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Endoscopic Ultrasound (EUS) stands as a remarkable innovation in the realm of gastroenterology and its allied disciplines. EUS has evolved to such an extent that it now assumes a pivotal role in both diagnosis and therapeutics. In addition, it has developed as a tool which is also capable of addressing complications arising from endoscopic and surgical procedures. This minimally invasive technique combines endoscopy with high-frequency ultrasound, facilitating, high-resolution images of the gastrointestinal tract and adjacent structures.

Background: Minor ischemic stroke, defined as National Institute of Health Stroke Scale score of 0–5 on admission, represents half of all acute ischemic strokes. The role of intravenous alteplase (IVA) among patients with minor stroke is inconclusive; therefore, we evaluated clinical outcomes of these patients treated with or without IVA.Materials and methods: We searched Medline, Embase, Scopus, and the Cochrane library until August 1, 2023. Inclusion was restricted to the English literature of studies that reported on minor nondisabling stroke patients treated with or without IVA. Odds ratios (ORs) with their corresponding 95% CIs were utilized using a random-effects model. Efficacy outcomes included rates of excellent (modified Rankin scale [mRS] of 0–1) and good (mRS of 0–2) functional outcome at 90 days. The main safety outcome was symptomatic intracerebral hemorrhage (sICH).Results: Five eligible studies, two RCTs and three observational studies, comprising 2764 patients (31.8% female) met inclusion criteria. IVA was administered to 1559 (56.4%) patients. Pooled analysis of the two RCTs revealed no difference between the two groups in terms of 90-days excellent functional outcomes (OR 0.76 [95% CI, 0.51–1.13]; I2= 0%) and sICH rates (OR 3.76 [95% CI, 0.61–23.20]). No significant differences were observed between the groups in terms of good functional outcomes, 90-day mortality, and 90-day stroke recurrence.Conclusion: This meta-analysis of minor nondisabling stroke suggests that IVA did not prove more beneficial compared to no-IVA.

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Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca2+transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat–response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18?000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case–control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10-8); for FS, rs1067327 within CAMKMTencoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10-9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

Exploring drug targets based on disease-associated molecular mechanisms during development is crucial for the generation of novel prevention and treatment strategies for neurodevelopmental psychiatric conditions. We report that prefrontal cortex (PFC)-specific postnatal knockdown of DISC1 via in uteroelectroporation combined with an inducible knockdown expression system drives deficits in synaptic GABAAfunction and dendritic development in pyramidal neurons, as well as abnormalities in sensorimotor gating, albeit without profound memory deficits. We show for the first time that DISC1 is specifically involved in regulating cell surface expression of a2 subunit-containing GABAAreceptors in immature developing neurons, but not after full maturation. Notably, pharmacological intervention with a2/3 subtype-selective GABAAreceptor positive allosteric modulators during the early postnatal period ameliorates dendritic deficits and behavioral abnormalities induced by knockdown of DISC1. These findings highlight a critical role of DISC1-mediated disruption of postnatal GABA signaling in aberrant PFC maturation and function.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as ‘response’ (n=514) or ‘non-response’ (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10-8), which is near the DISP1gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10-5) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10gene, gave P-values of 2.86 × 10-6and 8.41 × 10-6, respectively. The other 35 variations with signals of potential significance (P<10-4) involve multiple genes expressed in the brain, including GRIN2B, PCDH10and GPC6.Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Background: Despite evidence that obsessive‐compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. Methods: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2–4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. Results: Three SNPs are most strongly associated with OCD: rs11854486 (P= 0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR) = 11.1 homozygous and 1.6 heterozygous) and rs4625687 [P= 0.00007 (after adjustment = 0.06); GRR = 2.4] on 15q; and rs4387163 (P= 0.0002 (after adjustment = 0.08); GRR = 1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1and LMX1A. Conclusions: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1and MEIS2exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD. © 2011 Wiley Periodicals, Inc.

The ability of neutrophils to sense and migrate toward damaged tissue is a vital component of the innate immune response. Paradoxically, this same migration serves as the hallmark of a number of inflammatory conditions, including ischemic reperfusion injury, atherosclerosis, arthritis, and Crohn's disease. More recent evidence suggests that neutrophil infiltration into the cardiac allograft following transplantation is a contributing factor in allograft rejection. We have demonstrated previously a positive correlation between the degree of neutrophil migration and subsequent rejection grades in a cohort of cardiac transplant recipients. Intracellular signaling pathways that are intimately involved in neutrophil migration thus offer potential targets of manipulation in the treatment of such conditions. 3‐Hydroxy‐3‐methylyglutaryl‐coenzyme A reductase inhibitors or statins are emerging as potential anti‐inflammatory agents and have a proven survival benefit in the transplant population. Yet, little is known about their ability to modulate neutrophil function and their subsequent mechanism of action. We demonstrate here that pravastatin, simvastatin, and atorvastatin significantly reduce neutrophil transendothelial migration toward the chemoattractant fMLP. This effect is independent of any change in neutrophil adhesion or adhesion molecule expression but is related to the ability of statins to reduce fMLP‐induced Rho activity in neutrophils. This was confirmed by the ability of the Rho precursor geranylgeranyl pyrophosphate to rescue the statin‐mediated reduction in neutrophil transendothelial migration. Understanding the mechanisms of action of statins in the neutrophil allows for their use in targeting excessive migration in inappropriate inflammatory conditions.

