Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

Agomelatine: An Astounding Sui-generis Antidepressant?

Major depressive disorder (MDD) is one of the foremost causes of disability and premature death worldwide. Although the available antidepressants are effective and well tolerated, they also have many limitations. Therapeutic advances in developing a new drug's ultimate relation between MDD and chronobiology, which targets the circadian rhythm, led to a renewed focus on psychiatric disorders. In order to provide a critical analysis about antidepressant properties of agomelatine, a detailed PubMed (Medline), Scopus (Embase), Web of Science (Web of Knowledge), Cochrane Library, Google Scholar, and PsycInfo search was performed using the following keywords: melatonin analog, agomelatine, safety, efficacy, adverse effects, pharmacokinetics, pharmacodynamics, circadian rhythm, sleep disorders, neuroplasticity, MDD, bipolar disorder, anhedonia, anxiety, generalized anxiety disorder (GAD), and mood disorders. Agomelatine is a unique melatonin analog with antidepressant properties and a large therapeutic index that improves clinical safety. Published articles revealed that agomelatine is a melatonin receptors (MT1 and MT2) agonist and 5HT2C receptor antagonist. The effects receptors' on melatonin receptors enable the resynchronization of irregular circadian rhythms with beneficial effects on sleep architectures. In this way, agomelatine is accredited for its unique mode of action, which helps to exert antidepressant effects and resynchronize the sleep-wake cycle. To sum up, an agomelatine has not only antidepressant properties but also has anxiolytic effects.

Abnormal expression profile of plasma-derived exosomal microRNAs in patients with treatment-resistant depression.

Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.

New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation.

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.

A novel method for automatic pharmacological evaluation of sucrose preference change in depression mice.

Sucrose preference test (SPT) is a most frequently applied method for measuring anhedonia, a core symptom of depression, in rodents. However, the method of SPT still remains problematic mainly due to the primitive, irregular, and inaccurate various types of home-made equipment in laboratories, causing imprecise, inconsistent, and variable results. To overcome this issue, we devised a novel method for automatic detection of anhedonia in mice using an electronic apparatus with its program for automated detecting the behavior of drinking of mice instead of manual weighing the water bottles. In this system, the liquid surface of the bottles was monitored electronically by infrared monitoring elements which were assembled beside the plane of the water surface and the information of times and duration of each drinking was collected to the principal machine. A corresponding computer program was written and installed in a computer connected to the principal machine for outputting and analyzing the data. This new method, based on the automated system, was sensitive, reliable, and adaptable for evaluation of stress- or drug-induced anhedonia, as well as taste preference and effects of addictive drugs. Extensive application of this automated apparatus for SPT would greatly improve and standardize the behavioral assessment method of anhedonia, being instrumental in novel antidepressant screening and depression researching.

The Value of the Inferior Vena Cava Area Distensibility Index and its Diameter Ratio for Predicting Fluid Responsiveness in Mechanically Ventilated Patients.

INTRODUCTION: It is necessary to evaluate fluid responsiveness before fluid resuscitation. We evaluated the value of inferior vena cava (IVC) area respiratory variation and the IVC diameter ratio (IVC DR) for predicting fluid responsiveness in mechanically ventilated patients. METHODS: A prospective observational study was performed in the intensive care unit between December 2017 and March 2018. Mechanically ventilated patients were enrolled and received ultrasound monitoring. IVC diameter distensibility index from the subxiphoid area (IVC-sx DDI), IVC diameter distensibility index from the right midaxillary line (IVC-rm DDI), IVC area distensibility index (IVC ADI), and IVC DR in cross-section were calculated by ultrasound monitoring IVC parameters. The enrolled patients were classified as nonresponders group and responders group according to whether the cardiac output increased by >10% after passive leg raising. RESULTS: Data from 67 mechanically ventilated patients were analyzed. 55.2% of patients had positive fluid responsiveness. The area of receiver operating characteristic curves evaluating the ability of the IVC-sx DDI, IVC-rm DDI, IVC ADI, and IVC DR to predict the fluid responsiveness were 0.702, 0.686, 0.749, and 0.829, respectively. IVC DR level of 1.43 was predictive of positive fluid responsiveness with 90.0% specificity and 67.6% sensitivity. IVC ADI level of 10.2% was predictive of positive fluid responsiveness with 40.0% specificity and 97.3% sensitivity. CONCLUSIONS: IVC ADI and its diameter ratio in cross-section had more value than IVC diameter distensibility index for predicting fluid responsiveness in mechanically ventilated patients.

