Diabetic encephalopathy (DE) is a central nervous complication of diabetes mellitus which is characterized by cognitive impairment and neurochemical abnormalities. However, no effective approaches are available to prevent its progression and development. PDE4D serves many functions in the pathogenesis of neurodegenerative diseases involving PKA signaling. This study illustrated the role of PDE4D in DE and investigated whether resveratrol protected against DE via inhibiting PDE4D. db/db male mice and hippocampus cell line (HT22) were used to investigate the role of PDE4D and the protective effect of resveratrol on cognitive function under high glucose (HG). PDE4D overexpression or knockdown lentivirus and PKA specific inhibitor H89 were used to further identify the indispensable role of PDE4D/PKA signaling pathway in resveratrol's amelioration effect of neurotoxicity. Resveratrol attenuated cognitive impairment in db/db mice, reduced PDE4D protein, restored the impaired mitochondrial function in db/db mice. The in vitro study also confirmed the neuroprotective effect of resveratrol on neurotoxicity. PDE4D overexpression resulted in cell injury and downregulation of cAMP, PKA and pDrp1(Ser637) under normal condition. In contrast, PDE4D knockdown improved cell injury and elevated cAMP, PKA and pDrp1(Ser637) levels caused in HG-cultured HT22 cells. PDE4D over-expression blunted the improvement effects of resveratrol on PKA, pDrp1(Ser637) and mitochondrial function. Moreover, PKA inhibitor H89 blunted the inhibitory effects of resveratrol on pDrp1(Ser637) and mitochondrial function in HG-treated HT22. These data indicated that resveratrol may improve cognitive impairment in db/db mice by modulating mitochondrial function through the PDE4D dependent pathway.
The present study aimed to assess the effects of repairing ventricular septal defects (VSDs) with right vertical infra‑axillary mini‑incision (RVAI). A total of 116 patients with VSDs were prospectively enrolled and underwent cardiac surgery between June 2017 and December 2018 at the cardiac intensive care unit of Shanghai Children's Medical Center (Shanghai, China). Of these, 58 patients underwent the RVAI procedure and 58 patients matched 1:1 underwent the standard median sternotomy incision (MSI) procedure and were designated as the control group. The demographic data and clinical outcomes intra‑ and postoperatively were compared. A bedside lung ultrasound was performed to evaluate the degree of lung injury and the number of B‑lines was quantified and compared between the two groups. The sedation and analgesia levels were also assessed after the operation. No significant difference was identified between the two groups regarding the overall cardiopulmonary bypass or aortic cross‑clamp time. All patients were extubated within 8 h. The RVAI group had shorter incision lengths (median, 4.6 cm) and less drainage (median, 15 ml) than the MSI group. Furthermore, compared to the MSI group, the RVAI group had a significantly higher number of B‑lines in the right lung regions immediately after surgery and at 12 h postsurgery (24.1 and 5.2%, respectively) but eventually exhibited no differences at 24 and 36 h postsurgery; by contrast, there were no differences in the left lung regions. The bedside bispectral index score and the Face, Legs, Activity, Cry, Consolability scale score exhibited no significant differences after the operation. In conclusion, the RVAI procedure appears to be a safe alternative for repairing VSDs in addition to satisfactory cosmetic results and the incision does not interfere with postoperative analgosedation.
Although migraine is a major global public health problem, its impact on cognitive abilities remains controversial. Thus, the present study investigated the effects of repeated administration of inflammatory soup to the dura of rats, over three weeks, on spatial cognition, hippocampal synaptic plasticity, and the expression of N-methyl-D-aspartate receptor subunits. Additionally, low doses of amitriptyline (5 mg/kg) were applied to assess its therapeutic effects. The inflammatory soup group exhibited significant reductions in the cutaneous stimulation threshold, presence of mild cognitive impairment, and decreased long-term potentiation in right hippocampus. However, amitriptyline improved pain behaviors, enhanced cognitive function, and increased synaptic plasticity in the inflammatory soup rats. On the other hand, the administration of amitriptyline to normal rats negatively influenced synaptic plasticity and reduced the expression of N-methyl-D-aspartate receptor subunits. The present results indicate that inflammatory soup-induced dural nociception led to impairments in spatial cognition that could be attributed to reductions in hippocampal long-term potentiation and the decreased expression of N-methyl-D-aspartate receptor subunits.
Neuropathic pain (NP) is often caused by diabetic neuropathy, chemotherapy, or spinal cord lesions and is associated with significant economic burden and poor quality of life. Sophisticated etiology and pathology recognized different pharmacologic interventions, and hitherto, the reported analgesic efficacy and safety of guideline-recommended drugs are not satisfactory. Overall, this article reviews the mechanism of α 2 δ ligand, the clinical pharmacokinetics, efficacy, safety and cost-effectiveness of mirogabalin for the treatment of NP, offering clinical perspectives into potential benefits of NP-related syndrome or comorbidities. Mirogabalin, a novel voltage-gated Ca 2+ channel (VGCC) α 2 δ ligand with selective binding affinities to α 2 δ-1 than α 2 δ-2 subunit, exhibited a wider safety margin and a relatively lower incidence of adverse events compared with other gabapentinoids. Randomized-controlled trials and open-label studies have demonstrated the efficacy and long-term safety of mirogabalin in Asian patients with diabetic peripheral neuropathic pain (DPNP), postherpetic neuralgia (PHN), and central NP. Analgesic effects of mirogabalin for the single or add-on treatment on chemotherapy-induced peripheral neuropathy and orthopedic disease/postoperation-related NP were also evidenced. To date, mirogabalin is approved for the general indication of NP in Japan, PNP in South Korea, and DPNP in the Chinese Mainland and DPNP, PHN in Taiwan (China). In summary, mirogabalin emerges as a promising option for NP; further research is warranted to refine wider treatment strategies, flexible dosing in real-world setting.
