Presence of early CKD-related metabolic complications predict progression of stage 3 CKD: a case-controlled study

Cardiovascular events (CVE) are more prevalent in chronic kidney disease (CKD) than in general population, being the main cause of morbimortality. Specific risk factors related to CKD have been suggested, because traditional factors do not fully explain this increase in cardiovascular disease rates. However, the role of atheromatosis, its pathogenesis and evolution are still unclear. The potential use of diagnostic tests to detect subclinical atheromatosis has to be determined. NEFRONA is a prospective multicenter cohort study. 2445 CKD subjects were enrolled from 81 Spanish hospitals and dialysis clinics, from 2010 to 2012. Eligibility criteria included: 18 to 74 years old, CKD stage 3 or higher, and no previous CVE. 559 non-CKD controls were also recruited. Demographical, clinical and analytical data were collected. Carotid and femoral ultrasounds were performed by a single trained team to measure carotid intima-media thickness (cIMT) and detect atheromatous plaques. Ankle-brachial index (ABI) was measured. Differences in age, sex and prevalence and control of cardiovascular risk factors were found between controls and CKD patients. These differences are similar to those described in epidemiological studies. No difference was found regarding cIMT between controls and CKD (when subjects with plaques in common carotid arteries were omitted); earlier CKD stages had higher values. CKD patients had a higher rate of atheromatous plaques, with no difference between stages in the unadjusted analysis. A group of patients had plaques in femoral arteries but were plaque-free in carotid arteries, and would have gone underdiagnosed without the femoral study. The percentage of pathologic ABI was higher in CKD, with higher prevalence in more advanced stages, and a higher rate of ABI >1.4 than <0.9, suggesting more vascular calcification. NEFRONA is the first large study describing the actual prevalence of subclinical atheromatosis across different CKD stages. There is a very high rate of atheromatous plaques and pathologic ABI in CKD. Prospective data will add important information to the pathogenesis and evolution of atheromatosis in CKD, compared to non-CKD subjects.     

Inpatient Studies of a Kalman-Filter-Based Predictive Pump Shutoff Algorithm

Background

An insulin pump shutoff system can prevent nocturnal hypoglycemia and is a first step on the pathway toward a closed-loop artificial pancreas. In previous pump shutoff studies using a voting algorithm and a 1 min continuous glucose monitor (CGM), 80% of induced hypoglycemic events were prevented.

Methods

The pump shutoff algorithm used in previous studies was revised to a single Kalman filter to reduce complexity, incorporate CGMs with different sample times, handle sensor signal dropouts, and enforce safety constraints on the allowable pump shutoff time.

Results

Retrospective testing of the new algorithm on previous clinical data sets indicated that, for the four cases where the previous algorithm failed (minimum reference glucose less than 60 mg/dl), the mean suspension start time was 30 min earlier than the previous algorithm. Inpatient studies of the new algorithm have been conducted on 16 subjects. The algorithm prevented hypoglycemia in 73% of subjects. Suspension-induced hyperglycemia is not assessed, because this study forced excessive basal insulin infusion rates.

Conclusions

The new algorithm functioned well and is flexible enough to handle variable sensor sample times and sensor dropouts. It also provides a framework for handling sensor signal attenuations, which can be challenging, particularly when they occur overnight.     

The economic and social costs of visual impairment and blindness in India

Purpose:To provide a current estimate of the economic and social costs (or welfare costs) of visual impairment and blindness in India.Methods:Using evidence from the recently conducted Blindness and Visual Impairment Survey across India, the Lancet Global Health Commission on Global Eye Health and other sources, we developed an economic model that estimates the costs of reduced employment, elevated mortality risk, education loss for children, productivity loss in employment, welfare loss for the unemployed, and caregiver costs associated with moderate and severe visual impairment (MSVI) and blindness. Probabilistic sensitivity analyses were also conducted by varying key parameters simultaneously.Results:The costs of MSVI and blindness in India in 2019 are estimated at INR 1,158 billion (range: INR 947–1,427 billion) or $54.4 billion at purchasing power parity exchange rates (range: $44.5–67.0 billion), accounting for all six cost streams. The largest cost was for the loss of employment, whereas the the second largest cost was for caregiver time. A more conservative estimate focusing only on employment loss and elevated mortality risk yielded a cost of INR 504 billion (range: INR 348–621 billion) or $23.7 billion (range: $16.3–29.2 billion).Conclusion:Poor eye health imposes a non-trivial recurring cost to the Indian economy equivalent to 0.47% to 0.70% of GDP in the primary scenario, a substantial constraint on the country’s growth aspirations. Furthermore, the absolute costs of poor eye health will increase over time as India ages and becomes wealthier unless further progress is made in reducing the prevalence of MSVI and blindness.     

mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection

T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8⁺ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3⁺ cells, a part of which possesses effector-like properties. PD-1–targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3⁺ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3⁺ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3⁺ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3⁺ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.     

沙棘果实挥发油化学成分研究

胡颓子科植物沙棘Hippophae rhamnoides L.,在我国分布很广,资源十分丰富。沙棘果含有丰富的营养成分,如维生素C(高达2000 mg/100 g鲜果)、维生素E、胡萝卜素、氨基酸和多种黄酮类化合物。我国藏医、蒙医及西北、华北地区民间,早在二千年前就已将沙棘果作为药物,用于活血化瘀,化痰宽胸、补脾健胃等。成熟的沙棘果实能释放出一种特殊的令人愉快的芳香气味。有关沙棘黄酮、维生素、氨     

4-甲氧羰基芬太尼1-位衍生物的合成及生物活性

合成了5个4-甲氧羰基芬太尼1-位衍生物,有4个化合物的分子中带有可与阿片受体发生烷化反应的官能团。镇痛试验结果表明,它们都有典型的吗啡样镇痛活性。离体组织试验结果表明,这些新化合物均作用于阿片受体,其中化合物2,4和5为新型的阿片受体不可逆配体。     

土贝母水提物对体外培养人肝癌细胞增殖及代谢的影响

目的研究中药土贝母(BPF)水提物对体外培养的人肝癌细胞的抑癌活性.方法 BPF经粉碎、浸提、超速离心、减压浓缩、冷冻干燥得BPF水提物.人肝癌SMMC-7721细胞经BPF提取物处理不同时间后以MTT法测其对人肝癌细胞线粒体代谢活性的影响,以细胞记数法观察了其对细胞增殖的影响.结果①经200 mg/L BPF提取物处理48 h,人肝癌SMMC-7721细胞线粒体活性为对照组的31.3%,处理72 h为21.4%;②以100mg/L BPF提取物处理7d中,人肝癌细胞数分别为0.57,0.316,0.29,0.285,0.57,1.287,1.2,对照FCS组分别为1.82,3.67,6.2,9.4,10.1,11,9,NON组分别为1.7,3.35,5.6,8.4,8.9,9.3,7.6,实验组人肝癌细胞数不仅低于对照组,而且低于处理前细胞数(P＜0.01);③经BPF提取物处理24 h后,即使更换为正常培养基,人肝癌细胞数在96 h的恢复培养中基本无增加.结论中药BPF提取物能显著抑制体外培养的肝癌细胞增殖和降低线粒体代谢活性.     

INHERITANCE IN GUINEA PIGS OF THE SUSCEPTIBILITY TO SKIN SENSITIZATION WITH SIMPLE CHEMICAL COMPOUNDS

It has proved possible to set up lines of guinea pigs of significantly different susceptibilities towards a compound of simple structure, namely 2:4 dinitrochlorobenzene. This provides direct evidence that the type of sensitization under discussion is influenced by heredity.