妊娠期糖代谢异常孕妇血脂水平与围产结局的关系

目的 分析妊娠期糖代谢异常孕妇血脂水平与围产结局的关系。方法选 择确诊为妊娠期糖代谢异常的孕妇358例,包括妊娠合并糖尿病（DM）28例（DM组）,妊娠期糖尿病（GDM）178例（GDM组）,妊娠期糖耐量受损（GIGT）152例（GIGT组）,用Beckman—CX9型全自动生化分析仪测定血清总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL—C）及低密度脂蛋白胆固醇（LDL—C）,详细记录各组孕妇确诊时血脂水平及孕妇年龄、孕周、检测时间、治疗方法、并发症等。结果 （1）GIGT组与GDM组TG分别为（2．7±0．7）mmoL／L和（2．9±0．7）mmoL／L,TC分别为（6．2±1．1）mmol／L和（6．7±1．9）mmol／L,HDL—C分别为（1．78±0．22）mmol／L和（1．64±0．31）mmol／L,LDL-C分别为（3．8±0．9）mmol／L和（3．7±0．8）mmol／L,两两比较,差异均无统计学意义（P〉0．05）;DM组TG和LDL—C分别为（3．6±0．9）mmol／L和（4．8±0．6）mmol／L,均高于GIGT组和GDM组,而HDL-C[（1．24±0．19）mmol／L]低于GIGT组和GDM组,差异均有统计学意义（P〈0．05）。（2）DM组、GDM组、GIGT组,子痫前期发生率分别为35．7％（10／28）、16．8％（30／178）和14．5％（22／152）;早产发生率分别为39．3％（11／28）、16．8％（30／178）和19．7％（30／152）,分别比较,差异均有统计学意义（P均〈0．05）;羊水过多、胎膜早破发生率3组比较,差异无统计学意义（P〉0．05）;胎儿窘迫发生率GDM组低于GIGT和DM组,分别为9．8％（15／152）、20．2％（36／178）和21．4％（6／28）;GDM组和GIGT组巨大儿发生率高于DM组,分别为11．2％（20／178）、14．5％（22／152）和3．5％（1／28）,分别比较,差异均有统计学意义（P〈0．05）。结论 妊娠期糖代谢异常孕妇血脂水平是监测围产结局的有效指标之一,有效降低血脂水平能降低子痫前期和早产的发生率。     

The acquisition of cold sensitivity during TRPM8 ion channel evolution

To cope with temperature fluctuations, molecular thermosensors in animals play a pivotal role in accurately sensing ambient temperature. Transient receptor potential melastatin 8 (TRPM8) is the most established cold sensor. In order to understand how the evolutionary forces bestowed TRPM8 with cold sensitivity, insights into both emergence of cold sensing during evolution and the thermodynamic basis of cold activation are needed. Here, we show that the trpm8 gene evolved by forming and regulating two domains (MHR1-3 and pore domains), thus determining distinct cold-sensitive properties among vertebrate TRPM8 orthologs. The young trpm8 gene without function can be observed in the closest living relatives of tetrapods (lobe-finned fishes), while the mature MHR1-3 domain with independent cold sensitivity has formed in TRPM8s of amphibians and reptiles to enable channel activation by cold. Furthermore, positive selection in the TRPM8 pore domain that tuned the efficacy of cold activation appeared late among more advanced terrestrial tetrapods. Interestingly, the mature MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in TRPM8 cold activation. Our results reveal the domain-based evolution for TRPM8 functions and suggest that the acquisition of cold sensitivity in TRPM8 facilitated terrestrial adaptation during the water-to-land transition.

