住院糖尿病高危足患者临床特征及预后分析

目的 通过分析糖尿病高危足患者临床资料及预后，为糖尿病足溃疡的预防提供临床依据。方法 对2012年1月1日-2018年12月31日在四川大学华西医院住院的糖尿病高危足患者进行了回顾性分析，按照既往是否有足溃疡或者截肢（趾）史，分为高风险组和低风险组。比较两组患者的临床特征，并随访患者从出院至2021年1月31日，对患者生存及溃疡复发或新发状况进行了评估。结果 最终纳入患者123例，高风险组患者29例，低风险组患者94例。两组患者的糖尿病病程、吸烟史、饮酒史、受教育程度、接受正规治疗比例、定期监测血糖比例、体质量指数、合并糖尿病周围神经病变、胼胝、足畸形、糖尿病肾病、糖尿病视网膜病变、糖尿病心脏自主神经病变、糖尿病胃肠自主神经病变、高血压、冠心病的比例和实验室检查结果差异无统计学意义（P>0.05）。高风险组的女性比例（51.7%vs. 29.8%）、年龄[（69.8±10.3）vs.(64.4±11.3)岁]、合并下肢动脉病变比例（62.1%vs. 34.4%）、合并高尿酸血症比例（27.6%vs. 10.6%）高于低风险组（P<0.05）。在随访（67±20）个月后，有2...     

Cidea is associated with lipid droplets and insulin sensitivity in humans

Storage of energy as triglyceride in large adipose-specific lipid droplets is a fundamental need in all mammals. Efficient sequestration of fat in adipocytes also prevents fatty acid overload in skeletal muscle and liver, which can impair insulin signaling. Here we report that the Cide domain-containing protein Cidea, previously thought to be a mitochondrial protein, colocalizes around lipid droplets with perilipin, a regulator of lipolysis. Cidea-GFP greatly enhances lipid droplet size when ectopically expressed in preadipocytes or COS cells. These results explain previous findings showing that depletion of Cidea with RNAi markedly elevates lipolysis in human adipocytes. Like perilipin, Cidea and the related lipid droplet protein Cidec/FSP27 are controlled by peroxisome proliferator-activated receptor gamma (PPARgamma). Treatment of lean or obese mice with the PPARgamma agonist rosiglitazone markedly up-regulates Cidea expression in white adipose tissue (WAT), increasing lipid deposition. Strikingly, in both omental and s.c. WAT from BMI-matched obese humans, expression of Cidea, Cidec/FSP27, and perilipin correlates positively with insulin sensitivity (HOMA-IR index). Thus, Cidea and other lipid droplet proteins define a novel, highly regulated pathway of triglyceride deposition in human WAT. The data support a model whereby failure of this pathway results in ectopic lipid accumulation, insulin resistance, and its associated comorbidities in humans.     

Ca2+-dependent large conductance K+ currents in thalamocortical relay neurons of different rat strains

Mutations in genes coding for Ca²⁺ channels were found in patients with childhood absence epilepsy (CAE) indicating a contribution of Ca²⁺-dependent mechanisms to the generation of spike-wave discharges (SWD) in humans. Since the involvement of Ca²⁺ signals remains unclear, the aim of the present study was to elucidate the function of a Ca²⁺-dependent K⁺ channel (BK_Ca) under physiological conditions and in the pathophysiological state of CAE. The activation of BK_Ca channels is dependent on both voltage and intracellular Ca²⁺ concentrations. Moreover, these channels exhibit an outstandingly high level of regulatory heterogeneity that builds the basis for the influence of BK_Ca channels on different aspects of neuronal activity. Here, we analyse the contribution of BK_Ca channels to firing of thalamocortical relay neurons, and we test the hypothesis that BK_Ca channel activity affects the phenotype of a genetic rat model of CAE. We found that the activation of the β₂-adrenergic receptor/protein kinase A pathway resulted in BK_Ca channel inhibition. Furthermore, BK_Ca channels affect the number of action potentials fired in a burst and produced spike frequency adaptation during tonic activity. The latter result was confirmed by a computer modelling approach. We demonstrate that the β₂-adrenergic inhibition of BK_Ca channels prevents spike frequency adaptation and, thus, might significantly support the tonic firing mode of thalamocortical relay neurons. In addition, we show that BK_Ca channel functioning differs in epileptic WAG/Rij and thereby likely contributes to highly synchronised, epileptic network activity.     

Disease-modifying effects of edasalonexent,an NF-κB inhibitor,in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T₂ relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.     

The Role of Procurement Biopsies in Acceptance Decisions for Kidneys Retrieved for Transplant

Background and objectives

There is a shortage of kidneys for transplant, and many patients on the deceased donor kidney transplant waiting list would likely benefit from kidneys that are currently being discarded. In the United States, the most common reason given for discarding kidneys retrieved for transplant is procurement biopsy results. This study aimed to compare biopsy results from discarded kidneys with discard attributed to biopsy findings, with biopsy results from comparable kidneys that were successfully transplanted.

Design, setting, participants, & measurements

In this retrospective, observational, case-control study, biopsy reports were examined from 83 kidneys discarded in 2010 due to biopsy findings (cases), 83 contralateral transplanted kidneys from the same donor (contralateral controls), and 83 deceased donors randomly matched to cases by donor risk profile (randomly matched controls). A second procurement biopsy was obtained in 64 of 332 kidneys (19.3%).

