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Intravenous (IV) recombinant tissue plasminogen activator is the standard of care for patients with acute ischemic stroke (AIS) who present to the hospital within 4.5 hours of symptom onset. However, IV thrombolysis, even bridging thrombolysis (combining intravenous thrombolysis and mechanical thrombectomy) has limited efficacy among patients who had occlusive lesions associated with high-grade arterial stenosis requiring revascularization to improve neurological deficits. We evaluated whether rescue stenting results in good outcomes among patients after the failure of intravenous thrombolysis and bridging thrombolysis.We retrospectively analyzed patients with AIS who underwent rescue stenting for large vessel occlusion with severe atherosclerotic stenosis between May 2020 and August 2022 at Can Tho S.I.S General Hospital. Primary outcomes included the incidence of hemorrhagic transformation and the rate of good outcomes (modified Rankin Scale3) at 3-month follow-up.We identified 13 patients who received rescue stenting after the failure of IV alteplase and bridging thrombolysis, but only 11 patients met the inclusion criteria. All patients experienced successful recanalization, and 1 (9.1%) patient experienced new infarcts. Of these 11 patients, 10 (90.9%) had good outcomes 3 months after rescue stenting. Additionally, a loading dose of dual antiplatelet therapy (DAPT) applied concurrently with IV alteplase improved the recanalization rate for large target arteries but had no significant effect on the incidence of symptomatic intracranial hemorrhage.Rescue stenting appears to represent an additional therapeutic option in cases that fail to resolve with IV alteplase, which may improve clinical outcomes.

In cases of acute ischemic stroke (AIS) caused by intracranial large vessel occlusion, rescue intracranial stenting (RIS) has recently emerged as a treatment option for achieving recanalization when mechanical thrombectomy (MT) fails. However, few studies to date have reported on the beneficial outcomes of RIS. Our goal was to analyze whether RIS use can improve prognosis in patients 3 months post-treatment.A retrospective analysis was performed on a prospective cohort of patients with AIS treated with RIS at Can Tho S.I.S General Hospital. The study inclusion criteria were evidence of intracranial large vessel occlusion, absence of intracranial hemorrhage (ICH), and severe stenosis or reocclusion after MT. Patients with tandem occlusions, failure to follow up after discharge, or severe or fatal illness concomitant with AIS were excluded from the study. The primary outcome was the "non-poor" prognosis status rate at 3 months after RIS and post-procedural symptomatic ICH (sICH).The post-treatment outcomes of 85 eligible patients who received RIS between August 2019 and May 2021 were assessed. Of the 85 included patients, 82 (96.5%) achieved successful recanalization, and 4 (4.7%) experienced sICH. At 3-months post-treatment, 47 (55.3%) patients had "non-poor" outcomes, whereas 35 (41.2%) had good outcomes. The use of dual antiplatelet therapy was associated with new infarcts (relative risk [RR]: 0.1; 95% confidence interval [CI]: 0.01-0.7) and sICH occurrence (RR: 0.1; 95% CI: 0.01-0.9).Our study suggests that despite the occurrence of post-procedural sICH in a small proportion of cases, RIS could serve as a useful alternative or additional treatment in the event of MT failure.

Autoantibodies targeting brain antigens can mediate a wide range of neurological symptoms ranging from epileptic seizures to psychosis to dementia. Although earlier experimental work indicated that autoantibodies can be directly pathogenic, detailed studies on disease mechanisms, biophysical autoantibody properties, and target interactions were hampered by the availability of human material and the paucity of monospecific disease-related autoantibodies. The emerging generation of patient-derived monoclonal autoantibodies (mAbs) provides a novel platform for the detailed characterization of immunobiology and autoantibody pathogenicity in vitro and in animal models. This Feature Review focuses on recent advances in mAb generation and discusses their potential as powerful scientific tools for high-resolution imaging, antigenic target identification, atomic-level structural analyses, and the development of antibody-selective immunotherapies.

Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities. Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded. We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1–72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3–4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3–4 severity negatively impacted overall survival (OS) (p = 0.046). ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

