What you need to knowWeight loss of up to 10% of birthweight is common in the early days of life. Birthweight is usually regained before 3 weeks of age as feeding is establishedFaltering growth after...
Purpose. To evaluate transrectal (TR) and transperineal (TP) approaches for MRI/ultrasound (MRI/US) fusion-guided biopsy to detect prostate cancer (PCa). Materials and Methods. 154 men underwent multiparametric MRI and MRI/US fusion-guided biopsy between July 2012 and October 2016. 79/154 patients were biopsied with a TR approach and 75/154 with a TP approach. MRI was retrospectively analyzed according to PI-RADS version 2. PI-RADS scores were compared with histopathological results. Descriptive statistics, accuracy, and negative and positive predictive values were calculated. Histopathological results of first, second, and third MRI targeted biopsy cores were compared to evaluate the impact of one verus multiple targeted cores. Results. Detection rates of PCa were 39% for TR biopsy and 75% for TP biopsy. Sensitivity/specificity for tumor detection with PI-RADS ≥ 4 were 81/69% for TR biopsy and 86/84% for TP biopsy. In 31% for TR biopsy and 19% for TP biopsy, PCa was found in the second or third MRI targeted biopsy core only. Conclusion. MRI/US fusion-guided biopsy may be conducted with the TR as well as the TP approach with high accuracy, giving more flexibility for diagnosis and the option for focal treatment of PCa.
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Both the Wenchuan earthquake on May 12, 2008, and the Lushan earthquake on April 12, 2013, produced many coseismic landslides along the Nanya River in Shimian City. Subsequent debris flows that initiated from these landslides and are triggered by intense rainfall become the secondary hazard in the years after the earthquake; in particular, some debris flows led to a serious river blocking event. For example, the Guangyuanbao debris flow which occurred on July 04, 2013, partly blocked the Nanya River, presenting a major threat to the national highway and residential areas. To analyze the pattern of landslide damming, we analyzed numerical simulations of the movement characteristics of the Guangyuanbao debris flow using rainfall intensities with varying recurrence periods of 5, 20, and 50 years. The accuracy of the spreading of the numerical simulation is about 90%. The simulation indicated a small volume of sediment entering the river for a rainfall under 5-year return period. A debris flow induced by rainfall under 20-year return period partly blocked the river, while rainfall under 50-year return period has potential to block the river completely. This proposed analysis of river blocking induced by a debris flow could be used for disaster prevention in earthquake-stricken area.
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Human mitochondrial DNA (mtDNA) variants and haplogroups may contribute to susceptibility to various diseases and pathological conditions, but the underlying mechanisms are not well understood. To address this issue, we established a cytoplasmic hybrid (cybrid) system to investigate the role of mtDNA haplogroups in human disease; specifically, we examined the effects of East Asian mtDNA genetic backgrounds on oxidative phosphorylation (OxPhos). We found that mtDNA single nucleotide polymorphisms such as m.489T>C, m.10398A>G, m.10400C>T, m.C16223T, and m.T16362C affected mitochondrial function at the level of mtDNA, mtRNA, or the OxPhos complex. Macrohaplogroup M exhibited higher respiratory activity than haplogroup N owing to its higher mtDNA content, mtRNA transcript levels, and complex III abundance. Additionally, haplogroup M had higher reactive oxygen species levels and NAD+/NADH ratios than haplogroup N, suggesting difference in mitonuclear interactions. Notably, subhaplogroups G2, B4, and F1 appeared to contribute significantly to the differences between haplogroups M and N. Thus, our cybrid-based system can provide insight into the mechanistic basis for the role of mtDNA haplogroups in human diseases and the effect of mtDNA variants on mitochondrial OxPhos function. In addition, studies of mitonuclear interaction using this system can reveal predisposition to certain diseases conferred by variations in mtDNA.
