Regional Disparities in Hyperacute Treatment and Functional Outcomes after Acute Ischemic Stroke in Japan.

AIM: This study investigated the impact of rurality on acute ischemic stroke (AIS) outcomes, emphasizing the hyperacute phase, in which immediate care is crucial. METHODS: This retrospective cohort study analyzed data from a large Japanese hospital network covering AIS patients from 2013-2021, was analyzed. The focus was on patients admitted within 4.5 h of the onset, using the Rurality Index for Japan (RIJ) to categorize patients into rural or urban groups. This study examined treatment methods (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]) and functional outcomes measured using the modified Rankin Scale (mRS), where scores of 3-6 indicated poor outcomes. Multilevel logistic regression was used to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for poor outcomes baSed on rurality. The study also evaluated the population-attributable fraction (PAF) to estimate potential outcome improvements in urban settings. RESULTS: Of 27,691 patients, 17,516 were included in the total cohort and 4,954 in the hyperacute cohort. Urban patients constituted 73.7% (12,902), with higher IVT (5.2%) and MT (3.6%) rates than rural patients (4.1% IVT, 2.0% MT). Poor mRS outcomes were more common in rural areas than in urban areas, with adjusted ORs of 1.30 (1.18-1.43) in the total cohort and 1.43 (1.19-1.70) in the hyperacute cohort. The PAF for poor outcomes due to rural residency was 14.8% (0.5%-31.0%). CONCLUSION: This study demonstrated a notable association between rurality and poorer AIS outcomes in Japan, particularly in the hyperacute phase.

Zinc Administration Favorably Affects Prophylactic Therapy-refractory Migraine Attacks: A Case Series.

Notably, certain nutrients are effective in preventing migraine. Nonetheless, zinc replacement therapy for migraine treatment has yet to be explored. We herein report four patients with migraine who were refractory to prophylactic therapy and whose headache frequency and severity improved with zinc supplementation. Zinc administration may be an option for treating patients with prophylaxis-refractory migraine. Further investigation is required to determine the efficacy of zinc replacement therapy as a treatment option for migraine.

In-hospital recurrence and functional outcome between ischemic stroke caused by intracranial arterial dissection and intracranial atherosclerosis: Retrospective cohort study of the nationwide multicenter registry.

BACKGROUND: Intracranial arterial dissection (ICAD) and intracranial atherosclerotic stenosis (ICAS) are often difficult to differentiate, and studies on their background factors and prognosis are scarce. Information on prognosis, including recurrence, is necessary for stroke care, and clarification of epidemiological and clinical differences between the two diseases is important for appropriately handling their heterogeneity. This study aimed to determine the association of ICAD and ICAS with in-hospital recurrence and prognosis and compare their background and clinical findings. METHODS: In this multicenter cohort study, we retrospectively analyzed data from the Saiseikai Stroke Database. Adults with ischemic stroke caused by ICAD or ICAS were included in this study. Patients' backgrounds and clinical findings were compared between the ICAD and ICAS groups. The outcome showed an association of ICAD with in-hospital recurrence of ischemic stroke and poor functional outcome relative to ICAS. Multivariable logistic regression analyses were performed to calculate the adjusted odds ratios (ORs) for ICAD with 95% confidence intervals (CIs) for each outcome. RESULTS: Among 15,622 patients registered in the Saiseikai Stroke Database, 2,020 were enrolled (ICAD group: 89; ICAS group: 1,931). In the ICAD group, 65.2% of the patients were aged <64 years. Vascular lesion location was more common in ICAD with the vertebral artery [42 (47.2%)], anterior cerebral artery [20 (22.5%)], and middle cerebral artery (MCA) [16 (18.0%)], and in ICAS with MCA 1046 (52.3%). Multivariable logistic regression analyses of the association between ICAD and in-hospital recurrence and poor functional outcome yielded a crude OR (95% CI) of 3.26 (1.06-9.97) and 0.97 (0.54-1.74), respectively, relative to ICAS. CONCLUSION: ICAD was associated with a higher in-hospital recurrence than ICAS; however, there was no significant difference in prognosis between the two groups. Differences in background characteristics and vessel lesions may be of interest in these two diseases.