Background: Polycomb repressive complex 2 (PRC2) tri-methylates histone H3 at lysine 27 (H3K27me3) leading to transcriptionally silenced genes. ORIC-944 is a potent, highly selective allosteric small molecule inhibitor of PRC2’s embryonic ectoderm development (EED) subunit that is undergoing clinical development as an orally bioavailable monotherapy in patients with metastatic prostate cancer. We previously reported strong tumor growth inhibition with ORIC-944 in enzalutamide-resistant 22Rv1 prostate cancer xenografts. Here, to devise and implement a biomarker strategy aimed at ORIC-944 dose selection in the ongoing phase 1 study (NCT05413421), we undertook preclinical pharmacology studies and assay development. Methods: Naïve and 22Rv1-tumor bearing male mice were treated with vehicle, 10, 30 or 100 mg/kg ORIC-944 PO for up to 37 days. H3K27me3 was evaluated in dorsal skin (epidermal layer) and peripheral monocytes by IHC and an alphaLISA test, respectively. Since dying tumor cells release nucleosomes to circulation, cell-free (cf)-nucleosomal H3K27me3 levels normalized to cf-H3.1 were also assessed in plasma using a proprietary magnetic bead-based sandwich immunoassay. Tumors were profiled by RNA-sequencing and H3K27me3 chromatin immunoprecipitation sequencing. Results: In the epidermal skin layer, H3K27me3 was present in vehicle-treated naïve animals but strongly depleted in ORIC-944-treated mice in a dose-dependent manner. Likewise in monocytes, H3K27me3 was reduced to undetectable levels in 100 mg/kg ORIC-944-treated mice. In plasma, normalized cf-nucleosomal H3K27me3 levels significantly decreased in response to ORIC-944 in a dose- and time-dependent manner, selectively in 22Rv1-tumor bearing mice compared to non-tumor bearing mice. Putative PRC2 target genes were identified in 22Rv1 xenografts by focusing on those genes with H3K27me3 binding in the promoter, whose expression was de-repressed by ORIC-944 in a time-dependent manner and then re-expressed after dose suspension. In the ongoing phase 1 study, H3K27me3 levels are being evaluated in the stratum spinosum of skin and in blood-derived monocytes using a proprietary IHC assay and alphaLISA test, respectively. Modulation in the expression of the putative PRC2 target genes is being assessed in blood-derived peripheral blood mononuclear cells by RNA-sequencing. Conclusion: This comprehensive biomarker strategy enables us to establish target engagement and capture exposure-dependent pharmacodynamics in the ongoing phase 1 study evaluating ORIC-944 as a best-in-class PRC2 inhibitor for the treatment of patients with advanced prostate cancer. Citation Format: Anneleen Daemen, Natalie Yuen, Aleksandr Pankov, Eric A. Ariazi, Subhash D. Katewa, Frank L. Duong, Amber Wang, Shravani Barkund, Shelly Kaushik, Jessica D. Sun, Lori S. Friedman, Melissa R. Junttila. Biomarker strategy for a phase 1 study of ORIC-944, a potent and selective allosteric PRC2 inhibitor, in patients with metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2791.

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of behavioral tests was done to assess migraine-like behaviors. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. In contrast, significant responses to CGRP were seen only with female mice in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. In male mice, the responses had the same trend as females but did not reach statistical significance. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP in the MN causes light aversion in males, while in females, light aversion is accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine pathophysiology and possibly its prevalence in females.

The introduction of immune checkpoint inhibitors (ICIs) in oncologic therapies has led to a paradigm shift in cancer treatment. ICIs have increased the overall survival in patients with malignant melanoma, small-cell lung cancer, and many other tumor entities. Despite their clinical benefits, these novel cancer immunotherapies can induce neurological immune-related adverse events (irAEs). Such immune-mediated complications can manifest within the spectrum of paraneoplastic neurological syndromes (PNSs). PNSs are rare immune-mediated complications of systemic cancers that can involve every aspect of the nervous system. The emergence of PNSs with ICI treatment opens further pathways to study the complex immunopathological interplay of cancer immunity, cross-reactive neurological autoimmune phenomena, and effects of ICIs on the immune system. ICI-induced PNSs comprise a diverse antibody repertoire and phenotypic spectrum with severe and life-threatening disease progression in some cases. Timely diagnosis and urgent interventions are pivotal for a favorable neurologic and oncologic outcome. This review focuses on the pathogenesis of cancer immunotherapy and the disruption of immune tolerance in PNSs and provides an overview of the most pertinent clinical manifestations and principles of diagnostic and therapeutic managements in light of the expected increase in PNSs due to the widespread use of ICIs in clinical practice. This review further discusses potential and evolving concepts of therapeutic monoclonal antibodies for the treatment of PNSs.

