largely from local effects on the stimulated brain structure or are they also mediated by actions of HFS on distal structures? Indeed, HFS as an extracellular stimulation is expected to activate subsets of both afferent and efferent axons, leading to antidromic spikes that collide with ongoing spontaneous ones and orthodromic spikes that evoke synaptic responses in target neurons. The present review suggests that HFS interfere with spontaneous pathological patterns by introducing a regular activity in several nodal points of the network. Therefore, the best site of implantation of the HFS electrode may be in a region where the HFS-driven activity spreads to most of the identified, dysrhythmic, neuronal populations without causing additional side effects. This should help tackling the most difficult issue namely, how does the regular HFS-driven activity that dampens the spontaneous pathological one, restore neuronal processing along cortico-basal ganglia-thalamo-cortical loops?

Striatal dual cholinergic /GABAergic transmission in Parkinson disease: friends or foes?

The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex electrical activity in the targets. Our laboratory now showed that a subpopulation striatal cholinergic neurons also release the classical inhibitory transmitter GABA with a balance between excitation and inhibition being provided by acetylcholine and GABA, respectively. An illustration of the importance of this dual release comes from the fact that when dopamine signals are absent such as in Parkinson disease (PD) the GABAergic inhibition in these dual cholinergic/GABAergic cells fails because of high intracellular chloride ((Cl-)I) levels rendering the cholinergic excitatory component unmet by a parallel inhibitory drive. Restoring low (Cl-)I with the NKCC1 chloride importer antagonist bumetanide attenuates the electrical and motor disturbance. In addition to illustrating the complex interactions between two transmitters acting at the same synapse, this study paves the way to novel conceptual treatment of PD based on restoration of GABAergic inhibition in keeping with our pilot clinical trial showing indeed that bumetanide together with levodopa attenuates axial motor disturbance. It is also in keeping with extensive investigations showing increased (Cl-)I levels and weakened inhibition in a wide range of pathological insults and their restoration by bumetanide. It raises fundamental issues related to the operation of the striatum and basal ganglia in health and disease.

Mouse subthalamic nucleus neurons with local axon collaterals.

The neuronal population of the subthalamic nucleus (STN) has the ability to prolong incoming cortical excitation. This could result from intra-STN feedback excitation. The combination of inducible genetic fate mapping techniques with in vitro targeted patch-clamp recordings, allowed identifying a new type of STN neurons that possess a highly collateralized intrinsic axon. The time window of birth dates was found to be narrow (E10.5-E14.5) with very few STN neurons born at E10.5 or E14.5. The fate mapped E11.5-12.5 STN neuronal population included 20% of neurons with profuse axonal branching inside the nucleus and a dendritic arbor that differed from that of STN neurons without local axon collaterals. They had intrinsic electrophysiological properties and in particular, the ability to generate plateau potentials, similar to that of STN neurons without local axon collaterals and more generally to that of classically described STN neurons. This suggests that a subpopulation of STN neurons forms a local glutamatergic network, which together with plateau potentials, allow amplification of hyperdirect cortical inputs and synchronization of the STN neuronal population.

The Prevalence of Non-radiographic Axial Spondyloarthritis Among Patients with Inflammatory Back Pain from Northwest and South Africa: Data from a Noninterventional, Cross-Sectional Study.

INTRODUCTION: Information is limited on the prevalence and clinical characteristics of nonradiographic axial spondyloarthritis (nr-axSpA) among patients with inflammatory back pain (IBP) in African countries. A global study estimated the prevalence of nr-axSpA among patients with IBP from 19 countries in Latin America, Europe, Asia, and Africa. This post hoc subset analysis focused on estimating prevalence of nr-axSpA and clinical characteristics among patients with IBP from Northwest Africa (Morocco and Algeria) and South Africa. METHODS: Patients from Northwest Africa and South Africa diagnosed with nr-axSpA according to protocol completed patient-reported outcome measures to assess disease activity and functional limitations, including Ankylosing Spondylitis Disease Activity Score (ASDAS). RESULTS: Of the 206 patients with IBP from Africa (n = 168, Northwest Africa and n = 38, South Africa), 33 (16.0%) were diagnosed with nr-axSpA (n = 26, Northwest Africa and n = 7, South Africa), corresponding to prevalence rates of 15.5% and 18.4%, respectively. Disease activity per region, measured as mean ASDAS, was 2.4 ± 1.4 and 2.4 ± 0.9, respectively, based on erythrocyte sedimentation rate and 2.4 ± 1.3 and 2.7 ± 0.7 based on C-reactive protein. CONCLUSIONS: Although the number of patients available for the analysis was low, it appears that the prevalence of nr-axSpA among patients with IBP is similar between Northwest and South Africa, and the disease burden is substantial. Limited access to magnetic resonance imaging may hinder early detection in these areas, thereby affecting the assessment of prevalence. FUNDING: Pfizer.

