Neural correlates of visuospatial working memory in the ‘at-risk mental state’

Background. Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia. Method. fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 agematched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object–location paired-associate memory task, with experimental manipulation of mnemonic load. Results. In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS. Conclusions. Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis

Thermal Management of AlGaN-GaN HFETs on Sapphire Using Flip-Chip Bonding with Epoxy Underfill

Self-heating imposes the major limitation on the output power of GaN-based HFETs on sapphire or SiC. SiC substrates allow for a simple device thermal management scheme; however, they are about a factor 20-100 higher in cost than sapphire. Sapphire substrates of diameters exceeding 4 in are easily available but the heat removal through the substrate is inefficient due to its low thermal conductivity. The authors demonstrate that the thermal impedance of GaN based HFETs over sapphire substrates can be significantly reduced by implementing flip-chip bonding with thermal conductive epoxy,underfill. They also show that in sapphire-based flip-chip mounted devices the heat spread from the active region under the gate along the GaN buffer and the substrate is the key contributor to the overall thermal impedance

Neural correlates of executive function and working memory in the 'at risk mental state'

Background and Aims: People with ‘prodromal’ symptoms have a very high risk of developing psychosis. We used functional MRI to examine the neurocognitive basis of this vulnerability. Method: Cross-sectional comparison of subjects with an ARMS (n=17), first episode schizophreniform psychosis (n=10) and healthy volunteers (n=15). Subjects were studied using functional MRI while they performed an overt verbal fluency task, a random movement generation paradigm and an N-Back working memory task. Results: During an N-Back task the ARMS group engaged inferior frontal and posterior parietal cortex less than controls but more than the first episode group. During a motor generation task, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than the first episode group. During verbal fluency using ‘Easy’ letters, the ARMS group demonstrated intermediate activation in the left inferior frontal cortex, with first episode groups showing least, and controls most, activation. When processing ‘Hard’ letters, differential activation was evident in two left inferior frontal regions. In its dorsolateral portion, the ARMS group showed less activation than controls but more than the first episode group, while in the opercular part of the left inferior frontal gyrus / anterior insula activation was greatest in the first episode group, weakest in controls and intermediate in the ARMS group. Conclusions: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have just developed psychosis but less severe

Economic impact of hospitalisations among patients in the last year of life: An observational study

Background: Hospital admissions among patients at the end of life have a significant economic impact. Avoiding unnecessary hospitalisations has the potential for significant cost savings and is often in line with patient preference. Objective: To determine the extent of potentially avoidable hospital admissions among patients admitted to hospital in the last year of life and to cost these accordingly. Design: An observational retrospective case note review with economic impact assessment. Setting: Two large acute hospitals in the North of England, serving contrasting socio-demographic populations. Patients: A total of 483 patients who died within 1 year of admission to hospital. Measurements: Data were collected across a range of clinical, demographic, economic and service use variables and were collected from hospital case notes and routinely collected sources. Palliative medicine consultants identified admissions that were potentially avoidable. Results: Of 483 admissions, 35 were classified as potentially avoidable. Avoiding these admissions and caring for the patients in alternative locations would save the two hospitals £5.9 million per year. Reducing length of stay in all 483 patients by 14% has the potential to save the two hospitals £47.5 million per year; however, this cost would have to be offset against increased community care costs. Limitations: A lack of accurate cost data on alternative care provision in the community limits the accuracy of economic estimates. Conclusions: Reducing length of hospital stay in palliative care patients may offer the potential to achieve higher hospital cost savings than preventing avoidable admissions. Further research is required to determine both the feasibility of reducing length of hospital stay for patients with palliative care needs and the economic impact of doing so

Grey matter abnormalties in first episode schizophrenia and affective psychosis

Background: Grey matter and other structural brain abnormalities are consistently reported in first-onset schizophrenia, but less is known about the extent of neuroanatomical changes in first-onset affective psychosis. Aims: To determine which brain abnormalities are specific to (a) schizophrenia and (b) affective psychosis. Method: We obtained dual-echo (proton density/T2-weighted) MR images and carried out voxel-based analysis on the images of 73 first-episode psychosis patients (schizophrenia=44, affective psychosis=29) and 58 healthy controls. Results: Both patients with schizophrenia and patients with affective psychosis had enlarged lateral and third ventricle volumes. Regional cortical grey matter reductions (including bilateral anterior cingulate gyrus, left insula and left fusiform gyrus) were evident in affective psychosis but not in schizophrenia, although patients with schizophrenia displayed decreased hippocampal grey matter and increased striatal grey matter at a more liberal statistical threshold. Conclusions: Both schizophrenia and affective psychosis are associated with volumetric abnormalities at the onset of frank psychosis, with some of these evident in common brain areas

Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

Exploring the financial impact of caring for family members receiving palliative and end-of-life care: A systematic review of the literature

