Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2−/− mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.Swati Dawar, Nur Hezrin Shahrin, Nikolina Sladojevic, Richard J D, Andrea, Loretta Dorstyn, Devendra K Hiwase and Sharad Kuma

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Restless legs syndrome in patients on hemodialysis: Frequency, severity and risk factors

Objective. Restless legs syndrome is a neurologic disorder which especially affects patients on hemodialysis. The aim of our study was to estimate the frequency and severity of restless legs syndrome in hemodialysis patients' population and explore possible connection with some factors by analyzing differences in patients' sociodemographic characteristics, existence and severity of coexistent diseases, biochemical parameters and dialysis type between the patients with and without this syndrome. Methods. 96 subjects were included in our crosssectional study. The diagnosis of restless legs syndrome was made by using criteria of International Restless Legs Study Group. Severity of the syndrome was evaluated through the use of Restless Legs Syndrome Rating Scale questionnaire. Results. Restless legs syndrome was found in 39.6% of subjects. The most of patients had moderate (36.8%) or severe symptoms (50%). There was no statistically significant difference between the patients with and without restless legs syndrome regarding sociodemographic and biochemical characteristics and dialysis type. In terms of coexistent disease, it was found that patients with restless legs syndrome had a significantly greater frequency of ischemic heart disease and depression compared to the patients without the syndrome. There was no difference in index of coexistent disease. Severity of depression and insomnia was higher in patients with restless legs syndrome. Conclusion. This study confirmed that restless legs syndrome is very frequent in hemodialysis patients and indicated that even two-third of patients had severe to very severe symptoms. For future research, it is necessary to direct attention to influence of comorbidity in hemodialysis patient on restless legs syndrome, especially on influence of psychiatric disorders

Data Augmentation for Plant Classification

Data augmentation plays a crucial role in increasing the number of training images, which often aids to improve classification performances of deep learning techniques for computer vision problems. In this paper, we employ the deep learning framework and determine the effects of several data-augmentation (DA) techniques for plant classification problems. For this, we use two convolutional neural network (CNN) architectures, AlexNet and GoogleNet trained from scratch or using pre-trained weights. These CNN models are then trained and tested on both original and data-augmented image datasets for three plant classification problems: Folio, AgrilPlant, and the Swedish leaf dataset. We evaluate the utility of six individual DA techniques (rotation, blur, contrast, scaling, illumination, and projective transformation) and several combinations of these techniques, resulting in a total of 12 data-augmentation methods. The results show that the CNN methods with particular data-augmented datasets yield the highest accuracies, which also surpass previous results on the three datasets. Furthermore, the CNN models trained from scratch profit a lot from data augmentation, whereas the fine-tuned CNN models do not really profit from data augmentation. Finally, we observed that data-augmentation using combinations of rotation and different illuminations or different contrasts helped most for getting high performances with the scratch CNN models

The role of pericytes in brain disorders: from the periphery to the brain

It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now known to control the blood-brain barrier, regulate blood flow, influence immune cell entry and be crucial for angiogenesis. In this review we consider the under-explored possibility that peripheral diseases which affect the microvasculature, such as hypertension, kidney disease and diabetes, produce central nervous system (CNS) dysfunction by mechanisms affecting capillary pericytes within the CNS. We highlight how cellular messengers produced peripherally can act via signalling pathways within CNS pericytes to reshape blood vessels, restrict blood flow or compromise blood-brain barrier function, thus causing neuronal dysfunction. Increased understanding of how renin-angiotensin, Rho-kinase and PDGFRβ signalling affect CNS pericytes may suggest novel therapeutic approaches to reducing the CNS effects of peripheral disorders

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damage-induced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2−/−) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2−/− mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2−/− mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis.S Shalini, A Nikolic, CH Wilson, J Puccini, N Sladojevic, J Finnie, L Dorstyn and S Kuma