Stroke among highly active antiretroviral therapy-naive people living with the human immunodeficiency virus in China: a retrospective study of the characteristics, risk factors, and prognosis

Background We aimed to clarify the characteristics, risk factors, and prognosis of stroke among HAART-naive people living with HIV (PLWH) in China. Methods We selected HAART-naive PLWH admitted to Beijing Ditan Hospital, Capital Medical University, from 1 January 2009 to 31 December 2019. Demographic and clinical data were obtained by searching an anonymous electronic case system. Descriptive analysis and logistic regression and Cox proportional hazard models were used to determine the characteristics and predictors of stroke among all HAART-naive PLWH and evaluate the risk factors of mortality in HAART-naive PLWH with stroke. Results Stroke was diagnosed in 105 cases (3.7%) of 2867 HAART-naive PLWH. Multivariate logistic regression indicated that age of 30–55 years (OR 1.903, 95% CI 1.005–3.603, p = 0.048), age of ≥ 55 years (OR 4.104, 95% CI 1.928–8.737, p < 0.001), and CD4 count of < 200 cells/µL (OR 2.005, 95% CI 1.008–3.985, p = 0.047) were associated with increased odds of stroke. Diabetes (OR 3.268, 95% CI 1.744–6.125, p < 0.001), hypertension (OR 2.301, 95% CI 1.425–3.717, p = 0.001), syphilis (OR 2.003, 95% CI 1.300–3.089, p = 0.002), and complicated AIDS-defining CNS diseases (OR 7.719, 95% CI 4.348–13.703, p < 0.001) were risk factors for stroke. Of the 105 stroke patients, 12 (11.4%) died during hospitalisation, and the risk factors for mortality among patients with stroke were age of > 65 years (AHR: 8.783, 95% CI 1.522–50.668, p = 0.015), complicated severe pneumonia (AHR: 3.940, 95% CI 1.106–14.029, p = 0.034), and AIDS-defining CNS diseases (AHR: 19.766, 95% CI 3.586–108.961, p = 0.001). Conclusions For HAART-naive people living with HIV (PLWH), stroke occurred in various age groups, and early screening for stroke, timely intervention for risk factors among patients in various age groups, and controlling the CD4 count are extremely important in reducing the burden of stroke.

Pharmacological Investigations in Glia Culture Model of Inflammation

Astrocytes and microglia are the main cell population besides neurons in the central nervous system (CNS). Astrocytes support the neuronal network via maintenance of transmitter and ion homeostasis. They are part of the tripartite synapse, composed of pre- and postsynaptic neurons and perisynaptic astrocytic processes as a functional unit. There is an increasing evidence that astroglia are involved in the pathophysiology of CNS disorders such as epilepsy, autoimmune CNS diseases or neuropsychiatric disorders, especially with regard to glia-mediated inflammation. In addition to astrocytes, investigations on microglial cells, the main immune cells of the CNS, offer a whole network approach leading to better understanding of non-neuronal cells and their pathological role in CNS diseases and treatment. An in vitro astrocyte-microglia co-culture model of inflammation was developed by Faustmann et al. (2003), which allows to study the endogenous inflammatory reaction and the cytokine expression under drugs in a differentiated manner. Commonly used antiepileptic drugs (e.g., levetiracetam, valproic acid, carbamazepine, phenytoin, and gabapentin), immunomodulatory drugs (e.g., dexamethasone and interferon-beta), hormones and psychotropic drugs (e.g., venlafaxine) were already investigated, contributing to better understanding mechanisms of actions of CNS drugs and their pro- or anti-inflammatory properties concerning glial cells. Furthermore, the effects of drugs on glial cell viability, proliferation and astrocytic network were demonstrated. The in vitro astrocyte-microglia co-culture model of inflammation proved to be suitable as unique in vitro model for pharmacological investigations on astrocytes and microglia with future potential (e.g., cancer drugs, antidementia drugs, and toxicologic studies).

Trojan bacteria cross blood-brain barrier for glioblastoma photothermal immunotherapy

Bacteria can bypass the blood-brain barrier (BBB) transcellularly, paracellularly and/or in infected phagocytes, suggesting the possibility of employment of bacteria for combating central nervous system (CNS) diseases. However, the bacteria-based drug delivery vehicle crossing the BBB is still vacant up to present. Herein, we develop an innovative bacteria-based drug delivery system (dubbed Trojan bacteria) for glioblastoma (GBM) photothermal immunotherapy. Typically, Trojan bacteria are made of therapeutics internalized into bacteria (e.g., attenuated Salmonella typhimurium, Escherichia coli). The therapeutics are composed of glucose polymer (GP) (e.g., poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose])-conjugated and indocyanine green (ICG)-loaded silicon nanoparticles (GP-ICG-SiNPs). The GP-ICG-SiNPs can be selectively and robustly internalized into the bacterial intracellular volume through the bacteria-specific ATP-binding cassette (ABC) transporter. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected Trojan bacteria could take therapeutics together not only to bypass the BBB, but also to target and penetrate GBM tissues. Under 808 nm-laser irradiation, the photothermal effects (PTT) produced by ICG allow the destruction of Trojan bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens would promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual Trojan bacteria could be effectively eliminated from the body due to the distinct photothermal effects. We anticipate the proposed Trojan bacteria system would catalyze innovative therapies for various CNS diseases.

Efferocytosis in the Central Nervous System

The effective clearance of apoptotic cells is essential for maintaining central nervous system (CNS) homeostasis and restoring homeostasis after injury. In most cases of physiological apoptotic cell death, efferocytosis prevents inflammation and other pathological conditions. When apoptotic cells are not effectively cleared, destruction of the integrity of the apoptotic cell membrane integrity, leakage of intracellular contents, and secondary necrosis may occur. Efferocytosis is the mechanism by which efferocytes quickly remove apoptotic cells from tissues before they undergo secondary necrosis. Cells with efferocytosis functions, mainly microglia, help to eliminate apoptotic cells from the CNS. Here, we discuss the impacts of efferocytosis on homeostasis, the mechanism of efferocytosis, the associations of efferocytosis failure and CNS diseases, and the current clinical applications of efferocytosis. We also identify efferocytosis as a novel potential target for exploring the causes and treatments of CNS diseases.

Regulation of common neurological disorders by gut microbial metabolites

The gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.

Modulating the Blood–Brain Barrier: A Comprehensive Review

The highly secure blood–brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades—their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators.

Prevalence of oropharyngeal dysphagia in geriatric patients and real-life associations with diseases and drugs

Risk factors for oropharyngeal dysphagia (OD) in elderly patients are mainly central nervous system (CNS) and structural organic diseases or presbyphagia. We analysed the OD prevalence and association of OD with multimorbidity and polypharmacy using real-life data to complete this spectrum, with a focus on further and iatrogenic risk. This was a cross-sectional retrospective study based on a random sample of 200 patients admitted to a geriatric hospital. Data analysis included diagnoses, the detailed list of drugs, and an intense clinical investigation of swallowing according to Stanschus to screen for OD in each patient. The mean patient age was 84 ± 6.5 years. The prevalence of OD was 29.0%, without an effect of age, but a higher rate was found in men and in nursing home residents and an elevated risk of pneumonia. OD risk was slight in diabetes mellitus and COPD, and pronounced in CNS diseases. A relevant OD association was found, even after adjusting for CNS diseases, with antipsychotics, benzodiazepines, anti-Parkinson drugs, antidepressants, and antiepileptics. Further risk of OD was found with beta-blockers, alpha-blockers, opioids, antiemetics, antivertiginosa or antihistamines, metoclopramide, domperidone, anticholinergics, loop diuretics, urologics, and ophthalmics. From real-life data in patients with and without CNS diseases, we identified drug groups associated with a risk of aggravating/inducing OD. Restrictive indications for these drugs may be a preventative contribution, requiring implementation in dysphagia guidelines and an integrative dysphagia risk scale that considers all associated and cumulative medication risks in addition to diseases.

PPARα Modulation-Based Therapy in Central Nervous System Diseases

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

Fundamentally different roles of neuronal TNF receptors in CNS pathology: TNFR1 and IKKβ promote microglial responses and tissue injury in demyelination while TNFR2 protects against excitotoxicity in mice

Background During inflammatory demyelination, TNF receptor 1 (TNFR1) mediates detrimental proinflammatory effects of soluble TNF (solTNF), whereas TNFR2 mediates beneficial effects of transmembrane TNF (tmTNF) through oligodendroglia, microglia, and possibly other cell types. This model supports the use of selective inhibitors of solTNF/TNFR1 as anti-inflammatory drugs for central nervous system (CNS) diseases. A potential obstacle is the neuroprotective effect of solTNF pretreatment described in cultured neurons, but the relevance in vivo is unknown. Methods To address this question, we generated mice with neuron-specific depletion of TNFR1, TNFR2, or inhibitor of NF-κB kinase subunit β (IKKβ), a main downstream mediator of TNFR signaling, and applied experimental models of inflammatory demyelination and acute and preconditioning glutamate excitotoxicity. We also investigated the molecular and cellular requirements of solTNF neuroprotection by generating astrocyte-neuron co-cultures with different combinations of wild-type (WT) and TNF and TNFR knockout cells and measuring N-methyl-d-aspartate (NMDA) excitotoxicity in vitro. Results Neither neuronal TNFR1 nor TNFR2 protected mice during inflammatory demyelination. In fact, both neuronal TNFR1 and neuronal IKKβ promoted microglial responses and tissue injury, and TNFR1 was further required for oligodendrocyte loss and axonal damage in cuprizone-induced demyelination. In contrast, neuronal TNFR2 increased preconditioning protection in a kainic acid (KA) excitotoxicity model in mice and limited hippocampal neuron death. The protective effects of neuronal TNFR2 observed in vivo were further investigated in vitro. As previously described, pretreatment of astrocyte-neuron co-cultures with solTNF (and therefore TNFR1) protected them against NMDA excitotoxicity. However, protection was dependent on astrocyte, not neuronal TNFR1, on astrocyte tmTNF-neuronal TNFR2 interactions, and was reproduced by a TNFR2 agonist. Conclusions These results demonstrate that neuronal TNF receptors perform fundamentally different roles in CNS pathology in vivo, with neuronal TNFR1 and IKKβ promoting microglial inflammation and neurotoxicity in demyelination, and neuronal TNFR2 mediating neuroprotection in excitotoxicity. They also reveal that previously described neuroprotective effects of solTNF against glutamate excitotoxicity in vitro are indirect and mediated via astrocyte tmTNF-neuron TNFR2 interactions. These results consolidate the concept that selective inhibition of solTNF/TNFR1 with maintenance of TNFR2 function would have combined anti-inflammatory and neuroprotective properties required for safe treatment of CNS diseases.