Cerebrolysin for vascular dementia.

BACKGROUND: Although vascular dementia is the second most common cause of dementia globally, evidence-based treatments are still lacking. Cerebrolysin is a porcine brain-derived preparation that is said to have neurotrophic and neuroprotective activity. In many parts of the world Cerebrolysin, given as a series of daily intravenous infusions, is used as a potential intervention for vascular dementia. A previous Cochrane Review on Cerebrolysin in vascular dementia yielded inconsistent results. We wished to update the review to add new studies from the international literature and employ contemporary methods for appraising the strength of the evidence. This is the first update of a review first published in 2013. OBJECTIVES: Primary: to assess the effect of Cerebrolysin on cognitive function, global function, and all-cause mortality in people living with vascular dementia. Secondary: to assess the adverse effects of Cerebrolysin and to assess the effect of Cerebrolysin on quality of life and caregiver burden. SEARCH METHODS: We searched ALOIS, MEDLINE, Embase, PsycINFO, CINAHL, ISI Web of Knowledge, LILACS, the Cochrane Library, ClinicalTrials.gov, and the WHO ICTRP on 16 June 2017, 9 May 2018, and 9 May 2019. We expanded the search by adding four Chinese databases, searched from 1 January 2012 to 19 May 2019. We checked bibliographies of relevant papers identified and contacted pharmaceutical companies, trial authors, and experts in the field to identify any additional published or unpublished data. SELECTION CRITERIA: We included all randomised controlled trials of Cerebrolysin used in people living with vascular dementia. We applied no language restriction. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and evaluated their methodological quality. Data were extracted and analysed using mean differences (MDs) or standardised mean differences (SMDs) with 95% confidence intervals (95% CI) for continuous outcomes. We reported dichotomous outcomes as risk ratio (RR) with 95% CI. We assessed the strength of the available evidence using the GRADE approach. MAIN RESULTS: We identified six randomised controlled trials with a total of 597 participants that were eligible for inclusion in the 2013 review. No new studies were eligible for inclusion in this update. Participants in the included studies, where dementia severity was reported, had mild to moderate severity of vascular dementia (four trials). The included studies tested varying doses and duration of Cerebrolysin treatment. Follow-up ranged from 15 days to three years. Five of included studies were conducted in China (three studies), Russia (one study), and Romania (one study), while relevant information of other study was unclear. Where details of funding were available, all studies were supported by the pharmaceutical industry (three studies). Cognitive function was measured using the Mini-Mental State Examination (MMSE) or Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog+). Combining the MMSE and ADAS-cog+ data (three studies, 420 people), there was a beneficial effect of Cerebrolysin (SMD 0.36, 95% CI 0.13 to 0.58; very low-quality evidence). Global function was measured by Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC+) or Investigator's Clinical Global Impression (CGI). We assessed response rates on these measures (the proportion of participants with a CIBIC+ score of < 3; or at least moderate improvement of the CGI rating at the last visit). There was a beneficial effect of Cerebrolysin (two studies, 379 participants, RR 2.69, 95% CI 1.82 to 3.98; very low-quality evidence). Only one trial described mortality and reported no deaths. Four studies reported adverse events; data from two studies (379 people) were in a format that permitted meta-analysis, and there was no difference in rates of adverse effects (RR 0.91, 95% CI 0.29 to 2.85; very low-quality evidence). No studies reported on quality of life or caregiver burden. AUTHORS' CONCLUSIONS: Courses of intravenous Cerebrolysin improved cognition and general function in people living with vascular dementia, with no suggestion of adverse effects. However, these data are not definitive. Our analyses were limited by heterogeneity, and the included papers had high risk of bias. If there are benefits of Cerebrolysin, the effects may be too small to be clinically meaningful. There have been no new studies of Cerebrolysin in vascular dementia since the last Cochrane Review. Cerebrolysin continues to be used and promoted as a treatment for vascular dementia, but the supporting evidence base is weak. Adequately powered, methodologically robust trials are needed to properly assess the effects of Cerebrolysin in vascular dementia.

