Whole-Country and Regional Incidences of Giant Cell Arteritis in French Continental and Overseas Territories: A 7-Year Nationwide Database Analysis.

OBJECTIVE: The incidence rate of giant cell arteritis (GCA) is poorly studied in France. Therefore, we conducted a national hospital database study to assess the overall and regional incidence rates of GCA in France, including overseas territories. METHODS: Through the national hospitalization database of all patients hospitalized in France, new incidental GCA was identified using International Classification of Diseases, 10th Revision medical codes (M31.5 = GCA; M31.6 = GCA and polymyalgia rheumatica [PMR]) during 2013-2019. The regional incidences were analyzed by graphical methods and Poisson regression. RESULTS: A total of 16,540 new GCA with or without PMR diagnoses were identified in all French hospitals over 7 years. The female/male ratio was 1.8. The crude annual incidence rate of GCA with or without PMR was 9.64 (9.50-9.79) per 100,000 persons aged 50 years or older in continental France and 2.91 (2.35-3.47) in overseas areas. The GCA with or without PMR incidence rate regularly increased with age in both sexes but with a later peak in men (85 vs 80 years in women). The crude incidence rate was 11.43 (11.21-11.65) in women and 7.50 (7.31-7.70) in men. An east-western gradient was noted with an increasing standardized incident rate (SIR) from east to west (P < 10-3 ) using a departmental stratification of incident rates. Of note, all SIRs in continental regions were higher than those in overseas areas. CONCLUSION: This French nationwide study provides new and dynamic insights regarding GCA with or without PMR incident rates at the country and regional levels. Important rate differences were observed between continental France and the overseas areas.

Impact of Glucocorticoid Cumulative Doses in a Real-Life Cohort of Patients Affected by Giant Cell Arteritis.

OBJECTIVES: To describe the impact of cumulative glucocorticoid (GC) doses on related adverse events (AEs) in giant cell arteritis (GCA) in a real-life setting. METHODS: The medical charts of the last 139 consecutive GCA patients followed in a tertiary centre were retrospectively analysed. The cumulative GC doses were calculated, and the main GC-related AEs were collected during the follow-up. RESULTS: After a median follow-up duration of 35.6 (2-111) months, the median cumulative GC dose in the 139 patients was 9184 (1770-24,640) mg, and 131 patients (94%) presented at least one GC-related AE. Infections (63%) were the most frequently reported GC-related AE, followed by metabolic events (63%), including weight gain in 51% of them. Cardiovascular and neuropsychiatric events occurred in 51% and 47% of patients, respectively. Osteoporotic fractures, muscular involvement, digestive events, geriatric deterioration, skin fragility, ophthalmologic complications and hypokalaemia were reported in <35% of patients. Cardiovascular events (p = 0.01), osteoporotic fractures (p = 0.004), cataract occurrence (p = 0.03), weight gain (p = 0.04) and infections (p = 0.01) were significantly associated with GC cumulative doses > 9 g. Longer GC durations were associated with cataract occurrence (p = 0.01), weight gain (p = 0.03) and all-grade infections (p = 0.048), especially herpes zoster occurrence (p = 0.003). Neuropsychiatric and metabolic events appeared within the first months after GC introduction, whereas herpes zoster recurred, and most cardiovascular AEs emerged after 1 year. Geriatric events, especially osteoporotic fractures, occurred 2 years after GC introduction. CONCLUSION: This study highlights how frequent GC-related AEs are and the impact of prolonged GC and cumulative doses.

Tolerance of glucocorticoids in giant cell arteritis: a study of patient-reported adverse events.