A survey of the enteral nutrition practices in patients with neurological disorders in the tertiary hospitals of China.

BACKGROUND AND OBJECTIVES: With the development of enteral nutrition in patients with neurological disorders in China, related guidelines were published in 2011. The Chinese Society for Parenteral and Enteral Nutrition conducted a survey to evaluate the status quo of enteral nutrition practices in these patients. METHODS AND STUDY DESIGN: This multicenter prospective investigation was conducted from April 2012 to April 2013 and involved 18 tertiary hospitals in China. The survey using standardized questionnaires sought information about the basic protocols for enteral nutrition (devices and staffing) and specific information about patients with neurological conditions who received nutrition by way of enteral feeding. RESULTS: In the 18 hospitals from 13 provinces, 83.3% patients were configured with an enteral nutrition infusion pump, 77.8% had a percutaneous endoscopic gastrostomy (PEG) device, and 88.9% had a clinical nutrition support group. Four hundred four patients participated in this survey (259 men, 145 women; mean age 61.3±14.7 years), 85.7% had suffered a stroke, 83.9% had impaired consciousness, and 98.0% had dysphagia. Of the 10 guidelines for enteral nutrition practices, setting the energy target, choosing the enteral nutrition tube, and monitoring the patient received unsatisfactory ratings were in poor compliance (56.2%, 30.0% and 38.9%, respectively); the remaining seven guidelines were in good compliance (each >75%). CONCLUSION: The survey suggested that configuration of the enteral nutritional devices and staffing was adequate in China's tertiary hospitals. However, some associated practices had not yet reached the desired levels of competency, indicating a need for this to be understood and for improved training.

Effect of timing of tracheotomy on clinical outcomes: an update meta-analysis including 11 trials.

OBJECTIVE: To estimate the relative effect of early vs. late tracheotomy on clinical end-points in unselected intensive care unit (ICU) patients undergoing mechanical ventilation. METHODS: We searched electronic databases (up to February 27, 2013) for both randomized control trials and observational studies satisfying the predefined inclusion criteria. RESULTS: We retrieved 11 reports of studies including a total of 13 705 patients. Early tracheotomy was associated with significant reductions in mortality [33.3% vs. 36.3%; relative risk (RR); 0.92; 95% confidence interval (CI): 0.88, 0.97; I(2): 29%], length of ICU stay (mean difference: -6.55 days; 95% CI: -8.19, -4.90; I(2): 98%) and duration of mechanical ventilation (mean difference: -6.53 days; 95% CI: -11.43, -1.63; I(2): 100%). However, as compared with late tracheotomy, early tracheotomy did not reduce the incidence of hospital pneumonia (21.9% vs. 21.0%, RR: 0.85; 95% CI: 0.68, 1.06; I(2): 67%). CONCLUSIONS: Early tracheotomy can reduce length of ICU stay, duration of mechanical ventilation and mortality but has no influence on hospital pneumonia when compared with late tracheotomy. Once the decision has been made about tracheotomy, clinical physicians should not hesitate to perform the procedure.

[Relationship between antacid therapy and hospital acquired pneumonia in critically ill patients: a meta-analysis].