Introduction.In the mathematical finite element modeling, an average value of the mechanical characteristics of the deformable solid material is used. In aircraft, machine building, construction engineering, medicine and other fields, polymer composite materials and materials of natural origin are increasingly used. In the latter case, the actual change in the mechanical characteristics differs significantly from the averaged change; therefore, when using the averaged parameters to build and analyze finite element models, the results can be significantly distorted. This paper describes the creation of mathematical methods for studying changes in the mechanical characteristics of a material of inhomogeneous deformable solids. The results obtained in this way are used to construct finite element models and analyze their stress-strain state.Materials and Methods. Naturally occurring materials and composites are considered as inhomogeneous deformable solids. To study the changes in the mechanical characteristics of the material, a method was developed based on the use of two components: the pixel characteristics of raster images scanned by a computer tomograph and the experimental data of field tests of standard samples.Research Results.A complex of mathematical methods has been developed for modeling the interpretation of scanning raster images by a computer tomograph, which allows for the study of any complicated structures of real deformable solids. The results are used in the construction of finite element models of such bodies considering the heterogeneity of the mechanical characteristics of the material. The analysis of the stress-strain state of finite element models of test samples has proved the accuracy and convergence of the numerical solution of the finite element method in modeling the property of heterogeneity of the mechanical characteristics of the material.Discussion and Conclusions. The developed approach can be applied to any physical principles of scanning (X-ray, ultrasound, laser, etc.) and for any types of materials if the data obtained as a result of scanning is developed in the form of a digital (raster) image.

In the crystalline state, salicyl­aldehyde N(4)-morpholino­thio­semicarbazone forms sheets parallel to (002) and consisting of two parallel chains running in the a-axis direction and formed by N—H⋯O and C—H⋯O hydrogen bonds., The structure of the title compound (systematic name: N-{[(2-hy­droxy­phen­yl)methyl­idene]amino}­morpholine-4-carbo­thio­amide), C12H15N3O2S, was prev­iously determined (Koo et al., 1977 ▸) using multiple-film equi-inclination Weissenberg data, but has been redetermined with higher precision to explore its conformation and the hydrogen-bonding patterns and supra­molecular inter­actions. The mol­ecular structure shows intra­molecular O—H⋯N and C—H⋯S inter­actions. The configuration of the C=N bond is E. The mol­ecule is slightly twisted about the central N—N bond. The best planes through the phenyl ring and the morpholino ring make an angle of 43.44 (17)°. In the crystal, the mol­ecules are connected into chains by N—H⋯O and C—H⋯O hydrogen bonds, which combine to generate sheets lying parallel to (002). The most prominent contribution to the surface contacts are H⋯H contacts (51.6%), as concluded from a Hirshfeld surface analysis.

The title compound, C30H23KO8S2, contains one mol­ecule of (E)-2-{4-[3-(thio­phen-3-yl)acrylo­yl]phen­oxy}acetic acid and one mol­ecule of its potassium salt in the asymmetric unit. The distorted KO6 octa­hedra share edges, resulting in chains running in the [010] direction., The synthesis and spectroscopic data of (E)-2-{4-[3-(thio­phen-3-yl)acrylo­yl]phen­oxy}acetic acid are described. Crystallization from an ethanol–water mixture resulted in the title compound, C30H23KO8S2 or [K(C15H11O4S)(C15H12O4S)]n, containing one mol­ecule of the acid and one mol­ecule of the potassium salt in the asymmetric unit. Both mol­ecules share the H atom between their carboxyl groups and a potassium ion. The C=C bonds display an E configuration. The thio­phene and phenyl rings in the two mol­ecules are inclined by 43.3 (2) and 22.7 (2)°. The potassium ion is octa­hedrally coordinated by six O atoms. This distorted octa­hedron shares on opposite sides two oxygen atoms with inversion-related octa­hedra, resulting in chains of octa­hedra running in the [010] direction, which form ladder-like chains by C—H⋯π inter­actions. A Hirshfeld surface analysis indicates that the highest contributions to the surface contacts arise from inter­actions in which H atoms are involved, with the most important contribution being from H⋯H (31.6 and 31.9% for the two mol­ecules) inter­actions.

International audience; Background and purpose: Better understanding the incidence, predictors and mechanisms of early neurological deterioration (END) following intravenous thrombolysis (IVT) for acute stroke with mild symptoms and isolated internal carotid artery occlusion (iICAo) may inform therapeutic decisions.Methods: From a multicenter retrospective database, we extracted all patients with both National Institutes of Health Stroke Scale (NIHSS) score

Finding the Optimal Power Flow (OPF) which minimizes total generator cost is the answer to one of the most important problems in the electricity market operation. Independent System Operators (ISO) face many challenges while operating the system in order to obtain economic benefits and security. The solution to this problem is known as Security Constrained Optimal Power Flow (SCOPF). SCOPF is a very large-scale and nonlinear optimization problem with many complex constraints. This paper proposes the Sunflower Optimization (SFO) algorithm for solving the SCOPF problem. The proposed method is tested on the IEEE 30-bus and the IEEE 118-bus systems for both normal and outage cases. The result comparison with other known methods showed that the proposed SFO algorithm is an effective method for solving the SCOPF problem in the electricity market.