[Altered Functional Connectivity in Patients with Transient Ischemic Attack by Resting-state Functional MRI].

OBJECTIVE: To investigate longitudinal changes in functional connectivity during resting-state in patients with transient ischemic attack (TIA). METHODS: 35 patients first suffering TIA in the right hemisphere were recruited, with 35 healthy volunteers were recruited as control. At 1 week and 3 months after TIA attack, functional magnetic resonance imaging (fMRI) scans were performed, then resting-state functional connectivity was assessed and compared with that of healthy subjects. Right inferior prefrontal cortex (iPFC) and its mirror region was used as region of interest (ROI) in this analysis. RESULTS: Compared with controls, higher functional connectivity with the left cerebellum, right superior temporal gyrus (STG) and insula, and lower functional connectivity with the right middle frontal gyrus (MFG) was demonstrated in patients at 1 week after TIA; while decreased functional connectivity in right STG, left insula and bilateral thalamus was shown in patients at 3 month after TIA. Correlation analysis found that functional connectivity of right iPFC with the cerebellum and insula was positively correlated with 2-back reaction time at 1 week after TIA. CONCLUSION: Although the nervous system signs of TIA can be quickly recovered, abnormal activation of working memory-related brain regions will occur for a long time.

Correction to: Cost-effectiveness analysis of rotavirus vaccination in China: Projected possibility of scale-up from the current domestic option.

After the publication of our article [1] we have been made aware of a number of mislabelling and reporting errors, which were introduced in the preparation of the manuscript. The conclusions are not affected by these errors and thus remain unchanged.

Cost-effectiveness analysis of rotavirus vaccination in China: Projected possibility of scale-up from the current domestic option.

BACKGROUND: Rotavirus infection causes considerable disease burden of acute gastroenteritis (AGE) hospitalization and death among children less than 5 years in China. Although two rotavirus vaccines (Rotarix and RotaTeq) have been licensed in more than 100 countries in the world, the Lanzhou Lamb rotavirus vaccine (LLR) is the only vaccine licensed in China. This study aims to forecast the potential impacts of the two international vaccines compared to domestic LLR. METHODS: An economic evaluation was performed using a Markov simulation model. We compared costs at the societal aspect and health impacts with and without a vaccination program by LLR, Rotarix or RotaTeq. Parameters including demographic, epidemiological data, costs and efficacy of vaccines were obtained from literature review. The model incorporated the impact of vaccination on reduction of incidence of rotavirus infection and severity of AGE indicated by hospitalization, inpatient visits and deaths. Outcomes are presented in terms of quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratio (ICER) compared to status quo. RESULTS: In a hypothetical cohort of 100,000 infants, the two international vaccines showed very good cost-effectiveness, with ICER of Rotateq and Rotarix shifting from LLR of $1715.11/QALY and $2105.66/QALY, respectively. Rotateq and Rotarix had significantly decreased incidence compared to LLR, particularly among infants aged 6 months to 2 years. CONCLUSIONS: RotaTeq is expected to introduce in the national routine immunization program to reduce disease burden of rotavirus infection with universal coverage.

Can economic growth and carbon emissions reduction be owned: evidence from the convergence of digital services and manufacturing in China.

Under the background of the deep convergence of China's digital services and manufacturing, it is of great significance to investigate the effects of the convergence of digital services and manufacturing on economic growth and carbon emissions reduction to the application of digital technology in the whole world. This paper constructs a simultaneous equation model and uses three-stage least squares to estimate the effect and mechanism of industrial convergence on economic growth and carbon emissions. The results show that (i) industrial convergence improves the change of total factor productivity (TFP) and the change of technical efficiency, and the reduction of carbon emissions is the main factor driving the growth of TFP and technical efficiency; (ii) industrial convergence and carbon emissions show a significant U-shaped relationship; (iii) the heterogeneity analysis shows that the convergence of capital-intensive, technology-intensive and labor-intensive manufacturing with digital services will help to improve the growth of TFP, it can inhibit carbon emissions first and then promote it. Therefore, the government should take targeted measures to promote industrial convergence of digital services and manufacturing according to the economic development and industry characteristics, so as to give full play to its positive role in economic growth and emissions reduction.