DARE: Distill and Reinforce Ensemble Neural Networks for Climate-Domain Processing.

Natural-language processing is well positioned to help stakeholders study the dynamics of ambiguous Climate Change-related (CC) information. Recently, deep neural networks have achieved good results on a variety of NLP tasks depending on high-quality training data and complex and exquisite frameworks. This raises two dilemmas: (1) the networks are highly reliant on powerful hardware devices and processing is time-consuming, which is not only inconducive to execution on edge devices but also leads to resource consumption. (2) Obtaining large-scale effective annotated data is difficult and laborious, especially when it comes to a special domain such as CC. In this paper, we propose a CC-domain-adapted BERT distillation and reinforcement ensemble (DARE) model for tackling the problems above. Specifically, we propose a novel data-augmentation strategy which is a Generator-Reinforced Selector collaboration network for countering the dilemma of CC-related data scarcity. Extensive experimental results demonstrate that our proposed method outperforms baselines with a maximum of 26.83% on SoTA and 50.65× inference time speed-up. Furthermore, as a remedy for the lack of CC-related analysis in the NLP community, we also provide some interpretable conclusions for this global concern.

[A comparative study of three cases of neuronal intranuclear inclusion disease (NIID)].

All three patients were men in their 70s. All cases were solitary onset and the chief complaint was gait disturbance. All patients had miosis and limb and trunk ataxia, MMSE score was declined in two patients, and FAB score was declined in all patients. Head MRI showed leukoencephalopathy, cerebellar atrophy, and DWI high intensity signal in corticomedullary junction. However, two of the three patients were not followed up without further examination. Skin biopsies in all cases showed ubiquitin-positive and p62-positive intranuclear inclusions. Genetic testing showed CGG repeat expansion of NOTCH2NLC. The diagnosis of neuronal intranuclear inclusion disease (NIID) was made based on the above findings in all cases. Most patients are diagnosed with NIID due to memory loss, but sometimes they are diagnosed due to gait disturbance with ataxia. It is important to proceed with the diagnosis by skin biopsy and genetic diagnosis based on the characteristic MRI findings of the head.

Adult Krabbe Disease That Was Successfully Treated with Intravenous Immunoglobulin.

Krabbe disease involves the accumulation of neurotoxic metabolites due to lysosomal galactocerebrosidase enzyme deficiency, which results in widespread demyelination of central and peripheral nerves. Generally, Krabbe disease presents as spastic paraplegia with a slow progressive course; however, some cases may show clinical symptoms similar to those of chronic inflammatory demyelinating polyneuropathy (CIDP). No previously reported studies have investigated the efficacy of intravenous immunoglobulin (IVIg) for treating Krabbe disease, and reporting a case involving IVIg treatment may be informative in the clinical setting. A 14-year-old girl who developed Guillain-Barré syndrome-like limb weakness was administered IVIg, and her limb weakness improved. At 16 years old, she developed abnormal sensory perception and weakness of both upper limbs. A nerve conduction study revealed demyelination, which led us to suspect CIDP. IVIg was administered, and her symptoms gradually improved. A nerve biopsy, enzyme activity, and genetic test results indicated adult Krabbe disease. In some cases, IVIg may be an effective treatment for Krabbe disease.

Acute central nervous system vasculitis as a manifestation of neurosarcoidosis: A case report and literature review.

Neurosarcoidosis (NS) affects various sites of the central nervous system, including the cranial nerve, meninges, brain parenchyma, hypothalamus, and pituitary gland. NS rarely causes intracerebral vasculitis and subsequent strokes, or cerebral infarction and hemorrhage, which are associated with high mortality. Herein, we report a 71-year-old woman's case of stroke associated with NS, which showed aggressive cerebral vasculitis with brain herniation; it was resolved with corticosteroid therapy after accurate histopathological diagnosis. This case highlights the necessity of expecting NS to sometimes follow an aggressive course, presenting with vasculitis. Most patients with NS satisfactorily respond to corticosteroids, but this is not always the case. In cases of unfamiliar ischemic or hemorrhagic lesions, the possibility of NS must be considered.

