NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension.

BACKGROUND: Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The N-methyl-d-aspartate receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells, but its role in PAH is unknown. METHODS: We assessed the status of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and controls through mass spectrometry imaging, Western blotting, and immunohistochemistry. We measured the glutamate release from cultured pulmonary vascular cells using enzymatic assays and analyzed NMDAR regulation/phosphorylation through Western blot experiments. The effect of NMDAR blockade on human pulmonary arterial smooth muscle cell proliferation was determined using a BrdU incorporation assay. We assessed the role of NMDARs in vascular remodeling associated to pulmonary hypertension, in both smooth muscle-specific NMDAR knockout mice exposed to chronic hypoxia and the monocrotaline rat model of pulmonary hypertension using NMDAR blockers. RESULTS: We report glutamate accumulation, upregulation of the NMDAR, and NMDAR engagement reflected by increases in GluN1-subunit phosphorylation in the pulmonary arteries of human patients with PAH. Kv channel inhibition and type A-selective endothelin receptor activation amplified calcium-dependent glutamate release from human pulmonary arterial smooth muscle cell, and type A-selective endothelin receptor and platelet-derived growth factor receptor activation led to NMDAR engagement, highlighting crosstalk between the glutamate-NMDAR axis and major PAH-associated pathways. The platelet-derived growth factor-BB-induced proliferation of human pulmonary arterial smooth muscle cells involved NMDAR activation and phosphorylated GluN1 subunit localization to cell-cell contacts, consistent with glutamatergic communication between proliferating human pulmonary arterial smooth muscle cells via NMDARs. Smooth-muscle NMDAR deficiency in mice attenuated the vascular remodeling triggered by chronic hypoxia, highlighting the role of vascular NMDARs in pulmonary hypertension. Pharmacological NMDAR blockade in the monocrotaline rat model of pulmonary hypertension had beneficial effects on cardiac and vascular remodeling, decreasing endothelial dysfunction, cell proliferation, and apoptosis resistance while disrupting the glutamate-NMDAR pathway in pulmonary arteries. CONCLUSIONS: These results reveal a dysregulation of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and identify vascular NMDARs as targets for antiremodeling treatments in PAH.

Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Models.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD. METHODS AND RESULTS: We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats. CONCLUSIONS: MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.

Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats.

BACKGROUND: The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. METHODS: Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14-28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. RESULTS: The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 µm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). CONCLUSIONS: Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.

Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease.

RATIONALE: Pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) both display occlusive remodeling of the pulmonary vasculature responsible for increased pulmonary vascular resistances. Cytotoxic T (CTL), natural killer (NK), and natural killer T (NKT) cells play a critical role in vascular remodeling in different physiological and pathological conditions. Granulysin (GNLY) represents a powerful effector protein for all these subpopulations. OBJECTIVES: To analyze the cytolytic compartment of inflammatory cells in patients with PAH and PVOD. METHODS: The overall functional status of the cytolytic compartment was studied through epigenetic analysis of the GNLY gene in explanted lungs and in peripheral blood mononuclear cells. Flow cytometry technology allowed analysis of specific circulating cytolytic cells and GNLY contents. A GNLY-specific ELISA allowed measurement of GNLY serum concentrations. MEASUREMENTS AND MAIN RESULTS: A decrease in GNLY demethylation in the gDNA extracted from peripheral blood mononuclear cells and explanted lungs was found specifically in PVOD but not in PAH. This was associated with a decrease in populations and subpopulations of CTL and NKT and an increase of NK populations. Despite the reduced granulysin-containing cells in patients with PVOD, GNLY serum levels were higher, suggesting these cells were wasting their content. Furthermore, the increase of GNLY concentration in the serum of PVOD was significantly higher than in patients with PAH. CONCLUSIONS: PVOD is characterized by alterations of circulating cytotoxic cell subpopulations and by epigenetic dysregulation within the GNLY gene. Our findings may be helpful in the quest to develop needed diagnostic tools, including flow cytometry analyses, to screen for suspected PVOD in patients with pulmonary hypertension.

Lesion network guided delta frequency neuromodulation improves cognition in patients with psychosis spectrum disorders: A pilot study.