OBJECTIVE: To assess patients' self-reported glucocorticoid (GC)-related adverse events (AEs) in a GCA population. METHODS: A questionnaire was sent to the 100 patients most recently diagnosed with GCA in a tertiary centre. This questionnaire included open- and close-ended questions on the disease and GC effects. Eight primary AE areas were analysed: cardiovascular, metabolic, muscle, cognitive and psychologic, bone, cutaneous and hairiness, infective and visual complications. Including derivative subitems from preceding areas, a total of 18 GC-related AEs were analysed separately and according to GC duration. RESULTS: Ninety patients were analysed and 89 (99%) reported at least one GC-related AE [median 6 (range 1-11)]. Cognitive and psychological changes, primarily insomnia (72%), affected 90% of patients. Cutaneous changes and muscle loss affected 70% of patients, with frequent impairment of physical autonomy (P = 0.007) associated with this event. Metabolic issues, especially weight gain (40%) and diabetes mellitus (20%), affected 49% of patients. Conversely, vision troubles and bone fractures were mentioned by 42% and 9% of patients, respectively, and more frequently in patients who received GCs for >18 months (P = 0.01 and P = 0.007, respectively). Cardiovascular changes and infections affected 30% and 26% of patients, respectively. CONCLUSION: This real-life study of GC tolerance assessed using a self-evaluation provides pragmatic and updated data reminding us that GC tolerance remains more noteworthy than ever. This study suggests carefully monitoring GC-related AEs during follow-up and encourages GC-sparing strategies in some patients.

Impact of Giant Cell Arteritis and Its Treatment on the Patient's Quality of Life: A Single-Center Self-Assessment Study.

Little is known about the impact of giant cell arteritis (GCA) and its treatment on patient-reported physical, mental, and psychic quality of life (QoL). In this monocentric study, a questionnaire was sent to the 100 last patients diagnosed with GCA and followed-up in a single tertiary center. Their physical, mental and psychic status were self-assessed via close-ended questions, the 12-item short form survey (SF-12) and the 15-item geriatric depression scale (GDS). We aimed to identify parameters that were significantly associated with moderate-to-severe disability in both physical and mental domains. Ninety patients were analyzable. Moderate to severe physical disability was found in 41 (46%) patients. In multivariate analysis, walking difficulties (OR, 95% CI 8.42 [2.98-26.82], p <0.0001), muscle mass and strength reduction (OR, 95% CI 4.38 [1.37-16.31], p = 0.01) and age >80 (OR, 95% CI 4.21 [1.44-13.61], p = 0.008) were independent findings associated with moderate to severe physical disability. Moderate to severe mental disability was found in 30 (33%) patients. In multivariate analysis, depressive mood (OR, 95% CI 11.05 [3.78-37.11], p < 0.0001), felt adverse events attributable to glucocorticoids (OR, 95% CI 10.54 [1.65-213.1], p = 0.01) and use of immune-suppressants (OR, 95% CI 3.50 [1.14-11.87], p = 0.03) were independent findings associated with moderate to severe mental disability. There was a statistically significant negative correlation between GDS and the physical and/or mental disability scores (GDS and PCS-12: r = -0.33, p = 0.0013; GDS and MCS-12: r = -0.36, p = 0.0005). In conclusion, this study identified via a self-assessment of patients with GCA some medical and modifiable findings that significantly affect their physical and mental quality of life. A better knowledge of these factors may help improve the care of GCA patients.

Real-life analysis of the causes of death in patients consecutively followed for giant cell arteritis in a French centre of expertise.

OBJECTIVES: To describe, in a real-life setting, the direct causes of death in a cohort of consecutive patients with GCA. METHODS: We retrospectively analysed the deaths that occurred in a cohort of 470 consecutive GCA patients from a centre of expertise between January 2000 and December 2019. Among the 120 patients who died, we retrieved data from the medical files of 101 patients. RESULTS: Cardiovascular events were the dominant cause of death (n = 41, 41%) followed by infections (n = 22, 22%), geriatric situations (i.e. falls or senile deterioration; n = 17, 17%) and cancers (n = 15, 15%). Patients in each of these four groups were compared with the other deceased patients pooled together. Patients who died from cardiovascular events were more frequently male (46 vs 27%; P = 0.04) with a past history of coronary artery disease (29 vs 8%; P = 0.006). Patients who died from infections mostly had ongoing glucocorticoid treatment (82 vs 53%; P = 0.02) with higher cumulative doses (13 994 vs 9150 mg; P = 0.03). Patients who died from geriatric causes more frequently had osteoporosis (56 vs 17%; P = 0.0009) and had mostly discontinued glucocorticoid treatment (76 vs 33%; P = 0.001). The predictive factors of death in multivariate analysis were a history of coronary disease [hazard ratio (HR) 2.39; 95% CI 1.27, 4.21; P = 0.008], strokes at GCA diagnosis (HR 2.54; 95% CI 1.05, 5.24; P = 0.04), any infection during follow-up (HR 1.93; 95% CI 1.24, 2.98; P = 0.004) and fever at GCA diagnosis (HR 1.99; 95% CI 1.16, 3.28; P = 0.01). CONCLUSION: Our study provides real-life insight on the cause-specific mortality in GCA patients.