Effect of Lomerizine Hydrochloride on Preventing Strokes in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an orphan disease clinically characterized by migraine, recurrent strokes, and dementia. Currently, there are no disease-modifying therapies, and it is difficult to prevent cerebral ischemic events in CADASIL patients by conventional antithrombotic medication. We hypothesized that an antimigraine agent, lomerizine hydrochloride, may prevent strokes in CADASIL patients, based on its effect on increasing cerebral blood flow. SUBJECTS AND METHODS: This was an open-labeled clinical trial in which 30 adult CADASIL patients received lomerizine at 10 mg/d. Numbers of symptomatic strokes during the 2 years after the start of lomerizine administration were compared with those in the 2 years before its initiation. The effect of lomerizine on preventing strokes was evaluated based on the incidence rate ratio (IR) calculated with the Mantel-Haenszel method. RESULTS: When including all 30 patients (analysis 1), the IR was less than 1 (0.46; 95% confidence interval [CI], 0.19-1.12) but did not reach significance. To evaluate the effect of lomerizine on secondary prevention, subgroups of 15 patients with stroke episodes occurring any time before lomerizine administration (analysis 2) and 10 patients with stroke episodes during the 2 years before lomerizine administration (analysis 3) were analyzed. The IR values were 0.33 (95% CI, 0.12-0.94) in analysis 2 and 0.17 (95% CI, 0.04-0.67) in analysis 3. CONCLUSIONS: Our results suggest the effect of lomerizine on preventing secondary stroke in CADASIL patients.

[A case of myasthenia gravis developed during pembrolizumab administration, suggesting an excitation-contraction connection disorder].

The patient was a 50-year-old woman. Pembrolizumab was started for bladder cancer recurrence. From the day after the second administration, ptosis, diplopia, restriction of eye movement, muscle weakness, fatigue resistance, increase in serum creatine kinase (CK) level, and muscle pain were observed. Tests for anti-acetylcholine receptor (AChR) antibody and anti-muscle specific kinase (MuSK) antibody were negative. Electrophysiological examination of the neuromuscular junction showed negative results, and electromyography revealed no myogenic changes. We considered that the immune checkpoint inhibitor caused neuromuscular damage. The patient's symptoms were gradually improved by immunotherapy, such as steroid and plasma exchange. In this case, tests for the anti-titin antibody, an anti-striational antibody, were positive. We considered that myasthenia gravis-like symptoms and serum CK level elevation might have been caused by impairment of excitation-contraction coupling, and not the neuromuscular junction.

Case Report: Shortest Course of Pediatric Paroxysmal Hemicrania.

Paroxysmal hemicrania (PH) is a rare primary headache disorder, especially among children. We describe herein a case with the shortest course of pediatric PH among previously reported cases, and the first case report of Japanese pediatric PH. An 11-year-old boy was referred to our clinic by his primary care physician for a headache evaluation. He had been complaining of severe, sharp, pulsating headache for 5 days. Attacks were restricted to the left side with a duration ranging from 2 to 20 minutes, 20-30 times a day. Attacks were associated with left autonomic symptoms (conjunctival injection, lacrimation, nasal congestion, eyelid edema, and ptosis). Two days after we prescribed indomethacin at 0.9 mg/kg/day, the patient was headache free. He stopped taking indomethacin 14 days after consultation because of drug eruptions. As of the time of writing, more than 1 year later, he has experienced no recurrence of headache. This case indicates the importance of improving awareness among general doctors regarding PH in children, and of conducting further investigations about low-dose, short-term indomethacin treatment.

Unusual Clinical Sequelae of Kawasaki Disease-Symptomatic Extracranial Internal Carotid Stenosis in Young Adult.

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis that primarily affects the coronary artery, but it does not commonly affect the carotid artery. Cerebral infarction (CI) with internal carotid artery stenosis (ICS) in patients with KD has not been reported until now. We report a patient with CI as a remote-phase complication of KD. CASE PRESENTATION: A 32-year-old man presented with impaired consciousness. Magnetic resonance imaging and digital subtraction angiography confirmed CI and ICS. He successfully underwent carotid endarterectomy. The resected plaque had pathologic findings of KD, which suggested that the internal carotid artery suffered from chronic inflammation. CONCLUSION: KD in childhood may cause symptomatic ICS as a sequela of a remote phase.