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The scientific literature provides extensive evidence of widespread magnesium deficiency and the potential need for magnesium repletion in diverse medical conditions. Magnesium is an essential element required as a cofactor for over 300 enzymatic reactions and is thus necessary for the biochemical functioning of numerous metabolic pathways. Inadequate magnesium status may impair biochemical processes dependent on sufficiency of this element. Emerging evidence confirms that nearly two-thirds of the population in the western world is not achieving the recommended daily allowance for magnesium, a deficiency problem contributing to various health conditions. This review assesses available medical and scientific literature on health issues related to magnesium. A traditional integrated review format was utilized for this study. Level I evidence supports the use of magnesium in the prevention and treatment of many common health conditions including migraine headache, metabolic syndrome, diabetes, hyperlipidemia, asthma, premenstrual syndrome, preeclampsia, and various cardiac arrhythmias. Magnesium may also be considered for prevention of renal calculi and cataract formation, as an adjunct or treatment for depression, and as a therapeutic intervention for many other health-related disorders. In clinical practice, optimizing magnesium status through diet and supplementation appears to be a safe, useful, and well-documented therapy for several medical conditions.
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Background. The primary treatment of symptomatic aortic stenosis is aortic valve replacement. Instead of open chest surgery, transcatheter aortic valve replacement (TAVR) is an alternative intervention for high-risk surgical candidates. Clinical Case. A 92-year-old male presented with progressive exertional dyspnea and recurrent syncopal attacks secondary to severe AS. The patient underwent successful transfemoral TAVR with 29 mm Edwards SAPIEN XT valve. His postoperative course was complicated by aorto-right ventricular shunt. The patient's clinical course was followed up for one year. Conclusion. This case reports the incidence and clinical course of one of the rare complications of TAVR, aorto-right ventricular fistula. Conservative medical management is appropriate in hemodynamically stable patients with this specific complication.
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Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt's lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble.
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We propose a novel approach for low-light image enhancement. Based on illumination-reflection model, the guided image filter is employed to extract the illumination component of the underlying image. Afterwards, we obtain the reflection component and enhance it by nonlinear functions, sigmoid and gamma, respectively. We use the first-order edge-aware constraint in the gradient domain to achieve good edge preserving features of enhanced images and to eliminate halo artefact effectively. Moreover, the resulting images have high contrast and ample details due to the enhanced illumination and reflection component. We evaluate our method by operating on a large amount of low-light images, with comparison with other popular methods. The experimental results show that our approach outperforms the others in terms of visual perception and objective evaluation.
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A new study finds that immune response in prostate cancer may be able to forecast how patients will respond to radiation therapy, as well as their likelihood of disease recurrence and survival outcomes. The analysis of more than 9,000 prostate tumours...
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Cancers, Vol. 9, Pages 132: Regulation of mTOR, Metabolic Fitness, and Effector Functions by Cytokines in Natural Killer Cells
Cancers doi: 10.3390/cancers9100132
Authors: Sébastien Viel Laurie Besson Marie Marotel Thierry Walzer Antoine Marçais
The control of cellular metabolism is now recognized as key to regulate functional properties of immune effectors such as T or Natural Killer (NK) cells. During persistent infections or in the tumor microenvironment, multiple metabolic changes have been highlighted in T cells that contribute to their dysfunctional state or exhaustion. NK cells may also undergo major phenotypic and functional modifications when infiltrating tumors that could be linked to metabolic alterations. The mammalian target of rapamycin (mTOR) kinase is a central regulator of cellular metabolism. mTOR integrates various extrinsic growth or immune signals and modulates metabolic pathways to fulfill cellular bioenergetics needs. mTOR also regulates transcription and translation thereby adapting cellular pathways to the growth or activation signals that are received. Here, we review the role and regulation of mTOR in NK cells, with a special focus on cytokines that target mTOR such as IL-15 and TGF-β. We also discuss how NK cell metabolic activity could be enhanced or modulated to improve their effector anti-tumor functions in clinical settings.
Medical registrationTax evading consultant is suspendedA "world renowned" consultant radiologist has been suspended from the UK medical register for six months after being convicted of failing to pay...
The objective of this study was to compare the efficacy of biomarkers in assessing the risk of breast cancer recurrence in patients with node-negative or micrometastatic grade II breast cancer. Specifically, w...