The Portevin-Le Chatelier Effect of Cu-2.0Be Alloy during Hot Compression.

The Portevin-Le Chatelier effect of Cu-2.0Be alloy was investigated using hot isothermal compression at varying strain rates (0.01-10 s-1) and temperature (903-1063 K). An Arrhenius-type constitutive equation was developed, and the average activation was determined. Both strain-rate-sensitive and temperature-sensitive serrations were identified. The stress-strain curve exhibited three types of serrations: type A at high strain rates, type B (mixed A + B) at medium strain rates, and type C at low strain rates. The serration mechanism is mainly affected by the interaction between the velocity of solute atom diffusion and movable dislocations. As the strain rate increases, the dislocations outpace the diffusion speed of the solute atoms, limiting their ability to effectively pin the dislocations, resulting in lower dislocation density and serration amplitude. Moreover, the dynamic phase transformation triggers the formation of nanoscale dispersive ß phases, which impede dislocation and cause a rapid increase in the effective stress required for unpinning, leading to the formation of mixed A + B serrations at 1 s-1.

Clinical Performance of a Dedicated Urine-Based Assay for the Detection of Human Papillomavirus and Cervical Intraepithelial Neoplasia.

Objective: The objective of this study is to assess the clinical performance of a urine-based high-risk human papillomavirus (hrHPV) test for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). Methods: Between September and December 2021, women aged 20 to 65 years referred to colposcopy clinic were prospectively recruited at three clinical centers in China. Paired urine and cervical specimens from all enrolled women were obtained for hrHPV DNA fluorescence quantitative PCR test. The results of liquid-based cytology (LBC), colposcopy and diagnostic biopsies were collected. We evaluated the sensitivity and specificity for CIN and assessed the agreement/kappa value. Results: A total of 732 women (median age, 40 years) with valid results were included in the study, and 130 (17.8%) women were histologically confirmed as CIN2+. The sensitivity of urine and cervical test for CIN2+ and CIN3+ were 87.69% and 85.45%, respectively. The specificity of urine test performed better than cervical test in women with

[Characterization of Sludge Morphology and Bacterial Community Evolution in the Rapid Activation of Freeze-stored PN/A Granular Sludge].

Inoculating granular sludge is an alternative method for the quick start-up of a high-performance autotrophic nitrogen removal reactor. In order to establish the response relationship between sludge activation and reactor performance, the freeze-stored granular sludge was inoculated into a continuous-flow reactor, and a control strategy of the high loading rate and high hydraulic selective pressure was carried out in this study. As a result, a one-stage partial nitritation/ANAMMOX process was started up in 34 days, and the removal efficiency of total nitrogen was over 83%, with a removal loading rate of total nitrogen of 1.67 kg·(m3·d)-1. During this period, the Image pro-plus software was employed to analyze the evolution of the characteristic dimensions of particles. A good linear positive correlation (R2=0.988) between the projected area of the erythrine zone in the inner layer and the specific nitrogen removal rate of granules was found, which provide a simple method to estimate the activity of the PN/A granules. The results of MiSeq high-throughput sequencing showed that the enrichment of aerobic ammonia-oxidizing bacteria (Nitrosomonas) and the wash-out of heterotrophic bacteria (such as Denitratisoma and Haliangium, etc.) were achieved in the start-up of the reactor. Meanwhile, the improvement in granular compactness was in favor of activating anaerobic ammonia oxidizing bacteria (Candidatus_Kuenenia, abundance>30%) that colonized the inner layer of the granules.