OBJECTIVE: To systematically review the effect of antacid medication on stress-related mucosal disease (SRMD) bleeding, hospital acquired pneumonia (HAP), and hospital mortality in critically ill patients admitted to intensive care unit (ICU). METHODS: Related articles were retrieved from Medline Database (from January 1980 to December 2012). Randomized control trials (RCTs) focused on comparison between antacid and sucralfate were collected, and then a meta-analysis was performed. RESULTS: Twelve studies including a total of 2537 patients admitted to ICU were qualified for analysis. Antacid medication significantly increased the incidence of HAP when compared with sucralfate in 11 trials [19.36% (249/1286) vs. 15.23% (184/1208), odds ratio (OR)=1.27, 95% confidence interval (95%CI): 1.03-1.57, P=0.02]. Subgroup analyses showed that antacid therapy significantly reduce the incidence of clinically significant bleeding compared with sucralfate [1.80% (12/667) vs. 3.86% (26/673), OR=0.46, 95%CI: 0.23-0.91, P=0.03], however, it did not lower the incidence of overt bleeding [7.09% (40/564) vs. 7.35% (36/490), OR=1.00, 95%CI: 0.62-1.62, P=0.99]. There was no significant difference between antacid group and sucralfate group on neither ICU mortality nor hospitalization mortality in 11 studies [25.58% (288/1126) vs. 23.65% (268/1133), OR=1.11, 95%CI: 0.92-1.35, P=0.28]. CONCLUSIONS: Antacid therapy used in critically ill patients may increase the incidence of HAP while reduce the rate of upper gastrointestinal bleeding, while it exerts no influence on mortality rate when compared with sucralfate treatment in this meta-analysis. It is imperative to restrict the overuse of such medication, and further RCTs focused on indication and withdrawal should be encouraged.

Surgical treatment of symptomatic Rathke's cleft cysts: clinical features, therapy considerations and outcomes.

BACKGROUND: Rathke's cleft cyst (RCC) is one of the most common incidentally discovered sellar lesions, while symptomatic cases are relatively rare. Surgical treatment is recommended for symptomatic patients to drain the cyst content and to remove the capsule safely. The aim of this study was to clarify the clinical features, surgery considerations and therapy outcomes of symptomatic RCCs. METHODS: Totally 42 patients (19 males and 23 females) were retrospectively reviewed with the diagnosis of RCCs under surgery resection at the Affiliated Hospital of Medical College, Qingdao University between January 2005 and December 2010. RESULTS: Patients' age ranged from 6 to 67 years (mean of 41.6 years). The duration of symptoms ranged from 4 days to 10 years. Headache (69%), visual impairment (36%), and pituitary dysfunction (10%) were the most common presenting symptoms. The maximum diameter of cysts ranged from 6.0 to 46.7 mm (mean of 20.07 mm). Of the 42 patients, 36 underwent endonasal transsphenoidal approach and the others underwent transcranial approach. Thirty patients had a subtotal resection and decompression, while 12 patients had a total cyst resection. Cysts of 28 patients were lined by simple cubical or columnar epithelium, and cysts of 34 patients were filled by amorphous colloid material, that was the characteristic of RCCs. The majority of patients presented with a simple headache, and 93% of this group experienced a complete improvement after surgery. Twelve of 15 patients (80%) with preoperative visual deficits experienced an improvement in their vision after surgery. All of those patients with pituitary dysfunction experienced an improved endocrine status. The endocrinological complication usually was diabetes insipidus, and postoperative transient diabetes insipidus occurred in 13 (31%) patients without any permanent diabetes insipidus. The overall recurrence rate was 7% at a mean follow-up of 22 months (range 12 - 60 months). CONCLUSIONS: Surgical treatment is to drain the contents of the cyst and to remove the capsule as much as possible under the precondition that does not increase the complications. Biopsy and decompression procedures are recommended for most cases.

[Time trends, estimates and projects for breast cancer incidence and mortality in China].

OBJECTIVE: Using comprehensive available data on women breast cancer in China, to describe the mortality trends from late 1970s, estimate and project the profile in 2000 and 2005, and to aim to provide a reference for clinic, basic research and prevention and control strategy making for breast cancer in China. METHODS: Using Joinpoint model, the mortality trends were analyzed on the basis of routine surveillance data. Combining with the data from the second national mortality survey and several cancer registries, using the log-linear model (based on Poisson distribution), the breast cancer profile in 2000 and 2005 were estimated and projected. RESULTS: Although there was a slight decline in mortality between early 1970s and 1990s, the age-specific mortality rates among young and middle age women increased dramatically which followed a continuing increase trend on both rates and absolute numbers, in both urban and rural areas in recent 15 years. Compared with 2000, there are 470 thousands more new breast cancer cases and 130 thousands more deaths from breast cancer in 2005. CONCLUSION: Due to the double effects of both increasing risk factors and population growth and ageing, breast cancer will be one of the most extensively increasing cancers in Chinese women. The prevention and control of breast cancer will be of great emphasis for future cancer control strategy in China.

