The most common inherited form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motoneurons, is caused by dominant mutations in the ubiquitously expressed Cu 2؉ ͞Zn 2؉ superoxide dismutase (SOD1). Recent studies suggest that glia may contribute to motoneuron injury in animal models of familial ALS. To determine whether the expression of mutant SOD1 (mSOD1 G93A ) in CNS microglia contributes to motoneuron injury, PU.1 ؊/؊ mice that are unable to develop myeloid and lymphoid cells received bone marrow transplants resulting in donor-derived microglia. Donor-derived microglia from mice overexpressing mSOD1 G93A , an animal model of familial ALS, transplanted into PU.1 ؊/؊ mice could not induce weakness, motoneuron injury, or an ALS-like disease. To determine whether expression of mSOD1 G93A in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1 ؊/؊ mice were bred with mSOD1 G93A mice. In mSOD1 G93A ͞PU.1 ؊/؊ mice, wild-type donorderived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1 G93A expressing cells or mSOD1 G93A mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1 G93A microglia. Compared with wild-type microglia, mSOD1 G93A microglia produced and released more superoxide and nitrite؉nitrate, and induced more neuronal death. These data demonstrate that the expression of mSOD1 G93A results in activated and neurotoxic microglia, and suggests that the lack of mSOD1 G93A expression in microglia may contribute to motoneuron protection. This study confirms the importance of microglia as a double-edged sword, and focuses on the importance of targeting microglia to minimize cytotoxicity and maximize neuroprotection in neurodegenerative diseases.bone marrow transplant ͉ neuroprotection ͉ superoxide dismutase ͉ nitric oxide ͉ motoneurons
Recent studies suggest that motor neuron (MN) death may be non-cell autonomous, with cell injury mediated by interactions involving non-neuronal cells, such as microglia and astrocytes. To help define these interactions, we used primary MN cultures to investigate the effects of microglia activated by lipopolysaccharide or IgG immune complexes from patients with amyotrophic lateral sclerosis. Following activation, microglia induced MN injury, which was prevented by a microglial iNOS inhibitor as well as by catalase or glutathione. Glutamate was also required since inhibition of the MN AMPA/kainate receptor by CNQX prevented the toxic effects of activated microglia. Peroxynitrite and glutamate were synergistic in producing MN injury. Their toxic effects were also blocked by CNQX and prevented by calcium removal from the media. The addition of astrocytes to cocultures of MN and activated microglia prevented MN injury by removing glutamate from the media. The protective effects could be reversed by inhibiting astrocytic glutamate transport with dihydrokainic acid or pretreating astrocytes with H2O2. Astrocytic glutamate uptake was also decreased by activated microglia or by added peroxynitrite. These data suggest that free radicals released from activated microglia may initiate MN injury by increasing the susceptibility of the MN AMPA/kainate receptor to the toxic effects of glutamate.
In a large cohort of 1034 patients with the diagnosis of definite or probable amyotrophic lateral sclerosis (ALS), the association of forced vital capacity (FVC) at baseline with (a) time to progression of 20 points in Appel ALS (AALS) score or (b) tracheostomy free survival was investigated. The median survival of ALS patients with baseline FVC<75% was 2.91 years, compared with 4.08 years for patients with baseline FVC >75% (p<0.001). Patients with baseline FVC <75% progressed more rapidly (taking 8.0 months to progress 20 AALS points) compared with patients with baseline FVC >75% (10.0 months, p<0.001). Moreover, FVC at first examination was identified as a significant predictor of survival and disease progression in both univariate and multivariate Cox regression models, after adjustment for age, sex, site of onset, diagnostic delay, riluzole therapy, and use of bilateral positive airway pressure and percutaneous endoscopic gastrostomy (p<0.001). We conclude that a single FVC value obtained at an initial visit may serve as a clinically meaningful predictor of survival and disease progression in ALS.