Cerebral Toxoplasmosis Diagnosed by Nested-polymerase Chain Reaction in a Patient with Rheumatoid Arthritis.

A 65-year-old woman with rheumatoid arthritis (RA) visited our hospital because of right facial sensory hypoesthesia. Cerebral toxoplasmosis was suspected on brain magnetic resonance imaging. We discontinued methotrexate for RA and started a sulfamethoxazole/trimethoprim (ST) mixture. Although ST treatment was interrupted because of adverse reactions, her prognosis was favorable. The Toxoplasma 18S rDNA gene was detected by nested-polymerase chain reaction (PCR) from blood and cerebrospinal fluid. Detecting the Toxoplasma 18S rDNA gene by nested-PCR is useful for the diagnosis and safer than a brain biopsy. In addition, the discontinuation of immunosuppressants may be recommended in patients compromised by those immunosuppressants.

Sorghum DW1 positively regulates brassinosteroid signaling by inhibiting the nuclear localization of BRASSINOSTEROID INSENSITIVE 2.

Semi-dwarf traits have been widely introgressed into cereal crops to improve lodging resistance. In sorghum (Sorghum bicolor L. Moench), four major unlinked dwarfing genes, Dw1-Dw4, have been introduced to reduce plant height, and among them, Dw3 and Dw1 have been cloned. Dw3 encodes a gene involved in auxin transport, whereas, Dw1 was recently isolated and identified as a gene encoding a protein of unknown function. In this study, we show that DW1 is a novel component of brassinosteroid (BR) signaling. Sorghum possessing the mutated allele of Dw1 (dw1), showed similar phenotypes to rice BR-deficient mutants, such as reduced lamina joint bending, attenuated skotomorphogenesis, and insensitivity against feedback regulation of BR-related genes. Furthermore, DW1 interacted with a negative regulator of BR signaling, BRASSINOSTEROID INSENSITIVE 2 (BIN2), and inhibited its nuclear localization, indicating that DW1 positively regulates BR signaling by inhibiting the function of BIN2. In contrast to rice and wheat breeding which used gibberellin (GA) deficiency to reduce plant height, sorghum breeding modified auxin and BR signaling. This difference may result from GA deficiency in rice and wheat does not cause deleterious side effects on plant morphology, whereas in sorghum it leads to abnormal culm bending.

Sorghum Dw1, an agronomically important gene for lodging resistance, encodes a novel protein involved in cell proliferation.

Semi-dwarfing genes have contributed to enhanced lodging resistance, resulting in increased crop productivity. In the history of grain sorghum breeding, the spontaneous mutation, dw1 found in Memphis in 1905, was the first widely used semi-dwarfing gene. Here, we report the identification and characterization of Dw1. We performed quantitative trait locus (QTL) analysis and cloning, and revealed that Dw1 encodes a novel uncharacterized protein. Knockdown or T-DNA insertion lines of orthologous genes in rice and Arabidopsis also showed semi-dwarfism similar to that of a nearly isogenic line (NIL) carrying dw1 (NIL-dw1) of sorghum. A histological analysis of the NIL-dw1 revealed that the longitudinal parenchymal cell lengths of the internode were almost the same between NIL-dw1 and wildtype, while the number of cells per internode was significantly reduced in NIL-dw1. NIL-dw1dw3, carrying both dw1 and dw3 (involved in auxin transport), showed a synergistic phenotype. These observations demonstrate that the dw1 reduced the cell proliferation activity in the internodes, and the synergistic effect of dw1 and dw3 contributes to improved lodging resistance and mechanical harvesting.

Direct Microsurgical Embolectomy for Acute Occlusion of the Internal Carotid Artery and Middle Cerebral Artery.