Given that temperature influences all biological operations, the evolution of thermosensory adaptation is crucial in shaping the specialized temperature-dependent inhabitation of an organism. At the cellular level, thermosensory neurons in the dorsal root ganglia or trigeminal ganglia innervate the skin and transmit temperature information to the spinal cord and the brain. To bestow such neurons with thermal sensitivity, animals have a toolkit of temperature-sensitive ion channels located on the cell membrane at the molecular level. Accordingly, several members of the transient receptor potential (TRP) superfamily with steep thermosensitivity (referred to as thermoTRP) have attracted the general interest in the field of thermal biology, as they sufficiently cause steep changes in depolarizing currents upon either heating or cooling and thus are considered as the primary molecular sensors of temperature (1–4). Therefore, the evolutionary strategy for directly tuning the thermal activation in thermoTRPs can be employed by animals for their specialized thermosensory adaptation, as seen in vampire bats, pit-bearing snakes, platypus, penguins, squirrels, and camels (5–9).As heat sensation (warmth and extreme heat) provides the precondition of a fundamental and conserved biological survival process, the genes that encode heat sensors are considered ancient in many metazoan organisms. The annotation of trpv1 is consistently available in the genomes of fishes, insects, amphibians, reptiles, birds, and mammals. Despite the species-specific temperature-sensitive ranges, a growing number of studies have reported the functional convergence of these heat-sensitive thermoTRP orthologs at the protein level (10), suggesting the essential role of these channels in heat perception across species. Compared to heat sensors, the cold-sensitive thermoTRP likely evolved late. As the most established cold sensor responsive to low temperatures and cooling compounds, transient receptor potential melastatin 8 (TRPM8) was found in somatosensory neurons, and genetic ablation of trpm8 either in the neurons or mice led to a largely decreased cold sensitivity (4, 11–13). Interestingly, cold activation of amphibian TRPM8 has been tested (14), while sequencing efforts indicated the absence of the trpm8 gene in 12 fish species from 10 different orders (15). Several specific domains that may alter TRPM8 cold activation have been reported, including the pore domain, voltage sensing apparatus, and C terminus (8, 16–19). Notably, although the efficacy of cold activation is largely altered by residue substitutions in the pore domain, the channel mutants are still cold sensitive (8). Therefore, these findings based on domain/residue swapping among cold-sensitive TRPM8 orthologs may not draw an overall picture in functionally important domains responsible for cold sensitivity. How did the trpm8 gene originate? How did TRPM8 integrate and modulate cold sensitivity throughout evolution? The answers to such questions probably lead us to understand the evolution of temperature perception and identify the essential structural elements that shape TRPM8 cold activation.In this study, we show the presence of the young trpm8 gene in lobe-finned fishes, believed to be the ancestors that gave rise to all land vertebrates (20). Such a young type of trpm8 derived from the trpm2 exon shuffling was originated and formed during the expansion of lobe-finned fish genomes. By detecting the positive selection-rich domains, we described the formation of the thermosensitive MHR1-3 domain in amphibian and reptile species that enables TRPM8 to undergo conformational changes at low temperatures. Furthermore, we found that the TRPM8 pore domain of terrestrial vertebrates evolved to tune the efficacy of cold activation, in which a cold-sensitive MHR1-3 domain is indispensable to achieve such a modulatory mechanism. Together, our findings suggest that the trpm8 gene origination and formation of the TRPM8 MHR1-3 domain contributed to the transition of vertebrate life from water to land and that the efficacy of cold activation tuned by the TRPM8 pore domain diversified the setting of temperature-adaptive phenotypes in terrestrial vertebrates.     

A stable and reliable animal model for hepatocellular carcinoma with portal vein tumor thrombus

<正>To the Editor:Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1,2].Portal vein tumor thrombus (PVTT) has been demonstrated to be a poor prognostic indicator for HCC [3-5].However,effective treatment for the condition is still limited.Understanding the insight into the molecular mechanisms behind PVTT development may help to establish a new therapeutic strategy.Animal models which mimic the development of PVTT in humans are necessary to figure out the molecula...     

Association of body mass index with risk of prediabetes in Chinese adults: A population‐based cohort study

Aims/IntroductionOverweight and obesity in adults are strongly associated with an increased risk of prediabetes, and this study set out to gain a better understanding of the optimal body mass index (BMI) range for assessing the risk of prediabetes in the Chinese population.Materials and MethodsThe cohort study included 100,309 Chinese adults who underwent health screening. Participants were divided into six groups based on the cut‐off point for BMI recommended by the World Health Organization (underweight: <18.5 kg/m², normal‐weight: 18.5–24.9 kg/m², pre‐obese: 25.0–29.9 kg/m², obese class I: 30.0–34.9 kg/m², obese class II: 35.0–39.9 kg/m², and obese class III ≥40 kg/m²). The association of BMI with prediabetes and the shape of the correlation were modeled using multivariate Cox regression and restricted cubic spline regression, respectively.ResultsIn the multivariate Cox regression model, with normal weight as the control group, underweight people had a lower risk of developing prediabetes, whereas obese and pre‐obese people had a higher risk of prediabetes. Additionally, in the restricted cubic spline model, we found that the association of BMI with prediabetes follows a positive dose–response relationship, but does not conform to the pattern of obesity paradox. Among the general population in China, a BMI of 23.03 kg/m² might be a potential intervention threshold for prediabetes.ConclusionsThe national cohort study found that the association of BMI with prediabetes follows a positive dose–response relationship, rather than a pattern of obesity paradox. For Chinese people with normal weight, more attention should be paid to glucose metabolism when BMI exceeds 23.03 kg/m².     

