Dual energy CT (DECT) has been shown, in theoretical and phantom studies, to improve the stopping power ratio (SPR) determination used for proton treatment planning compared to the use of single ...energy CT (SECT). However, it has not been shown that this also extends to organic tissues. The purpose of this study was therefore to investigate the accuracy of SPR estimation for fresh pork and beef tissue samples used as surrogates of human tissues. The reference SPRs for fourteen tissue samples, which included fat, muscle and femur bone, were measured using proton pencil beams. The tissue samples were subsequently CT scanned using four different scanners with different dual energy acquisition modes, giving in total six DECT-based SPR estimations for each sample. The SPR was estimated using a proprietary algorithm (syngo.via DE Rho/Z Maps, Siemens Healthcare, Forchheim, Germany) for extracting the electron density and the effective atomic number. SECT images were also acquired and SECT-based SPR estimations were performed using a clinical Hounsfield look-up table. The mean and standard deviation of the SPR over large volume-of-interests were calculated. For the six different DECT acquisition methods, the root-mean-square errors (RMSEs) for the SPR estimates over all tissue samples were between 0.9% and 1.5%. For the SECT-based SPR estimation the RMSE was 2.8%. For one DECT acquisition method, a positive bias was seen in the SPR estimates, having a mean error of 1.3%. The largest errors were found in the very dense cortical bone from a beef femur. This study confirms the advantages of DECT-based SPR estimation although good results were also obtained using SECT for most tissues.
Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next‐generation ...sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in‐house‐designed kidney‐gene panel. In families where candidate variants were not identified, whole‐exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney‐gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses—presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney‐gene panel and additional variants were identified. Next‐generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT‐ROBO signaling is implicated in human bilateral kidney agenesis.
Obesity is an independent risk factor for malignancies, including hepatocellular carcinoma (HCC). However, it remains unknown whether maternal obesity affects the incidence of HCC in offspring. Thus, ...we aimed to investigate this association and its underlying mechanisms.
Diethylnitrosamine (DEN) was used to induce HCC in a high-fat diet (HFD)-induced multigenerational obesity model. RNA-sequencing was performed to identify the genes and microRNAs (miRNAs) that were altered over generations. The role of the miR-27a-3p-Acsl1/Aldh2 axis in HCC was evaluated in cell lines and HCC-bearing nude mice, and its intergenerational impact was studied in pregnant mice and their offspring.
Under HFD stress, maternal obesity caused susceptibility of offspring to DEN-induced HCC, and such susceptibility was cumulative over generations. We identified that Acsl1 and Aldh2, direct targets of miR-27a-3p, were gradually changed over generations. Under hyperlipidemic conditions, downregulation of Acsl1 and Aldh2 increased cell proliferation (in vitro) or tumor growth (in vivo) in synergy. Intratumor injection of an miR-27a-3p agomir exacerbated tumor growth by downregulating Acsl1 and Aldh2; while intratumor injection of an miR-27a-3p antagomir had the opposite effect. Moreover, serum miR-27a-3p levels gradually increased in the HFD-fed maternal lineage over generations. Injecting pregnant mice with an miR-27a-3p agomir not only upregulated hepatic miR-27a-3p and downregulated Acsl1/Aldh2 in offspring (fetus, young and adult stages), but also exacerbated HCC development in DEN-treated offspring. In human HCC, upregulated miR-27a-3p and downregulated Acsl1/Aldh2 were negatively correlated with survival on TCGA analysis; while, hepatic miR-27a-3p was negatively correlated with Acsl1/Aldh2 expression in tumor/non-tumor tissues from fatty/non-fatty livers.
Maternal obesity plays a role in regulating cumulative susceptibility to HCC development in offspring over multiple generations through the miR-27a-3p-Acsl1/Aldh2 axis.
It is not currently known how maternal obesity affects the incidence of liver cancer in offspring. In this study, we identified a microRNA (miR-27a-3p) that was upregulated in obese mothers and could be passed on to their offspring. This microRNA enhanced the risk of liver cancer in offspring by regulating 2 genes (Acsl1 and Aldh2). This mechanism could be a future therapeutic target.