BACKGROUND: Surgical embolectomy is the most promising therapy for physically removing emboli from major cerebral arteries. However, it requires an experienced surgical team, time-consuming steps, and is not incorporated into acute stroke therapy. METHODS: We established seamless collaboration between services, refined surgical techniques, and conducted a prospective trial of emergency surgical embolectomy. Surgical indications included the presence of acute hemispheric symptoms, absence of low-density area on computed tomography, evidence of internal carotid artery terminus or proximal middle cerebral artery occlusion, and availability of resources to start surgery within 3 hours of symptom onset. The indications were confirmed by an interdisciplinary team. We assessed revascularization rates, time from admission to surgery and from surgery to recanalization, procedural complications, and clinical outcomes. RESULTS: Between 2005 and 2014, 14 consecutive patients with acute proximal middle cerebral artery or internal carotid artery terminus occlusion underwent emergency surgical embolectomy. All patients showed complete recanalization. Twelve patients survived and 7 had fair functional outcome (Rankin Scale score, ≤3). No significant procedural adverse events occurred. The mean times from admission to start of surgery, from surgery to recanalization, and from onset to recanalization were 14 minutes, 79 minutes, and 223 minutes, respectively. CONCLUSIONS: Our results suggest that microsurgical embolectomy can rapidly, safely, and effectively retrieve clots and deserves reappraisal, although the choice largely depends on local institutional expertise.

Preparation of inorganic/organic polymer hybrid microcapsules with high encapsulation efficiency by an electrospray technique.

Microcapsules composed of calcium phosphate and chitosan were prepared in a single step by electrospraying. An aqueous solution containing calcium chloride and chitosan was electrosprayed into a phosphate solution to form a calcium phosphate shell on the sprayed droplets. The resulting microcapsules were 350 µm in average diameter. Investigation using fluorescently labeled chitosan and XRD measurements revealed that the shells of the microcapsules were composed of calcium phosphate (mainly hydroxyapatite) and chitosan. Instead of chitosan, poly(diallyldimethylammonium chloride) and polyethylene glycol were also available for microcapsule production by electrospraying. Variations in the electrospraying conditions resulted in a variety of microcapsule shapes. Various types of substrates were successfully encapsulated in microcapsules with a high encapsulation efficiency (more than 80%). Finally, we succeeded in the encapsulation of living yeast cells in microcapsules, and observed their growth within these microcapsules.

Intravenous immunoglobulin preparation prevents the production of pro-inflammatory cytokines by modulating NFκB and MAPKs pathways in the human monocytic THP-1 cells stimulated with procalcitonin.

OBJECTIVE: In the previous investigations, we showed that intravenous immunoglobulin (IVIG) prevented cytokine release in procalcitonin (PCT)-stimulated monocytic cells. The aim of the present study was to investigate the underlying mechanisms of inhibition of IVIG on cytokine production in PCT-stimulated THP-1 cells. METHODS: THP-1 cells treated with phorbol myristate acetate were stimulated with PCT. The protein levels of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and high-mobility group box 1 (HMGB1)] in the culture supernatants were determined using enzyme-linked immunosorbent assay kits. The mRNA level of TNF-α was determined by reverse transcription-polymerase chain reaction. The phosphorylations of nuclear factor kappa B (NFκB) and the mitogen-activated protein kinases (MAPKs) were determined by Western blotting. RESULTS: IVIG reduced mRNA expression and protein production of TNF-α in PCT-stimulated THP-1 cells. Not only IVIG but also both the Fc fragment and the F(ab')2 fragment inhibited PCT-induced TNF-α, IL-6, and HMGB1 production. Furthermore, IVIG and its fragments suppressed PCT-induced phosphorylations of NFκB, p38 MAPK, and c-Jun N-terminal kinase. CONCLUSIONS: Our results indicate that IVIG prevents PCT-induced cytokine production mediated by not only the Fab region but also the Fc region. The activity of IVIG and its fragments might be regulated by inhibiting NFκB and MAPKs pathways in THP-1 cells.

An fc gamma receptor-mediated upregulation of the production of interleukin 10 by intravenous immunoglobulin in bone-marrow-derived mouse dendritic cells stimulated with lipopolysaccharide in vitro.