Background: Anterior cruciate ligament (ACL) reconstruction can effectively return athletes to the playing field, but they are still at risk of developing posttraumatic osteoarthritis (PTOA). No studies have used multivariable analysis to evaluate the predictors of radiographic PTOA in the lateral compartment of the knee at short-term follow-up after ACL reconstruction. Purpose: To determine the predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in a young, active cohort. Study Design: Cohort study; Level of evidence, 2. Methods: A nested cohort of 358 patients from the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort who were aged ≤33 years, were injured playing a sport, and had never undergone surgery on the contralateral knee were followed up 2 years after ACL reconstruction with questionnaires and with weightbearing knee radiographs using the metatarsophalangeal (MTP) joint technique. The joint space width in the lateral compartment was measured using a semiautomatic computerized method, and multivariable predictive modeling was used to evaluate the relationship between meniscus treatment, cartilage injury, graft type, and joint space while adjusting for age, sex, body mass index, and Marx activity score. Results: The mean lateral joint space width was 0.11 mm narrower on the ACL-reconstructed knee compared with the contralateral healthy knee (7.69 mm vs 7.80 mm, respectively; P < .01). Statistically significant predictors of a narrower joint space width on the ACL-reconstructed knee included lateral meniscectomy ( P < .001) and a Marx activity score less than 16 points ( P < .001). Conclusion: This study identifies lateral meniscectomy and a lower baseline Marx activity score to be predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in young, active patients without a prior knee injury.

The purpose of this investigation was to explore the presumed relationship between the days of hospitalisation and microorganisms identified by endotracheal aspirate cultures in relation to adequate empirical treatment strategies of pneumonia in the intensive care unit (ICU). All potentially pathogenic microorganisms identified by (surveillance) cultures of endotracheal aspirates obtained in the ICUs of two Dutch teaching hospitals in 2007 and 2012 were retrospectively collected and analysed. Antibiotic susceptibilities to 11 antibiotics were calculated for several time points (days or weeks) after hospital admission and expressed per patient-day. In total, 4184 potentially pathogenic microorganisms identified in 782 patients were analysed. Prevalence of the classic early-onset pneumonia-causing microorganisms decreased from 55 % on the first four days to 34 % on days 4–6 after hospital admission (p

SummaryObjectiveTo identify risk factors for radiographic signs of post-traumatic osteoarthritis (OA) 2–3 years after anterior cruciate ligament (ACL) reconstruction through multivariable analysis of minimum joint space width (mJSW) differences in a specially designed nested cohort.MethodsA nested cohort within the Multicenter Orthopaedic Outcomes Network (MOON) cohort included 262 patients (148 females, average age 20) injured in sport who underwent ACL reconstruction in a previously uninjured knee, were 35 or younger, and did not have ACL revision or contralateral knee surgery. mJSW on semi-flexed radiographs was measured in the medial compartment using a validated computerized method. A multivariable generalized linear model was constructed to assess mJSW difference between the ACL reconstructed and contralateral control knees while adjusting for potential confounding factors.ResultsUnexpectedly, we found the mean mJSW was 0.35 mm wider in ACL reconstructed than in control knees (5.06 mm (95% CI 4.96–5.15 mm) vs 4.71 mm (95% CI 4.62–4.80 mm), P

Hybrid zones may serve as bridges permitting gene flow between species, including alleles influencing the evolution of breeding systems. Using greenhouse crosses, we assessed the likelihood that a hybrid zone could serve as a conduit for transfer of nuclear male-sterility alleles between a gynodioecious species and a hermaphroditic species with very rare females in some populations. Segregation patterns in progeny of crosses between rare females of hermaphroditic Schiedea menziesii and hermaphroditic plants of gynodioecious Schiedea salicaria heterozygous at the male-sterility locus, and between female S. salicaria and hermaphroditic plants from the hybrid zone, were used to determine whether male-sterility was controlled at the same locus in the parental species and the hybrid zone. Segregations of females and hermaphrodites in approximately equal ratios from many of the crosses indicate that the same nuclear male-sterility allele occurs in the parent species and the hybrid zone. These rare male-sterility alleles in S. menziesii may result from gene flow from S. salicaria through the hybrid zone, presumably facilitated by wind pollination in S. salicaria. Alternatively, rare male-sterility alleles might result from a reversal from gynodioecy to hermaphroditism in S. menziesii, or possibly de novo evolution of male sterility. Phylogenetic analysis indicates that some species of Schiedea have probably evolved separate sexes independently, but not in the lineage containing S. salicaria and S. menziesii. High levels of selfing and expression of strong inbreeding depression in S. menziesii, which together should favour females in populations, argue against a reversal from gynodioecy to hermaphroditism in S. menziesii.

