The electrocardiographic diagnosis of regional pericarditis in acute inferior myocardial infarction

The diagnosis of postinfarction localized (regional) pericarditishas remained elusive. During the course of a recent study ofpatients with fatal free-wall rupture, an atypical pattern ofT-wave evolution was observed during the days preceding death.It was learned, from autopsy examination, that these electrocardiographicchanges were due to the associated localized pericarditis, ratherthan the rupture, per se. Therefore, this investigation wasundertaken to ascertain if the same atypical T-wave changesoccur in patients with postinfarction localized pericarditis,but without free-wall rupture, and to determine if the frequencyof those changes differs between those patients with inferiorand those with anterior postinfarction pericarditis. Forty-three patients with regional postinfarction pericarditiswere identified clinically. They were divided into three groups,anterior (17), inferior (17) and lateral or posterior (9) myocardialinfarction. In this report those patients with anterior regionalpostinfarction pericarditis are compared with those with inferiorpostinfarction pericarditis. It was found that an atypical T-waveevolution pattern — either persistently positive T-wavesafter 48 h or reversal of initially inverted T-waves after 48h — existed in every patient irrespective of infarct location. However, the two atypical patterns of T-wave evolution occurredwith distinctly different frequencies between the two sitesof infarction. With inferior post infarction pericarditis, gradualreversal of initially inverted T-waves occurred in 14 patients(82%) while only three (18%) had persistently positive T-waves.Conversely, among patients with anterior postinfarction pericarditis,reversal after inversion occurred in five of 17 patients (29%)while 12 of 17 patients (71%) had persistently positive deflections(P<0.01). The only other processes observed which affected the T-waveevolution in a similar manner were patients who had had cardiopulmonaryresuscitation performed and four patients with very small, initialinfarcts who had rapid reversal of initially inverted T-wavesdue to the very early administration of lytic therapy. Therefore,atypical postinfarction T-wave evolution is a very sensitive(100%) and reasonably specific (77%) sign of postinfarctionregional pericarditis.     

Circumvention of P-glycoprotein-mediated drug resistance in human leukaemic cells by non-immunosuppressive cyclosporin D analogue, SDZ PSC 833

Summary. Cyclosporin A (CSA) exhibits greater multidrug resistance (MDR) modulating activity in vitro than other MDR modulators such as verapamil and quinidine. However, the immunosuppressive and nephrotoxic effects of CSA may limit its clinical use. PSC 833, a new cyclosporin D derivative, exerts a higher MDR reversal activity but lacks toxic or immunosuppressive effects. The drug-resistant sublines K/DAV₁₀.,, K/DAU₂₀₀. K/DAU₃₀o. K/DAU₄₀o, K/ DAU500 and K/DAU₆₀o have been derived from the drug-sensitive parental cell line, K562 cl.6 and CEM/VLB₁₀₀ is a drug-resistant derivative of CCRF-CEM. We report a comparison of the effects of PSC 833 and CSA on daunorubicin (DAU) transport kinetics and chemosensitivity in these cell lines. Both CEM/VBL₁₀₀ and KS62 cl.6 DAU-resistant cells displayed high levels of P-glycoprotein (PGP), decreased DAU accumulation and increased DAU efflux when compared to their parental cells. PSC 833 was 1-6-, 3-4-, 4-9- and 4-6-fold more effective than CSA in reversing DAU resistance in higher resistance CEM/VLB₁₀o, K/DAU₄₀o, K/DAU500 and K/DAU₆₀o cells respectively. DAU transport kinetics showed that PSC 833 was more effective than CSA in increasing cellular DAU accumulation and decreasing DAU efflux in higher resistant leukaemia subclones. PSC 833 could restore DAU retention at lower doses and was more active than CSA in all the resistant cells. A 89-100% restoration of intracellular DAU retention were gained by PSC 833 at 1-0ftM in K562 cl.6 DAU-resistant sublines, whereas a 73-100% restoration of DAU retention was obtained by CSA only at 30-0 β, M in the same resistant sublines. PSC 833 at 3-0/XM is sufficient to restore full DAU retention in all resistant cells. CSA, however, even at 30-0 pM, cannot confer full restoration of DAU retention in higher resistance K562 cl.6/DAU sublines. By measuring MDR modulator-mediated short-term inhibition of PGP function, PSC 833 was found to be at least 10-30 times more active than CSA. As no effect on DAU retention and sensitivity has been found in sensitive parental cells with PSC 833, it is suggested that PSC 833 may act by blocking the effluxing function of PGP in the resistant leukaemia cells.     