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•Multi-generational maternal exposure to high-fat diet causes increased incidence of DEN-induced HCC in offspring.•Gradually downregulated Acsl1 and Aldh2 are found in the offspring over generations, which promote tumor growth in synergy.•miR-27a-3p negatively regulates Acsl1 and Aldh2 in mouse and human HCC samples.•Increased serum miR-27a-3p is found in mothers fed a high-fat diet.•Offspring of miR-27a-3p agomir-injected mothers show increased HCC susceptibility.
The deposition of self-assembled amyloidogenic proteins is associated with multiple diseases, including Alzheimer's disease, Parkinson's disease and type 2 diabetes mellitus. The toxic misfolding and ...self-assembling of amyloidogenic proteins are believed to underlie protein misfolding diseases. Novel drug candidates targeting self-assembled amyloidogenic proteins represent a potential therapeutic approach for protein misfolding diseases.
In this perspective review, we provide an overview of the recent progress in identifying inhibitors that block the aggregation of amyloidogenic proteins and the clinical applications thereof.
Compounds such as polyphenols, certain short peptides, and monomer- or oligomer-specific antibodies, can interfere with the self-assembly of amyloidogenic proteins, prevent the formation of oligomers, amyloid fibrils and the consequent cytotoxicity.
Some inhibitors have been tested in clinical trials for treating protein misfolding diseases. Inhibitors that target the aggregation of amyloidogenic proteins bring new hope to therapy for protein misfolding diseases.
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•Membrane permeation is a key source for the cytotoxicity of misfolded proteins.•Small molecules prevent fibril formation and cytotoxicity of amyloidogenic proteins.•Structural optimization is critical to the design of anti-amyloidogenic inhibitors.•Chemical inhibitors may have opposite effects on different amyloidogenic proteins.•Amyloid inhibitors shed new lights on the therapy of protein misfolding diseases.
There has been a surge in interest and implementation of immersive virtual reality (IVR)-based lessons in education and training recently, which has resulted in many studies on the topic. There are ...recent reviews which summarize this research, but little work has been done that synthesizes the existing findings into a theoretical framework. The Cognitive Affective Model of Immersive Learning (CAMIL) synthesizes existing immersive educational research to describe the process of learning in IVR. The general theoretical framework of the model suggests that instructional methods which are based on evidence from research with less immersive media generalize to learning in IVR. However, the CAMIL builds on evidence that media interacts with method. That is, certain methods which facilitate the affordances of IVR are specifically relevant in this medium. The CAMIL identifies presence and agency as the general psychological affordances of learning in IVR, and describes how immersion, control factors, and representational fidelity facilitate these affordances. The model describes six affective and cognitive factors that can lead to IVR-based learning outcomes including interest, motivation, self-efficacy, embodiment, cognitive load, and self-regulation. The model also describes how these factors lead to factual, conceptual, and procedural knowledge acquisition and knowledge transfer. Implications for future research and instructional design are proposed.
Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia.
Aniridia is a severe, congenital ocular malformation inherited in an autosomal‐dominant fashion with high penetrance and variable ...expression. Eye morphogenesis in humans involves a molecular genetic cascade in which a number of developmental genes interact in a highly organized process during the embryonic period to produce functional ocular structures. Among these genes, paired box gene 6 (PAX6) has an essential role as it encodes a phylogenetically conserved transcription factor almost universally employed for eye formation in animals with bilateral symmetry, despite widely different embryological origins. To direct eye development, PAX6 regulates the tissue‐specific expression of diverse molecules, hormones, and structural proteins. In humans, PAX6 is located in chromosome 11p13, and its mutations lead to a variety of hereditary ocular malformations of the anterior and posterior segment, among which aniridia and most probably foveal hypoplasia are the major signs. Aniridia occurs due to decreased dosage of the PAX6 gene and exists in both sporadic and familial forms. The mutations are scattered throughout the gene and the vast majority of those reported so far are nonsense mutations, frameshift mutations, or splicing errors that are predicted to cause pre‐mature truncation of the PAX6 protein, causing haploinsufficiency. Here we review the data regarding the mechanisms and the mutations that relate to aniridia.