Increased expression of the multidrug efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) has been suggested as a potential mechanism for decreased drug availability at certain intracellular sites that provide sanctuary for HIV. Here we investigate the expression of these transporters in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients and healthy volunteers. Venous blood (30 ml) was taken from healthy volunteers (n = 21) and HIV-infected patients (n = 21; 4 antiretroviral drug naive, 17 antiretroviral drug experienced). PBMCs were isolated and fixed. To assess P-gp expression, PBMCs were incubated with an isotype control antibody or an antibody directed to an external epitope of P-gp (UIC2). To assess MRP expression, cells were permeabilized before incubation with either a control antibody or an antibody directed to an internal epitope of MRP (MRPm5). After washing, a secondary phycoerythrin-bound antibody was incubated. After additional wash steps, samples were fixed and analyzed by flow cytometry. The median fluorescence intensity of 5000 events was recorded. Results are expressed as fold increase between isotype control and UIC2/MRPm5 samples. Expression of P-gp in HIV-infected patients (1.42 ± 0.36) was significantly lower (p = 0.0021; 95% CI, -0.633 to -0.164) than in healthy volunteers (1.82 ± 0.55). However, MRP expression was similar in HIV-infected patients (1.37 ± 0.34) and healthy volunteers (1.37 ± 0.21; p = 0.91; 95% CI, -0.148941 to 0.165191). We conclude that in HIV infection, P-gp expression in total PBMCs is reduced whereas MRP expression appears to be unaltered.

ABSTRACTIntracellular phosphorylation of stavudine (d4T) and zidovudine (ZDV) was investigated in peripheral blood mononuclear cells (PBMCs) isolated from ZDV-naive and ZDV-experienced human immunodeficiency virus (HIV)-positive patients. An in vivo study measured the amount of d4T triphosphate (d4TTP), while an ex vivo study assessed the capacity of cells to phosphorylate added d4T. Endogenous dTTP was also measured. d4TTP and dTTP were determined in vivo using a reverse transcriptase chain termination assay. In ex vivo studies, d4T (1 μM) was incubated in resting and phytohemagglutinin-stimulated (10 μg ml−1; 72 h) PBMCs for 24 h. After washing and methanol extraction, radiolabeled anabolites were detected by high-performance liquid chromatography. d4TTP reached its highest level 2 to 4 h after dosing (0.21 ± 0.14 pmol/106cells; n= 27 [mean ± standard deviation]). Comparison of ZDV-naive and ZDV-experienced individuals showed no significant difference in levels of d4TTP (ZDV naive, 0.23 ± 0.17 pmol/106cells [n= 7] versus ZDV experienced, 0.20 ± 0.14 pmol/106cells [n= 20]; P= 0.473) or the d4TTP/dTTP ratio (0.14 ± 0.12 [n= 7] and 0.10 ± 0.08 [n= 20], respectively;p= 0.391). Ex vivo data demonstrated no significant difference in the formation of d4TTP or total d4T phosphates in naive and experienced patients (0.086 ± 0.055 pmol/106cells in ZDV-naive patients [n= 17] versus 0.081 ± 0.038 pmol/106cells in ZDV-experienced patients [n= 22]; P= 0.767). The ability of HIV-infected patients to phosphorylate d4T in vivo and ex vivo was unchanged with increasing exposure to ZDV.

An investigation of the behavior of bare, unprocessed silicon wafers during their loading and transport in wafer cassettes is documented. Semiconductor process tools can generate sufficient vibration to cause the current 200-mm diameter wafers to vibrate inside the cassettes leading to particle generation, mechanical misalignment, and wafer walking. The cassettes feature chamfered slots into which the wafers are inserted. In the interest of minimizing particle generation in the cleanroom environment, the wafers slide loosely into the slots. As a result, the wafers show distinct pitching and rattling behavior under certain excitation conditions. A study of the wafer dynamics, when positioned in the cassette slots, shows that the wafers make a transition to instability under repeatable conditions of excitation frequency and amplitude. The development of two models of the wafer behavior is included, as well as an experimental verification of the model's results for 200-mm wafers. The model is expected to predict the behavior of future wafer sizes including the 300-mm wafers now under development.

A general asymptotic expansion for the distribution of the studentized least squares estimate in multiple linear regression models is obtained without assuming normal errors and under simple easily verifiable conditions. This expansion provides a better than the normal approximation for estimation and testing . It is also shown that the bootstrap approximation for the distribution of the studentized least squares estimate has a valid asymptotic expansion and this shows that the bootstrap is better than the normal for approximating the distribution of the studentized least squares estimate. A comparison between the bootstrap approximation and the empirical Edgeworth expansion is also provided showing that the bootstrap approximation for the distribution of the studentized least squares estimate is better than the two-term Edgeworth expansion.