Characteristics and outcomes of patients with ophthalmologic involvement in giant-cell arteritis: A case-control study.

PURPOSE: To describe the characteristics and outcome of patients with giant-cell arteritis (GCA)-related ophthalmologic involvement at diagnosis. METHODS: In a retrospective single-center cohort of 409 consecutive patients with GCA, we retrieved 104 patients with visual symptoms at GCA diagnosis and we compared them to 104 age- and sex-matched controls without ophthalmologic involvement. Each visual symptom was associated to an ophthalmologic diagnosis that was centrally re-assessed by an ophthalmologist. RESULTS: Compared to controls, patients with visual symptoms showed less fever (p = 0.0006), less polymyalgia rheumatica (p = 0.02) and lower acute phase reactants (p = 0.004). Blurred vision (in 60% of patients), amaurosis fugax (in 18%), diplopia (in 13%) and permanent visual loss (in 9%) were the four visual symptoms described by patients before GCA diagnosis. Anterior ischemic optic neuropathy (AION) was found in 47 (45%) patients, followed by central retinal artery occlusion (CRAO) in 15 (15%). Two patients had both involvements. The delay of glucocorticoids initiation was not different between patients with and without visual symptoms (p = 0.06). Among the 60 patients with initial AION and/or CRAO, 39 (65%) kept definite blindness or important visual damage, although 45 (75%) had received intravenous (IV) pulses of methylprednisolone. A new ischemic event (AION in all cases) occurred in 4% of patients with visual symptoms despite the initiation of treatment. CONCLUSION: Ophthalmologic involvement was observed in one-quarter of our GCA patients. AION is still associated with the worst visual prognosis, and IV methylprednisolone pulses did not reduce the risk of blindness in our study.

Factors Associated with Relapse and Dependence on Glucocorticoids in Giant Cell Arteritis.

OBJECTIVE: To identify characteristics and factors associated with relapse and glucocorticoid (GC) dependence in patients with giant cell arteritis (GCA). METHODS: We retrospectively analyzed 326 consecutive patients with GCA followed for at least 12 months. Factors associated with relapse and GC dependence were identified in multivariable analyses. RESULTS: The 326 patients (73% women) were followed up for 62 (12-262) months. During followup, 171 (52%) patients relapsed, including 113 (35%) who developed GC dependence. Relapsing patients had less history of stroke (p = 0.01) and presented large-vessel vasculitis (LVV) more frequently on imaging (p = 0.01) than patients without relapse. During the first months, therapeutic strategy did not differ among relapsing and nonrelapsing patients. GC-dependent patients were less likely to have a history of stroke (p = 0.004) and presented LVV on imaging more frequently (p = 0.005) than patients without GC-dependent disease. In multivariable analyses, LVV was an independent predictive factor of relapse (HR 1.49, 95% CI 1.002-2.12; p = 0.04) and GC dependence (OR 2.19, 95% CI 1.19-4.05; p = 0.01). Conversely, stroke was a protective factor against relapse (HR 0.21, 95% CI 0.03-0.68; p = 0.005) and GC-dependent disease (OR 0.10, 95% CI 0.001-0.31; p = 0.0005). Patients with a GC-dependent disease who received a GC-sparing agent had a shorter GC treatment duration than those without (p = 0.008). CONCLUSION: In this study, LVV was an independent predictor of relapse and GC dependence. Further prospective studies are needed to confirm these findings and to determine whether patients with LVV require a different treatment approach.

