Acute ischemic stroke in tuberculous meningitis.

Background: The underlying mechanism for stroke in patients with tuberculous meningitis (TBM) remains unclear. This study aimed to investigate the predictors of acute ischemic stroke (AIS) in TBM and whether AIS mediates the relationship between inflammation markers and functional disability. Methods: TBM patients admitted to five hospitals between January 2011 and December 2021 were consecutively observed. Generalized linear mixed model and subgroup analyses were performed to investigate predictors of AIS in patients with and without vascular risk factors (VAFs). Mediation analyses were performed to explore the potential causal chain in which AIS may mediate the relationship between neuroimaging markers of inflammation and 90-day functional outcomes. Results: A total of 1,353 patients with TBM were included. The percentage rate of AIS within 30 days after admission was 20.4 (95% CI, 18.2-22.6). A multivariate analysis suggested that age ≥35 years (OR = 1.49; 95% CI, 1.06-2.09; P = 0.019), hypertension (OR = 3.56; 95% CI, 2.42-5.24; P < 0.001), diabetes (OR = 1.78; 95% CI, 1.11-2.86; P = 0.016), smoking (OR = 2.88; 95% CI, 1.68-4.95; P < 0.001), definite TBM (OR = 0.19; 95% CI, 0.06-0.42; P < 0.001), disease severity (OR = 2.11; 95% CI, 1.50-2.90; P = 0.056), meningeal enhancement (OR = 1.66; 95% CI, 1.19-2.31; P = 0.002), and hydrocephalus (OR = 2.98; 95% CI, 1.98-4.49; P < 0.001) were associated with AIS. Subgroup analyses indicated that disease severity (P for interaction = 0.003), tuberculoma (P for interaction = 0.008), and meningeal enhancement (P for interaction < 0.001) were significantly different in patients with and without VAFs. Mediation analyses revealed that the proportion of the association between neuroimaging markers of inflammation and functional disability mediated by AIS was 16.98% (95% CI, 7.82-35.12) for meningeal enhancement and 3.39% (95% CI, 1.22-6.91) for hydrocephalus. Conclusion: Neuroimaging markers of inflammation were predictors of AIS in TBM patients. AIS mediates < 20% of the association between inflammation and the functional outcome at 90 days. More attention should be paid to clinical therapies targeting inflammation and hydrocephalus to directly improve functional outcomes.

Abnormal flow pattern of low wall shear stress and high oscillatory shear index in spontaneous vertebral artery dissection with vertebral artery hypoplasia.

Introduction: Spontaneous vertebral artery dissection (sVAD) might tend to develop in vertebral artery hypoplasia (VAH) with hemodynamic dysfunction and it is crucial to assess hemodynamics in sVAD with VAH to investigate this hypothesis. This retrospective study aimed to quantify hemodynamic parameters in patients with sVAD with VAH. Methods: Patients who had suffered ischemic stroke due to an sVAD of VAH were enrolled in this retrospective study. The geometries of 14 patients (28 vessels) were reconstructed using Mimics and Geomagic Studio software from CT angiography (CTA). ANSYS ICEM and ANSYS FLUENT were utilized for mesh generation, set boundary conditions, solve governing equations, and perform numerical simulations. Slices were obtained at the upstream area, dissection or midstream area and downstream area of each VA. The blood flow patterns were visualized through instantaneous streamline and pressure at peak systole and late diastole. The hemodynamic parameters included pressure, velocity, time-averaged blood flow, time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), endothelial cell action potential (ECAP), relative residence time (RRT) and time-averaged nitric oxide production rate (TARNO). Results: Significant focal increased velocity was present in the dissection area of steno-occlusive sVAD with VAH compared to other nondissected areas (0.910 m/s vs. 0.449 vs. 0.566, p < 0.001), while focal slow flow velocity was observed in the dissection area of aneurysmal dilatative sVAD with VAH according to velocity streamlines. Steno-occlusive sVAD with VAH arteries had a lower time-averaged blood flow (0.499 cm3/s vs. 2.268, p < 0.001), lower TAWSS (1.115 Pa vs. 2.437, p = 0.001), higher OSI (0.248 vs. 0.173, p = 0.006), higher ECAP (0.328 Pa-1 vs. 0.094, p = 0.002), higher RRT (3.519 Pa-1 vs. 1.044, p = 0.001) and deceased TARNO (104.014 nM/s vs. 158.195, p < 0.001) than the contralateral VAs. Conclusion: Steno-occlusive sVAD with VAH patients had abnormal blood flow patterns of focal increased velocity, low time-averaged blood flow, low TAWSS, high OSI, high ECAP, high RRT and decreased TARNO. These results provide a good basis for further investigation of sVAD hemodynamics and support the applicability of the CFD method in testing the hemodynamic hypothesis of sVAD. More detailed hemodynamic conditions with different stages of sVAD are warranted in the future.

Roles of IL-11 in the regulation of bone metabolism.