Magnetic signals in deep‐sea sediments have the potential to unravel past continental environmental changes, via changes in primary terrigenous magnetic supply, but also record past marine environmental conditions, via in situ formation of secondary magnetic minerals, particularly when complemented by independent proxies. By combining environmagnetic, geochemical, and siliciclastic grain size data, we investigated marine sediment core GL‐1090 (24.92°S, 42.51°W, 2,225 m water depth) aiming to unravel changes in terrigenous sediment input and bottom water conditions during the last ∼184 ka at the western South Atlantic middepth. The Al/Si, Fe/κ and siliciclastic grain size data show that terrigenous sediments at this core location derived from the Plata River (southeastern South America). This material was transported northwards by the Brazilian Coastal Current and their delivery to our core site was modulated by sea‐level oscillations. Periods of low sea‐level were characterized by the input of coarser and more abundant terrigenous sediments. Environmagnetic parameters indicate significant downcore variations in the magnetic domain state, which we interpret as changes in the content of biogenic magnetite following glacial‐interglacial cycles. Coeval negative excursions in magnetic grain size and benthic δ13C suggests that concentrations of single domain magnetite (possibly magnetotactic bacterial magnetite) vary in response to middepth water ventilation. We suggest that reduced ventilation in the middepth western South Atlantic bottom waters during peak glaciations triggered a decrease in the production of biogenic magnetite. Peak glaciations were, in turn, linked with increases in the residence time of North Atlantic Deep Water (or its glacial counterpart). Multi‐proxy approach points to the Plata River as the main lithogenic sediment source to tropical SE South American continental margin, modulated by sea‐levelReduced biogenic magnetite formation coeval with negative benthic δ13C anomalies during glaciationsBiogenic magnetite formation hampered by decreased bottom water ventilation during glaciations Multi‐proxy approach points to the Plata River as the main lithogenic sediment source to tropical SE South American continental margin, modulated by sea‐level Reduced biogenic magnetite formation coeval with negative benthic δ13C anomalies during glaciations Biogenic magnetite formation hampered by decreased bottom water ventilation during glaciations

Correction to: Molecular Psychiatry (2015); advance online publication 12 January 2016; doi:10.1038/mp.2015.197 Following publication of the above article, the authors noticed that the fifteenth author’s name was presented incorrectly. The author’s name should have appeared as S Van der Auwera. The publisher regrets the error.

Palaeomagnetic studies of the Chinese loess provided the first firm chronology for these sediments and revealed that their depositional history reaches back over 2.5 Ma. Magnetic susceptibility records can provide an even more detailed chronology through correlation with the δ18O deep-sea stratigraphy. The susceptibility fluctuations have been used also, either alone or in combination with 10Be measurements, to reconstruct palaeoclimate. However, there is still debate as to the origin of the 10Be and magnetic minerals in the Chinese loess and hence their palaeoclimatic significance. Here we analyse magnetic data from six sites across the Loess Plateau, and reinterpret the 10Be data from Luochuan as largely reflecting primary 10Be dust loading rather than as a palaeorainfall indicator. We discount previous ideas of both constancy of the flux of magnetically susceptible minerals (i.e. susceptibility flux) or constancy of the ratio of the flux of 10Be and susceptibility. We explain the susceptibility of Chinese loess in terms of in situ pedogenic ferrimagnetic enhancement. The competing effects of reduction and oxidation are taken to control the degree of magnetic enhancement, such that magnetic susceptibility is a direct indicator of palaeorainfall. Our reconstructions yield variations in palaeorainfall of between +28 per cent and −12 per cent in the central Loess Plateau rather than +100 per cent to −50 per cent as suggested from previous 10Be and magnetic susceptibility studies.

The theory, measurement and interpretation of frequency-dependent susceptibility (χFD) are examined. A new model is proposed which explains χFD in terms of the behaviour of all superparamagnetic grains (SP) with diameters between 0 and ≈0.03 μm. The model predicts maximum χFD percentage values of 14–17 per cent for spherical SP ferrimagnetic grains in the grain-size range 0.01–0.025 μm, and a maximum value of 10–12 per cent for grain assemblages spanning a wider range of grain sizes (0–0.03 μm). Synthetic and experimental data support the model predictions in terms of both maximum χFD percentage values and the relationship between χFD percentage and mass specific χFD, which exhibits an envelope of data points partly related to grain-size distributions within the SP range. When the χFD percentage is at a maximum, the mass specific χFD term can be used to estimate the concentration of SP grains in a sample. Lower values of χFD percentage in soils are caused by the presence of narrow distributions of ultrafine SP grains, frequency-independent stable single and multi-domain ferrimagnetic grains. Some soils with low susceptibilities may have low χFD percentages because of an appreciable content of paramagnetic and canted antiferromagnetic minerals. A simple mixing model predicts proportions of SP grains in mixed grain assemblages, but model validation requiring further characterization of grain interaction and grain-size distributions is needed before it can be applied to environmental data.

Summary form only. An abstract of the above-titled article, taken from the 1963 IEEE International Convention (held March 25-28, New York, NY, USA), is presented.