Different patterns and specific outcomes of large-vessel involvements in giant cell arteritis.

Large-vessel involvement (LVI) in giant cell arteritis (GCA) includes different clinical and imaging patterns that are rarely described separately at diagnosis and whose specific cardiovascular outcomes are unknown. We conducted a nationwide retrospective study and included GCA patients with LVI demonstrated on imaging at diagnosis between 2007 and 2017. We analyzed the prognosis of three different imaging patterns of LVI present at diagnosis, with some of them overlapping but with the first one present in all patients: 1) inflammation of the aorta and/or its branches; 2) dilation of the aorta; and 3) stenosis of the aortic branches. A control group of GCA patients without LVI was constituted. We included 183 patients with LVI and 105 controls without LVI. Altogether, among the 183 patients who all showed inflammation of the aorta and/or its main branches, concomitant aortic dilation and large-vessel stenosis were observed in 27 (15%) and 55 (30%) patients, respectively. During the follow-up period, new cardiovascular events occurred in 49% and 11% of LVI patients and controls, respectively (p < 0.0001). Inflammation of the aorta and/or its branches (HR: 3.42 [2.09-5.83], p < 0.0001) and large-artery stenosis (HR: 2.75 [1.80-4.15], p < 0.0001) were independent predictive factors of new cardiovascular events. Conversely, the use of an immunosuppressant besides corticosteroids was a protective factor against new cardiovascular events (HR: 0.44 [0.29-0.66], p < 0.0001) and the development of aortic dilation (HR: 0.43 [0.23-0.77], p = 0.005). This study suggests different forms of cardiovascular events according to the initial imaging pattern of LVI.

Interest of immunodeficiency screening in adult after admission in medical intensive care unit for severe infection, a retrospective and a prospective study: the Intensive Care Unit and Primary and Secondary Immunodeficiency (ICUSPID) study.

BACKGROUND: Primary immunodeficiency (PID) in adults is rare and mostly revealed by infections. MATERIAL AND METHODS: Adults without predisposing factors who were admitted to an intensive care unit (ICU) for infection were screened for PID. RESULTS: Six PID cases were diagnosed, mostly revealed by encapsulated bacterial infections. CONCLUSION: Investigation of PID after ICU discharge should be considered to improve early detection.

Giant cell arteritis presenting as isolated inflammatory response and/or fever of unknown origin: a case-control study.

The objective of this study was to determine the proportion and characteristics of patients with giant cell arteritis (GCA) who present with isolated inflammatory response and/or fever of unknown origin (IFUO). Using a cohort of 693 consecutive patients in two centers with evidence of GCA on biopsy and/or imaging, we compared the characteristics and outcomes of patients with IFUO at diagnosis to a control group made up of the remaining patients with GCA. Sixty-one (9%) patients initially presented with IFUO. GCA diagnosis was proven by biopsy in 50 (82%) patients and/or imaging in 23 out of 39 (59%) patients who underwent large-vessel imaging. At diagnosis, patients with IFUO were younger (p = 0.008), had longer time to diagnosis (p = 0.001), and showed more intense inflammatory response, i.e., had higher levels of C-reactive protein (p = 0.02) and lower hemoglobin levels (p = 0.0001) than control patients. However, the therapeutic regimen did not differ between the two groups. Similarly, during a median follow-up period of 50 [0-279] months, the total rate of cardiovascular events, including ischemic cranial complications and overall outcomes, including relapse, glucocorticoids-dependence and death rates did not differ between the two groups. Five (16%) patients with initial IFUO exhibited cranial symptoms at relapse. Giant cell arteritis presenting with isolated inflammatory response and/or fever of unknown origin is a well-defined demographic and clinical pattern affecting nearly 10% of patients. This clinical form is not associated with a particular prognosis but remains a challenging diagnosis.