In addition to a range of functional impairments seen in individuals with a lower-limb amputation, this population is at a substantially elevated risk of falls. Studies postulate that the lack of ...sensory feedback from the prosthetic limb contributes heavily to these impairments, but the extent to which sensation affects functional measures remains unclear.
The purpose of this study is to determine how sensory impairments in the lower extremities relate to performance with common clinical functional measures of balance and gait in individuals with a lower-limb amputation. Here we evaluate the effects of somatosensory integrity to clinical and lab measures of static, reactive and dynamic balance, and gait stability.
In 20 individuals with lower-limb amputation (AMP) and 20 age and gender-matched able-bodied controls (CON), we evaluated the effects of sensory integrity (pressure, proprioception, and vibration) on measures of balance and gait. Static, reactive, and dynamic balance were assessed using the Sensory Organization Test (SOT), Motor Control Test (MCT), and Functional Gait Assessment (FGA), respectively. Gait stability was assessed through measures of step length asymmetry and step width variability. Sensation was categorized into intact or impaired sensation by pressure thresholds and differences across groups were analyzed.
There were significant differences between AMP and CON groups for reliance on vision for static balance in the SOT, MCT, and FGA (p < 0.01). Despite differences across groups, there were no significant differences within the AMP group based on intact or impaired sensation across all functional measures.
Despite being able to detect differences between able-bodied individuals and individuals with an amputation, these functional measures cannot distinguish between levels of impairment within participants with an amputation. These findings suggest that more challenging and robust metrics are needed to evaluate the effects of sensation and function in individuals with an amputation.
•Clinical tasks cannot detect differences in sensation in individuals with amputation.•Neither sensation in the residual limb or in the intact limb correlated with these measures.•More challenging tasks are needed to evaluate sensory differences in this population.
Objective
To assess the association between specific heart diseases and suicide.
Design
Nationwide retrospective cohort study.
Participants
A total of 7 298 002 individuals (3 640 632 males and ...3 657 370 females) aged ≥15 years and living in Denmark during 1980–2016.
Main outcome measures
Incidence rate ratios (IRR) with 95% confidence intervals. In multivariate analysis, we adjust for sex, period, age group, living status, income level, Charlson Comorbidity Index, psychiatric disorders prior to heart disease and self‐harm prior to heart disease.
Results
Excess suicide rate ratios were found for following disorders: heart failure (IRR: 1.48; 95% CI: 1.38–1.58); cardiomyopathy (IRR: 1.41; 95% CI: 1.16–1.70); acute myocardial infarction (IRR: 1.28; 95% CI: 1.21–1.36); cardiac arrest with successful resuscitation (IRR: 4.75; 95% CI: 3.57–6.33); atrial fibrillation and flutter (IRR: 1.42; 95% CI: 1.32–1.52); angina pectoris (IRR: 1.19; 95% CI: 1.12–1.26); and ventricular tachycardia (IRR: 1.53; 95% CI: 1.20–1.94). A higher rate of suicide was noted during the first 6 months after the diagnosis of heart failure (IRR: 2.38; 95% CI: 2.04–2.79); acute myocardial infarction (IRR: 2.24; 95% CI: 1.89–2.66); atrial fibrillation and flutter (IRR: 2.70; 95% CI: 2.30–3.18); and angina pectoris (IRR: 1.83; 95% CI: 1.53–2.19) when compared to later.
Conclusion
Several specific disorders were found to be associated with elevated rates of suicide. Additionally, we found temporal associations with higher suicide rates in the first time after diagnosis. Our results underscore the importance of being attentive towards psychological distress in individuals with heart disease.
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although ...SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.
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