Recent Progress in Asymmetric Domino Intramolecular Cyclization/Cascade Reactions of Substituted Olefins.

The domino cyclization/coupling strategy is one of the most effective methods to produce cyclized and multi-functionalized compounds from olefins, which has attracted huge attention from chemists and biochemists especially for its considerable potential of enantiocontrol. Nowadays, more and more studies are developed to achieve difunctionalization of substituted olefins through an asymmetric domino intramolecular cyclization/cascade reaction, which is still an elegant choice to accomplish several synthetic ideas such as complex natural products and drugs. This review surveys the recent advances in this field through reaction type classification. It might serve as useful knowledge desktop for the community and accelerate their research.

Emerging role of free triiodothyronine in patients with anti-N-methyl-D-aspartate receptor encephalitis.

We aimed to investigate the role of free triiodothyronine (FT3) in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. 137 consecutive inpatients (2016-2019) were registered prospectively and followed up for 12 months. 96 eligible patients were included in the study. The modified Rankin scale (mRS) score was collected, and the score of 3-6 was defined as a poor outcome. The patients were equally classified into 3 subgroups based on their FT3 levels obtained within 24 h of admission, and the subgroup differences were analyzed by parametric or nonparametric tests as appropriate. Logistic regression analysis was performed. We found that there was no difference in the mRS scores upon admission among 3 subgroups, however, patients in the low-FT3 subgroup tended to have higher disease severity during hospitalization and worse outcome in follow-up visits, represented by higher chances of intense care unit (ICU) admission (P < 0.001), longer hospital stay (P < 0.001), greater maximum mRS scores during hospitalization (P = 0.011), lower rates of getting clinical improvement within 4 weeks of starting treatment (P = 0.006), and higher percentages of poor 1-year outcome (P = 0.002). The level of FT3 was an independent factor correlated with ICU admission (P = 0.002) and might be a potential predictor for 1-year outcome. Our preliminary results suggest that the FT3 may be a risk factor involved in the evolution and progression of anti-NMDAR encephalitis, whereas the underline mechanisms remain to be explored. Attention should be paid to these patients with relatively low FT3 upon admission, which might possibly aid clinical prediction and guide clinical decision-making.

A rare case of anti-LGI1 limbic encephalitis with concomitant positive NMDAR antibodies.

BACKGROUND: N-methyl-D-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) antibodies define the most prevalently recognized autoimmune encephalitis syndromes, while the simultaneous occurrence of both conditions has hardly been published before. CASE PRESENTATION: We report the case of a 67-year-old patient who presented with generalized tonic-clonic seizures (GTCS) followed by behavioral changes, psychosis, sleep disorders, decreased consciousness, and faciobrachial dystonic seizures. Ancillary findings included serum hyponatremia and imaging evidence of high-intensity lesions within bilateral medial temporal lobes on T2-weighted fluid attenuation inversion recovery. Both LGI1 and NMDAR antibodies were positive in serum and cerebral spinal fluid using transfected cell based assays. Despite prominent clinical features of anti-LGI1 limbic encephalitis (LGI1-LE), the patient also exhibited overlapping symptoms of anti-NMDAR encephalitis, like early-onset GTCS, which might be related to the concomitant positive NMDAR antibodies. CONCLUSIONS: We report a rare case of LGI1-LE with overlapping symptoms and simultaneous positive NMDAR antibodies. It is necessary to evaluate the presence of NMDAR antibodies in certain LGI1-LE patients with unusual symptoms. However, caution should be exercised in interpreting the observation, given the fact of a single-case study.

Anti-N-methyl-D-aspartate receptor encephalitis: a prospective study focused on cerebrospinal fluid and clinical symptoms.

BACKGROUND AND OBJECTIVE: To analyze the relationship between brain MRI, clinical symptoms, and cerebrospinal fluid (CSF) and to provide a reference for early diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. MATERIALS AND METHODS: A total of 62 patients with anti-NMDAR encephalitis in Zhengzhou, China (2016-2018) were observed and registered prospectively. First, we analyzed the characteristics of clinical symptoms. Second, according to the disease duration, patients were divided into two groups, and then we analyzed the CSF features. In addition, they were divided into two groups according to the brain MRI, and then the CSF features were analyzed. Finally, the characteristics of cerebrospinal fluid in patients with seizure as the initial symptom were analyzed. RESULTS: Seizure presents as the initial symptom in 14 patients (22.5%), including 11 males (78.57%). The proportion and concentration of CSF total protein abnormalities in the early stage group were significantly higher than those in the middle and late group (P < 0.05). The total protein concentration in the abnormal brain MRI group was significantly higher than that in the normal MRI group (P < 0.05). CONCLUSION: Anti-NMDAR encephalitis should be suspected, when male patients complain of seizure as an initial symptom and have simultaneously had headaches or fever prior to onset. The sensitivity of anti-NMDAR antibody is higher in CSF than in serum. Total CSF protein is more prone to elevation in the middle and late stages of anti-NMDAR encephalitis. Brain MRI abnormalities with anti-NMDAR encephalitis are related to the total protein concentration of CSF, which may be related to the disease duration.