Clinical recommendations limit menopausal hormone therapy to a few years, yet the impact of a shorter treatment duration on cardiovascular health is unknown. We hypothesized that both short- and long-term estradiol (E2) treatment exerts positive and lasting effects on blood pressure, vascular reactivity, and renal health. This study was designed to mimic midlife menopause, followed by E2 treatment, that either followed or exceeded the current clinical recommendations. Female Long-Evans retired breeders were ovariectomized (OVX) at 11 mo of age and randomized into three groups: 80-day (80d) vehicle (Veh>Veh), 40-day (40d) E2 + 40d vehicle (E2>Veh), and 80d E2 (E2>E2). In comparison to Veh>Veh, both the E2>Veh and E2>E2 groups had lower systolic blood pressure and enhanced mesenteric relaxation in response to estrogen receptor-α stimulation. Despite the reduced blood pressure, E2>E2 induced renal and cardiac hypertrophy, reduced glomerular filtration, and increased proteinuria. Interestingly, kidneys from E2>Veh rats had significantly fewer tubular casts than both of the other groups. In conclusion, long-term E2 lowered blood pressure but exerted detrimental effects on kidney health in midlife OVX Long-Evans rats, whereas short-term E2 lowered blood pressure and reduced renal damage. These findings highlight that the duration of hormone therapy may be an important factor for renal health in aging postmenopausal women.

Menopause accelerates the development of hypertension, arterial stiffness, end organ damage, and diastolic dysfunction. Postmenopausal hormone therapy relieves menopausal symptoms but promotes adverse cardiovascular outcomes, which may be due to aging-induced alterations in estrogen receptors. We previously published that GPER expression as well as agonist-induced vasorelaxation is decreased in mesenteric arteries from 12 month-old mRen2 female rats. We hypothesized that aging-induced GPER downregulation is present in other rodent species and strains as well. Aortas from young (2-3 months) and aged (11-23 months) C57BL/6 and BALB/c mice were lysed and immunoblotted for GPER protein. In addition, mesenteric arteries from C57BL/6 mice were mounted on a wire myograph and assessed for vasorelaxation in response to estrogen receptor agonists. We found a significant downregulation of GPER in aging aortas (3.1 ± 0.6 vs. 0.63 ± 0.42, P=0.016, N=4 per group). Moreover, we found that vasodilation to the GPER agonist G-1 was significantly attenuated in aging resistance arteries (22 ± 7.5% vs 58 ± 6.5%, P=0.023, N=2-4). Interestingly, vasodilation to the nonselective receptor agonist estradiol was not altered by aging (24 ± 10% vs. 32 ± 2.0%, P=0.23, N=2-4). In light of our previous findings in the rat vasculature, our data indicate that aging-induced decreases in vascular GPER expression and function are conserved across vascular beds and rodent species. We propose that aging-induced GPER downregulation switches the vascular benefits of postmenopausal estrogen therapy from positive to negative. Our future goal is to determine whether therapies that target GPER improve cardiovascular outcomes to protect the aging female population.

The Data Acquisition System for the CDMS II dark matter experiment was designed and built when the experiment moved to its new underground installation at the Soudan Lab. The combination of remote operation and increased data load necessitated a completely new design. Elements of the original LabView system remained as stand-alone diagnostic programs, but the main data processing moved to a VME-based system with custom electronics for signal conditioning, trigger formation and buffering. The data rate was increased 100-fold and the automated cryogenic system was linked to the data acquisition. A modular server framework with associated user interfaces was implemented in Java to allow control and monitoring of the entire experiment remotely.

Background: Rheumatoid arthritis is a chronic progressive autoimmune disease affecting 1.5 million people in the United States. Uncontrolled disease can lead to irreversible joint damage, deformity...

Mutations in the gene for polycystin 2 (Pkd2) lead to polycystic kidney disease, however the main cause of mortality in humans is cardiac related. We previously showed that 5 month old Pkd2+/- mice have altered calcium-contractile activity in cardiomyocytes, but have preserved cardiac function. Here, we examined 1 and 9 month old Pkd2+/- mice to determine if decreased amounts of functional polycystin 2 leads to impaired cardiac function with aging. We observed changes in calcium handling proteins in 1 month old Pkd2+/- mice, and these changes were exacerbated in 9 month old Pkd2+/- mice. Anatomically, the 9 month old Pkd2+/- mice had thinner left ventricular walls, consistent with dilated cardiomyopathy, and the left ventricular ejection fraction was decreased. Intriguingly, in response to acute isoproterenol stimulation to examine β-adrenergic responses, the 9 month old Pkd2+/- mice exhibited a stronger contractile response, which also coincided with preserved localization of the β2 adrenergic receptor. Importantly, the Pkd2+/- mice did not have any renal impairment. We conclude that the cardiac-related impact of decreased polycystin 2 progresses over time towards cardiac dysfunction and altered adrenergic signaling. These results provide further evidence that polycystin 2 provides a critical function in the heart, independent of renal involvement.