ProNGF/NGF Modulates Autophagy and Apoptosis through PI3K/Akt/mTOR and ERK Signaling Pathways following Cerebral Ischemia-Reperfusion in Rats.

NGF is involved in the process of autophagy; however, the underlying mechanisms of proNGF/NGF on autophagy in cerebral ischemia-reperfusion (CIR) remain unclear. This study explored the potential pathway of proNGF/NGF in mediating autophagy and apoptosis and thereby contributed to poststroke neurological rehabilitation. In this study, PC12 cell lines and male SD rats were used to simulate CIR; it was found that within 24 h reperfusion, proNGF was the predominant form of Ngf while after 24 h NGF was produced by proNGF transformation. The mature NGF was found to protect neurons against autophagic and apoptotic damage caused by CIR, but proNGF can cause both autophagic and apoptotic neuronal damage. The protective effect of NGF is associated with the activation of the PI3K/Akt/mTOR and ERK pathway and, as well as the change of autophagy-related proteins. On the other hand, proNGF promoted the ERK pathway increasing autophagy and affected the apoptosis-related proteins in vivo and in vitro. These results were also verified in male SD rats with CIR that neurological deficit caused by CIR can be rescued by recombinant and wild-type NGF, and vice-versa by proNGF.

Low-dose statin pretreatment reduces stroke severity and improves functional outcomes.

OBJECTIVES: Pre-stroke statin use reduces stroke severity and improves functional outcomes; however, whether low-dose statins as a primary preventive measure have similar effects on the Chinese population remains unclear. METHODS: Consecutive cases of ischaemic stroke between May 2011 and January 2017 were retrospectively analysed. The primary endpoints were stroke severity on admission and functional outcomes at 90 days. The secondary endpoints were factors related to lower stroke severity on admission. Propensity score matching and logistic regression analyses were performed. RESULTS: Of the 1878 patients, 6.4% and 23.8% were pre-stroke statin users before and after propensity matching, respectively, reducing the National Institutes of Health Stroke Scale (NIHSS) score on admission from 5 (2-9) to 3 (2-4) (P < 0.001). Patients receiving pretreatment with low-dose statins tended to have a better mRS distribution (median mRS score 2 [1-3] vs. 3 [2-4], P = 0.007) and a higher likelihood of favourable functional outcomes (FFOs) at 90 days (61 [65.6%] vs. 151 [50.8%], P = 0.005). The logistic regression analysis showed that low-dose statins taken before stroke (odds ratio [OR] = 0.15, 95% confidence interval [CI] = 0.08-0.27, P < 0.001) and being male (OR = 0.81, 95% CI = 0.66-0.99, P = 0.035) were related to a lower stroke severity on admission but not among patients with atrial fibrillation (OR = 1.65, 95% CI = 1.12-2.44, P = 0.012) or elevated white blood cell (WBC) counts (OR = 1.12, 95% CI = 1.08-1.17, P < 0.001). CONCLUSIONS: Pretreatment with low-dose statins reduced initial stroke severity, improved functional outcomes at 90 days and was independently associated with a lower stroke severity on admission among Chinese patients.

A novel large animal model of recurrent migraine established by repeated administration of inflammatory soup into the dura mater of the rhesus monkey.

Several animal models of migraine have been established, and those based on trigeminovascular system activation are widely accepted. However, most of these models have been established on lower animals, such as rodents, and involve only a single administration of a noxious stimulus. In this study, an inflammatory soup (10 µL), consisting of prostaglandin E2 (0.2 mM), serotonin (2 mM), bradykinin (2 mM) and histamine (2 mM), was injected into the dura mater of conscious rhesus monkeys through an indwelling catheter. The infusion started on day 8 and was repeated every 3 days, for a total of six administrations, to induce neurogenic inflammation. We performed behavioral assessments and measured the expression of the oncogene c-fos, neuronal nitric oxide synthase (nNOS) and calcitonin gene related peptide (CGRP) in the trigeminal system and in multiple brain regions involved in pain processing by immunohistochemical staining. Compared with monkeys in the control group, three of the four animals in the inflammatory soup group displayed decreased motor behaviors, and two showed increased ipsilateral nose and mouth secretions during the stimulus period. Higher expression levels of c-fos, nNOS and CGRP were found in various brain areas of experimental animals compared with controls, including the trigeminal nucleus caudalis, thalamus, hypothalamus, midbrain, pons and other areas involved in pain perception. These results suggest that repeated inflammatory soup stimulation of the dura activates the trigeminovascular system and produces migraine-like pathological changes and abnormal behaviors in conscious rhesus monkeys.

