Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase

In addition to its role as an inhibitory neurotransmitter, γ-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 −/− mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 −/− mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 −/− mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.     

Oral iron chelators--development and application

Iron chelation therapy is the only therapeutic approach that leads to enhanced iron excretion in beta-thalassaemia major and other transfusion-dependent patients. Although desferrioxamine has been used in such treatment over the last three decades, it is not an ideal drug due to its poor oral availability. Consequently extensive research effort has been directed towards the identification of non-toxic, orally active iron chelators. An ideal candidate must possess a range of critical physicochemical and biological properties, such as high selectivity and affinity for iron(III), tightly controlled distribution and metabolic profiles and low toxicity. Unfortunately, hexadentate ligands are generally associated with poor oral bioavailability, whereas many tridentate and bidentate molecules are orally active. The tridentate triazoles have been investigated for clinical potential; they are readily absorbed from the gastrointestinal tract and promote iron excretion with high efficacy. In similar fashion, several bidentate hydroxypyridinones have been demonstrated to possess potential as oral chelating agents.     

The quest for improved air quality may push China to continue its CO2 reduction beyond the Paris Commitment

China is challenged with the simultaneous goals of improving air quality and mitigating climate change. The “Beautiful China” strategy, launched by the Chinese government in 2020, requires that all cities in China attain 35 μg/m³ or below for annual mean concentration of PM_2.5 (particulate matter with aerodynamic diameter less than 2.5 μm) by 2035. Meanwhile, China adopts a portfolio of low-carbon policies to meet its Nationally Determined Contribution (NDC) pledged in the Paris Agreement. Previous studies demonstrated the cobenefits to air pollution reduction from implementing low-carbon energy policies. Pathways for China to achieve dual targets of both air quality and CO₂ mitigation, however, have not been comprehensively explored. Here, we couple an integrated assessment model and an air quality model to evaluate air quality in China through 2035 under the NDC scenario and an alternative scenario (Co-Benefit Energy [CBE]) with enhanced low-carbon policies. Results indicate that some Chinese cities cannot meet the PM_2.5 target under the NDC scenario by 2035, even with the strictest end-of-pipe controls. Achieving the air quality target would require further reduction in emissions of multiple air pollutants by 6 to 32%, driving additional 22% reduction in CO₂ emissions relative to the NDC scenario. Results show that the incremental health benefit from improved air quality of CBE exceeds 8 times the additional costs of CO₂ mitigation, attributed particularly to the cost-effective reduction in household PM_2.5 exposure. The additional low-carbon energy polices required for China’s air quality targets would lay an important foundation for its deep decarbonization aligned with the 2 °C global temperature target.