BACKGROUND: Transcranial electric stimulation (tES) may improve cognition in psychosis spectrum disorders. However, few studies have used novel tES approaches, such as high definition tES (HD-tES) to target specific brain circuits. Recently, the extrastriate visual cortex (V5/MT) has been causally linked to visual hallucinations through lesion network mapping and this may be a promising approach for improving cognition. OBJECTIVE: We aim to determine if causal lesion network guided HD-tES to V5/MT improves cognitive performance as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). METHODS: A single-blind pilot study with a within-subjects crossover design was performed to characterize the effect of cathodal HD-transcranial direct current stimulation (tDCS) and 2 Hz HD-transcranial alternating current stimulation (tACS) on cognition. Enrolled patients received 20 mins of HD-tES twice daily for 5 consecutive days applied bilaterally to V5/MT with a washout between conditions. BACS assessments were performed at baseline, day-5, and 1-month. RESULTS: 6 participants with psychosis spectrum disorder were enrolled. 6 individuals received cathodal HD-tDCS. 4 individuals received 2 Hz HD-tACS. HD-tACS resulted in significant (p < 0.1 baseline to 1-month improvements for Digit Sequencing, Verbal Fluency, and Tower of London. HD-tDCS did not result in significant improvement on any task. CONCLUSIONS: HD-tACS targeting V5/MT may be a promising treatment to improve cognitive abilities in individuals with psychosis. By promoting delta oscillations, tACS may enhance cortico-cortico communications across brain networks to improve verbal working memory, processing speed, and executive function. Large-scale investigations are needed to replicate these results.

Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension.

RATIONALE: Patients with idiopathic pulmonary arterial hypertension (IPAH) present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (ectopic) lymphoid tissues (tLTs). OBJECTIVES: To assess the frequency of tLTs in IPAH lungs, as compared with control subjects and flow-induced PAH in patients with Eisenmenger syndrome, and to identify local mechanisms responsible for their formation, perpetuation, and function. METHODS: tLT composition and structure were studied by multiple immunostainings. Cytokine/chemokine and growth factor expression was quantified by real-time polymerase chain reaction and localized by immunofluorescence. The systemic mark of pulmonary lymphoid neogenesis was investigated by flow cytometry analyses of circulating lymphocytes. MEASUREMENTS AND MAIN RESULTS: As opposed to lungs from control subjects and patients with Eisenmenger syndrome, IPAH lungs contained perivascular tLTs, comprising B- and T-cell areas with high endothelial venules and dendritic cells. Lymphocyte survival factors, such as IL-7 and platelet-derived growth factor-A, were expressed in tLTs as well as the lymphorganogenic cytokines/chemokines, lymphotoxin-α/-ß, CCL19, CCL20, CCL21, and CXCL13, which might explain the depletion of circulating CCR6(+) and CXCR5(+) lymphocytes. tLTs were connected with remodeled vessels via an ER-TR7(+) stromal network and supplied by lymphatic channels. The presence of germinal center centroblasts, follicular dendritic cells, activation-induced cytidine deaminase, and IL-21(+)PD1(+) follicular helper T cells in tLTs together with CD138(+) plasma cell accumulation around remodeled vessels in areas of immunoglobulin deposition argued for local immunoglobulin class switching and ongoing production. CONCLUSIONS: We highlight the main features of lymphoid neogenesis specifically in the lungs of patients with IPAH, providing new evidence of immunological mechanisms in this severe condition.

NREM sleep oscillations and their relations with sleep-dependent memory consolidation in early course psychosis and first-degree relatives.

Sleep spindles are believed to mediate sleep-dependent memory consolidation, particularly when coupled to neocortical slow oscillations. Schizophrenia is characterized by a deficit in sleep spindles that correlates with reduced overnight memory consolidation. Here, we examined sleep spindle activity, slow oscillation-spindle coupling, and both motor procedural and verbal declarative memory consolidation in early course, minimally medicated psychosis patients and non-psychotic first-degree relatives. Using a four-night experimental procedure, we observed significant deficits in spindle density and amplitude in patients relative to controls that were driven by individuals with schizophrenia. Schizophrenia patients also showed reduced sleep-dependent consolidation of motor procedural memory, which correlated with spindle density. Contrary to expectations, there were no group differences in the consolidation of declarative memory on a word pairs task. Nor did the relatives of patients differ in spindle activity or memory consolidation compared with controls, however increased consistency in the timing of SO-spindle coupling were seen in both patient and relatives. Our results extend prior work by demonstrating correlated deficits in sleep spindles and sleep-dependent motor procedural memory consolidation in early course, minimally medicated patients with schizophrenia, but not in first-degree relatives. This is consistent with other work in suggesting that impaired sleep-dependent memory consolidation has some specificity for schizophrenia and is a core feature rather than reflecting the effects of medication or chronicity.

