Intravenous thrombolysis with 0.9 mg/kg alteplase for acute ischaemic stroke: a network meta-analysis of treatment delay.

OBJECTIVES: The aim of this study was to evaluate the effect of alteplase in intravenous thrombolysis of acute ischaemic stroke (AIS) regarding the different time windows of treatment (<3 hours, 3-4.5 hours, >4.5 hours). METHODS: A systematic literature search was conducted from PubMed, Cochrane Library and Embase. 12 clinical randomised controlled trials with 3402 patients with AIS met the inclusion criteria. The primary, secondary and tertiary outcomes were modified Rankin Scale (mRS) scores 0-1, mortality at 90th day after treatment and symptomatic intracerebral haemorrhage within 36 hours, respectively. Network meta-analysis and conventional meta-analysis were carried out for calculating odds ratio (OR), the surface under cumulative ranking curve (SUCRA) and the probabilities of being the best. RESULTS: For mRS, alteplase regardless of time delay was significantly more effective than placebo (OR 1.33-2.17). However, alteplase used within 3 hours after AIS occurrence (SUCRA=98.3%) was significantly more effective (OR=1.64) than that at 3-4.5 hours (SUCRA=43%) and showed the trend of priority (OR=1.47) compared with that beyond 4.5 hours (SUCRA=58%). For the mortality, compared with placebo (SUCRA=64.7%), alteplase within 3 hours was similar to that of 3-4.5 hours whereas alteplase beyond 4.5 hours (SUCRA=7.3%) showed the trend of significantly increasing 85% mortality. For the tertiary outcome, alteplase within 3 hours (SUCRA=19.0%) was comparable with placebo (SUCRA=99.9%) whereas alteplase beyond 3 hours significantly increased (OR 5.89-6.67) the symptomatic intracerebral haemorrhage. CONCLUSIONS: Alteplase within 3 hours should be recommended as the best treatment delay for its best efficacy among all the intervention and equivalent safety compared with placebo. Alteplase beyond 3 hours was less effective compared with that within 3 hours and increased the risk of mortality on 3 months as well as symptomatic intracerebral haemorrhage at 36 hours. More head-to-head clinical trials are needed to confirm those findings.

The central trend in crop yields under climate change in China: A systematic review.

Evidence from numerous studies has confirmed the impact of climate change on crop yields in China since the IPCC AR4. However, the results from different studies can differ widely due to differences in crops, regions, scenarios, and analytical approaches. We assessed the projected impacts of climate change on the yield of major crops (wheat, rice, and maize) in China using a systematic review at the national and subregional levels based on a data set of 667 published simulations. The results show that (1) the impact of climate change on crop yields was mainly reflected in temperature increases, with an average yield loss of 2.58% per °C at the national level. Subregional yield changes ranged from -12.70% to -2.57% per °C, with crop yields being more vulnerable in Northeast China and Northwest China than in other subregions. (2) The yields of crop samples that included CO2 effects were 9.23% higher than the yields of those without CO2 effects. (3) Evidence of the impacts of precipitation on crop yield was robust for Northeast China, Northwest China and North China and was absent or contradictory for the other subregions. (4) Of the three different crops, the response of wheat yields to warming was the most evident, especially in Northwest China, followed by that of maize yields in Northeast China. The negative effects of temperature increases on rice yields were significant at the national level but not at the subregional level. This study synthesized the results from all available studies in a systematic and unbiased manner and provided a robust assessment of the likely impacts of climate change on crop yields.

What Is the Consensus from Multiple Conclusions of Future Crop Yield Changes Affected by Climate Change in China?

Many studies have shown that climate change has a significant impact on crop yield in China, while results have varied due to uncertain factors. This study has drawn a highly consistent consensus from the scientific evidence based on numerous existing studies. By a highly rational systematic review methodology, we obtained 737 result samples with the theme of climate change affecting China's crop yields. Then, we used likelihood scale and trend analysis methods to quantify the consensus level and uncertainty interval of these samples. The results showed that: (i) The crop yield decrease in the second half of the 21st century will be greater than 5% of that in the first half. (ii) The crop most affected by climate change will be maize, with the decreased value exceeding -25% at the end of this century, followed by rice and wheat exceeding -10% and -5%. (iii) The positive impact of CO2 on crop yield will change by nearly 10%. Our conclusions clarify the consensus of the impact of future climate change on China's crop yield, and this study helps exclude the differences and examine the policies and actions that China has taken and should take in response to climate change.

JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro.

The present study shows that JAK2-STAT3 inflammatory signaling mediates thrombin-stimulated microglia activation. In rat primary microglia, thrombin rapidly activated JAK2 and induced phosphorylation of STAT3. In addition, thrombin increased transcription of the inflammation-associated genes tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), production of TNF-alpha, NO and induced neurodegeneration of dopaminergic neurons in mesencephalic cultures. AG490, a JAK inhibitor, markedly reduced activation of JAK2 and STAT3 in thrombin-treated microglia. AG490 also inhibited thrombin-induced transcription and expression of TNF-alpha, iNOS and/or NO release, moreover rescued dopaminergic neurons. These results suggest that JAK2-STAT3 signaling pathway plays a critical role in mediating thrombin-induced activation of microglia and degeneration of dopaminergic neurons.