[Analysis of mortality rate of stomach cancer and its trend in twenty years in China].

OBJECTIVE: To analyze and predict the trend in mortality rate of stomach cancer in twenty years in China. METHODS: Stomach cancer mortality data collected from the China national survey over the period 1970s - 1990s for the cause of death were analyzed. RESULTS: The adjusted mortality rate of stomach cancer in 1990s increased by 11.0% and 6.3% for males and females, respectively. The urban mortality in 1970s was slightly higher than the rural mortality, while in 1990s the rural mortality rate was about 60% higher than the urban mortality. In 1990s, the adjusted urban mortality rate decreased by 22.2% and 26.7% for males and females, respectively. In contrast, the rural mortality rate increased by 26.4% and 22.1% for males and females, respectively. The sex ratio of stomach cancer deaths in 1990s, both in cities and rural areas, was slightly greater than that in 1970s, being more marked in the latter areas. In 1990s, the mortality rate decreased in 12 provinces, accounting for 44% in both sexes (12/27), but the decrease was more marked for females than for males except in Kiangs province. In provinces where the increased rates ranked top six positions, the magnitude of increase in rates was higher in males than in females. CONCLUSION: The overall mortality rates of stomach cancer in the past 20 years in China presented an increasing trend, despite there were upward and downward changes in 27 provinces and decrease in cities while increase in rural areas. Compared with other countries, the world-adjusted mortality rate of stomach cancer for both sexes in China ranks first. The increasing trend in stomach cancer mortality was seen in the older age groups (> 60 years) while a decreasing trend was seen in the younger age groups (30 - 59 years). Aging of the population could be an important factor responsible for the increase in mortality rates of stomach cancer in China.

Regional variations in mortality rates of pancreatic cancer in China: results from 1990-1992 national mortality survey.

AIM: To examine the regional variations in mortality rates of pancreatic cancer in China. METHODS: Aggregated mortality data of pancreatic cancer were extracted from the 1990-1992 national death of all causes and its mortality survey in China. Age specific and standardized mortality rates were calculated at both national and provincial levels with selected characteristics including sex and residence status. RESULTS: Mortality of pancreatic cancer ranked the ninth and accounted for 1.38 percent of the total malignancy deaths. The crude and age standardized mortality rates of pancreatic cancer in China in the period of 1990-1992 were 1.48/100,000 and 1.30/100,000, respectively. Substantial regional variations in mortality rates across China were observed with adjusted mortality rates ranging from 0.43/100,000 to 3.70/100,000 with an extremal value of 8.7. Urban residents had significant higher pancreatic mortality than rural residents. CONCLUSION: The findings of this study show different mortality rates of this disease and highlight the importance of further investigation on factors, which might contribute to the observed epidemiological patterns.

[Changes of mortality rate for cervical cancer during 1970's and 1990's periods in China].

OBJECTIVE: To describe the distribution changes of the mortality rate for cervical cancer in China between the 1970's and 1990's and provide the scientific evidence for the prevention and control strategies for cervical cancer campaign in China between next century. METHODS: Data from two National Surveys for the Causes of Death in 1970's and 1990's in China. The crude and adjusted mortality rates for the cervical cancer and the distributions based on age and area were calculated and described. The comparison of the differences of changes between two mortality rates periods and together with its trends were shown based on the age-standardized. RESULTS: During two decades, the mortality rate for cervical cancer was 10.7 per 100,000 in 1970's which declined to 3.89 per 100,000 in 1990's, and from the 3rd ranking among all female malignant tumors to the 6th in 1990's (decreased about 63.64%). But the declination was not evenly. There have still been some high-risk areas, most located in rural countries in the mid-west of China, with rates remain unchanged and even at the highest level in the world, such as Wudu in Gansu and Yangcheng in Shanxi. A big difference was showed between rural country and city, but in both of them, the mortality rates in 1990's were significantly much lower than in 1970's (P = 0.001) at each five-year age group. And in the city, there was a much sharper increased trend in young women in 1990's. CONCLUSIONS: The mortality rate for cervical cancer campaign in China has been substantially declined during past twenty years, but it's still a major health problem for women, especially in rural China. The focus of the prevention and control for the cervical cancer in the next century should put on rural areas, especially in mid-west of China and young women in the city.