[Evaluation of genomic amplification of the human telomerase RNA component gene in the screening of cervical lesions].

OBJECTIVE: To investigate the genomic amplification of the human telomerase RNA component (hTERC) gene in cervical cytology and evaluate its role in screening of cervical lesions. METHODS: A total of 301 cases were recruited, with liquid-based cytology diagnoses as normal (n = 203), atypical squamous cells (ASC, n = 66), low-grade squamous intraepithelial lesions (LSIL, n = 18), and high-grade squamous intraepithelial lesions (HSIL, n = 14). Following cytological examination, the slides were analyzed using a two-color fluorescence in situ hybridization (FISH) probe targeted to chromosome 3q26 containing hTERC. The hTERC findings were compared to the cytologic and histologic results, as well as high-risk human papilloma viruses (HPV) results. RESULTS: Genomic amplification of hTERC was found in 3.0% (6/203) of normal specimens, 21.2% (14/66) of ASC, 44.4% (8/18) of LSIL and 92.9% (13/14) of HSIL, with a significant difference in each pair wise (all P < 0.05). Significantly more cells with 3q26 gain were found in cervical intraepithelial lesion (CIN)II than in CINI (75.0% vs. 20.0%), as well as in CINIII (86.7% vs. 20.0%) and squamous cervical cancer (SCC) than in CINI (100.0% vs. 20.0%)(all P < 0.01). The sensitivity of hTERC amplification was significantly higher than cytological screening (82.6% vs. 17.4%, P < 0.01), and its specificity was higher than high-risk HPV test (67.8% - 73.5% vs. 25.6% - 27.7%, P < 0.01) in the diagnosis of HSIL (CINII - III). The abnormal hTERC signal type mostly was 2:3 in CINI (84.9%); whereas in CINII - III, 2:3, 2:4 and 4:4 accounted for 44.6%, 24.8% and 17.8%, respectively. CONCLUSION: Testing the gain of chromosome 3q26 in cytological specimens using specific probe for hTERC is powerful in screening of HSIL, and the amplification patterns of 2:4 and 4:4 may serve as potential prognosis markers.

[Study on the correlation between human papillomavirus infection and cervical lesion among women living in community of Beijing].

OBJECTIVE: To observe the correlation between human papillomavirus (HPV) infection and cervical lesion among women living in community of Beijing. METHODS: A total of 795 women at age 20-54, living in Zhanlanlu District of Beijing were screened for cervical lesion. Samples of cervical cytology (LCT) and HPV test (hc2) were collected. Colposcopy and biopsy were conducted in women with positive LCT. RESULTS: In those 795 women, the infection rate of HPV was 14.1% (112/795). In 40 women who were LCT positive 1 early invasive cervical cancer, 4 cervical intra-epithelial neoplasia (CIN3), 3 CIN2 and 7 CIN1 were noticed. In 750 women with negative LCT, 5 CIN1 and 1 low-grade CGIN were diagnosed. In those women who were Cyto(+) and HPV(+), 15 cases (55.6%, 15/27) were diagnosed with > or = CIN1 (including 7 CIN1, 3 CIN2, 4 CIN3 and 1 early invasive cancer). CONCLUSION: The risk of cervical lesion significantly increased in women showing positive in cytology and HPV test.