Results

The quality of biopsy reports was low, with amounts of tubular atrophy, interstitial inflammation, arteriolar hyalinosis, and acute tubular necrosis often not indicated; 69% were wedge biopsies and 94% used frozen tissue. The correlation between first and second procurement biopsies was poor; only 25% of the variability (R²) in glomerulosclerosis was explained by biopsies being from the same kidney. The percentages of glomerulosclerosis overlapped substantially between cases, contralateral controls, and randomly matched controls: 17.1%±15.3%, 9.0%±6.6%, and 5.0%±5.9%, respectively. Of all biopsy findings, only glomerulosclerosis>20% was independently correlated with discard (cases versus contralateral controls; odds ratio, 15.09; 95% confidence interval, 2.47 to 92.41; P=0.003), suggesting that only this biopsy result was used in acceptance decisions. One-year graft survival was 79.5% and 90.7% in contralateral and randomly matched controls, respectively, versus 91.6% among all deceased donor transplants in the Scientific Registry of Transplant Recipients.

Conclusions

Routine use of biopsies could lead to unnecessary kidney discards.     

Cultural and Contextual Analysis of Quality of Life Among Older Nepali Women

The quality-of-life construct can be used to assess how well an individual's needs are met or being met by the society. However, in the dominant narratives of quality of life in old age, exploration of the impact of cultural differences on how older adults define and assess their quality of life has been limited. Moreover, the examination of heterogeneity within one culture and its influence on quality of life has been largely ignored. The present study compares the quality of life as defined by two samples of Nepali elderly women, those who live with their families and those who live in an old-age home, and presents data on factors associated with quality of life in the two samples. The results show that social and cultural norms, informed by religious principles that prescribe familial elder care, impact how quality of life is described by both groups of women.     

Autonomic dysfunction in adult-onset alexander disease

Background

Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized.

Objective

We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population.

Results

A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47 mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD.

Conclusion

Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways.     

初发与复发性糖尿病足溃疡临床特征分析

  目的  分析四川大学华西医院住院糖尿病足溃疡（diabetic foot ulcer, DFU）患者的临床特征,探究足溃疡复发的危险因素。  方法  回顾性分析2012年1月1日–2020年12月31日在四川大学华西医院住院的817例DFU患者的临床资料,按照既往是否发生足溃疡,分为初发组（502例）和复发组（315例）。比较两组患者临床特征的差异,采用多因素logistic回归分析足溃疡复发的危险因素。  结果  初发和复发性DFU患者以神经缺血性足溃疡为主,均好发于第一足趾和第五足趾。与初发DFU患者相比,Wagner 3级和创面位于胼胝的复发性DFU患者更多（P<0.05）,但足坏疽（Wagner 4～5级）的患者更少（P<0.05）。复发性DFU患者的糖化血红蛋白、血小板计数和纤维蛋白原水平更低（P<0.05）,血尿酸和血肌酐水平更高（P<0.05）;两组患者的血红蛋白、白细胞计数、估算肾小球滤过率、血沉和C-反应蛋白水平均无明显差异（P>0.05）。多因素logistic回归分析显示,男性（OR=1.555,95%CI:1.097～2.072,P=0.013）、糖尿病病程≥10年（OR=2.369,95%CI:1.473～3.810,P<0.001）、既往截肢史（OR=4.518,95%CI:2.386～8.553,P<0.001）、足部骨质疏松（OR=1.711,95%CI:1.065～2.751,P=0.027）、创面位于胼胝（OR=1.786,95%CI:1.058～3.012,P=0.030）和冠心病（OR=0.668,95%CI:0.453～0.987,P=0.043）与足溃疡复发相关。  结论  男性、糖尿病病程超过10年、既往截肢史、足部骨质疏松和创面位于胼胝是DFU患者足溃疡复发的独立危险因素。因此,DFU患者即使足溃疡愈合,也应加强足部护理,降低足溃疡复发率。     

Potential use of NOACs in developing countries: pros and cons

Purpose

Although vitamin K antagonists (VKAs) are effective for long-term thromboprophylaxis in atrial fibrillation (AF), their limitations have led to widespread underutilisation, especially in the developing world. Novel oral anticoagulants (NOACs) have emerged as promising alternatives to VKAs, although there are some particular considerations and challenges to their introduction in developing countries. This review summarises the current state of antithrombotic management of AF in the developing world, explores the early evidence for the NOACs and describes some of the special considerations that must be taken into account when considering the role of the NOACs within developing countries’ health care systems.

Methods

A literature search was conducted via PubMed and Google Scholar to find articles published in English between the years 2000 to 2014. Search terms used were “atrial fibrillation”, “oral anticoagulants”, “warfarin”, “NOACs”, “dabigatran”, “rivaroxaban”, “apixaban”, “edoxaban”, “time in therapeutic range”, “International Normalized Ratio” “cost-effectiveness”, “stroke”, “adverse-drug reactions” and “drug–drug interactions”, together with the individual names of developing countries as listed by the World Bank. We reviewed the results of randomized clinical trials, relevant retrospective and prospective studies, case-studies and review articles.

Results

Many developing countries lack or have sporadic data on the quality of AF management, making it difficult to anticipate the potential impact of NOACs in these settings. The utilisation of anticoagulants for AF appears highly variable in developing countries. Given the issues associated with VKA therapy in many developing countries, NOACs offer some potential advantages; however, there is insufficient evidence to advocate the widespread replacement of warfarin at present. VKAs may continue to have a role in selected patients or countries, especially if alternative monitoring strategies can be utilised.

Conclusion

The evaluation of the introduction of NOACs should consider safety, budget concerns and the quality of oral anticoagulation care achieved by each country. Prospective registries will be important in developing countries to better elucidate the comparative safety, efficacy and cost-effectiveness of NOACs and VKAs as NOACs are introduced into practice.