Purpose Age-related macular degeneration (AMD), the most common cause of incurable blindness in the western world, is characterized by the dysfunction and eventual death of choroidal endothelial (CECs), RPE, and photoreceptor cells. Stem cell-based treatment strategies designed to replace photoreceptor and RPE cells currently are a major scientific focus. However, the success of these approaches likely also will require replacement of the underlying, supportive choroidal vasculature. The purpose of this study was to generate stem cell-derived CECs to develop efficient differentiation and transplantation protocols. Methods Dermal fibroblasts from the Tie2-GFP mouse were isolated and reprogrammed into two independent induced pluripotent stem cell (iPSC) lines via viral transduction of the transcription factors Oct4, Sox2, Klf4, and c-Myc. Tie2-GFP iPSCs were differentiated into CECs using a coculture method with either the RF6A CEC line or primary mouse CECs. Induced pluripotent stem cell-derived CECs were characterized via RT-PCR and immunocytochemistry for EC- and CEC-specific markers. Results Induced pluripotent stem cells generated from mice expressing green fluorescent protein (GFP) under control of the endothelial Tie2 promoter display classic pluripotency markers and stem cell morphology. Induced pluripotent stem cell-derived CECs express carbonic anhydrase IV, eNOS, FOXA2, PLVAP, CD31, CD34, ICAM-1, Tie2, TTR, VE-cadherin, and vWF. Conclusions Induced pluripotent stem cell-derived CECs will be a valuable tool for modeling of choriocapillaris-specific insults in AMD and for use in future choroidal endothelial cell replacement approaches.

The experimental method together with the analysis method and results of the data taken in 2000 and prospects of the muon anomalous magnetic and electric dipole moment experiments are presented here., 12 pages, 20 figures. Proceedings of my plenary talk at ICHEP02, Amsterdam, 31 July 2002

We have studied sublethal injury in Salmonella enterica serovar Typhimurium caused by mild heat and by different emerging nonthermal food preservation treatments, i.e., high-pressure homogenization, high hydrostatic pressure, pulsed white light, and pulsed electric field. Sublethal injury was determined by plating on different selective media, i.e., tryptic soy agar (TSA) plus 3% NaCl, TSA adjusted to pH 5.5, and violet red bile glucose agar. For each inactivation technique, at least five treatments using different doses were applied in order to cover an inactivation range of 0 to 5 log units. For all of the treatments performed with a technique, the logarithm of the viability reductions measured on each of the selective plating media was plotted against the logarithm of the viability reduction on TSA as a nonselective medium, and these points were fined by a straight line. Sublethal injury between different techniques was then compared by the slope and the y intercept of these regression lines. The highest levels of sublethal injury were observed for the heat and high hydrostatic pressure treatments. Sublethal injury after those treatments was observed on all selective plating media. For the heat treatment, but not for the high-pressure treatment, sublethal injury occurred at low doses, which were not yet lethal. The other nonthermal techniques resulted in sublethal injury on only some of the selective plating media, and the levels of injury were much lower. The different manifestations of sublethal injury were attributed to different inactivation mechanisms by each of the techniques, and a mechanistic model is proposed to explain these differences.

The measurement of the (g−2) value of leptons provides a unique test of theory since it is the only quantity (unlike charge and mass) calculable in the framework of the Standard Model of elementary particles. The muon (g−2) experiment E821 is currently in progress at Brookhaven National Laboratory. Four data taking runs for positive muons and one run for negative muons were successfully accomplished in 1997–2000 and 2001, respectively. Results of the 1997–2000 runs have been published, thus completing our experiment for μ+. Data analysis for the 2001 run for μ− is currently in progress. To provide measurement of \(a_\mu = \tfrac{1} {2}(g - 2)_{\mu ^ - }\) at the same level of accuracy as for \(a_{\mu ^ + } = \tfrac{1} {2}(g - 2)_{\mu ^ + }\), we need to have one more data taking run.

The conjunctival microcirculation of 18 homozygous sickle cell disease (SCD) patients during steady-state, painful crisis, and postcrisis conditions was recorded on high-resolution videotapes using intravital microscopy. Selected videotape sequences were subsequently coded, frame-captured, studied, and blindly analyzed using computer-assisted image analysis protocols. At steady-state (baseline), all SCD patients exhibited some of the following morphometric abnormalities: abnormal vessel diameter, comma signs, blood sludging, boxcar blood flow phenomenon, distended vessels, damaged vessels, hemosiderin deposits, vessel tortuosity, and microaneurysms. There was a decrease in vascularity (diminished presence of conjunctival vessels) in SCD patients compared with non-SCD controls, giving the bulbar conjunctiva a “blanched” avascular appearance in most but not all SCD patients during steady-state. Averaged steady-state red cell velocity in SCD patients was slower than in non-SCD controls. During painful crisis, a further decrease in vascularity (caused by flow stoppage in small vessels) and a 36.7% ± 5.2% decrease in large vessel (mostly venular) diameter resulted. In addition, the conjunctival red cell velocities either slowed significantly (6.6% ± 13.1%; P