A pilot study to investigate the efficacy and tolerability of lesion network guided transcranial electrical stimulation in outpatients with psychosis spectrum illness.

BACKGROUND: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. OBJECTIVE: To determine if lesion network guided High Definition-tES (HD-tES) to the eVC is safe and efficacious in reducing symptoms related to psychosis. METHODS: We conducted a single-blind crossover pilot study (NCT04870710) in patients with psychosis spectrum disorders. Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 2 Hz HD-tACS (alternating current). Participants received 5 days of daily (2×20 min) stimulation bilaterally to the eVC. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS), biological motion task, and Event Related Potentials (ERP) from a steady state visual evoked potential (SSVEP) paradigm. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale, Global Assessment of Functioning (GAF), velocity discrimination and visual working memory task, and emotional ERP. RESULTS: HD-tDCS improved PANSS general psychopathology in the short-term (d=0.47; pfdr=0.03), with long-term improvements in general psychopathology (d=0.62; pfdr=0.05) and GAF (d=-0.56; pfdr=0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; pfdr=0.005), which correlated with general psychopathology (ß = 0.274, t = 3.59, p = 0.04). No significant differences in safety or tolerability measures were identified. CONCLUSION: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis.

Efficacy and Tolerability of Lesion Network Guided Transcranial Electrical Stimulation in Outpatients with Psychosis Spectrum Illness: A Nonrandomized Controlled Trial.

Importance: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. Objective: To determine if lesion network guided HD-tES to the eVC is safe and efficacious in reducing symptoms related to psychosis. Design Setting and Participants: Single-center, nonrandomized, single-blind trial using a crossover design conducted in two 4-week phases beginning November 2020, and ending January 2022. Participants were adults 18-55 years of age with a diagnosis of schizophrenia, schizoaffective or psychotic bipolar disorder as confirmed by the Structured Clinical Interview for DSM-V, without an antipsychotic medication change for at least 4 weeks. A total of 8 participants consented and 6 participants enrolled. Significance threshold set to <0.1 due to small sample size. Interventions: 6 Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 4 received 2Hz HD-tACS (alternating current). Participants received 5 consecutive days of daily (2 × 20min) stimulation applied bilaterally to the eVC. Main Outcomes and Measures: Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, biological motion task, and Event Related Potential (ERP) measures obtained from a steady state visual evoked potential (SSVEP) task across each 4-week phase. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), velocity discrimination task, visual working memory task, and emotional ERP across each 4-week phase. Results: HD-tDCS improved general psychopathology in the short-term (d=0.47; p fdr =0.03), with long-term improvements in general psychopathology (d=0.62; p fdr =0.05) and GAF (d=-0.56; p fdr =0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; p fdr =0.005), which correlated with general psychopathology (ß=0.274, t=3.59, p=0.04). No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04870710. Key Points: Question: Is lesion network guided neurostimulation an efficacious, safe, and targeted approach for treating psychosis?Findings: In this single-center, nonrandomized, crossover, single-blind trial of 6 outpatients with psychosis, improvement in general psychopathology was seen in the short-term with HD-tDCS (high-definition transcranial direct current stimulation) and long-term with HD-tACS (alternating current) targeting the extrastriate visual cortex (eVC). HD-tDCS reduced early visual evoked responses which linked to general psychopathology improvements. Overall, both stimulations were well tolerated.Meaning: Study findings suggest that lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via neuroplastic changes.

An Integrated Neuroimaging Approach to Inform Transcranial Electrical Stimulation Targeting in Visual Hallucinations.

ABSTRACT: For decades, noninvasive brain stimulation (NIBS), such as transcranial electrical stimulation (tES), has been used to directly modulate human brain mechanisms of visual perception, setting the groundwork for the development of novel circuit-based therapies. While the field of NIBS has grown considerably over recent years, few studies have used these technologies to treat visual hallucinations (VH). Here, we review the NIBS-VH literature and find mixed results due to shortcomings that may potentially be addressed with a unique multimodal neuroimaging-NIBS approach. We highlight methodological advances in NIBS research that have provided researchers with more precise anatomical measurements that may improve our ability to influence brain activity. Specifically, we propose a methodology that combines neuroimaging advances, clinical neuroscience developments such as the identification of brain regions causally involved in VH, and personalized NIBS approaches that improve anatomical targeting. This methodology may enable us to reconcile existing discrepancies in tES-VH research and pave the way for more effective, VH-specific protocols for treating a number of neuropsychiatric disorders with VH as a core symptom.