China is facing serious air pollution problems, particularly for ambient PM_2.5 (particulate matter with aerodynamic diameter less than 2.5 μm) which has harmful effects on human health (1–3). To protect human health, strengthened air pollution control policies were recently implemented in China targeting 35 μg⋅m⁻³ or less for all cities by 2035 (4). The Action Plan on Prevention and Control of Air Pollution, released in 2013, has resulted in noticeable reductions in urban ambient PM_2.5 concentrations (5, 6). In 2018, however, China’s national PM_2.5 standard of 35 μg⋅m⁻³ annual average was exceeded in 217 of China’s 338 cities at the prefecture or higher level, not to mention exceedance of the World Health Organization (WHO) guideline (annual mean PM_2.5 concentration <10 μg⋅m⁻³). A big challenge for future improvement is that advanced end-of-pipe control technologies have already been widely applied in electric and industrial sectors (7, 8). For example, over 90% of coal-fired power plants had installed end-of-pipe control technologies by 2018 (8). Therefore, the potential for further reductions using end-of-pipe control measures might be limited, and implementation of low-carbon energy policies to constrain total energy consumption and promote a transition to clean energy is expected to be an inevitable option for further reducing air pollution (9).The impacts of climate change on humans and ecosystems have also received considerable attention in China over the past few decades, and strategies for mitigating these impacts have been adopted (10). In 2016, China officially signed its Nationally Determined Contribution (NDC) in the Paris Commitment, which pledges for CO₂ emissions per unit of GDP in 2030 to fall by 60 to 65% compared to 2005. A big concern arises as to whether China will continue its carbon reduction even under a pessimistic international situation after the US withdrawal from the Paris Agreement in 2019. Previous studies (11–18) have suggested that climate mitigation-oriented low-carbon energy policies can result in a reduction in air pollution.Therefore, there is a question as to whether China needs the application of low-carbon energy technologies and fuels to meet its air quality target. Such synergy is important, since many developing countries (e.g., China, India) are currently experiencing serious air pollution problems, and reducing air pollution is typically a more pressing national concern than climate mitigation (19). This could lead to continuous reductions in CO₂ emissions even under a pessimistic international situation for mitigating climate change.Here, we project future air quality attainment in China through 2035, assess the CO₂ reduction cobenefits associated with attaining the ambient PM_2.5 standards, and evaluate the health and climate impacts associated with air quality attainment-oriented energy policies. We accomplish this by coupling an integrated assessment model [GCAM, the Global Climate Assessment Model (20)], tuned with a detailed bottom-up emission inventory (21), and an air quality model [CMAQ, the Community Multiscale Air Quality model (22)] to evaluate future air quality and CO₂ emissions, and an integrated exposure−response (IER) model to evaluate the health effects due to the long-term ambient O₃ and both ambient and household PM_2.5 exposures in China. This integrated approach captures the nonlinearities among energy, emissions, concentrations, and health, thus allowing us to assess the cobenefits of air quality attainment on protecting health and mitigating CO₂ in an internally consistent framework.This study investigates future emissions of air pollutants and CO₂ in China under three future pathways with different considerations of two energy scenarios and two end-of-pipe control levels (Table 1). We first designed the NDC−current legislation (CLE) pathway to represent the CO₂ intensity reduction targets outlined by China’s NDC to meet the Paris Commitment (23), with CLE level of end-of-pipe controls. This pathway represents the current ongoing energy policies and end-of-pipe control measures to be conducted in China following CLE. For the purpose of air quality attainment, we first designed the NDC−maximum feasible reduction (MFR) pathway to represent the same ongoing energy policies as the NDC−CLE scenario, but with MFR level realized by end-of-pipe controls. Additionally, to achieve the air quality attainment in 2035, we also introduce the CBE−MFR pathway, in which low-carbon energy policies beyond the NDC requirements are implemented (i.e., the cobenefit energy scenario [CBE]) with the MFR level of end-of-pipe controls.Table 1.Design of future projection of air pollutant and CO₂ emissions

Simplified 13C-urea breath test for the diagnosis of Helicobacter pylori infection--the availability of without fasting and without test meal

The conventional 13C-urea breath test (13C-UBT) for detecting Helicobacter pylori infection was performed during fasting state and with a test meal to delay gastric emptying during the test. For the convenience of propagating this test, we assessed the availability of non-fast and without test meal in 13C-UBT for the diagnosis of H. pylori infection. One hundred and five consecutive patients who received endoscopic examination were studied. All of them received endoscopic biopsy for urease test, culture and histopathology to determine whether there was a presence of H. pylori infection. Each patient received four separate 13C-UBT under the following four testing conditions. Test I) fasting state with test meal (100 ml fresh milk), Test II) non-fast (taking usual food) but with test meal, Test III) fasting state without test meal, and Test IV) non-fast and without test meal. The excess delta 13CO2 values were calculated via the breathed samples that were collected at 15 minutes after ingestion of 13C-urea. There were 61 H. pylori positive and 44 negative patients in this study, with an excess delta 13CO2 values 3.0, 4.0, 3.5 and 4.0 as a cut-off value in the four tests respectively, according to the ROC curve. The results of test I, a conventional procedure, had a good correlation with the gold standard. The sensitivity and specificity were 100% and 95% respectively. The alternative procedures in other tests also have high sensitivity and specificity at 15-minute detecting time. The sensitivity of the tests II, III and IV at 15-minute detecting times were 98%, 98% and 100%, and the specificities of those were 95%, 98% and 95% respectively. We therefore suggest that fasting and test meal possibly be omitted when the cut-off value is 4.0 per mil in the simplified 13C-UBT (non-fast and without test meal, and detection at 15 minutes after ingestion of 13C-urea) which is a simple and available procedure for clinical diagnosis of H. pylori infection.     

HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner

Erythropoiesis in the adult mammal depends critically on erythropoietin, an inducible cytokine with pluripotent effects. Erythropoietin gene expression increases under conditions associated with lowered oxygen content such as anemia and hypoxia. HIF-1alpha, the founding member of the hypoxia-inducible factor (HIF) alpha class, was identified by its ability to bind and activate the hypoxia-responsive enhancer in the erythropoietin regulatory region in vitro. The existence of multiple HIF alpha members raises the question of which HIF alpha member or members regulates erythropoietin expression in vivo. We previously reported that mice lacking wild-type HIF-2alpha, encoded by the EPAS1 gene, exhibit pancytopenia. In this study, we have characterized the etiology of this hematopoietic phenotype. Molecular studies of EPAS1-null kidneys reveal dramatically decreased erythropoietin gene expression. EPAS1-null as well as heterozygous mice have impaired renal erythropoietin induction in response to hypoxia. Treatment of EPAS1-null mice with exogenous erythropoietin reverses the hematopoietic and other defects. We propose that HIF-2alpha is an essential regulator of murine erythropoietin production. Impairments in HIF signaling, involving either HIF-1alpha or HIF-2alpha, may play a prominent role in conditions involving altered hematopoietic or erythropoietin homeostasis.     

Factors associated with hip cartilage volume measured by magnetic resonance imaging: the Tasmanian Older Adult Cohort Study

OBJECTIVE: To compare associations between anthropometric and lifestyle factors and femoral head cartilage volume/thickness and radiographic features of osteoarthritis (OA) and to provide evidence of construct validity for magnetic resonance imaging (MRI) assessment of femoral cartilage volume and thickness. METHODS: We studied a cross-sectional sample of 151 randomly selected subjects (79 men, 72 women; mean age 63 years) from the Tasmanian Older Adult Cohort Study. A sagittal T1-weighted fat-suppression MRI scan of the right hip was performed to determine femoral head cartilage volume, cartilage thickness, and size. An anteroposterior radiograph of the pelvis with weight bearing was performed and scored for radiographic evidence of OA in the right hip. Other factors measured were height, weight, leg strength, serum vitamin D levels, and bone mineral density. RESULTS: Hip cartilage volume was significantly associated with female sex, body mass index, and femoral head size, whereas hip cartilage thickness was significantly associated only with the size of the femoral head. Only female sex was significantly associated with the total radiographic OA score and the joint space narrowing (JSN) score, but not the osteophyte score. Radiographic JSN of the hip, especially axial JSN (but not osteophytes), was significantly correlated with hip cartilage volume and thickness. CONCLUSION: Femoral head cartilage volume and thickness have modest but significant construct validity when correlated with radiographic findings. Furthermore, the generally stronger associations with volume compared with radiographic OA suggest that MRI may be superior at identifying risk factors for hip OA.     