Intravenous immunoglobulin (IVIG), a highly purified immunoglobulin fraction prepared from pooled plasma of several thousand donors, increased anti-inflammatory cytokine IL-10 production, while decreased proinflammatory cytokine IL-12p70 production in bone-marrow-derived mouse dendritic cells (BMDCs) stimulated with lipopolysaccharide (LPS). The changes of cytokine production were confirmed with the transcription levels of these cytokines. To study the mechanisms of this bidirectional effect, we investigated changes of intracellular molecules in the LPS-induced signaling pathway and observed that IVIG upregulated ERK1/2 phosphorylation while downregulated p38 MAPK phosphorylation. Using chemical inhibitors specific to protein kinases involved in activation of Fc gamma receptors (FcγRs), which mediate IgG signals, we found that hyperphosphorylation of ERK1/2 and Syk phosphorylation occurred after stimulation of BMDC with LPS and IVIG, and the increasing effect on IL-10 production was abolished by these inhibitors. Furthermore, an antibody specific to FcγRI, one of FcγRs involved in immune activation, inhibited IVIG-induced increases in IL-10 production, but not IL-12p70 decreases, whereas the anti-IL-10 antibody restored the decrease in IL-12p70 induced by IVIG. These findings suggest that IVIG induced the upregulation of IL-10 production through FcγRI activation, and IL-10 was indispensable to the suppressing effect of IVIG on the production of IL-12p70 in LPS-stimulated BMDC.

Hashimoto's encephalopathy as a treatable adult-onset cerebellar ataxia mimicking spinocerebellar degeneration.

BACKGROUND: Hashimoto's encephalopathy (HE) presents with a variety of neurologic and neuropsychiatric features. In this study, we investigated the clinical and immunological profiles of the cerebellar ataxic form of HE. METHODS: The clinical features, treatments, laboratory features, brain imaging, and serum anti-NH(2)-terminal of α-enolase autoantibodies (anti-NAE Abs), a useful diagnostic marker for HE, were investigated in 13 patients who presented with sporadic adult-onset cerebellar ataxia and fulfilled the HE diagnostic criteria (antithyroid Abs and responsiveness to immunotherapy). RESULTS: All of the patients presented with truncal ataxia, but nystagmus was uncommon (17%). Eight patients had an insidious onset that mimicked spinocerebellar degeneration (SCD), but brain imaging showed little or no cerebellar atrophy in all of the patients. Those patients with serum anti-NAE Abs (n = 8) did not have nystagmus and tended to respond better to immunotherapy than the anti-NAE Ab-negative patients. CONCLUSION: The present study suggests that insidious adult-onset and truncal ataxia are common in the cerebellar ataxic form of HE, which mimics SCD, but that nystagmus and severe cerebellar atrophy are uncommon. Antithyroid and anti-NAE Abs may be useful for diagnosing cerebellar ataxic HE.

Intravenous immunoglobulin preparation attenuates LPS-induced production of pro-inflammatory cytokines in human monocytic cells by modulating TLR4-mediated signaling pathways.

Intravenous immunoglobulin (IVIG) has been used for the treatment of inflammatory and autoimmune diseases. The ability to modulate cytokine production has been formerly described as one of the mechanisms of its action. This study aimed to investigate the effect of IVIG on the production of pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated monocytic cells. Peripheral blood mononuclear cells (PBMCs) or THP-1 cells treated with phorbol myristate acetate (PMA) were stimulated with LPS. The protein levels of pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-6, and high-mobility group box 1 (HMGB1)] in the culture supernatants were determined using appropriate enzyme-linked immunosorbent assay kits. The mRNA of TNF-α was determined by reverse transcription-polymerase chain reaction. The phosphorylation of nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinases was examined by Western blot analyses. IVIG suppressed the production of pro-inflammatory cytokines such as TNF-α and IL-6 in LPS-stimulated PBMCs. Furthermore, IVIG inhibited TNF-α, IL-6, and HMGB1 production from LPS-stimulated THP-1 cells treated with PMA. In addition, Fc fragment prepared from the IVIG inhibited production of these cytokines from the cells to the same degree as IVIG, whereas Fab and F(ab')(2) fragments inhibited this only partially. We showed that IVIG and Fc fragments suppressed LPS-induced signal transduction pathways involving phosphorylation of NF-κB, p38, and c-Jun N-terminal kinase (JNK). Taken together, our results suggest that IVIG attenuates LPS-induced cytokine production predominantly mediated by its Fc region. The activity might be regulated by inhibiting NF-κB, p38, and JNK pathways in human monocytic cells.