Cortical Surface Area Differentiates Familial High Risk Individuals Who Go on to Develop Schizophrenia

BACKGROUND: Schizophrenia is associated with structural brain abnormalities that may be present before disease onset. It remains unclear whether these represent general vulnerability indicators or are associated with the clinical state itself. METHODS: To investigate this, structural brain scans were acquired at two time points (mean scan interval 1.87 years) in a cohort of individuals at high familial risk of schizophrenia (n 5 142) and control subjects (n 5 36). Cortical reconstructions were generated using FreeSurfer. The high-risk cohort was subdivided into individuals that remained well during the study, individuals that had transient psychotic symptoms, and individuals that subsequently became ill. Baseline measures and longitudinal change in global estimates of thickness and surface area and lobar values were compared, focusing on overall differences between high-risk individuals and control subjects and then on group differences within the high-risk cohort. RESULTS: Longitudinally, control subjects showed a significantly greater reduction in cortical surface area compared with the high-risk group. Within the high-risk group, differences in surface area at baseline predicted clinical course, with individuals that subsequently became ill having significantly larger surface area than individuals that remained well during the study. For thickness, longitudinal reductions were most prominent in the frontal, cingulate, and occipital lobes in all high-risk individuals compared with control subjects. CONCLUSIONS: Our results suggest that larger surface areas at baseline may be associated with mechanisms that go above and beyond a general familial disposition. A relative preservation over time of surface area, coupled with a thinning of the cortex compared with control subjects, may serve as vulnerability markers of schizophrenia

Theory of finite temperature crossovers near quantum critical points close to, or above, their upper-critical dimension

A systematic method for the computation of finite temperature ($T$) crossover functions near quantum critical points close to, or above, their upper-critical dimension is devised. We describe the physics of the various regions in the $T$ and critical tuning parameter ($t$) plane. The quantum critical point is at $T=0$, $t=0$, and in many cases there is a line of finite temperature transitions at $T = T_c (t)$, $t < 0$ with $T_c (0) = 0$. For the relativistic, $n$-component $\phi^4$ continuum quantum field theory (which describes lattice quantum rotor ($n \geq 2$) and transverse field Ising ($n=1$) models) the upper critical dimension is $d=3$, and for $d<3$, $\epsilon=3-d$ is the control parameter over the entire phase diagram. In the region $|T - T_c (t)| \ll T_c (t)$, we obtain an $\epsilon$ expansion for coupling constants which then are input as arguments of known {\em classical, tricritical,} crossover functions. In the high $T$ region of the continuum theory, an expansion in integer powers of $\sqrt{\epsilon}$, modulo powers of $\ln \epsilon$, holds for all thermodynamic observables, static correlators, and dynamic properties at all Matsubara frequencies; for the imaginary part of correlators at real frequencies ($\omega$), the perturbative $\sqrt{\epsilon}$ expansion describes quantum relaxation at $\hbar \omega \sim k_B T$ or larger, but fails for $\hbar \omega \sim \sqrt{\epsilon} k_B T$ or smaller. An important principle, underlying the whole calculation, is the analyticity of all observables as functions of $t$ at $t=0$, for $T>0$; indeed, analytic continuation in $t$ is used to obtain results in a portion of the phase diagram. Our method also applies to a large class of other quantum critical points and their associated continuum quantum field theories.Comment: 36 pages, 4 eps figure

Verbal working memory and functional large-scale networks in schizophrenia

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia

Social responsiveness to inanimate entities: Altered white matter in a ‘social synaesthesia’

Judgments about personalities and social traits can be made by relatively brief exposure to animate living things. Here we show that unusual architecture in the microstructure of the human brain is related to atypical mental projections of personality and social structure onto things that are neither living nor animate. Our participants experience automatic, life-long and consistent crossmodal associations between language sequences (e.g., letters, numbers and days) and complex personifications (e.g., A is a businessman; 7 a good-natured woman). Participants with this 'Ordinal Linguistic Personification' (Simner and Hubbard, 2006) which we describe here as a form of social synaesthesia, showed lower fractional anisotropy (FA) values in five clusters at whole-brain significance, compared with non-synaesthetes (in the pre-postcentral gyrus/dorsal corticospinal tract, left superior corona radiata, and the genu, body and left side of the corpus callosum). We found no regions of the brain with increased FA in synaesthetes. A number of these regions with reduced FA play a role in social responsiveness, and our study is the first to show that unusual differences in white matter microstructure in these regions is associated with compelling feelings of social cohesion and personality towards non-animate entities. We show too that altered patterns of connectivity known to typify synaesthesia are not limited to variants involving a 'merging of the senses', but also extend to what might be thought of as a cogno-social variant of synaesthesia, linking language and personality attributes in this surprising way

Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity

Objective Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). Method Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). Results We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. Conclusions We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis

Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin

Background: Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in coronavirus disease 2019 (COVID-19) and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Methods: Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3–4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays. Results: Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to lipopolysaccharide (LPS) compared to cells from healthy control subjects. A subset of patients was captured at follow-up clinics (3–4 months post-acute sampling), and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and phorbol myristate acetate (PMA)-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Conclusion: Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19

Incremental Shuttle Walking Test Distance and Autonomic Dysfunction Predict Survival in Pulmonary Arterial Hypertension

Background To ensure effective monitoring of pulmonary arterial hypertension (PAH), a simple, reliable assessment of exercise capacity applicable over a range of disease severity is needed. The aim of this study was to assess the ability of the incremental shuttle walk test (ISWT) to correlate with disease severity, measure sensitivity to change, and predict survival in PAH. Methods We enrolled 418 treatment-naïve patients with PAH with baseline ISWT within 3 months of cardiac catheterization. Clinical validity and prognostic value of ISWT distance were assessed at baseline and 1 year. Results ISWT distance was found to correlate at baseline with World Health Organization functional class, Borg score, and hemodynamics without a ceiling effect (all p 18 beats/min, highest SBP, change in SBP, and 3-minute SBP ratio) were significant predictors of survival (all p < 0.05). Conclusions In patients with PAH, the ISWT is simple to perform, allows assessment of maximal exercise capacity, is sensitive to treatment effect, predicts outcome, and has no ceiling effect. Also, measures of autonomic function made post-exercise predict survival in PAH

The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension

Pulmonary endarterectomy (PEA) is the gold standard treatment for operable chronic thromboembolic pulmonary hypertension (CTEPH). However, a proportion of patients with operable disease decline surgery. There are currently no published data on this patient group. The aim of this study was to identify outcomes and prognostic factors in a large cohort of consecutive patients with CTEPH. Data were collected for consecutive, treatment-naive CTEPH patients at the Pulmonary Vascular Disease Unit of the Royal Hallamshire Hospital (Sheffield, UK) between 2001 and 2014. Of 550 CTEPH patients (mean±sd age 63±15 years, follow-up 4±3 years), 49% underwent surgery, 32% had technically operable disease and did not undergo surgery (including patient choice n=72 and unfit for surgery n=63), and 19% had inoperable disease due to disease distribution. The 5-year survival was superior in patients undergoing PEA (83%) versus technically operable disease who did not undergo surgery (53%) and inoperable due to disease distribution (59%) (p<0.001). Survival was superior in patients following PEA compared with those offered but declining surgery (55%) (p<0.001). In patients offered PEA, independent prognostic factors included mixed venous oxygen saturation, gas transfer and patient decision to proceed to surgery. Outcomes in CTEPH following PEA are excellent and superior to patients declining surgery, and strongly favour consideration of a surgical intervention in eligible patients

Human vaccination against Plasmodium vivax Duffy-binding protein induces strain-transcending antibodies

BACKGROUND. Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite’s Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination. METHODS. Safety and immunogenicity of replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and modified vaccinia virus Ankara (MVA) viral vectored vaccines targeting PvDBP_RII (Salvador I strain) were assessed in an open-label dose-escalation phase Ia study in 24 healthy UK adults. Vaccines were delivered by the intramuscular route in a ChAd63-MVA heterologous prime-boost regimen using an 8-week interval. RESULTS. Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. PvDBP_RII–specific ex-vivo IFN-γ T cell, antibody-secreting cell, memory B cell, and serum IgG responses were observed after the MVA boost immunization. Vaccine-induced antibodies inhibited the binding of vaccine homologous and heterologous variants of recombinant PvDBP_RII to the DARC receptor, with median 50% binding-inhibition titers greater than 1:100. CONCLUSION. We have demonstrated for the first time to our knowledge that strain-transcending antibodies can be induced against the PvDBP_RII antigen by vaccination in humans. These vaccine candidates warrant further clinical evaluation of efficacy against the blood-stage P. vivax parasite