Large-vessel involvement and aortic dilation in giant-cell arteritis. A multicenter study of 549 patients.

OBJECTIVES: Large-vessel involvement (LVI) can occur in giant-cell arteritis (GCA) and may represent a distinct disease subgroup with a higher risk for aortic dilation. This study aimed to better characterize the presentation and evolution of LVI in patients with GCA. PATIENTS AND METHODS: A retrospective multicenter study enrolled 248 GCA patients with LVI and 301 GCA patients without LVI on imaging. Factors associated with aortic dilation were identified in a multivariable model. RESULTS: The patients with LVI were younger (p<0.0001), more likely to be women (p=0.01), and showed fewer cephalic symptoms (p<0.0001) and polymyalgia rheumatica (p=0.001) but more extracranial vascular symptoms (p=0.05) than the patients without LVI. Glucocorticoids (GC) management did not differ between the two groups, but the GC discontinuation rate was lower in the patients with LVI (p=0.0003). Repeated aortic imaging procedures were performed at 19months [range: 5-162months] and 17months [range: 6-168months] after diagnosis in 154 patients with LVI and 123 patients without LVI, respectively, of whom 21% and 7%, respectively, presented new aortic dilations (p=0.0008). In the patients with LVI, aortic dilation occurred on an aorta segment shown to be inflammatory on previous imaging in 94% of patients. In the multivariate analysis, LVI was the strongest predictor of aortic dilation (hazard ratio: 3.16 [range: 1.34-7.48], p=0.009). CONCLUSIONS: LVI represents a distinct disease pattern of GCA with an increased risk of aortic dilation. Control of the aortic morphology during follow-up is required.

Giant-cell arteritis: concordance study between aortic CT angiography and FDG-PET/CT in detection of large-vessel involvement.

PURPOSE: The purpose of our study was to assess the concordance of aortic CT angiography (CTA) and FDG-PET/CT in the detection of large-vessel involvement at diagnosis in patients with giant-cell arteritis (GCA). METHODS: We created a multicenter cohort of patients with GCA diagnosed between 2010 and 2015, and who underwent both FDG-PET/CT and aortic CTA before or in the first ten days following treatment introduction. Eight vascular segments were studied on each procedure. We calculated concordance between both imaging techniques in a per-patient and a per-segment analysis, using Cohen's kappa concordance index. RESULTS: We included 28 patients (21/7 women/men, median age 67 [56-82]). Nineteen patients had large-vessel involvement on PET/CT and 18 of these patients also presented positive findings on CTA. In a per-segment analysis, a median of 5 [1-7] and 3 [1-6] vascular territories were involved on positive PET/CT and CTA, respectively (p = 0.03). In qualitative analysis, i.e., positivity of the procedure suggesting a large-vessel involvement, the concordance rate between both procedures was 0.85 [0.64-1]. In quantitative analysis, i.e., per-segment analysis in both procedures, the global concordance rate was 0.64 [0.54-0.75]. Using FDG-PET/CT as a reference, CTA showed excellent sensitivity (95%) and specificity (100%) in a per-patient analysis. In a per-segment analysis, sensitivity and specificity were 61% and 97.9%, respectively. CONCLUSIONS: CTA and FDG-PET/CT were both able to detect large-vessel involvement in GCA with comparable results in a per-patient analysis. However, PET/CT showed higher performance in a per-segment analysis, especially in the detection of inflammation of the aorta's branches.

Ehlers-Danlos Syndrome, Hypermobility Type: Impact of Somatosensory Orthoses on Postural Control (A Pilot Study).

