13 research outputs found
Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis
Peptidyl
arginine deiminases have been shown to be hyperactive
in neurodegenerative diseases including multiple sclerosis. An α-amino
acid-based core structure, derived from a hydantoin core, with unique
heterocycles on the side chains were synthesized as potential noncovalent
inhibitors of PAD enzymes. Among the various heterocycles investigated,
compound <b>23</b>, carrying an imidazole moiety, exhibited
the highest potency in this series with some selectivity for PAD2,
and was further investigated in vivo. Pharmacokinetics in mice suggested
the <i>C</i><sub>max</sub> to be 12.0 ± 2.5 μg/mL
and 170 ± 10 ng/mL in the serum and brain, respectively, when
compound <b>23</b> was administered at 50 mg/kg via single dose
ip. At the same dose, compound <b>23</b> also reversed physical
disability and cleared the brain of T-cell infiltration in an EAE
mouse model of multiple sclerosis (MS). This novel series of compounds
show promise for further development as disease modifying agents for
the potential treatment of MS
Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis
Peptidyl
arginine deiminases have been shown to be hyperactive
in neurodegenerative diseases including multiple sclerosis. An α-amino
acid-based core structure, derived from a hydantoin core, with unique
heterocycles on the side chains were synthesized as potential noncovalent
inhibitors of PAD enzymes. Among the various heterocycles investigated,
compound <b>23</b>, carrying an imidazole moiety, exhibited
the highest potency in this series with some selectivity for PAD2,
and was further investigated in vivo. Pharmacokinetics in mice suggested
the <i>C</i><sub>max</sub> to be 12.0 ± 2.5 μg/mL
and 170 ± 10 ng/mL in the serum and brain, respectively, when
compound <b>23</b> was administered at 50 mg/kg via single dose
ip. At the same dose, compound <b>23</b> also reversed physical
disability and cleared the brain of T-cell infiltration in an EAE
mouse model of multiple sclerosis (MS). This novel series of compounds
show promise for further development as disease modifying agents for
the potential treatment of MS
An investigation on Michaelis - Menten kinetics based complex dynamics of tumor - immune interaction
Fluorescent nanodiamond tracking reveals intraneuronal transport abnormalities induced by brain-disease-related genetic risk factors
Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration ( approximately 30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes
Management of patients with pulmonary mycobacteriosis in France: a multicenter retrospective cohort study
Background: Recent studies report very low adherence of practitioners to ATS/IDSA recommendations for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD), as well as a great variability of practices. Type of management could impact prognosis.Methods: To evaluate management and prognosis of patients with NTM-PD cases with respect to ATS recommendations, we conducted a multicenter retrospective cohort study (18 sentinel sites distributed throughout France), over a period of six years. We collected clinical, radiological, microbiological characteristics, management and outcome of the patients (especially death or not).Results: 477 patients with NTM-PD were included. Respiratory comorbidities were found in 68% of cases, tuberculosis sequelae in 31.4% of patients, and immunosuppression in 16.8% of cases. The three most common NTM species were Mycobacterium avium complex (60%), M. xenopi (20%) and M. kansasii (5.7%). Smear-positive was found in one third of NTM-PD. Nodulobronchiectatic forms were observed in 54.3% of cases, and cavitary forms in 19.1% of patients. Sixty-three percent of patients were treated, 72.4% of patients with smear-positive samples, and 57.5% of patients with smear-negative samples. Treatment was in adequacy with ATS guidelines in 73.5%. The 2-year mortality was 14.4%. In the Cox regression, treatment (HR = 0.51), age (HR = 1.02), and M. abscessus (3.19) appeared as the 3 significant independent prognostic factors.Conclusion: These findings highlight the adequacy between French practices and the ATS/IDSA guidelines. Treatment was associated with a better survival
Fluorescent nanodiamond tracking reveals intraneuronal transport abnormalities induced by brain-disease-related genetic risk factors
International audienceBrain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration (∼30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes