Visuospatial Processing Deficits Linked to Posterior Brain Regions in Premanifest and Early Stage Huntington's Disease

OBJECTIVES: Visuospatial processing deficits have been reported in Huntington’s disease (HD). To date, no study has examined associations between visuospatial cognition and posterior brain findings in HD. METHODS: We compared 119 premanifest (55> and 64<10.8 years to expected disease onset) and 104 early symptomatic (59 stage-1 and 45 stage-2) gene carriers, with 110 controls on visual search and mental rotation performance at baseline and 12 months. In the disease groups, we also examined associations between task performance and disease severity, functional capacity and structural brain measures. RESULTS: Cross-sectionally, there were strong differences between all disease groups and controls on visual search, and between diagnosed groups and controls on mental rotation accuracy. Only the premanifest participants close to onset took longer than controls to respond correctly to mental rotation. Visual search negatively correlated with disease burden and motor symptoms in diagnosed individuals, and positively correlated with functional capacity. Mental rotation (“same”) was negatively correlated with motor symptoms in stage-2 individuals, and positively correlated with functional capacity. Visual search and mental rotation were associated with parieto-occipital (pre-/cuneus, calcarine, lingual) and temporal (posterior fusiform) volume and cortical thickness. Longitudinally, visual search deteriorated over 12 months in stage-2 individuals, with no evidence of declines in mental rotation. Conclusions: Our findings provide evidence linking early visuospatial deficits to functioning and posterior cortical dysfunction in HD. The findings are important since large research efforts have focused on fronto-striatal mediated cognitive changes, with little attention given to aspects of cognition outside of these areas. (JINS, 2016, 22, 595–608

Applying machine learning to automated segmentation of head and neck tumour volumes and organs at risk on radiotherapy planning CT and MRI scans

Radiotherapy is one of the main ways head and neck cancers are treated; radiation is used to kill cancerous cells and prevent their recurrence. Complex treatment planning is required to ensure that enough radiation is given to the tumour, and little to other sensitive structures (known as organs at risk) such as the eyes and nerves which might otherwise be damaged. This is especially difficult in the head and neck, where multiple at-risk structures often lie in extremely close proximity to the tumour. It can take radiotherapy experts four hours or more to pick out the important areas on planning scans (known as segmentation). This research will focus on applying machine learning algorithms to automatic segmentation of head and neck planning computed tomography (CT) and magnetic resonance imaging (MRI) scans at University College London Hospital NHS Foundation Trust patients. Through analysis of the images used in radiotherapy DeepMind Health will investigate improvements in efficiency of cancer treatment pathways

Effects of acute fatigue on the volitional and magnetically-evoked electromechanical delay of the knee flexors in males and females

Neuromuscular performance capabilities, including those measured by evoked responses, may be adversely affected by fatigue; however, the capability of the neuromuscular system to initiate muscle force rapidly under these circumstances is yet to be established. Sex-differences in the acute responses of neuromuscular performance to exercise stress may be linked to evidence that females are much more vulnerable to ACL injury than males. Optimal functioning of the knee flexors is paramount to the dynamic stabilisation of the knee joint, therefore the aim of this investigation was to examine the effects of acute maximal intensity fatiguing exercise on the voluntary and magnetically-evoked electromechanical delay in the knee flexors of males and females. Knee flexor volitional and magnetically-evoked neuromuscular performance was assessed in seven male and nine females prior to and immediately after: (i) an intervention condition comprising a fatigue trial of 30-seconds maximal static exercise of the knee flexors, (ii) a control condition consisting of no exercise. The results showed that the fatigue intervention was associated with a substantive reduction in volitional peak force (PFV) that was greater in males compared to females (15.0%, 10.2%, respectively, p < 0.01) and impairment to volitional electromechanical delay (EMDV) in females exclusively (19.3%, p < 0.05). Similar improvements in magnetically-evoked electromechanical delay in males and females following fatigue (21%, p < 0.001), however, may suggest a vital facilitatory mechanism to overcome the effects of impaired voluntary capabilities, and a faster neuromuscular response that can be deployed during critical times to protect the joint system

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study

BACKGROUND: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. METHODS: We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. FINDINGS: Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. INTERPRETATION: Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy

The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents

Any difference? Use of a CAM provider among cancer patients, coronary heart disease (CHD) patients and individuals with no cancer/CHD

<p>Abstract</p> <p>Background</p> <p>Although use of complementary and alternative medicine (CAM) among cancer patients has been described previously, prevalence of use has not commonly been compared to other disease groups in a true population sample where CAM use or cancer is not the main focus. The aims of the present study are to (1) examine how CAM use in cancer patients differs from people with a previous CHD diagnosis and people with no cancer or CHD diagnosis in an unselected general population and (2), investigate the use of a CAM provider among individuals with a previous cancer diagnosis.</p> <p>Methods</p> <p>A total of 8040 men and women aged 29 to 87 in the city of Tromsø, Norway filled in a questionnaire developed specifically for the Tromsø V study with questions on life style and health issues. Visits to a CAM provider within the last 12 months and information on cancer, heart attack and angina pectoris (heart cramp) were among the questions. 1449 respondents were excluded from the analyses.</p> <p>Results</p> <p>Among the 6591 analysed respondents 331 had a prior cancer diagnosis, of whom 7.9% reported to have seen a CAM provider within the last 12 months. This did not differ significantly from neither the CHD group (6.4%, p = 0.402) nor the no cancer/CHD group (9.5%, p = 0.325).</p> <p>Conclusion</p> <p>According to this study, the proportion of cancer patients seeing a CAM provider was not statistically significantly different from patients with CHD or individuals without cancer or CHD.</p

Is Bacterial Persistence a Social Trait?

The ability of bacteria to evolve resistance to antibiotics has been much reported in recent years. It is less well-known that within populations of bacteria there are cells which are resistant due to a non-inherited phenotypic switch to a slow-growing state. Although such ‘persister’ cells are receiving increasing attention, the evolutionary forces involved have been relatively ignored. Persistence has a direct benefit to cells because it allows survival during catastrophes–a form of bet-hedging. However, persistence can also provide an indirect benefit to other individuals, because the reduced growth rate can reduce competition for limiting resources. This raises the possibility that persistence is a social trait, which can be influenced by kin selection. We develop a theoretical model to investigate the social consequences of persistence. We predict that selection for persistence is increased when: (a) cells are related (e.g. a single, clonal lineage); and (b) resources are scarce. Our model allows us to predict how the level of persistence should vary with time, across populations, in response to intervention strategies and the level of competition. More generally, our results clarify the links between persistence and other bet-hedging or social behaviours

Microbiological contamination of cubicle curtains in an out-patient podiatry clinic

<p>Abstract</p> <p>Background</p> <p>Exposure to potential pathogens on contaminated healthcare garments and curtains can occur through direct or indirect contact. This study aimed to identify the microorganisms present on podiatry clinic curtains and measure the contamination pre and post a standard hospital laundry process.</p> <p>Method</p> <p>Baseline swabs were taken to determine colony counts present on cubical curtains before laundering. Curtains were swabbed again immediately after, one and three weeks post laundering. Total colony counts were calculated and compared to baseline, with identification of micro-organisms.</p> <p>Results</p> <p>Total colony counts increased very slightly by 3% immediately after laundry, which was not statistically significant, and declined significantly (p = 0.0002) by 56% one-week post laundry. Three weeks post laundry colony counts had increased by 16%; although clinically relevant, this was not statistically significant. The two most frequent microorganisms present throughout were <it>Coagulase Negative Staphylococcus </it>and <it>Micrococcus </it>species. Laundering was not completely effective, as both species demonstrated no significant change following laundry.</p> <p>Conclusion</p> <p>This work suggests current laundry procedures may not be 100% effective in killing all microorganisms found on curtains, although a delayed decrease in total colony counts was evident. Cubicle curtains may act as a reservoir for microorganisms creating potential for cross contamination. This highlights the need for additional cleaning methods to decrease the risk of cross infection and the importance of maintaining good hand hygiene.</p

Retuning of Inferior Colliculus Neurons Following Spiral Ganglion Lesions: A Single-Neuron Model of Converging Inputs

Lesions of spiral ganglion cells, representing a restricted sector of the auditory nerve array, produce immediate changes in the frequency tuning of inferior colliculus (IC) neurons. There is a loss of excitation at the lesion frequencies, yet responses to adjacent frequencies remain intact and new regions of activity appear. This leads to immediate changes in tuning and in tonotopic progression. Similar effects are seen after different methods of peripheral damage and in auditory neurons in other nuclei. The mechanisms that underlie these postlesion changes are unknown, but the acute effects seen in IC strongly suggest the “unmasking” of latent inputs by the removal of inhibition. In this study, we explore computational models of single neurons with a convergence of excitatory and inhibitory inputs from a range of characteristic frequencies (CFs), which can simulate the narrow prelesion tuning of IC neurons, and account for the changes in CF tuning after a lesion. The models can reproduce the data if inputs are aligned relative to one another in a precise order along the dendrites of model IC neurons. Frequency tuning in these neurons approximates that seen physiologically. Removal of inputs representing a narrow range of frequencies leads to unmasking of previously subthreshold excitatory inputs, which causes changes in CF. Conversely, if all of the inputs converge at the same point on the cell body, receptive fields are broad and unmasking rarely results in CF changes. However, if the inhibition is tonic with no stimulus-driven component, then unmasking can still produce changes in CF