Abstract Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) have not been evaluated sufficiently due to limited data, particularly in China. Methods Patients with SUNCT or SUNA treated in a tertiary headache centre or seven other headache clinics of China between April 2009 and July 2022 were studied; we compared their demographics and clinical phenotypes. Results The 45 patients with SUNCT and 31 patients with SUNA had mean ages at onset of 37.22 ± 14.54 years and 42.45 ± 14.72 years, respectively. The mean ages at diagnosis of SUNCT and SUNA were 41.62 ± 12.70 years and 48.68 ± 13.80 years, respectively ( p = 0.024). The correct diagnosis of SUNCT or SUNA was made after an average of 2.5 (0–20.5) years or 3.0 (0–20.7) years, respectively. Both diseases had a female predominance (SUNCT: 1.14:1; SUNA: 2.10:1). The two diseases differed in the most common attack site (temporal area in SUNCT, p = 0.017; parietal area in SUNA, p = 0.002). Qualitative descriptions of the attacks included stabbing pain (44.7%), electric-shock-like pain (36.8%), shooting pain (25.0%), and slashing pain (18.4%). Lacrimation was the most common autonomic symptom in both SUNCT and SUNA patients, while eyelid oedema, ptosis, and miosis were less frequent. Triggers such as cold air and face washing were shared by the two diseases, and they were consistently ipsilateral to the attack site. Conclusions In contrast to Western countries, SUNCT and SUNA in China have a greater female predominance and an earlier onset. The shared core phenotype of SUNCT and SUNA, despite their partial differences, suggests that they are the same clinical entity.
Migraines are a common medical condition, currently without effective treatment. The recently developed CGRP treatment is expensive and with limited beneficial effect. From a basic science point of view, the central mechanism for migraine and headache is largely unknown. In the present study, we demonstrate that cortical excitatory transmission is significantly enhanced in the ACC - a brain region which is critical for pain perception. Biochemical studies found that both of NMDA receptor GluN2B serine 1303 phosphorylation and AMPA receptor GluA1 serine 831 and serine 845 phosphorylation levels were enhanced in ACC of migraine rats. Both the presynaptic release of glutamate, and postsynaptic responses of AMPA receptors and NMDA receptors were enhanced. Furthermore, behavioral anxiety and nociceptive responses, were increased. Synaptic long-term potentiation (LTP) is occluded since theta-burst stimulation (TBS) failed to induce LTP in migraine rats. Inhibition of cortical excitation by application of a selective AC1 chemical inhibitor NB001 within the ACC significantly reduced behavioral sensitization and anxiety. Our results provide strong evidence that cortical LTPs contribute to migraine-related pain and anxiety, and drugs that inhibit cortical excitation such as NB001 may serves as potential new medicines for treating migraine in the future.
Headache disorders are widely prevalent and pose a considerable economic burden on individuals and society. Globally, misdiagnosis and inadequate treatment of primary headache disorders remain significant challenges, impeding the effective management of such conditions. Despite advancements in headache management over the last decade, a need for comprehensive evaluations of the status of primary headache disorders in China regarding diagnosis and preventative treatments persists.In the present study, we analyzed the established queries in the Survey of Fibromyalgia Comorbidity with Headache (SEARCH), focusing on previous diagnoses and preventative treatment regimens for primary headache disorders. This cross-sectional study encompassed adults diagnosed with primary headache disorders who sought treatment at 23 hospitals across China between September 2020 to May 2021.The study comprised 2,868 participants who were systematically examined. Migraine and tension-type headaches (TTH) constituted a majority of the primary headache disorders, accounting for 74.1% (2,124/2,868) and 23.3% (668/2,868) of the participants, respectively. Medication overuse headache (MOH) affected 8.1% (231/2,868) of individuals with primary headache disorders. Over half of the individuals with primary headache disorders (56.6%, 1,624/2,868) remained undiagnosed. The previously correct diagnosis rates for migraine, TTH, TACs, and MOH were 27.3% (580/2,124), 8.1% (54/668), 23.2% (13/56), and 3.5% (8/231), respectively. The misdiagnosis of "Nervous headache" was found to be the most prevalent among individuals with migraine (9.9%, 211/2,124), TTH (10.0%, 67/668), trigeminal autonomic cephalalgias (TACs) (17.9%, 10/56), and other primary headache disorders (10.0%, 2/20) respectively. Only a minor proportion of individuals with migraine (16.5%, 77/468) and TTH (4.7%, 2/43) had received preventive medication before participating in the study.While there has been progress made in the rate of correct diagnosis of primary headache disorders in China compared to a decade ago, the prevalence of misdiagnosis and inadequate treatment of primary headaches remains a veritable issue. As such, focused efforts are essential to augment the diagnosis and preventive treatment measures related to primary headache disorders in the future.
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