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension.

BACKGROUND: Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. METHODS: We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE). RESULTS: Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68+/vimentin+ cells. CONCLUSION: Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.

Thalamic, Amygdalar, and hippocampal nuclei morphology and their trajectories in first episode psychosis: A preliminary longitudinal study✰.

The thalamus, amygdala, and hippocampus play important pathophysiologic roles in psychosis. Few studies have prospectively examined subcortical nuclei in relation to predicting clinical outcomes after a first-episode of psychosis (FEP). Here, we examined volumetric differences and trajectories among subcortical nuclei in FEP patients and their associations with illness severity. Clinical and brain volume measures were collected using a 1.5T MRI scanner and processed using FreeSurfer 6.0 from a prospective study of antipsychotic-naïve FEP patients of FEP-schizophrenia (FEP-SZ) (baseline, n = 38; follow-up, n = 17), FEP non-schizophrenia (FEP-NSZ) (baseline, n = 23; follow-up, n = 13), and healthy controls (HCs) (baseline, n = 47; follow-up, n = 29). Compared to FEP-NSZ and HCs, FEP-SZ had significantly smaller thalamic anterior nuclei volume at baseline. Longitudinally, FEP-SZ showed a positive rate of change in the amygdala compared to controls or FEP-NSZ, as well as in the basal, central and accessory basal nuclei compared to FEP-NSZ. Enlargement in the thalamic anterior nuclei predicted a worsening in overall psychosis symptoms. Baseline thalamic anterior nuclei alterations further specify key subcortical regions associated with FEP-SZ pathophysiology. Longitudinally, anterior nuclei volume enlargement may signal symptomatic worsening. The amygdala and thalamus structures may show diagnostic differences between schizophrenia and non-schizophrenia psychoses, while the thalamus changes may reflect disease or treatment related changes in clinical outcome.

The effect of alignment on knee osteoarthritis initiation and progression differs based on anterior cruciate ligament status: data from the Osteoarthritis Initiative.

INTRODUCTION/OBJECTIVE: Knee alignment and anterior cruciate ligament (ACL) injury are risk factors for knee osteoarthritis (OA). The objective was to examine interactions between knee alignment and ACL status on cartilage volume loss in participants with or at risk of knee OA. METHOD: Participants were from the Osteoarthritis Initiative, a longitudinal cohort study. Data were from baseline and 24- and 72-month follow-up visits. Participants with knee OA (progression subcohort) or at risk of knee OA (incidence subcohort) that had partial or full ACL tears (OA-ACL group; n=66) or an intact ACL (OA-only group, n=367) were selected. Femur-tibia angles from radiographs quantified knee alignment. Changes in tibial and femoral cartilage volumes were measured using magnetic resonance imaging. Hierarchical linear models examined if knee alignment, presence of ACL, and their interaction were related to cartilage volume loss after accounting for other variables. RESULTS: Interactions between alignment and ACL status were significantly related to cartilage volume loss in the lateral plateau (ß=-20.19, 95% confidence interval [CI]=-34.65 to -5.73) and lateral condyle (ß=-23.64, 95%CI=-43.06 to -4.23). Valgus alignment was related to lateral compartment cartilage loss in the OA-ACL group, but not in the OA-only group. Varus alignment was related to cartilage loss in the medial plateau (ß=7.49, 95%CI=0.17 to 14.80) and medial condyle (ß=19.70, 95%CI=5.96 to 33.44) in both groups. CONCLUSION: The impact of knee alignment on knee OA initiation and progression varies based on ACL status. Initial lateral compartment damage or changes in joint kinematics after ACL rupture might account for these findings.Key Points• The relationship between knee alignment and lateral compartment cartilage loss depended on the status of the anterior cruciate ligament in participants with knee osteoarthritis or at risk for knee osteoarthritis.• Valgus alignment was related to lateral compartment cartilage loss in participants with a deficient anterior cruciate ligament.• Varus alignment was related to medial compartment cartilage loss regardless of the status of the anterior cruciate ligament.

A constrained singular value decomposition method that integrates sparsity and orthogonality.