Background: Research regarding the economic dimensions of palliative care is relatively limited. The economic implications of providing informal care are well recognised; however, within the context of palliative care, little is known about the costs and implications of providing care for a loved one at the end of life. Aim: To explore the financial costs and the financial impact of caring for family members receiving palliative/end-of-life care. Design: A systematic literature review of empirical research following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data Sources: Seven electronic databases were searched from inception to April 2012. Inclusion criteria were as follows: articles relating to the financial costs or implications of family caregiving at the end-of-life care, English language articles, empirical research or systematic reviews and articles relating to adults. Results: The review identified 21 relevant articles; however, evidence relating to the costs and implications of caregiving was relatively limited. The results indicate that the financial costs of caring for someone at the end of life are substantial. Financial costs can result in significant and multidimensional caregiver burden. Various factors were found to mediate the extent of financial burden. Conclusions: This review identified a significant gap in the evidence base regarding the economic implications of providing care to a family member within a palliative care context. Economic costs and implications are likely to be significant, and research to address this gap is urgently needed, particularly given policy initiatives in a number of developed countries to move the provision of palliative and end-of-life care from hospital to community settings

Plasmodium falciparum Reticulocyte Binding-Like Homologue Protein 2 (PfRH2) Is a Key Adhesive Molecule Involved in Erythrocyte Invasion

Erythrocyte invasion by Plasmodium merozoites is a complex, multistep process that is mediated by a number of parasite ligand-erythrocyte receptor interactions. One such family of parasite ligands includes the P. falciparum reticulocyte binding homologue (PfRH) proteins that are homologous with the P. vivax reticulocyte binding proteins and have been shown to play a role in erythrocyte invasion. There are five functional PfRH proteins of which only PfRH2a/2b have not yet been demonstrated to bind erythrocytes. In this study, we demonstrated that native PfRH2a/2b is processed near the N-terminus yielding fragments of 220 kDa and 80 kDa that exhibit differential erythrocyte binding specificities. The erythrocyte binding specificity of the 220 kDa processed fragment of native PfRH2a/2b was sialic acid-independent, trypsin resistant and chymotrypsin sensitive. This specific binding phenotype is consistent with previous studies that disrupted the PfRH2a/2b genes and demonstrated that PfRH2b is involved in a sialic acid independent, trypsin resistant, chymotrypsin sensitive invasion pathway. Interestingly, we found that the smaller 80 kDa PfRH2a/2b fragment is processed from the larger 220 kDa fragment and binds erythrocytes in a sialic acid dependent, trypsin resistant and chymotrypsin sensitive manner. Thus, the two processed fragments of PfRH2a/2b differed with respect to their dependence on sialic acids for erythrocyte binding. Further, we mapped the erythrocyte binding domain of PfRH2a/2b to a conserved 40 kDa N-terminal region (rPfRH240) in the ectodomain that is common to both PfRH2a and PfRH2b. We demonstrated that recombinant rPfRH240 bound human erythrocytes with the same specificity as the native 220 kDa processed protein. Moreover, antibodies generated against rPfRH240 blocked erythrocyte invasion by P. falciparum through a sialic acid independent pathway. PfRH2a/2b thus plays a key role in erythrocyte invasion and its conserved receptor-binding domain deserves attention as a promising candidate for inclusion in a blood-stage malaria vaccine

Redox-Induced Src Kinase and Caveolin-1 Signaling in TGF-β1-Initiated SMAD2/3 Activation and PAI-1 Expression

Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade, is significantly increased in human arterial plaques contributing to vessel fibrosis, arteriosclerosis and thrombosis, particularly in the context of elevated tissue TGF-β1. Identification of molecular events underlying to PAI-1 induction in response to TGF-β1 may yield novel targets for the therapy of cardiovascular disease.Reactive oxygen species are generated within 5 minutes after addition of TGF-β1 to quiescent vascular smooth muscle cells (VSMCs) resulting in pp60(c-src) activation and PAI-1 expression. TGF-β1-stimulated Src kinase signaling sustained the duration (but not the initiation) of SMAD3 phosphorylation in VSMC by reducing the levels of PPM1A, a recently identified C-terminal SMAD2/3 phosphatase, thereby maintaining SMAD2/3 in an active state with retention of PAI-1 transcription. The markedly increased PPM1A levels in triple Src kinase (c-Src, Yes, Fyn)-null fibroblasts are consistent with reductions in both SMAD3 phosphorylation and PAI-1 expression in response to TGF-β1 compared to wild-type cells. Activation of the Rho-ROCK pathway was mediated by Src kinases and required for PAI-1 induction in TGF-β1-stimulated VSMCs. Inhibition of Rho-ROCK signaling blocked the TGF-β1-mediated decrease in nuclear PPM1A content and effectively attenuated PAI-1 expression. TGF-β1-induced PAI-1 expression was undetectable in caveolin-1-null cells, correlating with the reduced Rho-GTP loading and SMAD2/3 phosphorylation evident in TGF-β1-treated caveolin-1-deficient cells relative to their wild-type counterparts. Src kinases, moreover, were critical upstream effectors of caveolin-1(Y14) phosphoryation and initiation of downstream signaling.TGF-β1-initiated Src-dependent caveolin-1(Y14) phosphorylation is a critical event in Rho-ROCK-mediated suppression of nuclear PPM1A levels maintaining, thereby, SMAD2/3-dependent transcription of the PAI-1 gene