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Secreted clusterin (sCLU), a 75–80 kDa disulfide-linked heterodimeric protein, plays crucial roles in various pathophysiological processes, including lipid transport, tissue remodeling, cell apoptosis and repr...
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Genes, Vol. 8, Pages 245: BARHL1 Is Downregulated in Alzheimer's Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways
Genes doi: 10.3390/genes8100245
Authors: Debmalya Barh María García-Solano Sandeep Tiwari Antaripa Bhattacharya Neha Jain Daniel Torres-Moreno Belén Ferri Artur Silva Vasco Azevedo Preetam Ghosh Kenneth Blum Pablo Conesa-Zamora George Perry
The Transcription factor BarH like homeobox 1 (BARHL1) is overexpressed in medulloblastoma and plays a role in neurogenesis. However, much about the BARHL1 regulatory networks and their functions in neurodegenerative and neoplastic disorders is not yet known. In this study, using a tissue microarray (TMA), we report for the first time that BARHL1 is downregulated in hormone-negative breast cancers and Alzheimer's disease (AD). Furthermore, using an integrative bioinformatics approach and mining knockout mouse data, we show that: (i) BARHL1 and Estrogen Receptor 1 (ESR1) may constitute a network that regulates Neurotrophin 3 (NTF3)- and Brain Derived Neurotrophic Factor (BDNF)-mediated neurogenesis and neural survival; (ii) this is probably linked to AD pathways affecting aberrant post-translational modifications including SUMOylation and ubiquitination; (iii) the BARHL1-ESR1 network possibly regulates β-amyloid metabolism and memory; and (iv) hsa-mir-18a, having common key targets in the BARHL1-ESR1 network and AD pathway, may modulate neuron death, reduce β-amyloid processing and might also be involved in hearing and cognitive decline associated with AD. We have also hypothesized why estrogen replacement therapy improves AD condition. In addition, we have provided a feasible new mechanism to explain the abnormal function of mossy fibers and cerebellar granule cells related to memory and cognitive decline in AD apart from the Tau and amyloid pathogenesis through our BARHL1-ESR1 axis.
Even the most basic and seemingly simple living biological systems exist far from thermodynamic equilibrium and studying their dynamic behavior represents a crucial step towards a better understanding of their fundamental properties. Here, we present the investigations of two different, out-of-equilibrium biological systems, namely single cell studies on the human red blood cell (RBC) and single macromolecule analysis of actin filaments, both by exploiting the exceptional physics at the micro-scale and the corresponding unique capabilities of experimental control. In particular, existing approaches to RBC analysis on the single-cell level usually rely on chemical or physical manipulations that often cause difficulties with preserving the RBC's integrity in a controlled microenvironment. We introduce a straightforward, self-filling microfluidic device that autonomously separates and isolates single RBCs directly from unprocessed human blood samples and confines them in diffusion-controlled microchambers by solely exploiting their unique intrinsic properties. Using bright-field microscopy, this noninvasive approach enables the time-resolved analysis of RBC flickering during the reversible shape evolution from the discocyte to the echinocyte morphology. A better understanding of this central shape transformation is especially relevant for blood storage applications as the formation of echinocytes can affect blood handling. We are further able to study the photo-induced oxygenation cycle of single functional RBCs by Raman microscopy without the limitations typically observed in optical tweezers based methods. Due to its specialized geometry, our device is particularly suited for studies on single RBCs under precise control of their environment. The provision of important insights into the RBC's biomedical and biophysical properties will improve the understanding of RBC microcirculation and can further contribute to advances in pathology diagnosis. Furthermore, we study the non-equilibrium conformational dynamics of semiflexible actin filaments experiencing hydrodynamic forces. Improving the knowledge about these dynamic processes of semiflexible polymers is of particular importance for the description of unusual transport in cellular flows and pattern formation processes in cytoplasmic streaming. The actin filaments are flowing through structured microchannels with alternating high- and low-velocity segments. These flow fields of spatially varying flow strength result in a compressive force on the filaments when they are entering the low-velocity regions and conversely an extensional force is acting on them when they are reentering the high-velocity segments. The semiflexible actin filaments undergo a length-dependent buckling transition under compression with a corresponding change in end-to-end distance and a rise in bending energy. However, the degree of increase of the length-normalized bending energy shows no evident dependence on the contour length. Increasing the fluid flow velocity results in a large rise of the compressive hydrodynamic force with a strong increase in storage of elastic energy due to the bending of the semiflexible filaments. At the passage from the low-velocity segments to the high-velocity ones, an extensional force is acting on the partially elastically relaxed filaments and a conformational transition from a coiled to a stretched state with a suppression of thermal fluctuations can be observed. Despite the symmetry of the microfluidic channels and therefore a similar rate of the absolute values of extension or compression in the specific channel segments, the observed stretch-coil and coil-stretch transitions distinctly differ in the evolution of the conformational changes and bending energies. This asymmetry of the non-equilibrium and non-stationary conformational transitions shows a strong dependence on the contour and persistence length, the degree of relaxation and the extensional or compressional rate. Many polymer solutions are non-Newtonian fluids and our studies may therefore have an impact on the analysis as well as sorting of polymers by elucidating the non-Newtonian flow behavior of semiflexible filaments in specific microflows, which may consequently lead to a better understanding of intercellular flows.