We propose a new sparsification method for the singular value decomposition-called the constrained singular value decomposition (CSVD)-that can incorporate multiple constraints such as sparsification and orthogonality for the left and right singular vectors. The CSVD can combine different constraints because it implements each constraint as a projection onto a convex set, and because it integrates these constraints as projections onto the intersection of multiple convex sets. We show that, with appropriate sparsification constants, the algorithm is guaranteed to converge to a stable point. We also propose and analyze the convergence of an efficient algorithm for the specific case of the projection onto the balls defined by the norms L1 and L2. We illustrate the CSVD and compare it to the standard singular value decomposition and to a non-orthogonal related sparsification method with: 1) a simulated example, 2) a small set of face images (corresponding to a configuration with a number of variables much larger than the number of observations), and 3) a psychometric application with a large number of observations and a small number of variables. The companion R-package, csvd, that implements the algorithms described in this paper, along with reproducible examples, are available for download from https://github.com/vguillemot/csvd.

Neuropathic pain in leprosy: symptom profile characterization and comparison with neuropathic pain of other etiologies.

INTRODUCTION: Previous studies reported a high prevalence of neuropathic pain in leprosy, being especially present in "pharmacologically cured" patients. The presence of neuropathic pain in leprosy poses a supplementary burden in patient's quality of life, daily activities, and mood. OBJECTIVES: The aim of this study was to assess whether neuropathic pain in leprosy has similar symptom profile as neuropathic pain of other etiologies and to retrospectively assess the efficacy of neuropathic pain medications regularly prescribed to leprosy. METHODS: Leprosy and nonleprosy patients had their neuropathic pain characterized by the neuropathic pain symptom inventory (NPSI, ranges from 0 to 100, with 100 being the maximal neuropathic pain intensity) in a first visit. In a second visit, leprosy patients who had significant pain and received pharmacological treatment in the first evaluation were reassessed (NPSI) and had their pain profile and treatment response further characterized, including information on drugs prescribed for neuropathic pain and their respective pain relief. RESULTS: The pain characteristics based on NPSI did not significantly differ between leprosy and nonleprosy neuropathic pain patients in visit 1 after correction for multiple analyses, and cluster analyses confirmed these findings (ie, no discrimination between leprosy and nonleprosy groups; Pearson χ2 = 0.072, P = 0.788). The assessment of pain relief response and the drugs taken by each patient, linear regression analysis showed that amitriptyline, when effective, had the highest percentage of analgesic relief. CONCLUSIONS: Neuropathic pain in leprosy is as heterogeneous as neuropathic pain of other etiologies, further supporting the concept that neuropathic pain is a transetiological entity. Neuropathic pain in leprosy may respond to drugs usually used to control pain of neuropathic profile in general, and amitriptiline may constitute a potential candidate drug for future formal clinical trials aimed at controlling neuropathic pain in leprosy.

Neuropathic pain in leprosy.

Nerve impairment is a key clinical aspect of leprosy and may present the distribution of mononeuropathy or multiple nerve trunks, small cutaneous nerve fibers, and free nerve endings. The clinical range of leprosy is determined by individual cell-mediated immune response to infection that also may play a role in different types of pain syndromes in leprosy. Previous studies reported a high prevalence of neuropathic pain in leprosy. In an Ethiopian study with 48 patients, pure nociceptive pain was experienced by 43% of patients and pure neuropathic pain (NeP) by 11% of patients. In an Indian study, 21.8% of leprosy patients had pain with neuropathic characteristics. These rates underlie the need to develop tools for the early diagnosis and detection of infection and its complications, such as nerve damage and pain. In a larger sample with leprosy-associated NeP (n = 90), we have applied the Douleur Neuropathique en 4 questions (DN4) and found sensitivity = 97.1% and specificity = 57.9%. The high sensitivity of this tool in leprosy patients suggests that it could be a valuable tool to screen for neuropathic pain in this population and could be used as part of health care programs aimed at detecting, treating, and rehabilitating leprosy in endemic areas.

Mechanisms and clinical management of pain.

Pain is an unpleasant, sensitive and emotional experience associated with or described in terms of tissue lesion, and may be acute or chronic. It may also be classified as nociceptive, neuropathic or psychogenic. Nociceptive pain involves the transformation of environmental stimuli into action potentials carried to the central nervous system, where they are modulated and integrated up to final interpretation in the cerebral cortex. Neuropathic pain may arise as a consequence of the direct lesion of axons, or of an increase in the production of neurotrophic factors. Chronic pain is always associated with anxiety and some degree of depression. Drug therapy should be selected according to its efficacy; nonetheless, the professional should also consider the tolerability and adverse effects that may occur, for example, in elderly individuals. It is necessary to emphasize the safety-considering the possibility of drug interactions-and define the posology to promote better adherence. However, the treatment of neuropathic pain should not be limited to the use of analgesic drugs, which are just one among several options enabling patients to participate in bio-psycho-social rehabilitation programs.