Cluster phenotypes in a non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases cohort in Singapore

BackgroundNon-idiopathic pulmonary fibrosis fibrosing interstitial lung diseases (F-ILDs) may demonstrate a progressive disease trajectory similar to idiopathic pulmonary fibrosis (IPF). We aimed to identify novel F-ILD phenotypes in a multi-ethnic South-East Asian population.MethodsF-ILD subjects (n=201) were analysed using unsupervised hierarchical cluster analysis and their outcomes compared against IPF (n=86).ResultsFour clusters were identified. Cluster 1 (n=53, 26.4%) comprised older Chinese males with high body mass index (BMI) and comorbidity burden, higher baseline forced vital capacity (FVC) percentage predicted and lower diffusing capacity of the lung for carbon monoxide (DLCO) percentage predicted. They had similar mortality to IPF. Cluster 2 (n=67, 33.3%) had younger female non-smokers with low comorbidity burden, groundglass changes on high-resolution chest computed tomography (HRCT) and a positive anti-nuclear antibody (ANA) titre ≥1:160. They had lower baseline FVC and higher DLCO, low mortality and slower lung function decline. Cluster 3 (n=42, 20.9%) consisted male smokers with low comorbidity burden, emphysema on HRCT and high baseline lung function. They had low mortality and slow lung function decline. Cluster 4 (n=39, 19.4%) was the highest risk and comprised of mainly Indians with high BMI. They had the highest proportion of ischemic heart disease (IHD) and previous pulmonary tuberculosis. Subjects had the lowest baseline lung function, highest mortality, and fastest lung function decline. Survival differences across clusters remained significant following adjustment for treatment.ConclusionsWe identified four distinct F-ILD clinical phenotypes with varying disease trajectories. This demonstrates heterogeneity in F-ILD and the need for complementary approaches for classification and prognostication beyond ATS/ERS guideline diagnosis.     

Integrating Patient Concerns into Parkinson’s Disease Management

Parkinson’s disease (PD) is a complex motor and non-motor disorder and management is often challenging. In this review, we explore emerging approaches to improve the care of patients, drawing from the literature regarding patient-centred care, patient and caregiver perspectives and priorities, gaps in knowledge among patients and caregivers and the need for accurate information, individual variability in disease manifestations, prognostication of disease course, new developments in health technologies and personalized medicine, specialty care, pharmacological and non-pharmacological management, financial burden, lifestyle and work-related issues, support groups and palliative care.     

Combination of CRAFITY score with Alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma

Immune checkpoint inhibitors (ICIs) with atezolizumab plus bevacizumab are promising agents for unresectable hepatocellular carcinoma (HCC). We tried to guide the treatment based on recent developed CRAFITY score combining with on-treatment AFP response. Eighty-nine patients who received atezolizumab plus bevacizumab regardless of as a first-line therapy or not for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 65.5%, respectively. Multivariate analysis showed that low CRAFITY score (AFP<100 ng/ml or CRP<10 mg/l) and satisfactory AFP response at 6 weeks (≥75% decrease or ≤10% increase from baseline) were independent factors determining good overall survival (OS) (hazard ratio [HR]=0.143, P=0.002 & HR=0.337, P=0.031), progression-free survival (PFS) (HR=0.419, P=0.022 & HR=0.429, P=0.025) and good responder (odds ratio [OR]=1.763, P=0.044 & OR=3.881, P=0.011). Patients were further divided into three classes by combination of CRAFITY score and AFP response at 6 weeks [The CAR (CRAFITY score and AFP-Response) classification)]: low CRAFITY score with satisfactory AFP response at 6 weeks (class I), either high CRAFITY score or unsatisfactory AFP response at 6 weeks (class II) and high CRAFITY score together with unsatisfactory AFP response at 6 weeks (class III). ORR was 35.0%, 18.2%, and 0% in class I, II and III patients, respectively (overall P=0.034). Patients in the class I had the best OS and PFS, followed by class II and class III (median OS: not reached vs. 11.1 vs. 4.3 months, log-rank P<0.001; median PFS: 7.9 vs. 6.6 vs. 2.6 months, log-rank P=0.001). Combination CRAFITY score and AFP response at 6 weeks with AUROC predicts OS and tumor response to be 0.809 and 0.798, respectively, better than either CRAFITY score (0.771 & 0.750) or AFP response at 6 weeks (0.725 & 0.680) alone. In conclusions, the CAR classification which combining CRAFITY score and AFP response at 6 weeks provides a practical guidance for atezolizumab plus bevacizumab therapy in unresectable HCC patients.     