Protective effect of erythropoietin on beta-amyloid-induced PC12 cell death through antioxidant mechanisms.

Erythropoietin (EPO), a haematopoietic growth factor has been reported to display neuroprotective properties in different animal models. In the present study, we investigated the neuroprotective effects of EPO on Abeta(25-35)-induced neuronal toxicity and its potential mechanisms in PC12 cells. Abeta(25-35) significantly reduced cell viability and increased the number of apoptotic-like cells. In addition, increased ROS production and decreased mitochondrial membrane potential were also found after Abeta(25-35) exposure. All of these phenotypes induced by Abeta(25-35) were markedly reversed by EPO. Pretreatment with EPO prior to Abeta(25-35) exposure significantly elevated cell viability, reduced Abeta(25-35)-induced apoptosis, decreased ROS production, and stabilized mitochondrial membrane potential. Furthermore, EPO also attenuated the downstream cascade following ROS, including Bcl-2/Bax, and caspase-3 activation. Our results suggest that EPO holds potential for neuroprotection and therefore, may be promising for the treatment of Alzheimer's disease.

Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy.

PURPOSE: To present the biochemical cure rates (biochemically no evidence of disease) after external irradiation (RT) in patients with high-risk prostate cancer after radical prostatectomy. METHODS AND MATERIALS: Seventy-six patients who underwent radical prostatectomy and subsequent RT were included in this analysis. No patient received hormonal therapy. Adjuvant RT was administered in 35 patients (46%), and 41 patients (54%) underwent salvage RT. After prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy and 65 Gy, respectively. The biochemical cure rate was defined as a serum prostate-specific antigen of < or =0.2 ng/mL. RESULTS: The overall 5-year Kaplan-Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical cure rate for adjuvant RT was significantly superior to that after salvage RT (86% vs. 57%). The significant predictors of biochemical failure were seminal vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or 5 in the salvage RT group. The clinical local control rate in the prostate bed was 100%. CONCLUSION: This report demonstrates the efficacy of RT in achieving high biochemical cure rates after radical prostatectomy. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT.

JAK2/STAT5/Bcl-xL signalling is essential for erythropoietin-mediated protection against apoptosis induced in PC12 cells by the amyloid ß-peptide Aß25-35.

BACKGROUND AND PURPOSE: Erythropoietin (EPO) exerts neuroprotective actions in the CNS, including protection against apoptosis induced by the amyloid ß-peptide Aß25-35 . However, it remains unclear which signalling pathway activated by EPO is involved in this neuroprotection. Here, we have investigated whether JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways are essential for EPO-mediated protection against apoptosis induced by Aß25-35 . EXPERIMENTAL APPROACH: EPO was added to cultures of PC12 cells, 1 h before Aß25-35 . For kinase inhibitor studies, AG490 and PD98059 were added to PC12 cells, 0.5 h before the addition of EPO. Transfection with siRNA was used to knockdown STAT5. Activation of JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways were investigated by Western blotting. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide assay and apoptosis was detected by TUNEL and acridine orange-ethidium bromide double staining. KEY RESULTS: EPO increased phosphorylation of JAK2 and STAT5 in PC12 cells treated with Aß25-35 . Furthermore, EPO modulated the nuclear translocation of phospho-STAT5, which increased expression of Bcl-xL and decreased levels of caspase-3. These beneficial effects were blocked by the JAK2 inhibitor, AG490 or STAT5 knockdown. However, the ERK1/2 pathway did not play a crucial role in our model. CONCLUSIONS AND IMPLICATIONS: EPO protected PC12 cells against Aß25-35 -induced neurotoxicity. Activation of JAK2/STAT5/Bcl-xL pathway was important in EPO-mediated neuroprotection. EPO may serve as a novel protective agent against Aß25-35 -induced cytotoxicity in, for instance, Alzheimer's disease.

Erythropoietin protects PC12 cells from beta-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway.

Although the etiology of Alzheimer's disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-beta (Abeta) in the initiation/progression of the disease. In this study, we investigated protective effects of erythropoietin (EPO) on Abeta(25-35)-induced cell death in cultured rat pheochromocytoma cells (PC12 cells). EPO (2U/ml) in combination with Abeta(25-35) increased the cell viability and reduced the number of apoptotic cells by MTT assay, Trypan blue dye exclusion method, TUNEL staining and Hoechst 33342 staining. In mechanistic study, EPO induced time-dependent phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. Treatment of PC12 cells with PI3K inhibitors LY294002 abolished the protective effects of EPO. EPO also induced the phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3K/Akt, and GSK-3beta inhibitors lithium chloride blocked Abeta(25-35)-induced cell apoptosis in a manner similar to EPO, suggesting that GSK-3beta inhibition is involved in EPO-mediated cytoprotection. Moreover, the expression of anti-apoptotic protein Bcl-2 was increased by EPO involving PI3K/Akt pathway. These studies demonstrate that EPO is an effective neuroprotective agent and is a viable candidate for treating AD.