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bmj;358/sep28_6/j4153/FAF1faBiographyBen Maruthappu, 29, is a public health registrar in northwest London and cofounder of Cera, a technology enabled social care provider. Cera aims to link patients...
The Rho GTPase Rac1 is a multifunctional protein involved in distinct pathways ranging from development to pathology. The aim of the present study was to unravel the contribution of neuronal Rac1 in regulating the response to brain injury induced by permanent focal cerebral ischemia (pMCAO). Our results show that pMCAO significantly increased total Rac1 levels in wild type mice, mainly through rising nuclear Rac1, while a reduction in Rac1 activation was observed. Such changes preceded cell death induced by excitotoxic stress. Pharmacological inhibition of Rac1 in primary neuronal cortical cells prevented the increase in oxidative stress induced after overactivation of glutamate receptors. However, this was not sufficient to prevent the associated neuronal cell death. In contrast, RNAi-mediated knock down of Rac1 in primary cortical neurons prevented cell death elicited by glutamate excitotoxicity and decreased the activity of NADPH oxidase. To test whether in vivo down regulation of neuronal Rac1 was neuroprotective after pMCAO, we used tamoxifen-inducible neuron-specific conditional Rac1-knockout mice. We observed a significant 50% decrease in brain infarct volume of knockout mice and a concomitant increase in HIF-1α expression compared to littermate control mice, demonstrating that ablation of Rac1 in neurons is neuroprotective. Transmission electron microscopy performed in the ischemic brain showed that lysosomes in the infarct of Rac1- knockout mice were preserved at similar levels to those of non-infarcted tissue, while littermate mice displayed a decrease in the number of lysosomes, further corroborating the notion that Rac1 ablation in neurons is neuroprotective.
Our results demonstrate that Rac1 plays important roles in the ischemic pathological cascade and that modulation of its levels is of therapeutic interest. This article is protected by copyright. All rights reserved.
Objective: To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD).
Methods: We studied 162 prospective autopsies from older adults with PD (N=6) and without PD (N=156). We documented the presence of LBs in cerebrum and brainstem structures from each of the 6 regions used for Braak PD staging and 4 spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if 2 or more of the 4 signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS).
Results: Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of 6 cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs 32%; Chi-Square х2 = 5.368, df = 1, p = 0.0.021) and more severe nigral neuronal loss (48%% vs 11%; Chi-Square х2 = 9.049, df = 1, p = 0.003). These findings were unchanged when we included cases with a history of PD.
Conclusion: Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss. This article is protected by copyright. All rights reserved.
Selling off unused or underused estate sounds like a good idea for any organisation in need of funds, and the NHS is certainly that. The Naylor Review, published in March (doi:10.1136/bmj.j2072),...
A 64 year old woman presented with left upper abdominal pain, which was first felt as a "pins and needles" sensation five years earlier and gradually evolved to stabbing pain. There was no abdominal...