Jornada do paciente com lombalgia crônica no Brasil: uma revisão semi-sistemática sobre a melhor abordagem / Patient journey for those with chronic low back pain in Brazil: a semi-systematic review on the best approach

Histórico -O tratamento de pacientes com lombalgia crônica (LC) em muitos países, incluindo o Brasil, é um grande desafio no nível de atendimento primário e especializado. Além disso, as informações sobre epidemiologia e tratamento de pacientes com LC são escassas. O objetivo principal desta revisão semi-sistemática foi a construção de evidências locais sobre a prevalência e o padrão de tratamento da LC. Métodos: Esta revisão semi-sistemática utilizou Medline, Embase e Biosis via plataforma Ovid e recursos adicionais (Google, Google Scholar, Banco de dados de incidência e prevalência, Organização Mundial da Saúde, Ministério da Saúde do Brasil e informações anedóticas de especialistas locais) para identificar literatura relevante entre 2002 e 2020 para mapear a jornada do paciente. Artigos de texto completos e originais do Brasil em inglês contendo dados sobre pontos de contato predefinidos na jornada do paciente (conscientização, triagem, diagnóstico, tratamento, adesão e controle) foram selecionados. Os dados foram obtidos usando uma média simples ou ponderada, conforme aplicável para os componentes da jornada do paciente. Resultados: De 297 registros, incluindo os fornecidos por especialistas locais, oito estudos foram incluídos para análise. A conscientização da LC e da LC-NeP foi de 30,4% e 12%, respetivamente. De acordo com estudos publicados, a adesão e o controle dos sintomas dos pacientes foram estimados com percentual semelhante de 38% e 18%, respetivamente para a LC e a LC-NeP. A prevalência de LC-NeP (3,6%) foi menor que a de LC (20,6%). Com exceção de uma porcentagem comparável da população tratada, para LC (39,1%) e LC-NeP (38%), a porcentagem de pontos de contato restantes foi maior no caso de LC do que no LC-NeP, o que implicava uma melhora no trajeto do paciente para a LC. Conclusão: O estudo destaca a necessidade de melhorar os resultados dos pacientes em nível nacional, medindo esses pontos de contato da jornada do paciente. O resultado deste estudo baseado em evidências é importante para preencher a lacuna de conhecimento do paciente com LC. Portanto, recomenda-se garantir a educação médica contínua, a conscientização do paciente e a restruturação do sistema de saúde brasileiro, ao mesmo tempo em que adota novas práticas sobre o gerenciamento da dor. [au]

Background: Managing patients with chronic low back pain (CLBP) in many countries, including Brazil, is a major challenge at the primary and specialty care level. Moreover, the information about epidemiology and patient management with CLBP is sparse. The primary objective of this semi-systematic review was to build local evidence about the prevalence and management pattern of CLBP. Methods: This semi-systematic review used Medline, Embase, and Biosis via Ovid the platform and additional resources (Google, Google Scholar, Incidence and Prevalence Database, World Health Organization, Brazilian Ministry of Health, and anecdotal information from local experts) to identify relevant literature between 2002­2020 to map the patient journey. Original full-text articles from Brazil in English containing data on pre-defined patient journey touchpoints (awareness, screening, diagnosis, treatment, adherence, and control) were screened. Data were synthesized using a simple or weighted mean, as applicable for patient journey components. Results. Of 297 records including those provided by local experts, eight studies were included for analysis. Awareness of CLBP and CLBP-NeP was 30.4% and 12%, respectively. According to published studies, adherence and symptoms control of patients was estimated with a similar percentage of 38% and 18%, respectively for CLBP and CLBP-NeP. CLBP-NeP prevalence (3.6%) was lower than that of CLBP (20.6%). Except for a comparable percentage of the treated population, for CLBP (39.1%) and CLBP-NeP (38%), the percentage of remaining touchpoints are higher in the case of CLBP than in CLBP-NeP, implying an improved patient journey for CLBP. Conclusion: The study highlights the usefulness to improve patient outcomes at the national level by measuring these mapping patient journey touchpoints. The outcome of this evidence-based study was fruitful to bridges the know-do gap in CLBP patients. Therefore, it is recommended to ensure continuing medical education, patient awareness, and health system preparedness while embracing the emerging insights on pain management. [au]