Bone metabolism is the basis for maintaining the normal physiological state of bone, and imbalance of bone metabolism can lead to a series of metabolic bone diseases. As a member of the IL-6 family, IL-11 acts primarily through the classical signaling pathway IL-11/Receptors, IL-11 (IL-11R)/Glycoprotein 130 (gp130). The regulatory role of IL-11 in bone metabolism has been found earlier, but mainly focuses on the effects on osteogenesis and osteoclasis. In recent years, more studies have focused on IL-11's roles and related mechanisms in different bone metabolism activities. IL-11 regulates osteoblasts, osteoclasts, BM stromal cells, adipose tissue-derived mesenchymal stem cells, and chondrocytes. It's involved in bone homeostasis, including osteogenesis, osteolysis, bone marrow (BM) hematopoiesis, BM adipogenesis, and bone metastasis. This review exams IL-11's role in pathology and bone tissue, the cytokines and pathways that regulate IL-11 expression, and the feedback regulations of these pathways.

Pulsed Electromagnetic Fields May Be Effective for the Management of Primary Osteoporosis: A Systematic Review and Meta-Analysis.

Little is known about the effect of pulsed electromagnetic fields (PEMFs) as an option for preventing osteoporosis. This study sought to investigate the effectiveness of PEMFs for the management of primary osteoporosis in older adults. We searched databases from the inception to date to target trials examining the effects of PEMFs compared to placebo or sham or other agents for the management of primary osteoporosis for a meta-analysis using random effects model. Eight trials including 411 participants were included. PEMFs was non-inferior to conventional pharmacological agents and exercise respectively in preventing the decline of Bone Mineral Density (BMD) at the lumbar (MD 8.76; CI -9.64 to 27.16 and MD 1.33; CI -2.73 to 5.39) and femur neck (MD 0.04; CI -1.09 to 1.16 and MD 1.50; CI -0.26 to 3.26), and significantly improving balance function measured by Berg Balance Scale (BBS) (MD 0.91; CI 0.32 to 1.49) and Timed Up and Go test (MD -3.61; CI -6.37 to -0.85), directly after intervention. The similar trends were observed in BMD and BBS at 12- and 24-weeks follow-up from baseline. PEMFs had positive effects non-inferior to first-line treatment on BMD and better over placebo on balance function in older adults with primary osteoporosis, but with moderate to very low certainty evidence and short-term follow-ups. There is a need for high-quality randomised controlled trials evaluating PEMFs for the management of primary osteoporosis.

Targeted tPA overexpression in denervated spinal motor neurons promotes stroke recovery in mice.

Our previous studies demonstrated that axonal remodeling of the corticospinal tract (CST) contributes to neurological recovery after stroke in rodents. The present study employed a novel non-invasive peripheral approach, to over-express tPA in denervated spinal motor neurons via recombinant adeno-associated virus (AAV) intramuscular injection in transgenic mice subjected to permanent middle cerebral artery occlusion (MCAo), in which the CST axons are specifically and completely labeled with yellow fluorescent protein (YFP). One day after surgery, mice were randomly selected to receive saline, AAV5-RFP, or tPA (1 × 1010 viral particles) injected into the stroke-impaired forelimb muscles (n = 10/group). Functional deficits and recovery were monitored with foot-fault and single pellet reaching tests. At day 28 after MCAo, mice received intramuscular injection of PRV-614-mRFP (1.52 × 107 pfu) as above, and were euthanized four days later. Compared with saline or AAV-RFP-treated mice, AAV-tPA significantly enhanced behavioral recovery (p < 0.01, both tests), as well as increased CST axonal density in the denervated gray matter of the cervical cord (p < 0.001), and RFP-positive pyramidal neurons in both ipsilesional and contralesional cortices (p < 0.001). Behavioral outcomes were significantly correlated to neural remodeling (p < 0.05). Our results provide a fundamental basis for the development of therapeutic approaches aimed at promoting corticospinal innervation for stroke treatment.

MiR-17-92 enriched exosomes derived from multipotent mesenchymal stromal cells enhance axon-myelin remodeling and motor electrophysiological recovery after stroke.

MiR-17-92 cluster enriched exosomes derived from multipotent mesenchymal stromal cells (MSCs) increase functional recovery after stroke. Here, we investigate the mechanisms underlying this recovery. At 24 h (h) post transient middle cerebral artery occlusion, rats received control liposomes or exosomes derived from MSCs infected with pre-miR-17-92 expression lentivirus (Exo-miR-17-92+) or control lentivirus (Exo-Con) intravenously. Compared to the liposomes, exosomes significantly reduced the intracortical microstimulation threshold current of the contralateral cortex for evoking impaired forelimb movements (day 21), increased the neurite and myelin density in the ischemic boundary area, and contralesional axonal sprouting into the caudal forelimb area of ipsilateral side and in the denervated spinal cord (day 28), respectively. The Exo-miR-17-92+ further enhanced axon-myelin remodeling and electrophysiological recovery compared with the EXO-Con. Ex vivo cultured rat brain slice data showed that myelin and neuronal fiber density were significantly increased by Exo-miR-17-92+, while significantly inhibited by application of the PI3K/Akt/mTOR pathway inhibitors. Our studies suggest that the miR-17-92 cluster enriched MSC exosomes enhanced neuro-functional recovery of stroke may be attributed to an increase of axonal extension and myelination, and this enhanced axon-myelin remodeling may be mediated in part via the activation of the PI3K/Akt/mTOR pathway induced by the downregulation of PTEN.