肝硬化少见并发症的诊治

乳糜性及血性腹水、肝性胸水、少见病原菌感染的自发性腹膜炎、肝硬化心肌病、门静脉性肺动脉高压、肝硬化神经系统损伤等肝硬化少见并发症,临床医生尚缺乏充分的认识和/或及时有效的诊治。现介绍上述肝硬化少见并发症的临床特征、治疗及预后,以提高临床医生的认识和诊疗水平。     

南通市血吸虫病疫情预警监测研究

目的探索建立南通市血吸虫病疫情预警监测系统,为及时处置突发疫情提供依据。方法全市设立13个监测点,开展当地居民和外来流动人员监测查病,监测调查历史有螺区和输入性钉螺等。结果当地居民查病23426人,血检阳性率为0.38%,居民感染率为0;外来渔船民等流动人员监测查病3401人,血检阳性率为0.62%,外来居民感染率为0.029%,发现1例输入性急性感染病人。查出钉螺复现面积1.38hm^2,未发现感染性钉螺。未查到输入性钉螺。历史有螺环境改造率为34.90%。结论南通市仍有一定数量的残存钉螺孳生;有外来输入性病人存在,对本市血吸虫病的再流行将会构成潜在威胁,今后应加强疫情预警监测。     

5-脂氧合酶抑制TNF-α诱导的胰腺癌细胞凋亡

目的:检测胰腺癌细胞中5-脂氧合酶(5-lipoxygenase,5-LOX)及其代谢产物的表达情况,分析高表达5-LOX及LTB4对胰腺癌细胞生长凋亡的影响.方法:体外培养人胰腺癌细胞株ASPC-1,PANC-1和SW1990,并构建5-LOX基因稳定转染细胞株.用RT-PCR和Western blot检测细胞5-LOX mRNA和蛋白的表达,ELISA检测细胞培养上清中LTB4的含量,采用流式细胞仪、Annexin V/PI双染法检测TNF-α诱导细胞的细胞凋亡.结果:三种胰腺癌细胞株均表达5-LOX mRNA和蛋白,细胞上清中也都检测到一定量LTB4分泌.5-LOX基因稳定转染细胞株表达5-LOX和LTB4的水平上升.TNF-α(20μg/L)处理野生型SW1990细胞,12和24 h后凋亡率分别为25.4%±3.65%和43.5%±5.23%,但该效应在高表达5-LOX的细胞株中明显减弱,分别为13.2%±2.01%和21.7%±3.65%.在野生型SW1990细胞培养中加入外源性LTB4(10 nmol/L)能抑制TNF-α诱导的细胞凋亡,野生型与处理组细胞24 h后凋亡率有显著性差异(47.6%±5.32%vs 18.5%±5.69%,P<0.01).用LTB4受体阻断剂处理5-LOX高表达细胞株,能恢复其对凋亡诱导的敏感性.结论:胰腺癌细胞均能表达5-LOX并产生LTB4,高表达5-LOX能抑制TNF-α诱导的胰腺癌细胞凋亡.     

碱性成纤维细胞生长因子对自发性高血压大鼠血管平滑肌细胞肾素-血管紧张素系统的作用

以培养的自发性高血压大鼠（SHR）和正常血压（WKY）大鼠主动脉平滑肌细胞（ASMC）为模型,采用Northern印迹和逆转录-聚合酶链式反应（RT-PCR）技术分别检测ASMC中血管紧张素原（Ang N）和血管紧张素Ⅱ（Ang Ⅱ）的AT_1型受体的基因表达,并用紫外法和放射免疫法分别测定培养液中的血管紧张素Ⅰ转换酶（ACE）活性和AngⅡ的含量。结果表明,基础状态及给予外源性碱性成纤维细胞生长因子（bFGF,10 ng/ml）刺激后,SHR的ASMC中上述4种实验参数的水平均明显高于WKY大鼠。提示SHR ASMC中的肾素—血管紧张素系统（RAS）处于高功能状态;bFGF能促进Ang N基因表达、激活ACE,进而导致Ang Ⅱ生成增加,同时它对AT_1受体基因表达也有调节作用,bFGF的上述作用可能是高血压时血管RAS高功能状态发生和维持的一个重要机制。