Men who have sex with men (MSM) are one of the largest HIV risk groups in Viet Nam and have been understudied. Sexual concurrency and multiple sex partnerships may contribute to high HIV incidence among MSM in Viet Nam. Limited information is available on concurrency and multiple sexual partnerships among MSM in Viet Nam or on the extent to which this population engages in concurrent and multiple unprotected anal intercourse. Data are from a self-administered Internet-based survey of Vietnamese MSM aged 18 years or older, having sex with male partner(s) in the last 12 months and recruited from social networking MSM-specific websites in Viet Nam. Multiple partnerships and concurrency were measured using the UNAIDS-recommended sexual partner matrix, a key component in the questionnaire. Concurrent and multiple sexual partnerships were analyzed at the individual level. Logistic regression analyses were conducted to assess the demographic characteristics and behaviors associated with multiple sexual partnerships. A total of 1695 MSM reported on multiple sexual partnerships; 69.5% indicated multiple sexual partnerships in the last 6 months. A total of 257 MSM reported on concurrent sexual partnerships, with 51.0% reporting penetrative sex with concurrent partners in the last 6 months. Respondents were more likely to engage in multiple sexual partnerships if they were no longer a student, consumed alcohol before and/or during sex, used the Internet to meet casual sex partners and had never participated in a behavioral HIV intervention. Multiple sexual partnerships in the previous 6 months were common among MSM surveyed, as was sexual concurrency. High levels of multiple and concurrent sexual partnerships may be catalyzing the transmission of HIV among MSM in Viet Nam. Given the high prevalence of this high-risk sexual behavior, our findings underscore the urgent need for targeted prevention efforts, focusing on the reduction of multiple and concurrent sexual partners among this key population.

The development of a hematopoietic reporter is crucial for determining the fate of lineages derived from cell-based therapies. A marking system will enable safer embryonic stem and induced pluripotent stem cell-based derivation of blood lineages and facilitate the development of efficient cellular reprogramming strategies based on direct fibroblast conversion. Here we report that the protein tyrosine phosphatase CD45 is an ideal candidate gene on which to base a hematopoietic reporter. CD45 regulatory elements were discovered by analyzing transcription factor chromatin occupancy (ChIP-seq) and promoter nuclease sensitivity (DNase-seq) to identify minimally sufficient sequences required for expression. After cloning the CD45 regulatory elements into an attenuated lentiviral backbone, we found that two transcriptional initiation regions were essential for high-level expression. Expressing CD45 promoters containing these regions and tethered to green fluorescent protein (GFP) in a primary B-cell differentiation assay and a transplantation model resulted in high levels of GFP in lymphoid, myeloid, and nucleated erythroid cells in mouse and human blood cell lineages. Moreover, GFP levels remained high 5 months after secondary transplantation, indicating persistence of the reporter. No CD45-driven GFP expression is observed after fibroblast or embryonic stem cell transduction. The GFP reporter is seen only after embryonic stem cells differentiate into hematopoietic cell progenitors and lineages, suggesting that this hematopoietic reporter system could be useful in validating potential autologous blood cell therapies.

The muon (g-2) experiment at Brookhaven completed a first run in June and July 1997. The main components of the experiment, which include the superconducting inflector, the superferric storage ring, the electrostatic quadrupoles and the lead-scintillating fiber electron calorimeters, have been commissioned satisfactorily. Our first measurement of the ratio R of the spin precession frequency of the positive muon relative to that of a free proton, R=(3.707219/spl plusmn/0.000048)/spl times/10/sup -3/, is in good agreement with the previous CERN measurements for /spl mu//sup +/ and /spl mu//sup -/, and has approximately the same uncertainty as each of these measurements. In spring 1998 a muon kicker was installed and successfully tested in the storage ring magnet and a significant improvement in the knowledge of the muon g-factor is expected from upcoming runs in August 1998 and January 1999.

The muon g-2 experiment at Brookhaven has successfully completed two exploratory runs using pion injection and direct muon injection for checkout and initial data taking. The main components of the experiment, which include the pion beam line, the superconducting storage ring and inflector magnets, the muon kicker and the lead-scintillating fiber calorimeters have been satisfactorily commissioned. First results on the anomalous magnetic moment of the positive muon from pion injection are in good agreement with previous experimental results for a(mu+) and a(mu-) from CERN and of comparable accuracy (13 ppm). Analysis of the 1998 muon injection run is in progress and expected to improve the precision to about 4 ppm. A first production run is scheduled for January 1999 with the goal of reaching the 1 ppm error level.