Elhers-Danlos syndrome (EDS) is the clinical manifestation of connective tissue disorders, and comprises several clinical forms with no specific symptoms and selective medical examinations which result in a delay in diagnosis of about 10 years. The EDS hypermobility type (hEDS) is characterized by generalized joint hypermobility, variable skin hyperextensibility and impaired proprioception. Since somatosensory processing and multisensory integration are crucial for both perception and action, we put forth the hypothesis that somatosensory deficits in hEDS patients may lead, among other clinical symptoms, to misperception of verticality and postural instability. Therefore, the purpose of this study was twofold: (i) to assess the impact of somatosensory deficit on subjective visual vertical (SVV) and postural stability; and (ii) to quantify the effect of wearing somatosensory orthoses (i.e., compressive garments and insoles) on postural stability. Six hEDS patients and six age- and gender-matched controls underwent a SVV (sitting, standing, lying on the right side) evaluation and a postural control evaluation on a force platform (Synapsys), with or without visual information (eyes open (EO)/eyes closed (EC)). These two latter conditions performed either without orthoses, or with compression garments (CG), or insoles, or both. Results showed that patients did not exhibit a substantial perceived tilt of the visual vertical in the direction of the body tilt (Aubert effect) as did the control subjects. Interestingly, such differential effects were only apparent when the rod was initially positioned to the left of the vertical axis (opposite the longitudinal body axis). In addition, patients showed greater postural instability (sway area) than the controls. The removal of vision exacerbated this instability, especially in the mediolateral (ML) direction. The wearing of orthoses improved postural stability, especially in the eyes-closed condition, with a particularly marked effect in the anteroposterior (AP) direction. Hence, this study suggests that hEDS is associated with changes in the relative contributions of somatosensory and vestibular inputs to verticality perception. Moreover, postural control impairment was offset, at least partially, by wearing somatosensory orthoses.

Is it relevant to screen young women hospitalized in psychiatric department for neuropsychiatric systemic lupus erythematosus (NPSLE)?: A prospective study of 100 psychiatric inpatients.

On the basis that diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is sometimes difficult and systemic lupus erythematosus (SLE) can present with isolated psychiatric symptoms, we initiated a survey in a psychiatric department to screen for NPSLE in young female inpatients.We prospectively studied consecutive young female patients referred to the department of psychiatry. Antinuclear antibodies (ANA), anti-deoxyribonucleic acid (DNA), and antiextractable soluble nuclear antigens (ENA) in the serum of patients were screened. In case of positive anti-DNA or anti-ENA, the patient was referred to the department of internal medicine.One hundred patients were enrolled, mean age 33.1 ±â€Š8.4 years. Most patients presented underlying psychiatric disorders: depression (46%), schizophrenia (13%), anxiety disorder (6%), and personality disorder (10%). A quarter of the cohort did not display underlying psychiatric disorders before hospitalization. Positive ANA ≥1:160 were found in 32 of the 100 patients tested (32%). No patients presented anti-DNA antibodies. One patient had positive anti-sjogrën's syndrome related antigen A (SSA), but did not present any features of SLE or Sjögren syndrome.Thus, systematic screening of SLE is not relevant in young women hospitalized in psychiatric department. However, clinicians should keep in mind that SLE can present with pure psychiatric symptoms.

Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin.

Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer's disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons.

Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide.

OBJECTIVE: To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). METHODS: We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR) was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. RESULTS: Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. CONCLUSION: This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

Prefibrillar Tau oligomers alter the nucleic acid protective function of Tau in hippocampal neurons in vivo.

The accumulation of DNA and RNA oxidative damage is observed in cortical and hippocampal neurons from Alzheimer's disease (AD) brains at early stages of pathology. We recently reported that Tau is a key nuclear player in the protection of neuronal nucleic acid integrity in vivo under physiological conditions and hyperthermia, a strong inducer of oxidative stress. In a mouse model of tauopathy (THY-Tau22), we demonstrate that hyperthermia selectively induces nucleic acid oxidative damage and nucleic acid strand breaks in the nucleus and cytoplasm of hippocampal neurons that display early Tau phosphorylation but no Tau fibrils. Nucleic acid-damaged neurons were exclusively immunoreactive for prefibrillar Tau oligomers. A similar association between prefibrillar Tau oligomers and nucleic acid oxidative damage was observed in AD brains. Pretreatment with Methylene Blue (MB), a Tau aggregation inhibitor and a redox cycler, reduced hyperthermia-induced Tau oligomerization as well as nucleic acid damage. This study clearly highlights the existence of an early and critical time frame for hyperthermia-induced Tau oligomerization, which most likely occurs through increased oxidative stress, and nucleic acid vulnerability during the progression of Tau pathology. These results suggest that at early stages of AD, Tau oligomerization triggers the loss of the nucleic acid protective function of monomeric Tau. This study highlights the existence of a short therapeutic window in which to prevent the formation of pathological forms of Tau and their harmful consequences on nucleic acid integrity during the progression of Tau pathology.