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo.

OBJECTIVE: To evaluate the role of thrombin-activated microglia in the neurodegeneration of nigral dopaminergic neurons in the rat substantia nigra (SN) in vivo. METHODS: After stereotaxic thrombin injection into unilateral SN of rats, immunostaining, reverse transcription polymerase chain reaction (RT-PCR) and biochemical methods were used to observe tyrosine hydroxylase (TH) immunoreactive positive cells, microglia activation, nitric oxide (NO) amount and inducible nitric-oxide synthase (iNOS) expression. RESULTS: (1) Selective damage to dopaminergic neurons was produced after thrombin injection, which was evidenced by loss of TH immunostaining in time-dependent manner; (2) Strong microglial activation was observed in the SN; (3) RT-PCR demonstrated the early and transient expression of neurotoxic factors iNOS mRNA in the SN. Immunofluorescence results found that thrombin induced expression of iNOS in microglia. The NO production in the thrombin-injected rats was significantly higher than that of controls (P < 0.05). CONCLUSION: Thrombin intranigral injection can injure the dopaminergic neurons in the SN. Thrombin-induced microglia activation precedes dopaminergic neuron degeneration, which suggest that activation of microglia and release of NO may play important roles in dopaminergic neuronal death in the SN.

An analysis of lesion size and location in newly diagnosed cytomegalovirus retinitis.

OBJECTIVE: To investigate the size and distribution of lesions in newly diagnosed cytomegalovirus retinitis (CMVR). DESIGN: Retrospective, observational case series. PARTICIPANTS: Fundus photographs of 252 newly diagnosed CMVR lesions in 173 eyes of 130 patients (123 male, 7 female). METHODS: Thirty-five millimeter (60 degrees ) color transparencies were digitized. A montage of the retina was assembled for each involved eye and was superimposed on a specially designed map of the postequatorial retina. Cytomegalovius retinitis lesions were delineated, and the size and location of each lesion was measured. The size of newly diagnosed CMVR lesions was computed in terms of percent postequatorial retinal surface area (PERSA), and the location of lesions was plotted on a polar coordinate system. MAIN OUTCOME MEASURES: Size and location of patches of newly diagnosed CMVR. RESULTS: The median lesion size was 3% PERSA. Peripheral CMVR lesions were larger than posterior ones (P < 0.001). The mean number of lesions was 1.6 per eye. The total area of CMVR involvement ranged from 1% to 76% PERSA, with a median of 5% PERSA. There was no difference between left and right eyes in the distribution of lesion centers (P = 0.27). The concentric distribution of lesion centers appeared to be homogeneous, except for fewer centers in the most peripheral 14 degrees (P < 0.001), and a greater than expected number of lesion centers in the macula (central 11.6 degrees, P < 0.001). Eyes of patients with unilateral retinitis had 1.3 lesions per involved eye compared with eyes of patients with bilateral retinitis, which had 1.6 lesions per eye (P = 0.003). CONCLUSIONS: Most newly diagnosed CMVR lesions were small. Peripheral lesions were larger than more posterior lesions. Variations from a homogeneous distribution of lesions were noted only at the extreme peripheral and central locations and are probably explained by ascertainment bias. The macula was not spared from new CMVR lesions in this patient population.

Effects of two types of tongue strengthening exercises in young normals.

This pilot study examines the effects of two types of tongue strengthening exercises on tongue function measures of strength and endurance in a group of 31 healthy young subjects. Subjects underwent baseline and 1 month post-baseline assessments of tongue function and were randomized to one of three groups, including: (1) no exercise; (2) exercise group receiving standard tongue strength exercises using a tongue depressor, and (3) exercise group receiving tongue strengthening exercises using the Iowa Oral Performance Instrument. Results revealed a significantly greater change in maximum tongue strength in the group that received any treatment compared with the group receiving no treatment (p = 0.04). Results provide support for the theory that tongue strengthening exercises improve tongue strength in healthy young subjects.

A factor analysis of chronic fatigue symptoms in a community-based sample.

BACKGROUND: This study examined characteristics of fatigue in individuals with chronic fatigue from a community-based study. Most studies of chronic fatigue have been based on patients recruited from primary or tertiary care settings. Samples such as these might not be representative of patients within the general population. The purpose of this study was to determine the factor structure of participants' symptoms in a random community sample of individuals with chronic fatigue. METHOD: A random sample of 18,675 respondents in Chicago received a brief telephone questionnaire designed to identify individuals with chronic fatigue. A group of 780 (4.2%) with chronic fatigue received further interview via telephone questionnaire involving characteristics of their fatigue. The analyses for this study were based on those people identified with having chronic fatigue. A factor analysis was conducted on responses to questionnaire items, and a four-factor solution emerged. Mean factor scores were derived and analyzed in relation to sociodemographic characteristics and sample subgroups. RESULTS: The four factors were labeled: Lack of Energy, Physical Exertion, Cognitive Functioning, and Fatigue and Rest. CONCLUSIONS: Results indicated that individuals with chronic fatigue have symptoms that can be differentiated into theoretically distinct factors.