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n = 11 540; P = 3.89 x 10(-9), odds ratio (OR) = 1.25). This finding was replicated in 23 206 independent samples of European ancestry (P = 0.0029, OR= 1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder. Molecular Psychiatry (2012) 17, 906-917; doi: 10.1038/mp.2011.80; published online 12 July 2011

Results are presented from a reanalysis of the entire five-tower data set acquired with the Cryogenic Dark Matter Search (CDMS II) experiment at the Soudan Underground Laboratory, with an exposure of 969 kg-days. The analysis window was extended to a recoil energy of 150 keV, and an improved surface-event background-rejection cut was defined to increase the sensitivity of the experiment to the inelastic dark matter (iDM) model. Three dark matter candidates were found between 25 keV and 150 keV. The probability to observe three or more background events in this energy range is 11%. Because of the occurrence of these events the constraints on the iDM parameter space are slightly less stringent than those from our previous analysis, which used an energy window of 10-100 keV., 10 pages, 10 figures, minor changes to match published version, conclusion unchanged

We report results from a reanalysis of data from the Cryogenic Dark Matter Search (CDMS II) experiment at the Soudan Underground Laboratory. Data taken between October 2006 and September 2008 using eight germanium detectors are reanalyzed with a lowered, 2 keV recoil-energy threshold, to give increased sensitivity to interactions from Weakly Interacting Massive Particles (WIMPs) with masses below ~10 GeV/c^2. This analysis provides stronger constraints than previous CDMS II results for WIMP masses below 9 GeV/c^2 and excludes parameter space associated with possible low-mass WIMP signals from the DAMA/LIBRA and CoGeNT experiments., 9 pages, 8 figures. Supplemental material included as ancillary files. v3) Added appendix with additional details regarding energy scale and backgrounds

News from the Dark Side? Dark matter is thought to represent 85% of all matter in the universe and to have been responsible for the formation of structure in the early universe, but its nature is still a mystery. Ahmed et al. (p. 1619 , published online 11 February; see the Perspective by Lang ) describe the results from the completed Cryogenic Dark Matter Search (CDMS II) experiment, which searched for dark matter in the form of weakly interacting massive particles (WIMP). Two candidate signals were observed, whereas only one background event was expected. The probability of having two or more events from the background would have been 23%. The results of this analysis cannot be interpreted with confidence as evidence for WIMP interactions, but, at the same time, neither event can be ruled out as representing signal.

The Cryogenic Dark Matter Search experiment (CDMS) is using Phonon+Ionization detectors to search for Dark Matter in the form of Weakly Interactive Massive Particles (WIMPs). We report on new results from the operation of CDMS five “towers” at Soudan underground laboratory. With new and more massive detectors, SuperCDMS project has been started since March 2009. We report on the current status of SuperCDMS and its perspective.

The newly commissioned SuperCDMS Soudan experiment aims to search for WIMP dark matter with a sensitivity to cross sections of 5×10^(−45)cm^2 and larger (90% CL upper limit). This goal is facilitated by a new set of germanium detectors, 2.5 times more massive than the ones used in the CDMS-II experiment, and with a different athermal phonon sensor layout that eliminates radial degeneracy in position reconstruction of high radius events. We present characterization data on these detectors, as well as improved techniques for correcting position-dependent variations in pulse shape across the detector. These improvements provide surface-event discrimination sufficient for a reach of 5×10^(−45)cm^2.

The Cryogenic Dark Matter Search (CDMS) searches for Weakly Interacting Massive Particles (WIMPs) with cryogenic germanium particle detectors. These detectors discriminate between nuclear‐recoil candidate and electron‐recoil background events by collecting both phonon and ionization energy from interactions in the crystal. Incomplete ionization collection results in the largest background in the CDMS detectors as this causes electron‐recoil background interactions to appear as false candidate events. Two primary causes of incomplete ionization collection are suface and bulk charge trapping. Recent work has been focused on reducing surface trapping through the modification of fabrication methods for future detectors. Analyzing data taken with test devices shows that hydrogen passivation of the amorphous silicon blocking layer does not reduce the effects of surface trapping. Other data shows that the iron‐ion implantation used to lower the critical temperature of the tungsten transition‐edge sensors increases surface trapping, causing a degradation of the ionization collection. Using selective implantation on future detectors may improve ionization collection for events near the phonon side detector surface. Bulk trapping is minimized by neutralizing ionized lattice impurities. Detector investigations at testing facilities and at the experimental site in Soudan, MN have provided methods to optimize the neutralization process and monitor running conditions to maintain maximal ionization collection.