Traumatic Brain Injury in Patients Receiving Direct Oral Anticoagulants

BackgroundEmergency departments (EDs) are faced with a growing number of patients with traumatic brain injury (TBI) using direct oral anticoagulants (DOACs). However, there remains uncertainty about the bleeding risk, rate of hematoma expansion, and the efficacy of reversal strategies in these patients.ObjectiveThis study aims to identify the risk of traumatic hemorrhagic complications in patients with TBI using DOACs.MethodsIn this retrospective study we included patients with TBI. All TBI patients were using DOACs, attended one of the three EDs of our hospital between January 2016 and October 2019, and received a computed tomography (CT) scan of the brain. The primary outcome was any traumatic intracranial hemorrhage on CT. Secondary outcomes were the use of reversal agents, secondary neurological deterioration, a neurosurgical intervention within 30 days after the injury, length of stay (LOS), Glasgow Outcome Scale (GOS) at discharge, and mortality.ResultsOf the included patients (N = 316), 24 patients (7.6%, 95% confidence interval [CI] 4.2–9.8) presented with a traumatic intracranial hematoma (ICH). Seven patients (2.2%, 95% CI 0.6–3.8) received a reversal agent and 1 patient (0.3%, 95% CI ?0.3–0.9) underwent a neurosurgical intervention. Of the 24 patients with a traumatic ICH, progression of the lesion was seen in 6 patients (1.9%, 95% CI 0.4–3.4). The mean LOS was 6.5 days (95% CI 3.0–10.1) and the mean GOS at discharge was 4 (95% CI 3.6–4.6). Death occurred in 1 patient (0.3%, 95% CI ?0.3–0.9) suffering from an ICH.ConclusionBased on the present findings it can be postulated that TBI patients using DOACs have a low risk for ICH. Hematoma progression occurred, however, in a substantial number of patients. Considering the retrospective nature of the present study, future prospective trials are needed to confirm this finding.     

Induction and stability of the anergic phenotype in T cells

One of the mechanisms that are in place to control the activation of mature T cells that bear self-reactive antigen receptors is anergy, a long-term state of hyporesponsiveness that is established in T cells in response to suboptimal stimulation. T cells receive signals that result not only from antigen recognition and costimulation but also from other sources, including cytokine receptors, inhibitory receptors or metabolic sensors. Integration of those signals will determine T cell fate. Under conditions that induce anergy, T cells activate a program of gene expression that leads to the production of proteins that block T cell receptor signaling and inhibit cytokine gene expression. In this review we will examine those signals that determine functional outcome following antigen encounter, review current knowledge of the factors that ensure signaling inhibition and epigenetic gene silencing in anergic cells and explore the mechanisms that lead to the reversal of anergy and the reacquisition of effector functions.     

Independent influences upon mother–toddler role reversal: infant–mother attachment disorganization and role reversal in mother's childhood

In role reversal a child takes an inappropriate parental, spousal, or peer role with the caregiver. The study assessed attachment disorganization with mother in infancy in the Strange Situation (Ainsworth, Blehar, Waters, & Wall, 1978 Ainsworth, M. D.S., Blehar, M. C., Waters, E. and Wall, S. 1978. Patterns of attachment: A psychological study of the strange situation, Hillsdale, NJ: Erlbaum.  [Google Scholar]) and role reversal at 2 years old in videotaped mother–child interactions. By closely observing role reversal at this early age, results fill in the picture concerning the link between disorganized infant–mother attachment and controlling role reversal at 6 years old (Main & Cassidy, 1988 Main, M. and Cassidy, J. 1988. Categories of response to reunion with the parent at age 6: Predictable from infant attachment classifications and stable over a 1-month period. Developmental Psychology, 24: 415–426. [Crossref], [Web of Science ®] , [Google Scholar]; Main, Kaplan, & Cassidy, 1985 Main, M., Kaplan, N. and Cassidy, J. C. 1985. “Security in infancy, childhood, and adulthood: A move to the level of representation”. In Monographs of the Society for Research in Child Development Edited by: Bretherton, I. and Waters, E. 50(Serial No. 209, 1–2), 66–104[Crossref] , [Google Scholar]). As hypothesized, infant–mother disorganization significantly predicted mother–toddler role reversal. The study also deepened research that predicted role reversal from parent Adult Attachment Interview (AAI) role reversal assessed before the child was born (Macfie, McElwain, Houts, & Cox, 2005 Macfie, J., McElwain, N. L., Houts, R. M. and Cox, M. J. 2005. Intergenerational transmission of role reversal between parent and child: Dyadic and family systems internal working models. Attachment & Human Development, 7: 51–65. [Taylor & Francis Online], [Web of Science ®] , [Google Scholar]). As hypothesized, mother AAI role reversal with her mother in childhood significantly predicted mother–toddler role reversal over and above infant–mother disorganization. Results are discussed within a developmental psychopathology framework including opportunities for developmentally sensitive interventions.     

Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients

Although idiopathic hypogonadotropic hypogonadism (IHH) has traditionally been viewed as a life-long disease caused by a deficiency of gonadotropin-releasing hormone neurons, a portion of patients may gradually regain normal reproductive axis function during hormonal replacement therapy. The predictive factors for potential IHH reversal are largely unknown. The aim of our study was to investigate the incidence and clinical features of IHH male patients who had reversed reproductive axis function. In this retrospective cohort study, male IHH patients were classified into a reversal group (n = 18) and a nonreversal group (n = 336). Concentration of gonadotropins and testosterone, as well as testicle sizes and sperm counts, were determined. Of 354 IHH patients, 18 (5.1%) acquired normal reproductive function during treatment. The median age for reversal was 24 years old (range 21–34 years). Compared with the nonreversal group, the reversible group had higher basal luteinizing hormone (LH) (1.0 ± 0.7 IU l^-1 vs 0.4 ± 0.4 IU l⁻¹, P < 0.05) and stimulated LH (28.3 ± 22.6 IU l⁻¹ vs 1.9 ± 1.1 IU l⁻¹, P < 0.01) levels, as well as larger testicle size (5.1 ± 2.6 ml vs 1.5 ± 0.3 ml, P < 0.01), at the initial visit. In summary, larger testicle size and higher stimulated LH concentrations are favorite parameters for reversal. Our finding suggests that reversible patients may retain partially active reproductive axis function at initial diagnosis.     

Early reversal cardiac with esmolol in hypertensive rats: The role of subcellular organelle phenotype

BackgroundOur group has previously shown that short-term treatment (48 h) with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, we do not know the mechanism that explain this effect. The aim of this study was to assess the role that the subcellular organelle phenotype plays in early cardiac reverse after short-term treatment with esmolol.Methods14-Month-old male SHRs were randomly assigned to receive esmolol (300 μg/kg/min) (SHR-E) or vehicle (SHR). Age-matched male Wistar-Kyoto rats (WKY) served as controls. After 48 h of treatment, an ultrastructural analysis of heart tissue (left ventricle) was performed. We studied cardiomyocyte ultrastructural remodeling of subcellular organelles by electronic microcopy in all groups.ResultsSHR group showed significant morphometric and stereological changes in mitochondria and subcellular organelles (cytoplasm and nucleus, myofibril structure, mitochondria structure, Z-Disk, intercalated disk, T-system and cystern), and also changes in the extracellular matrix (collagen) with respect to WKY group. Esmolol significantly improved the morphology and stereology mitochondrial, reduced the organelle phenotype abnormalities but no produced changes in the extracellular matrix with respect to SHR group. Interesantly, parameters of mitochondria (regularity factor, ellipsoidal form factor and density of volume), and all parameters of subcellular organelles returned to the normality in SHR-E.ConclusionOur results show that left ventricular hypertrophy reversal after short-term treatment with esmolol is associated with reversal of subcellular organelle phenotype.     

ALK抑制剂在NSCLC中的耐药机制及逆转策略的研究进展

间变性淋巴瘤激酶（ALK）抑制剂是目前治疗NSCLC伴ALK阳性的有效药物,然而,耐药性的产生严重限制了其临床应用。本文对ALK抑制剂耐药产生的主要机制如二次基因突变、基因扩增、旁路通路激活等进行了简要介绍,并对联合用药、开发新型PROTAC降解剂等逆转耐药策略进行了综述,以期为ALK抑制剂药物的未来发展提供参考。