Decreased synapse-associated proteins are associated with the onset of epileptic memory impairment in endothelial CDK5-deficient mice.

Accumulating evidence indicates that epilepsy has a higher risk of inducing memory impairment and dementia. However, the underlying onset mechanism remains unclear. Here, we found that mice with spontaneous epilepsy induced by endothelial CDK5 deficiency exhibited hippocampal-dependent memory impairment at 6 months of age, but not at 2 months of age. Moreover, the persistent epileptic seizures induce aberrant changes in phosphorylation of CaMKII protein in the hippocampus of spontaneous epileptic mice. Using genome-wide RNA sequencing and intergenic interaction analysis of STRING, we found that in addition to epilepsy-related genes, there are changes in synaptic organization pathway node genes, such as Bdnf and Grin1. The synapse-related proteins by Western blot analysis, such as NMDA receptors (NR1 and NR2B), PSD95, and the phosphorylation of synapsin1, are progressively decreased during epileptic seizures in Cdh5-CreERT2;CDK5f/f mice. Notably, we found that valproate (VPA) and phenytoin (PHT) augment mRNA expression and protein levels of synapse-related genes and ameliorate memory impairment in Cdh5-CreERT2;CDK5f/f mice. Our study elucidates a potential mechanism of memory deficits in epilepsy, and pharmacological reversal of synaptic pathology targeting might provide a new therapeutic intervention for epileptic memory deficits.

Endothelial peroxynitrite causes disturbance of neuronal oscillations by targeting caspase-1 in the arcuate nucleus.

Severe anorexia limits the clinical application of cisplatin, and even leads to the discontinuation of treatment. However, the mechanisms underlying cisplatin-induced anorexia are unknown. Herein, we demonstrated that cisplatin could affect neuronal gamma oscillations and induce abnormal neuronal theta-gamma phase-amplitude coupling in the arcuate nucleus (Arc) of the hypothalamus, and these findings were associated with significantly decreased food intake and weight loss in mice. Chemogenetic activation of AgRP neurons in the Arc reversed the cisplatin-induced food intake reduction in mice. We further demonstrated that endothelial peroxynitrite (ONOO-) formation in the Arc induced nitrosative stress following cisplatin treatment via a previously uncharacterized pathway involving neuronal caspase-1 activation. Strikingly, treatment with the ONOO- scavenger uric acid (UA) reversed the reduced action potential (AP) frequency of AgRP neurons and increased the AP frequency of POMC neurons induced by SIN1, a donor of ONOO-, in the Arc, as determined by whole-cell patch-clamp electrophysiological recording. Consistent with these findings, UA treatment effectively alleviated cisplatin-induced dysfunction of neuronal oscillations and neuronal theta-gamma phase-amplitude coupling in the Arc of mice. Taken together, these results suggest, for the first time, that targeting the overproduction of endothelial ONOO- can regulate cisplatin-induced neurotoxicity through neuronal caspase-1, and thereby serve as a potential therapeutic approach to alleviate chemotherapy-induced anorexia and weight loss.

Trend and disease burden of bacillary dysentery in China (1991-2000).

OBJECTIVE: We aimed to determine the burden of bacillary dysentery in China, its cross-regional variations, trends in morbidity and mortality, the causative bacterial species and antimicrobial resistance patterns. METHODS: We extracted and integrated governmental statistics and relevant medical literature published from 1991 to 2000. Data were also collected from one general hospital each for the six provinces and Jin-an district, Shanghai, representative of six geographical regions and a modern city. FINDINGS: In 2000, 0.8-1.7 million episodes of bacillary dysentery occurred of which 0.5 to 0.7 million were treated at health-care facilities and 0.15-0.20 million patients were hospitalized. The highest morbidity and mortality rates were among the youngest and oldest age groups. Bacillary dysentery peaked during the summer months. The major causative species was Shigella flexneri (86%) and the predominant S. flexneri serotype was 2a (80%). About 74-80% of Shigella isolates remained susceptible to fluorinated quinolones. CONCLUSION: We conclude that while morbidity and mortality due to bacillary dysentery has decreased considerably in China in the past decade due to increasing access to affordable health care and antibiotics, a considerable burden exists among the youngest and oldest age groups and in regions with low economic development. We suggest that while a vaccine would be effective for short- and medium-term control of bacillary dysentery, improved water supply, sanitation, and hygiene are likely to be required for long-term control.

[Epidemiologic characteristics of influenza in China, from 2001 to 2003].

OBJECTIVE: To understand the epidemiologic characters of influenza in China from 2001 to 2003. METHODS: Data of outpatient visits for influenza-like illness (ILI) each week and outbreaks of influenza were collected through National Influenza Surveillance Network, which includes 11 northern and 12 southern provinces of China. Samples were collected in the outpatients of ILI from 2001 to 2003 and influenza viruses were isolated and identified. RESULTS: Epidemiological and laboratory surveillance data showed that the annual seasonality of influenza epidemic was clear. The peak of epidemic of influenza in northern areas was in winter season, during December to January. However, there were three peaks distributed to Spring (Apr.-May.), Summer (Jun.-Aug.) and Winter (Dec.-Jan.) seasons in the southern areas. In the peak months, the number of ILI visits per day and per surveillance hospital had increased two-fold in northern and by 37% in southern China. The baseline of percentages for ILI visits, which calculated with 75th percentiles (P75), was 13.68% in the north and 13.08% in southern China. The age distribution of ILI was related to seasonal types of influenza. When the predominated strain of the season was influenza B virus, the ratio of the ILI visits younger than 15 year-old, increased obviously. When the predominated stains became influenza A virus, the ratio of patient visits for ILI aged over 25 year-old increased. Of 63 outbreaks of influenza, 92% of them occurred at primary and middle schools and usually occurred in May (32%). The type of strains usually changed around June. CONCLUSION: The quality of national influenza surveillance system is reliable since it was matched between percentages of ILI visits and rates of influenza virus isolation. The different epidemiologic characteristics in north and south of China was noticed. Peak in spring was shown in southern area and which called for more analysis. The change of the types of strains in the outbreaks during April to June in the southern China could provide data for better understanding on the trend of epidemics in the next season.