Background Studies have demonstrated that the current US guidelines based on American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations Risk Calculator may underestimate risk of atherosclerotic cardiovascular disease ( CVD ) in certain high‐risk individuals, therefore missing opportunities for intensive therapy and preventing CVD events. Similarly, the guidelines may overestimate risk in low risk populations resulting in unnecessary statin therapy. We used Machine Learning ( ML ) to tackle this problem. Methods and Results We developed a ML Risk Calculator based on Support Vector Machines ( SVM s) using a 13‐year follow up data set from MESA (the Multi‐Ethnic Study of Atherosclerosis) of 6459 participants who were atherosclerotic CVD‐free at baseline. We provided identical input to both risk calculators and compared their performance. We then used the FLEMENGHO study (the Flemish Study of Environment, Genes and Health Outcomes) to validate the model in an external cohort. ACC / AHA Risk Calculator, based on 7.5% 10‐year risk threshold, recommended statin to 46.0%. Despite this high proportion, 23.8% of the 480 “Hard CVD ” events occurred in those not recommended statin, resulting in sensitivity 0.76, specificity 0.56, and AUC 0.71. In contrast, ML Risk Calculator recommended only 11.4% to take statin, and only 14.4% of “Hard CVD ” events occurred in those not recommended statin, resulting in sensitivity 0.86, specificity 0.95, and AUC 0.92. Similar results were found for prediction of “All CVD ” events. Conclusions The ML Risk Calculator outperformed the ACC/AHA Risk Calculator by recommending less drug therapy, yet missing fewer events. Additional studies are underway to validate the ML model in other cohorts and to explore its ability in short‐term CVD risk prediction.
Recent studies suggest that microglia over-expressing mutant human superoxide dismutase (mSOD1(G93A)) may contribute to motoneuron death in a transgenic mouse model of familial amyotrophic lateral sclerosis. To further assess the relative neurotoxicity of wild-type microglia, mSOD1(G93A) microglia, and microglia over-expressing wild-type human SOD1, we used primary cultures of microglia and motoneurons in the presence and absence of lipopolysaccharide stimulation. Following activation with lipopolysaccharide, mSOD1(G93A) microglia released more nitric oxide, more superoxide, and less insulin-like growth factor-1 than wild-type microglia. In microglia/motoneuron co-cultures, mSOD1(G93A) microglia induced more motoneuron death and decreased neurite numbers and length compared with wild-type microglia. Mutant SOD1(G93A) microglia also induced more motoneuron injury than microglia over-expressing wild-type human SOD1 in microglia/motoneuron co-cultures. Motoneuron survival was inversely correlated with nitrate + nitrite concentrations in mSOD1(G93A) co-cultures, suggesting the important role of nitric oxide in microglia-induced motoneuron injury. Thus, relative to wild-type microglia, mSOD1(G93A) microglia were more neurotoxic and induced more motoneuron injury than similarly treated wild-type microglia.
The identification of younger age, limb site of onset and longer diagnostic delay as predictors of prolonged survival in ALS clinic population supports the findings of several, earlier studies that were based on smaller groups of patients. More significantly, several additional variables assessed at the first examination predict longer survival: lower baseline AALSS, lower AALSS- preslope and higher baseline FVC. All of these parameters are of value in patient management and in clinical trial development.
Root canal therapy (RCT) represents a standard of treatment that addresses infected pulp tissue in teeth and protects against future infection. RCT involves removing dental pulp comprising blood vessels and nerve tissue, decontaminating residually infected tissue through biomechanical instrumentation, and root canal obturation using a filler material to replace the space that was previously composed of dental pulp. Gutta percha (GP) is typically used as the filler material, as it is malleable, inert, and biocompatible. While filling the root canal space with GP is the standard of care for endodontic therapies, it has exhibited limitations including leakage, root canal reinfection, and poor mechanical properties. To address these challenges, clinicians have explored the use of alternative root filling materials other than GP. Among the classes of materials that are being explored as novel endodontic therapy platforms, nanodiamonds (NDs) may offer unique advantages due to their favorable properties, particularly for dental applications. These include versatile faceted surface chemistry, biocompatibility, and their role in improving mechanical properties, among others. This study developed a ND-embedded GP (NDGP) that was functionalized with amoxicillin, a broad-spectrum antibiotic commonly used for endodontic infection. Comprehensive materials characterization confirmed improved mechanical properties of NDGP over unmodified GP. In addition, digital radiography and microcomputed tomography imaging demonstrated that obturation of root canals with NDGP could be achieved using clinically relevant techniques. Furthermore, bacterial growth inhibition assays confirmed drug functionality of NDGP functionalized with amoxicillin. This study demonstrates a promising path toward NDGP implementation in future endodontic therapy for improved treatment outcomes.
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