High-frequency stimulation in Parkinson's disease: more or less?

Deep-brain stimulation at high frequency is now considered the most effective neurosurgical therapy for movement disorders. An electrode is chronically implanted in a particular area of the brain and, when continuously stimulated, it significantly alleviates motor symptoms. In Parkinson's disease, common target nuclei of high-frequency stimulation (HFS) are ventral thalamic nuclei and basal ganglia nuclei, such as the internal segment of the pallidum and the subthalamic nucleus (STN), with a preference for the STN in recent years. Two fundamental mechanisms have been proposed to underlie the beneficial effects of HFS: silencing or excitation of STN neurons. Relying on recent experimental data, we suggest that both are instrumental: HFS switches off a pathological disrupted activity in the STN (a 'less' mechanism) and imposes a new type of discharge in the upper gamma-band frequency that is endowed with beneficial effects (a 'more' mechanism). The intrinsic capacity of basal ganglia and particular STN neurons to generate oscillations and shift rapidly from a physiological to a pathogenic pattern is pivotal in the operation of these circuits in health and disease.

Bumetanide to Treat Parkinson Disease: A Report of 4 Cases.

Relying on recent experimental data in 2 animal models of Parkinson disease (PD), we have tested the effects of the loop diuretic bumetanide as an add-on treatment to dopaminergic drugs in 4 volunteered patients with PD using the Unified Parkinson's Disease Rating Scale. Bumetanide is a specific antagonist of the chloride importer NKCC1 (sodium/potassium/chloride cotransporter isoform 1) that ameliorates neuronal inhibition by reducing intracellular chloride levels in a variety of pathological conditions. Bumetanide is however not labeled for use in PD. We report an improvement of PD motor symptoms in the 4 patients treated with bumetanide (5 mg/d for 2 months). Bumetanide also improved gait and freezing in 2 of these patients. Our results suggest that bumetanide is well tolerated and call for double-blind, placebo-controlled, randomized trials to confirm the therapeutic efficacy of bumetanide.

Abnormal Development of Glutamatergic Synapses Afferent to Dopaminergic Neurons of the Pink1(-/-) Mouse Model of Parkinson's Disease.

In a preceding study, we showed that in adult pink1(-/-) mice, a monogenic animal model of Parkinson's disease (PD), striatal neurons display aberrant electrical activities that precede the onset of overt clinical manifestations. Here, we tested the hypothesis that the maturation of dopaminergic (DA) neurons of the pink1(-/-) substantia nigra compacta (SNc) follows, from early stages on, a different developmental trajectory from age-matched wild type (wt) SNc DA neurons. We used immature (postnatal days P2-P10) and young adult (P30-P90) midbrain slices of pink1(-/-) mice expressing the green fluorescent protein in tyrosine hydroxylase (TH)-positive neurons. We report that the developmental sequence of N-Methyl-D-aspartic acid (NMDA) spontaneous excitatory postsynaptic currents (sEPSCs) is altered in pink1(-/-) SNc DA neurons, starting from shortly after birth. They lack the transient episode of high NMDA receptor-mediated neuronal activity characteristic of the immature stage of wt SNc DA neurons. The maturation of the membrane resistance of pink1(-/-) SNc DA neurons is also altered. Collectively, these observations suggest that electrical manifestations occurring shortly after birth in SNc DA neurons might lead to dysfunction in dopamine release and constitute an early pathogenic mechanism of PD.

The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study.