Intranasal Delivery of Botulinum Neurotoxin A Protects against Hippocampal Neuron Death in the Lithium-Pilocarpine Rat Model.

Botulinum neurotoxins (BoNTs) block the release of a series of neurotransmitters, which are pivotal for neuron action. Intrahippocampal administration of BoNTs inhibits glutamate release, protects neurons against cell death, and attenuates epileptic seizures. Compared with intrahippocampal administration, intranasal delivery is less invasive and more practical for chronic drug administration. To assess whether intranasal administration is feasible, we examined the role of botulinum neurotoxin A (BoNT/A) in hippocampal neuronal injury after status epilepticus (SE) induced by pilocarpine. Our data showed BoNT/A could bypass the blood-brain barrier (BBB) and entered the olfactory bulb and hippocampal neurons. In addition, SE could result in up-regulation of pro-apoptotic proteins (Caspase-3, Bax), down-regulation of anti-apoptotic protein Bcl-2 and neuronal death in hippocampus. BoNT/A could suppress the expression of Caspase-3 and Bax, attenuate the decrease of Bcl-2, and inhibit hippocampal neuron death induced by SE. Meanwhile, there was no significant difference in cognitive behavior between the BoNT/A-pretreated rats and normal rats. Thus, we provided a more convenient and less invasive route for taking advantage of BoNT/A in the field of anti-epilepsy.

Emerging role of prodromal headache in patients with anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients often present with psychiatric symptoms, cognitive dysfunction, epilepsy and memory deficits. A previous study has suggested that headache can occurr during the early stages of anti-NMDAR encephalitis. However, the exact association between headache and anti-NMDAR encephalitis has hardly been investigated, apart from a few case studies. This is probably due to the severity of encephalitis symptoms, and the mechanism underlying headache-associated anti-NMDAR encephalitis remains largely unclear. OBJECTIVE: This study aimed to investigate the role of prodromal headache in 28 patients diagnosed with anti-NMDAR encephalitis. METHODS: Clinical data related to the prodromal headache characteristics of anti-NMDAR encephalitis patients were prospectively collected from January first 2017 to June first 2018. Autoimmune antibodies in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients were detected by an indirect immunofluorescence staining kit. The differences between age, sex, clinical symptoms (fever, epilepsy, psychiatric symptoms, cognitive impairment, disturbance of consciousness), CSF, brain MRI abnormalities, and modified Rankin Scale (mRS) score were compared between patients with and without headache. In addition, the association of headache severity with brain MRI abnormalities, antibody titers, and mRS score was examined. RESULTS: Twenty-eight patients with anti-NMDAR encephalitis (median, 29 years; range, 15-62 years) reported headache. Among them, 18 (64%) were female, 24 (86%) had fever, 21 (75%) were positive for serum virus antibody, 19 (68%) had severe pain intensity (scored 4-7 out of 10 on the visual analog scale), 18 (64%) presented with pulsating character, and 5 (18%) patients accompanied by vomiting. Moreover, headache was detected in the frontal lobe of 14 (50%) patients and temporal lobe of 12 (43%) patients. Encephalitic symptoms (psychiatric symptoms, cognitive dysfunction, epilepsy, and memory deficits) appeared in 23 patients at average 5.5 days (range, 1-21 days) followed by headache attack. In five patients, the headache was lasted for 21 days. CONCLUSION: Prodromal headache is commonly found in the temporal lobe and frontal lobe of young patients, and hardly accompanied by vomiting. Headache is rapidly substituted by encephalitis symptoms in the majority of patients, while gradually relieved in a few patients after the recovering from encephalitis symptoms. The results strongly suggest that the NR1 subunit of NMDAR is involved in prodromal headache. In sum, the symptom of prodromal headache is crucial for the diagnosis of anti-NMDAR encephalitis.