A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions.

Nucleic acid protection is a substantial challenge for neurons, which are continuously exposed to oxidative stress in the brain. Neurons require powerful mechanisms to protect DNA and RNA integrity and ensure their functionality and longevity. Beside its well known role in microtubule dynamics, we recently discovered that Tau is also a key nuclear player in the protection of neuronal genomic DNA integrity under reactive oxygen species (ROS)-inducing heat stress (HS) conditions in primary neuronal cultures. In this report, we analyzed the capacity of Tau to protect neuronal DNA integrity in vivo in adult mice under physiological and HS conditions. We designed an in vivo mouse model of hyperthermia/HS to induce a transient increase in ROS production in the brain. Comet and Terminal deoxyribonucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assays demonstrated that Tau protected genomic DNA in adult cortical and hippocampal neurons in vivo under physiological conditions in wild-type (WT) and Tau-deficient (KO-Tau) mice. HS increased DNA breaks in KO-Tau neurons. Notably, KO-Tau hippocampal neurons in the CA1 subfield restored DNA integrity after HS more weakly than the dentate gyrus (DG) neurons. The formation of phosphorylated histone H2AX foci, a double-strand break marker, was observed in KO-Tau neurons only after HS, indicating that Tau deletion did not trigger similar DNA damage under physiological or HS conditions. Moreover, genomic DNA and cytoplasmic and nuclear RNA integrity were altered under HS in hippocampal neurons exhibiting Tau deficiency, which suggests that Tau also modulates RNA metabolism. Our results suggest that Tau alterations lead to a loss of its nucleic acid safeguarding functions and participate in the accumulation of DNA and RNA oxidative damage observed in the Alzheimer's disease (AD) brain.

Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology.

Tau pathology is encountered in many neurodegenerative disorders known as tauopathies, including Alzheimer's disease. Physical activity is a lifestyle factor affecting processes crucial for memory and synaptic plasticity. Whether long-term voluntary exercise has an impact on Tau pathology and its pathophysiological consequences is currently unknown. To address this question, we investigated the effects of long-term voluntary exercise in the THY-Tau22 transgenic model of Alzheimer's disease-like Tau pathology, characterized by the progressive development of Tau pathology, cholinergic alterations and subsequent memory impairments. Three-month-old THY-Tau22 mice and wild-type littermates were assigned to standard housing or housing supplemented with a running wheel. After 9 months of exercise, mice were evaluated for memory performance and examined for hippocampal Tau pathology, cholinergic defects, inflammation and genes related to cholesterol metabolism. Exercise prevented memory alterations in THY-Tau22 mice. This was accompanied by a decrease in hippocampal Tau pathology and a prevention of the loss of expression of choline acetyltransferase within the medial septum. Whereas the expression of most cholesterol-related genes remained unchanged in the hippocampus of running THY-Tau22 mice, we observed a significant upregulation in mRNA levels of NPC1 and NPC2, genes involved in cholesterol trafficking from the lysosomes. Our data support the view that long-term voluntary physical exercise is an effective strategy capable of mitigating Tau pathology and its pathophysiological consequences.

Nuclear tau, a key player in neuronal DNA protection.

Tau, a neuronal protein involved in neurodegenerative disorders such as Alzheimer disease, which is primarily described as a microtubule-associated protein, has also been observed in the nuclei of neuronal and non-neuronal cells. However, the function of the nuclear form of Tau in neurons has not yet been elucidated. In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wild-type and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. These results highlight a novel role for nuclear Tau as a key player in early stress response.