Персональные данные в автоматизированных системах финансовых организаций

Previous studies have shown that patients with Takotsubo syndrome (TS) have supranormal nitric oxide signaling, and post-mortem studies of TS heart samples revealed nitrosative stress. Therefore, we first showed in a female rat model that isoproterenol induces TS-like echocardiographic changes, evidence of nitrosative stress, and consequent activation of the energy-depleting enzyme poly(ADP-ribose) polymerase-1. We subsequently showed that pre-treatment with an inhibitor of poly(ADP-ribose) polymerase-1 ameliorated contractile abnormalities. These findings thus add to previous reports of aberrant β-adrenoceptor signaling (coupled with nitric oxide synthase activation) to elucidate mechanisms of impaired cardiac function in TS and point to potential methods of treatment.Sven Y. Surikow, Thanh H. Nguyen, Irene Stafford, Matthew Chapman, Sujith Chacko, Kuljit Singh, Giovanni Licari, Betty Raman, Darren J. Kelly, Yuan Zhang, Mark T. Waddingham, Doan T. Ngo, Alexander P. Bate, Su Jen Chua, Michael P. Frenneaux, John D. Horowit

Can human amblyopia be treated in adulthood?

Amblyopia is a common visual disorder that results in a spatial acuity deficit in the affected eye. Orthodox treatment is to occlude the unaffected eye for lengthy periods, largely determined by the severity of the visual deficit at diagnosis. Although this treatment is not without its problems (poor compliance, potential to reduce binocular function, etc) it is effective in many children with moderate to severe amblyopia. Diagnosis and initiation of treatment early in life are thought to be critical to the success of this form of therapy. Occlusion is rarely undertaken in older children (more than 10 years old) as the visual benefits are considered to be marginal. Therefore, in subjects where occlusion is not effective or those missed by mass screening programs, there is no alternative therapy available later in life. More recently, burgeoning evidence has begun to reveal previously unrecognized levels of residual neural plasticity in the adult brain and scientists have developed new genetic, pharmacological, and behavioral interventions to activate these latent mechanisms in order to harness their potential for visual recovery. Prominent amongst these is the concept of perceptual learning—the fact that repeatedly practicing a challenging visual task leads to substantial and enduring improvements in visual performance over time. In the normal visual system the improvements are highly specific to the attributes of the trained stimulus. However, in the amblyopic visual system, learned improvements have been shown to generalize to novel tasks. In this paper we ask whether amblyopic deficits can be reduced in adulthood and explore the pattern of transfer of learned improvements. We also show that developing training protocols that target the deficit in stereo acuity allows the recovery of normal stereo function even in adulthood. This information will help guide further development of learning-based interventions in this clinical group

Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model

Reduced clearance of lipoproteins by HDL scavenger receptor class B1 (SR-B1) plays an important role in occlusive coronary artery disease. However, it is not clear how much microvascular dysfunction contributes to ischemic cardiomyopathy. Our aim was to determine the distribution of vascular dysfunction in vivo in the coronary circulation of male mice after brief exposure to Paigen high fat diet, and whether this vasomotor dysfunction involved nitric oxide (NO) and or endothelium derived hyperpolarization factors (EDHF). We utilised mice with hypomorphic ApoE lipoprotein that lacked SR-B1 (SR-B1-/-/ApoER61h/h, n = 8) or were heterozygous for SR-B1 (SR-B1+/-/ApoER61h/h, n = 8) to investigate coronary dilator function with synchrotron microangiography. Partially occlusive stenoses were observed in vivo in SR-B1 deficient mice only. Increases in artery-arteriole calibre to acetylcholine and sodium nitroprusside stimulation were absent in SR-B1 deficient mice. Residual dilation to acetylcholine following L-NAME (50 mg/kg) and sodium meclofenamate (3 mg/kg) blockade was present in both mouse groups, except at occlusions, indicating that EDHF was not impaired. We show that SR-B1 deficiency caused impairment of NO-mediated dilation of conductance and microvessels. Our findings also suggest EDHF and prostanoids are important for global perfusion, but ultimately the loss of NO-mediated vasodilation contributes to atherothrombotic progression in ischemic cardiomyopathy

Interactive binocular treatment (I-BiT) for amblyopia: results of a pilot study of 3D shutter glasses system

NoPURPOSE: A computer-based interactive binocular treatment system (I-BiT) for amblyopia has been developed, which utilises commercially available 3D 'shutter glasses'. The purpose of this pilot study was to report the effect of treatment on visual acuity (VA) in children with amblyopia. METHODS: Thirty minutes of I-BiT treatment was given once weekly for 6 weeks. Treatment sessions consisted of playing a computer game and watching a DVD through the I-BiT system. VA was assessed at baseline, mid-treatment, at the end of treatment, and at 4 weeks post treatment. Standard summary statistics and an exploratory one-way analysis of variance (ANOVA) were performed. RESULTS: Ten patients were enrolled with strabismic, anisometropic, or mixed amblyopia. The mean age was 5.4 years. Nine patients (90%) completed the full course of I-BiT treatment with a mean improvement of 0.18 (SD=0.143). Six out of nine patients (67%) who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more at follow-up. The exploratory one-way ANOVA showed an overall effect over time (F=7.95, P=0.01). No adverse effects were reported. CONCLUSION: This small, uncontrolled study has shown VA gains with 3 hours of I-BiT treatment. Although it is recognised that this pilot study had significant limitations-it was unblinded, uncontrolled, and too small to permit formal statistical analysis-these results suggest that further investigation of I-BiT treatment is worthwhile

Geranylgeranylacetone reduces cardiomyocyte stiffness and attenuates diastolic dysfunction in a rat model of cardiometabolic syndrome

Abstract Titin‐dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure‐overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty‐one‐week‐old male lean (n = 10) and obese (n = 20) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200 mg/kg/day) or vehicle by oral gavage for 4 weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25 weeks of age. Titin‐based stiffness (Fpassive) was determined by force measurements in relaxing solution with 100 nM [Ca2+] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4 μm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament‐bound HSPB5 and HSPB1 expression. Vehicle‐treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0 μm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament‐bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome

Evaluating the feasibility of a real world pharmacovigilance study (OPTIMISE:MS).

BACKGROUND: Clinical trial populations do not fully reflect routine practice. The power of routinely collected data to inform clinical practice is increasingly recognised. METHODS: The OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres. Data were collected at the time of routine clinical visits. The first participant was recruited on 24th May 2019; data were extracted on 11th November 2021. RESULTS: 2112 participants were included (median age 44.0 years; 1570 (72%) female; 1981 (94%) relapsing-remitting MS). 639 (30%) were untreated at study entry, 205 (10%) taking interferon beta/copaxone, 1004 (47%) second/third generation DMT first line and 264 (13%) had escalated from a platform DMT. 342 clinical events were reported, of which 108 infections. There was an increased risk of adverse events in people taking second/third generation DMT (RR 3.45, 95%CI 1.57-7.60, p<0.01 vs no DMT). Unadjusted Poisson regression demonstrated increased incident adverse events in people taking natalizumab (IRR 5.28, 95%CI 1.41-19.74, p<0.05), ocrelizumab (IRR 3.24, 95%CI 1.22-8.62, p<0.05), and GA biosimilar (Brabio) (IRR 4.89, 95%CI 1.31-18.21, p<0.05) vs no DMT. CONCLUSIONS: Routinely collected healthcare data can be used to evaluate DMT safety in people with MS. These data highlight the potential of pragmatic studies to guide understanding of risks and benefits associated with DMT