BACKGROUND: Patients with ankylosing spondylitis (AS), who by definition have radiographic sacroiliitis, typically experience symptoms for a decade or more before being diagnosed. Yet, even patients without radiographic sacroiliitis (i.e., nonradiographic axial spondyloarthritis [nr-axSpA]) report a significant disease burden. The primary objective of this study was to estimate the prevalence and clinical characteristics of nr-axSpA among patients with inflammatory back pain (IBP) in rheumatology clinics in a number of countries across the world. A secondary objective was to estimate the prevalence of IBP among patients with chronic low back pain (CLBP). METHODS: Data were collected from 51 rheumatology outpatient clinics in 19 countries in Latin America, Africa, Europe, and Asia. As consecutive patients with CLBP (N = 2517) were seen by physicians at the sites, their clinical histories were evaluated to determine whether they met the new Assessment of SpondyloArthritis international Society criteria for IBP. For those who did, their available clinical history (e.g., family history, C-reactive protein [CRP] levels) was documented in a case report form to establish whether they met criteria for nr-axSpA, AS, or other IBP. Patients diagnosed with nr-axSpA or AS completed patient-reported outcome measures to assess disease activity and functional limitations. RESULTS: A total of 2517 patients with CLBP were identified across all sites. Of these, 974 (38.70 %) fulfilled the criteria for IBP. Among IBP patients, 29.10 % met criteria for nr-axSpA, and 53.72 % met criteria for AS. The prevalence of nr-axSpA varied significantly by region (p < 0.05), with the highest prevalence reported in Asia (36.46 %) and the lowest reported in Africa (16.02 %). Patients with nr-axSpA reported mean ± SD Ankylosing Spondylitis Disease Activity Scores based on erythrocyte sedimentation rate and CRP of 2.62 ± 1.17 and 2.52 ± 1.21, respectively, indicating high levels of disease activity (patients with AS reported corresponding scores of 2.97 ± 1.13 and 2.93 ± 1.18). Similarly, the overall Bath Ankylosing Spondylitis Disease Activity Index score of 4.03 ± 2.23 for patients with nr-axSpA (4.56 ± 2.17 for patients with AS) suggested suboptimal disease control. CONCLUSIONS: These results suggest that, in the centers that participated in the study, 29 % of patients with IBP met the criteria for nr-axSpA and 39 % of patients with CLBP had IBP. The disease burden in nr-axSpA is substantial and similar to that of AS, with both groups of patients experiencing inadequate disease control. These findings suggest the need for early detection of nr-axSpA and initiation of available treatment options to slow disease progression and improve patient well-being.

Dual effect of high-frequency stimulation on subthalamic neuron activity.

Although it is well known that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) alleviates the cardinal symptoms of Parkinson's disease, the underlying mechanisms are not fully understood. We investigated the effect of stimulation from low to high frequencies on rat STN neurons in naive and dopamine-depleted slices using whole-cell, current-clamp techniques and on-line artifact suppression. Stimulation at 10 Hz evoked 10 Hz single spikes but did not significantly modify ongoing STN activity. In contrast, at therapeutically relevant frequencies (80-185 Hz), stimulation had a dual effect: it fully suppressed STN spontaneous activity and generated a robust pattern of recurrent bursts of spikes, with each spike being time-locked to a stimulus pulse. Neither the suppression of spontaneous activity nor the generation of spikes was prevented by the antagonists of the metabotropic and ionotropic receptors of glutamate and gamma-aminobutyric acid. Tetrodotoxin, the Na+ channel blocker, suppressed all HFS-evoked spikes, whereas nifedipin, an L-type Ca2+-channel blocker, abolished the membrane oscillations underlying bursts. Therefore, we conclude that HFS drives the STN neuronal activity by directly activating the neuronal membrane. We suggest that this pattern may remove the deleterious activity of the basal ganglia network in the parkinsonian state and drive target neurons to a high-frequency state of activity, dependent on the characteristics of STN efferent synapses and resonant properties of target membranes.

Glutamatergic synaptic currents of nigral dopaminergic neurons follow a postnatal developmental sequence.

The spontaneous activity pattern of adult dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) results from interactions between intrinsic membrane conductances and afferent inputs. In adult SNc DA neurons, low-frequency tonic background activity is generated by intrinsic pacemaker mechanisms, whereas burst generation depends on intact synaptic inputs in particular the glutamatergic ones. Tonic DA release in the striatum during pacemaking is required to maintain motor activity, and burst firing evokes phasic DA release, necessary for cue-dependent learning tasks. However, it is still unknown how the firing properties of SNc DA neurons mature during postnatal development before reaching the adult state. We studied the postnatal developmental profile of spontaneous and evoked AMPA and NMDA (N-Methyl-D-aspartic acid) receptor-mediated excitatory postsynaptic currents (EPSCs) in SNc DA neurons in brain slices from immature (postnatal days P4-P10) and young adult (P30-P50) tyrosine hydroxylase (TH)-green fluorescent protein mice. We found that somato-dendritic fields of SNc DA neurons are already mature at P4-P10. In contrast, spontaneous glutamatergic EPSCs show a developmental sequence. Spontaneous NMDA EPSCs in particular are larger and more frequent in immature SNc DA neurons than in young adult ones and have a bursty pattern. They are mediated by GluN2B and GluN2D subunit-containing NMDA receptors. The latter generate long-lasting, DQP 1105-sensitive, spontaneous EPSCs, which are transiently recorded during this early period. Due to high NMDA activity, immature SNc DA neurons generate large and long lasting NMDA receptor-dependent (APV-sensitive) bursts in response to the stimulation of the subthalamic nucleus. We conclude that the transient high NMDA activity allows calcium influx into the dendrites of developing SNc DA neurons.