Effect of goal-directed fluid therapy on renal function in critically ill patients: a systematic review and meta-analysis

ObjectiveTo evaluate whether goal-directed fluid therapy (GDFT) reduces the risk of renal injury in critical illness.MethodsMEDLINE via PubMed, EMBASE, CENTRAL and CBM was searched from inception to 13 March 2022, for studies comparing the effect of GDFT with usual care on renal function in critically ill patients. GDFT was defined as a protocolized intervention based on hemodynamic and/or oxygen delivery parameters. A fixed or random effects model was applied to calculate the pooled odds ratio (OR) based on heterogeneity through the included studies.ResultsA total of 28 studies with 9,019 patients were included. The pooled data showed that compared with usual care, GDFT reduced the incidence of acute kidney injury (AKI) in critical illness (OR 0.62, 95% confidence interval (CI) 0.47 to 0.80, p< 0.001). Sensitivity analysis with only low risk of bias studies showed the same result. Subgroup analyses found that GDFT was associated with a lower AKI incidence in both postoperative and medical patients. The reduction was significant in GDFT aimed at dynamic indicators. However, no significant difference was found between groups in RRT support (OR 0.88, 95% CI 0.74 to 1.05, p= 0.17). GDFT tended to increase fluid administration within the first 6 h, decrease fluid administration after 24 h, and was associated with more vasopressor requirements.ConclusionsThis meta-analysis suggests that GDFT aimed at dynamic indicators may be an effective way to prevent AKI in critical illness. This may indicate a benefit from early adequate fluid resuscitation and the combined effect of vasopressors.     

Bioaccumulation of PBDE congener 2,2′,4,4′-tetrabromodiphenyl ether by Heterosigma akashiwo in response to different nutrient concentrations

Changes in the bioaccumulation of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) in the marine alga Heterosigma akashiwo (Raphidophyceae) were examined for different concentrations of nitrate (0, 128, and 512 μmol dm^?3) and phosphate (0, 8, and 32 μmol dm^?3) in the semi-continuous culture with 20% renewal rate. The BDE-47 content per cell and per culture, as well as the accumulated percentage of available BDE-47, presented a significant decreasing trend with the increase in nitrate and phosphate concentrations. The N-0 (4.0 × 10^?6 ng cell^?1) and P-0 (5.8 × 10^?6 ng cell^?1) treatments had significantly higher BDE-47 content per cell than other treatments. In comparison, the difference in BDE-47 per algal culture and accumulated percentage between the nitrate treatments or phosphate treatments was not as obvious as the BDE-47 content per cell. BDE-47 per cell presented significantly negative correlation with nitrate and phosphate concentrations, and the accumulated BDE-47 was in positive correlation with lipid content. log BAF_lip for BDE-47 in H. akashiwo ranged from 6.70 to 7.25. The results of this study indicate that variation in BDE-47 accumulation by H. akashiwo corresponds to the change in cellular lipid content induced by different nitrate and phosphate concentrations.     

TNF-α对大鼠Leydig细胞的作用及机制研究

目的观察TNF-α对睾丸细胞功能的影响并探讨其可能机制。方法通过Percoll不连续密度梯度分离获取大鼠Leydig细胞进行原代培养。HE染色进行细胞形态学观察。Leydig细胞培养48h后在培养液中分别加入不同浓度的大鼠TNF-α,使其终浓度达到0.1、1、10、100ng/ml,分别在培养的第1、2、3、4天取上清,通过放免法测定上清液中睾酮的含量,应用MTT法测定细胞增殖情况,流式细胞术与丫啶橙(AO)染色检测及观察Leydig细胞凋亡情况。结果原代细胞通过提纯后的细胞纯度可达70%~80%。HE染色后可见细胞胞质含量丰富,含有分泌颗粒,胞核圆。TNF-α在0.1~100ng/ml浓度范围内能呈剂量依赖的方式抑制Leydig细胞睾酮的基础分泌。0.1、1、10、100ng/mlTNF-α作用24h后,对Leydig细胞睾酮分泌量的抑制率分别为22.03%、34.98%、52.95%、74.83%。各组Leydig细胞睾酮的分泌量随时间延长呈减少的趋势,但除100ng/ml组外,其他各组各时间点比较差异无统计学意义。高浓度TNF-α(10、100ng/ml)组具有抑制Leydig细胞增殖和促进其凋亡作用,其增殖抑制率分别达到38.35%±4.17%、76.35%±8.65%,而凋亡率分别为13.23%±1.11%、26.43%±5.82%,与对照组比较有统计学意义(P<0.01)。AO染色见高浓度TNF-α(10、100ng/ml)组出现明显的细胞凋亡。结论TNF-α对Leydig细胞睾酮的基础分泌具有抑制作用,在较高浓度时该作用可能与其抑制Leydig细胞增殖并促进细胞凋亡有相关。